Document ID: EPA-HQ-OPP-2008-0731-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-07-08T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES,

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		20-MAY-2009

SUBJECT:	Cyazofamid.  Human Health Risk Assessment for Proposed Uses on
Fruiting Vegetables and Okra, Grapes East of the Rocky Mountains,
Vegetable Greenhouse Transplants, and Commercial Application on
Residential Turf and Residential Ornamentals.

PC Code:  085651	DP Barcodes:  D356837, D356878  

Decision Nos.: 399077, 399610	Registration Nos.: 71512-3, 71512-13

Petition No.:  8E7427 	Regulatory Action:  Section 3 Registration 

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

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

MRID No.:  NA	40 CFR: 180.601

FROM:	Nancy J. Tsaur, Risk Assessor

	Amelia Acierto, Chemist

	Barry O’Keefe, Sr. Biologist

	Whang Phang, Toxicologist

	Risk Assessment Branch 3 (RAB3)

	Health Effects Division (7509P)

THROUGH:	Paula Deschamp, Branch Chief 

Risk Assessment Branch 3 (RAB3)

Health Effects Division (7509P)

TO:	Janet Whitehurst/Tony Kish, Risk Management Team 22 

	Fungicide Branch (FB)

	Registration Division (7505P)

		and

	Laura Nollen/Daniel Rosenblatt, Risk Management Team 05

	Fungicide Branch/RIMUERB

	Registration Division (7505P)

Introduction

This document addresses two different actions submitted to the Agency
regarding cyazofamid.  In one action, ISK Biosciences Corporation (ISK)
has requested the registration of the broad spectrum fungicide
cyazofamid (400SC) for commercial use on residential turf and
ornamentals.  In another action, Interregional Research Project No. 4
(IR-4) of Rutgers, New Jersey, has submitted a petition (PP#8E7427) to
register the agricultural end-use product, Ranman® 400SC Fungicide, for
use on the fruiting vegetable crop group and okra, grapes east of the
Rocky Mountains, and greenhouse vegetable transplants.  The Health
Effects Division (HED) of the Office of Pesticide Programs (OPP) is
charged with estimating the risk to human health from exposure to
pesticides.  The Registration Division (RD) of OPP has requested that
HED evaluate hazard and exposure data and conduct dietary, occupational,
residential, and aggregate exposure assessments, as needed, to estimate
the risk to human health that will result from the proposed new uses of
cyazofamid.  

Both 400SC and Ranman® 400SC are 34.5% active ingredient (ai)
suspension concentrates (SC) of the fungicide cyazofamid
(4-chloro-2-cyano-N,N-dimethyl-5-p-tolylimidazole-1-sulfonamide).  In
addition to ISK’s  proposed label amendment to add residential turf
and ornamentals to the 400SC label, IR-4 is proposing the following
tolerances for use of Ranman® 400SC in/on fruiting vegetables (crop
group 8) and okra, and grapes east of the Rocky Mountains:

Commodity	Proposed Tolerance (ppm)

Vegetable, fruiting, group 8	0.80

Okra	0.80

Grape – East of Rocky Mountains	1.5

Concomitantly, IR-4 has proposed to delete the established tolerances
for the combined residues of cyazofamid and its metabolite, CCIM
(4-chloro-5-p-tolylimidazole-2-carbonitrile; see Appendix A), in/on:

Commodity	Proposed Tolerance (ppm)

Tomato	0.20

Grape, wine (import)	1.5

IR-4 also wishes to include a greenhouse application of cyazofamid as a
drench treatment to fruiting vegetables and okra, and cucurbit
vegetables.  For fruiting and cucurbit vegetable transplants, a single
drench application is proposed, made at the time of seeding or any time
thereafter up to 1 week prior to transplant, at 0.078 lb ai/A.

The most recent human-health risk assessment was conducted in
conjunction with a request for use of cyazofamid on carrots (K.
O’Rourke, 03/19/08, DP#342612).  The following information from the
03/19/08 risk assessment can be applied directly to this action:

Section 2.0: Physical/Chemical Properties Characterization, and

Section 3.0: Hazard Characterization/Assessment*.

*With the exception of consideration of the completeness of the database
with respect to new Part 158 requirements for immunotoxicity and
subchronic neurotoxicity studies and consideration of a 28-day oral
range finding study in the rat to select a point of departure from
short- and intermediate-term incidential oral exposure, the hazard
characterization and endpoint selection from the previous risk
assessment are applied directly to this action.

This document contains only those aspects of the risk assessment which
are affected by the proposed ISK Section 3 request for use of cyazofamid
on residential turf and ornamentals, and the IR-4 petition to establish
tolerances in/on fruiting vegetables and okra, grapes east of the
Rockies, and greenhouse vegetable transplants.

This document provides a summary of the findings from the data
evaluation and subsequent assessment of human health risk resulting from
these requests.  The hazard assessment and characterization were
conducted by Whang Phang (RAB3), the occupational exposure data review
for the tolerance petition was performed by Barry O’Keefe (RAB3), the
residue chemistry data review and dietary exposure assessment were
completed by Amelia Acierto (RAB3), and the occupational exposure
assessment for residential turf and ornamentals and the overall human
health risk assessment were conducted by Nancy J. Tsaur (RAB3);
additionally, the drinking water assessment was conducted by José
Meléndez of OPP’s Environmental Fate and Effects Division (EFED).

Table of Contents

  TOC \f  1.0	EXECUTIVE SUMMARY	  PAGEREF _Toc230601090 \h  5 

2.0	PROPOSED USE PATTERN	  PAGEREF _Toc230601091 \h  10 

3.0	HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS	  PAGEREF _Toc230601092
\h  13 

3.1	FQPA Considerations	  PAGEREF _Toc230601093 \h  13 

3.2	Dose-Response Assessment	  PAGEREF _Toc230601094 \h  14 

3.3	Endocrine Disruption	  PAGEREF _Toc230601095 \h  18 

4.0	DIETARY EXPOSURE/RISK CHARACTERIZATION	  PAGEREF _Toc230601096 \h 
18 

4.1	Food Residue Profile	  PAGEREF _Toc230601097 \h  19 

4.2	International Residue Limits	  PAGEREF _Toc230601098 \h  24 

4.3	Drinking Water Residue Profile	  PAGEREF _Toc230601099 \h  24 

4.4	Dietary Exposure and Risk	  PAGEREF _Toc230601100 \h  25 

4.1	Cancer Dietary Exposure and Risk	  PAGEREF _Toc230601101 \h  28 

5.0	NON-OCCUPATIONAL/RESIDENTIAL EXPOSURE/RISK PATHWAY	  PAGEREF
_Toc230601102 \h  28 

5.1	Handler Exposure and Risk	  PAGEREF _Toc230601103 \h  29 

5.2	Postapplication Exposure and Risk	  PAGEREF _Toc230601104 \h  29 

5.3	Other Exposure Sources (Spray Drift)	  PAGEREF _Toc230601105 \h  32 

6.0	AGGREGATE RISK ASSESSMENTS and RISK CHARACTERIZATION	  PAGEREF
_Toc230601106 \h  33 

6.1	Acute Aggregate Risk Assessment (Food and Drinking Water)	  PAGEREF
_Toc230601107 \h  33 

6.2  Short- and Intermediate-Term Aggregate Risk Assessment	  PAGEREF
_Toc230601108 \h  33 

6.3	Chronic Aggregate Risk Assessment (Food and Drinking Water)	 
PAGEREF _Toc230601109 \h  34 

6.4	Cancer Aggregate Risk Assessment	  PAGEREF _Toc230601110 \h  34 

7.0	CUMULATIVE RISK	  PAGEREF _Toc230601111 \h  34 

8.0	OCCUPATIONAL EXPOSURE	  PAGEREF _Toc230601112 \h  34 

8.1	Occupational Handler	  PAGEREF _Toc230601113 \h  34 

8.2	Occupational Postapplication Exposure and Risk	  PAGEREF
_Toc230601114 \h  39 

9.0	DATA NEEDS AND LABEL REQUIREMENTS	  PAGEREF _Toc230601115 \h  43 

9.1	Chemistry	  PAGEREF _Toc230601116 \h  43 

9.2	Toxicology	  PAGEREF _Toc230601117 \h  43 

10.0	ATTACHMENTS	  PAGEREF _Toc230601118 \h  43 

Appendix A	ATTACHMENTS	  PAGEREF _Toc230601119 \h  45 

Appendix B	International Residue Limit Status	  PAGEREF _Toc230601120 \h
 46 

Appendix C	Toxicology Assessment	  PAGEREF _Toc230601121 \h  47 

C.1	Toxicity Profile of Cyazofamid Technical	  PAGEREF _Toc230601122 \h 
47 

C.2	Acute Toxicity of Cyazofamid	  PAGEREF _Toc230601123 \h  52 

Appendix D: Rationale for Toxicity Data Requirement	  PAGEREF
_Toc230601124 \h  53 

Appendix E: Rationale for Toxicity Data Requirement	  PAGEREF
_Toc230601125 \h  54 

 

1.0	EXECUTIVE SUMMARY tc \l1 "1.0	EXECUTIVE SUMMARY 

Cyazofamid is a fungicide which belongs to a novel chemical class based
on the cyanoimidazole moiety.  Cyazofamid is a broad spectrum fungicide
active against oomycete fungi (such as Phytophthora, Plasmopara,
Pseudoperonospora, and Pythium) and Plasmodiophoromycetes
(Plasmodiospora brassicae).  It specifically interferes with the
cytochrome bc1 complex (ubiquinol cytochrome c oxidoreductase) in the
mitochondrial respiratory chain of oomycetes fungi.  

Background

The most recent human health risk assessment for cyazofamid was
conducted in March of 2008 for Section 3 registration on carrots (  SEQ
CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 DP#342612, K. O’Rourke,
03/19/08).  There are currently no established Codex or Mexican maximum
residue limits (MRLs) for residues of cyazofamid in/on plant or
livestock commodities.  A Canadian MRL has been established for residues
of cyazofamid and CCIM at 0.20 ppm for tomatoes (See Appendix B).  

Proposed Uses on Turf and Ornamentals

Cyazofamid 400SC is proposed for a new use to control: 1) Pythium and
Downy mildew diseases on professionally managed turf areas such as golf
courses and other non-residential turf areas including sod farms, seed
farms, college and professional sports fields, and commercial lawns; and
2) Pythium, Phytophthora, and Downy mildew diseases on ornamental plants
in landscapes and those grown in commercial greenhouses and nurseries. 
The proposed use rates on turf range from 0.51 to 1.02 lb ai/A, with 14-
to 21-day application intervals, and on ornamentals range from 0.039 to
1.56 lb ai/A, with 14- to 28-day application intervals.  The maximum
number of applications for turf and ornamentals is 3 and 4,
respectively.

Proposed Uses on Fruiting Vegetables and Okra, Grapes East of the Rocky
Mountains, and Greenhouse Vegetable Transplants

Broadcast foliar applications of cyazofamid may be applied to okra,
fruiting vegetables, and grapes at an application rate of 0.071 lb ai/A,
for up to 6 applications.  Re-treatment intervals are from 7 to 10 days
for okra and fruiting vegetables, and 10 to 14 days for grapes.  Spot
treatments may also be applied to the base of okra, fruiting vegetables,
and cucurbit vegetables at time of transplanting at the same rate.  As
part of greenhouse transplant production for okra, fruiting vegetables,
and cucurbit vegetables, cyazofamid may be applied as a drench to
seedling trays at time of planting or any time thereafter up until one
week before transplanting at a rate of 0.078 lb ai/A one time.  Handlers
may apply Ranman® 400SC using aerial, groundboom, airblast,
chemigation, handgun, and low pressure handwand equipment. 

Hazard Assessment

Cyazofamid has a low order of acute toxicity via the oral, dermal, and
inhalation routes of exposure.  It produces minimal but reversible eye
irritation, is a slight dermal irritant, and is a weak dermal
sensitizer.  The propensity of cyazofamid to be a slight dermal irritant
and a weak sensitizer might be due to the sulfonamide moiety in the
compound.

Following repeated administration in more than one species, cyazofamid
seems to have mild or low toxicity. In rats, the kidney is the major
target organ following subchronic dosing. No adverse kidney effects or
other toxicity findings were observed following chronic exposures.  In
mice, skin lesions likely due to systemic allergy, were observed in the
males only.  In dogs, there were no major toxicity findings. In the
acute neurotoxicity study, there were no indications of
treatment-related adverse neurotoxicity.

The pre- and post-natal toxicology database for cyazofamid includes rat
and rabbit developmental toxicity studies and a two-generation
reproduction toxicity study in rats.  There was some evidence of
increased susceptibility following in utero exposure to rats in the
prenatal developmental toxicity study; the increased incidence of bent
ribs in the high dose fetuses was considered adverse and was used for
setting the developmental NOAEL/LOAEL
(no-observed-adverse-effect-level/lowest-observed-adverse-effect-level).
 HED considers this approach conservative and highly protective because
bent ribs are a reversible developmental anomaly rather than a
malformation.

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

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

On February 10, 2004, HED’s Hazard Identification Assessment Review
Committee (HIARC) reviewed the recommendations of the toxicology
reviewer for cyazofamid with regard to the acute and chronic Reference
Doses (RfDs) and the toxicological endpoint selection for use as
appropriate in occupational/residential exposure assessments.  The
potential for increased susceptibility of infants and children from
exposure to cyazofamid was also evaluated as required by the FQPA of
1996.  For this action, the RAB3 risk assessment team has examined and
concurs with the previous HIARC conclusions that there are no concerns
or residual uncertainties for pre- and or postnatal toxicity.  On this
basis, the FQPA safety factor should be removed (i.e., reduced to 1X)
for all potential exposure scenarios of cyazofamid.  Furthermore, HED
does not believe that conducting either a functional immunotoxicity
study or an acute neurotoxicity study will result in lower NOAELs than
the regulatory doses for risk assessment, and an additional factor
(UFDB) for database uncertainty is not needed to account for lack of
these studies.  Additionally, the cyazofamid risk assessment team
evaluated the quality of the exposure data, and based on these data,
agreed that the FQPA SF could be reduced to 1X

Dietary Exposure Estimates

For the acute analysis, an acute endpoint was not identified for the
general population including infants and children, because no effects
were observed which could be attributed to a single-dose exposure. 
Dietary (food and drinking water) exposure of females 13-49 years old is
well below HED’s level of concern at the 95th percentile of exposure. 
Combined dietary exposure from food and drinking water is estimated at
0.003472 mg/kg/day, equivalent to <1% of the acute Population Adjusted
Dose (aPAD).

For the chronic analysis, dietary (food and drinking water) exposure is
estimated at 0.0038 mg/kg/day for the general U.S. population (<1% of
the chronic Population Adjusted Dose (cPAD)) and 0.003984 mg/kg/day
(1.1% of the cPAD) for infants <1 year old, the population subgroup with
the highest estimated chronic dietary exposure to cyazofamid.

Drinking Water Assessment

The highest acute (peak) and chronic (mean) EDWCs were estimated for
surface water using the PRZM/EXAMS model.  For the purpose of this
unrefined dietary assessment, HED used the highest calculated screening
EDWCs for surface water based on the conservative screen-level
estimates: 136 ppb for the acute analysis and 133 ppb for the chronic
analysis.  This approach may significantly overestimate dietary exposure
to cyazofamid from drinking water.  

Residential Exposure Estimates

Cyazofamid is proposed for use on commercially treated residential turf
and ornamentals.  The proposed label states that “application by
home-owners to residential turf is prohibited.”  Therefore,
non-occupational handler exposure is not expected.  However,
postapplication exposure is possible for children and adults.  The
postapplication risk assessment is based on generic assumptions as
specified by the Recommended Revisions to the Residential Standard
Operating Procedures (SOPs) and recommended approaches by HED’s
Exposure Science Advisory Committee (ExpoSAC). 
Non-occupational/residential MOEs were estimated for “Day 0" exposure
(i.e., the day of application).  The postapplication children’s
aggregate MOE (including incidental oral exposures) is 1,600.  All MOEs,
including the children’s aggregate, are greater than 100, and
therefore, are not of concern to HED.

Aggregate Exposure Scenarios and Risk Conclusions

Human health aggregate risk assessments have been conducted for acute
aggregate exposure (food + drinking water), short-/intermediate-term
aggregate exposure (food + residential exposure + drinking water), and
chronic aggregate exposure (food + drinking water) scenarios.  A cancer
aggregate risk assessment was not performed because cyazofamid is
classified as “not likely to be carcinogenic to humans”.  All
potential exposure pathways were assessed in the aggregate risk
assessment.  MOEs for aggregate exposure range from 1,100 to 1,500. 
None of the aggregate exposure and risk estimates exceed HED’s level
of concern.

Occupational Exposure Estimates

Residential Turf/Ornamentals Uses – EPA Registration No. 71512-13: 
For residential turf and ornamentals, occupational postapplication MOEs
ranged from 340 to 98,000; and therefore, are not of concern to HED.

Agricultural Crop Uses – Petition 8E7427 – EPA Registration No.
71512-3:  No chemical-specific handler exposure data were submitted to
support the agricultural uses petition (PP#8E7427).  In accordance with
HED policy, occupational handler exposures were estimated using the
Pesticide Handlers Exposure Database (PHED) Surrogate Exposure Guide
(revised August, 1998) and the Outdoor Residential Exposure Task Force
(ORETF) studies (G. Bangs, 03/05/03).  The results of the handler
occupational exposure and risk assessment indicate that risks are not of
concern with baseline clothing, or when gloves are worn (which is
required on the proposed label for agricultural uses such as nurseries
and greenhouses).  The total MOEs range from 23,000 to 220,000; and
therefore, are not of concern to HED. 

The results of the occupational postapplication exposure and risk
assessment indicate that the MOEs are greater than 100 on the day of
application, and therefore, are not of concern to HED.  The cyazofamid
technical material has been classified in Toxicity Category III for
acute dermal and primary skin irritation, and Category IV for primary
eye irritation.  Per the Worker Protection Standard (WPS), a 12-hr
restricted entry interval (REI) is required for chemicals classified
under Toxicity Category III/IV.  This product is intended for
agricultural uses as well as use on sod and seed farms, nurseries, and
greenhouses, which are within the scope of the WPS; therefore, the
proposed REI of 12 hours is protective of workers.  Cyazofamid is also
intended for non-agricultural use sites to which the WPS does not apply,
and correctly contains language cautioning unprotected persons to keep
out of treated areas until sprays have dried.  

Environmental Justice Considerations

Potential areas of environmental justice concern, to the extent
possible, were considered in the human-health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,"
(http://www.eh.doe.gov/nepa/tools/guidance/Volume1/2-6-EO_12898envjustic
e.pdf).  OPP typically considers the highest potential exposures from
the legal use of a pesticide when conducting human health risk
assessments including, but not limited to, people who obtain drinking
water from sources near agricultural areas, the variability of diets
within the U.S., and people who may be exposed when harvesting crops. 
Should these highest exposures indicate potential risks of concern, OPP
further refines the risk assessments to ensure that the risk estimates
are based on the best available information.

Review of Human Research

This risk assessment relies in part on data from PHED and ORETF studies
in which adult human subjects were intentionally exposed to a pesticide
or other chemical.  These studies have been determined to require a
review of their ethical conduct, have received that review, and have
been determined to be ethical.

Deficiencies/Label Recommendations

860.1200 Directions for Use

The maximum seasonal use rates for grapes, okra, fruiting vegetables,
and cucurbits (excluding drench uses) in the Section B/label must be
revised to reflect the total of the maximum number of applications at
the maximum proposed use rate.  This corresponds to 0.43 lb ai/A for all
crop types.  

The Section B/label for cucurbit vegetables, fruiting vegetables, and
okra must be amended: “3 fl oz/100 gallons of water (0.078 lb
a.i./A)” should be clarified to indicate that the maximum gal water/A
is 100.

.

The Section B/label must be revised to state that applications may be
made to tomatoes in greenhouse transplant production but that no other
greenhouse applications may be made.  The statement on the label “for
use on all transplants” must be deleted.

 860.1550 Proposed Tolerances

The petitioner should submit a revised Section F reflecting the
following recommended tolerances and commodity definitions for the
combined residues of cyazofamid, 4-chloro-2-cyano- N,N
-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonamide, and its
metabolite CCIM,
4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile, expressed as
cyazofamid, in or on the following commodities:

Commodity	Proposed Tolerance (ppm)

Vegetable, Fruiting, Group 8	0.80

Okra	0.80

Grape, wine (import)	1.5

Tomato	0.20

Grape*	1.5

	*Tolerance to be listed under 40 CFR §180.601(c).2.0	PROPOSED USE
PATTERN tc \l1 "2.0	PROPOSED USE PATTERN 

Residential Turf/Ornamentals Uses – EPA Registration No. 71512-13

ISK submitted a new label specifying the proposed residential use of the
3.33 lb ai/gal formulation of cyazofamid (400SC; EPA Reg. No. 71512-13)
on residential turf and ornamentals.  A summary of the proposed use
directions is presented below in Table 2.2.

Table 2.2.	Summary of Directions for Use of Cyazofamid 400SC.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate 

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	Applic.

Interval	Use Directions and

Limitations1, 2

Residential Turf

Handgun Sprayer, Backpack Sprayer, Low Pressure Handwand, or 

High Pressure Handwand	3.33 lb ai/gal SC

[71512-13]	0.51 – 1.02 lb ai/A	3	3.0 lb ai/A	14 to 21

days	Applications are to be made within the rate range given for turf:
use the lower rate with the shortest interval and the higher rate with
the longest interval. Under severe disease conditions, use the highest
rate with the shortest interval.

Residential Field/Bed-Grown and Container-Grown Ornamentals

Handgun Sprayer, Backpack Sprayer, Low Pressure Handwand, or 

High Pressure Handwand	3.33 lb ai/gal SC

[71512-13]	0.39 – 1.56 lb ai/A	4	3.12 lb ai/A	14 to 28

days	For use as a soil drench or soil surface spray.  For drench, do not
exceed 5% run-through.  For spray, thoroughly wet foliage to the point
of run-off (generally not to exceed 100 gallons per acre).

Agricultural Crop Uses – Petition 8E7427 – EPA Registration No.
71512-3

IR-4 submitted a Section B specifying the proposed uses of the 3.33 lb
ai/gal FlC formulation of cyazofamid (Ranman® 400SC; EPA Reg. No.
71512-3) on grapes east of the Rocky Mountains, fruiting vegetables and
okra, and cucurbit vegetables, along with a specimen label (dated
2/6/07) reflecting general use directions.  HED notes that the specimen
label is essentially identical to the accepted label (dated 12/1/06)
except that fewer tank mix partners are listed.  A summary of the
proposed use directions for cyazofamid is presented below in Table 2.1. 

Table 2.1.	Summary of Directions for Use of Ranman® 400SC.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate 

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and 

Limitations1, 2

Grapes (East of the Rocky Mountains)

Foliar, Broadcast,

Ground, or Aerial	3.33 lb ai/gal FlC

[71512-3]	0.054-0.071	6	0.568	30	Applications are to be made beginning
when disease infection periods are forecast or when conditions are
favorable for disease development by ground application in ≥100 gal/A
or by air in ≥ 5 gal/A at a 10- to 14-day retreatment interval (RTI). 
Use of any surfactant is prohibited.

Okra and Crop Group 8, includes all members of Fruiting Vegetables: 
tomato, ground cherry, tomatillo, pepper (including bell pepper, chili
pepper, cooking pepper, pimento, sweet pepper), eggplant, and pepino

Foliar, Broadcast,

Ground, Aerial, or Chemigation	3.33 lb ai/gal FlC

[71512-3]	0.054-0.071	6	0.455	0	Applications are to be made beginning at
flower initiation or when conditions are favorable for disease
development at a 7- to 10-day RTI.3

At transplant,

directed to the base of the plant or in transplant water	3.33 lb ai/gal
FlC

[71512-3]	0.054-0.071	1	0.455	0	Initial application is to be made at
transplant to the base of the plants or in transplant water in ≥50
gal/A.  Additional applications are to be made when conditions are
favorable for disease development at a 7- to 10-day RTI.  

+ Foliar, Broadcast,

Ground, Aerial, or Chemigation

	+

5

(implied)

	Drench to seedling tray at the time of seeding or any time thereafter
up to 1 week prior to transplant	3.33 lb ai/gal FlC

[71512-3]	0.078 lb ai/

100 gal	1	0.078 lb ai/

100 gal

(0.078 lb ai/A)	0	Greenhouse transplant production.  Use of any
surfactant is prohibited. 



Crop Group 9, includes all members of Cucurbit Vegetables:  cantaloupe,
chayote, Chinese-waxgourd, citron melon, cucumbers, gherkin, gourds,
honeydew melons, Momordica spp., muskmelon, watermelon, pumpkin, squash,
and zucchini

Registered uses4

Foliar, Broadcast,

Ground, Aerial, or Chemigation	3.33 lb ai/gal FlC

[71512-3]	0.054-0.071	6	0.429	0	Applications are to be made beginning at
flower initiation or when conditions are favorable for disease
development at a 7- to 10-day RTI.

Foliar, Broadcast,

Ground, Aerial, or Chemigation

0.071	6

	Applications are to be made beginning when conditions are favorable for
disease development at weekly intervals.

Proposed uses4

At transplant,

directed to the base of the plant or in transplant water	3.33 lb ai/gal
FlC

[71512-3]	0.054-0.071	1	0.429	0	Initial application is to be made at
transplant to the base of the plants or in transplant water in ≥50
gal/A.  Additional applications are to be made when conditions are
favorable for disease development at a 7- to 10-day RTI.

+ Foliar, Broadcast,

Ground, Aerial, or Chemigation

	+

5

(implied)

	Drench to seedling tray at the time of seeding or any time thereafter
up to 1 week prior to transplant	3.33 lb ai/gal FlC

[71512-3]	0.078 lb ai/

100 gal	1	0.078 lb ai/

100 gal

 (0.078 lb ai/A)	0	Greenhouse transplant production.  Use of any
surfactant is prohibited.

1 The use directions specify the following resistance management
restriction for all listed crops:  Do not make more than three
consecutive applications of the 3.33 lb ai/gal FlC formulation followed
by at least three applications of fungicides having different modes of
action before making additional applications of the 3.33 lb ai/gal FlC
formulation.

2 For foliar applications to fruiting and cucurbit vegetables: use of an
organosilicone and/or nonionic surfactant is recommended for
applications made in volumes up to 60 gal/A; application may be made
through sprinkler irrigation equipment.  

3 This use pattern is identical to the registered use on tomato.  

4 Section B of the petition refers to the cucurbits section of the label
for the 3.33 lb ai/gal FlC formulation for further directions and
restrictions.

The following general use directions appear on the specimen/accepted
label for the 3.33 lb ai/gal FlC formulation:    SEQ CHAPTER \h \r 1 (1)
applications may be made as dilute (20-100 gal/A) or concentrate (5-10
gal/A) sprays using ground or aerial equipment; (2) aerial applications
are to be made in ≥5 gal/A; and (3) application through sprinkler
irrigation systems is not recommended unless specific directions are
given for a crop.  

The following rotational crop restriction is specified:  “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.”

The specimen/accepted label states that the 3.33 lb ai/gal FlC
formulation is not to be used for disease control on tomatoes or
cucurbit vegetables grown for fruit production in greenhouses.  

3.0	HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS tc \l1 "3.0	HAZARD
CHARACTERIZATION/FQPA CONSIDERATIONS 

References: 

Cyazofamid [IFK-916] – Report of the Hazard Identification Assessment
Review Committee.  Ghazi Dannan, 03/03/04.

Human Health Risk Assessment to Support the Registration of Cyazofamid
for Use on Carrot.  Kelly O’Rourke, DP#336983, 03/07/08.

The toxicology database for cyazofamid is sufficient to characterize the
hazard, to conduct FQPA assessment, and to select toxicity endpoints for
risk assessment. Data quality is acceptable and meets the criteria set
in the OPPTS guidelines and 40 CFR 158.500. However, under the current
data requirement guidelines, functional immunotoxicity data (OPPTS
780.7800) shall be required as a condition of registration. To address
the issue of the immunotoxicity data gap and the associated database
uncertainty factor, RAB3 has examined the entire database of cyazofamid
and concluded that the  toxicology database of this chemical does not
show any evidence of biologically relevant effects on the immune system
that related to this chemical. The overall weight of evidence suggests
that this chemical does not directly target the immune system. The
Agency does not believe that conducting a functional immunotoxicity
study will result in a lower NOAEL than the regulatory dose for risk
assessment, and an additional factor (UFDB) for database uncertainty is
not needed to account for lack of this study.

In addition, a subchronic neurotoxicity study is not available. Under
the current rules (40 CFR 158.500), a subchronic neurotoxicity study is
required.  However, based on the available data, conducting a subchronic
neurotoxicity study is unlikely to result in a lower NOAEL than the
available relevant toxicity results because the acute neurotoxicity
study, which tested dose levels as high as 2000 mg/kg, shows no
neurotoxic effects with gavage dosing. Neurotoxicity is also not
demonstrated in subchronic, chronic, reproduction, or developmental
toxicity studies. At this time, the lack of a subchronic neurotoxicity
study does not present any uncertainty for evaluating the toxicity of
cyazofamid. Therefore, a database uncertainty factor (UFDB) for lack of
a subchronic neurotoxicity is not needed.  

The hazard characterization, dose response considerations, absorption,
distribution, metabolism, excretion (ADME) determinations, FQPA safety
factor determination, mode of action, and toxicological effects are
detailed in the previous risk assessment (DP#342612, K. O’Rourke,
03/19/08).  

3.1 	FQPA Considerations  TC \l2 "3.1	FQPA Considerations 

Based on the hazard and exposure data, the HED cyazofamid risk
assessment team recommends that the FQPA SF be reduced to 1x.  The
recommendation is based on the following:

The toxicology database for cyazofamid is complete for the purposes of
this risk assessment and the characterization of potential pre- and
postnatal risks to infants and children.

In the rat developmental toxicity study, there was quantitative evidence
of in utero susceptibility; increases in fetuses with bent ribs were
seen at 1,000 mg/kg/day (top dose) in the absence of maternal toxicity. 
The developmental NOAEL was 100 mg/kg/day and the maternal NOAEL was
1,000 mg/kg/day.  The HIARC concluded that bent ribs are a reversible
developmental anomaly rather than a malformation and that using this
endpoint for setting the developmental NOAEL/LOAEL is a conservative
approach.  

In the prenatal developmental toxicity study in rabbits, there was no
indication of increased susceptibility (qualitative or quantitative) of
rabbit fetuses to in utero exposure to cyazofamid.  No maternal or
developmental effects were seen at any dose up to the limit dose of
1,000 mg/kg/day.

In the two-generation reproduction study, the highest dose tested
(>1,000 mg/kg/day) did not cause maternal systemic toxicity nor did it
elicit reproductive or offspring toxicity.

The HIARC concluded that the concern is low for the quantitative
susceptibility seen in the rat developmental toxicity study and there
are no residual uncertainties because: 1) The developmental effect is
well identified with clear NOAEL/LOAEL; 2) the developmental effect
(increased bent ribs) is a variation rather than a malformation; 3) the
developmental effect is seen only at the limit dose of 1,000 mg/kg/day;
4) this endpoint is used to establish the acute RfD for Females 13-49;
and 5) the overall toxicity profile indicates that cyazofamid is not a
very toxic compound. 

There were no indications of pre- or postnatal toxicity and no residual
uncertainties from the rabbit developmental study or the rat
two-generation reproduction study.

The exposure assessments are conservative, high-end assessments and will
not underestimate the potential dietary (food and water) exposures.  The
drinking water component of the dietary assessment utilizes water
concentration values generated by model and associated modeling
parameters which are designed to provide conservative, health
protective, high-end estimates of water concentrations (EDWCs) which
will not likely be exceeded.  Dietary exposure assessments were
conducted using tolerance level residues and assumed 100% crop treated. 
Therefore, the acute and chronic dietary exposures are considered upper
bound conservative estimates.

While there is potential for postapplication residential exposure, the
best data and approaches currently available were used in the cyazofamid
residential assessment.  The Agency used the current conservative
approaches for residential assessment included in the SOPs.  The Agency
believes that the calculated risks represent conservative estimates of
exposure because maximum application rates are used to define residue
levels upon which the calculations are based.  Exposures are unlikely to
be under estimated because the assessment was a screening level
assessment.

3.2 	Dose-Response Assessment  TC \l2 "3.2	Dose-Response Assessment 

Tables 3.2.1 and 3.2.2 summarizes the toxicological endpoints for
cyazofamid for use in dietary and occupational human health risk
assessments, respectively.  In addition to the detailed overview from
the previous assessment, a study (28-day dose-range finding study in
rats) has been added to the toxicity profile in Appendix C.  Also, a new
toxicological endpoint has been selected with respect to
short-/intermediate-term incidental oral exposures for toddlers as shown
in Table 3.2.1.  Please refer to the listed references for further
extensive details and refer to Appendix C for the toxicity profile
tables.  Aside from consideration of the 28-day oral range-finding study
in the rat for selection of an incidental oral endpoint, the hazard
characterization and endpoint selection from the previous risk
assessment are applied directly to this section.  



Table 3.2.1.  Toxicological Doses and Endpoints for Cyazofamid for Use
in Dietary and Non-Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty/

FQPA Safety Factors	RfD, PAD, Level of Concern for Risk Assessment	Study
and Toxicological Effects

Acute Dietary (General Population, including Infants and Children)	No
adverse effects were observed which could be attributed to a single-dose
exposure for the general population

Acute Dietary

(Females 13-49 years of age)	NOAEL = 100 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Acute RfD = 1.0 mg/kg/day	Rat Prenatal Developmental Toxicity (MRID
45408933)

LOAEL = 1,000 mg/kg/day based on developmental toxicity findings of
increased incidence of bent ribs.

Chronic Dietary (All Populations)	NOAEL= 94.8 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Chronic RfD = 0.948

mg/kg/day

	18-Month Mouse Oral Carcinogenicity (MRID 45408932)

LOAEL = 985 mg/kg/day based on increased skin lesions.

Incidental Oral Short-Term (1-30 days) and Intermediate-Term (1-6
months)	NOAEL= 30 mg/kg/day 	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Residential LOC for MOE = 100	 90-Day oral toxicity study in rats.
LOAEL= 295 mg/kg based on 

Increased number of basophilic tubules of the kidneys, increased urinary
volume, pH, & protein.  This toxicity endpoint is also supported by the
results of a 28-day oral dose- range- finding study in rats. In this
study, at 370 mg/kg/day or above   increased incidence of basophilic
tubules in the kidneys was found.  

Dermal Short-Term (1-30 days) and Intermediate-Term (1-6 months)	For
CHILDREN:

No toxicity was found at 1000 mg/kg in a 28-day dermal toxicity study,
therefore, in the absence of hazard identified for this population, a
risk assessment is not necessary.

	For ADULTS:

NOAEL = 100 mg/kg/day

(Dermal Absorption Rate = 37%)	

UFA= 10x

UFH= 10x

FQPA SF= 1x

	

Acute RfD = 1.0 mg/kg/day	

Rat Prenatal Developmental Toxicity (MRID 45408933)

LOAEL = 1,000 mg/kg/day based on developmental toxicity findings of
increased incidence of bent ribs.

Inhalation Short- Term (1-30 days) and Intermediate-Term (1-6 months)	No
residential exposure is expected via inhalation route.

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

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (intraspecies).  UFH =
potential variation in sensitivity among members of the human population
(interspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key date (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  N/A = not applicable.

Table 3.2.2.  Summary of Toxicological Doses and Endpoints for
Cyazofamid for Use in Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Dermal Short-Term (1-30 days) and Intermediate-Term (1-6 months)	Oral
Study NOAEL= 100 mg/kg/day (Dermal Absorption Rate = 37%)	UFA=10x

UFH=10x	Occupational LOC for MOE = 100	Rat Prenatal Developmental
Toxicity (MRID 45408933)

LOAEL = 1,000 mg/kg based on developmental toxicity findings of
increased incidence of bent ribs.

Dermal Long Term (>6 months)	NOAEL= 94.8 mg/kg/day

(Dermal Absorption Rate = 37%)	UFA=10x

UFH=10x	Occupational LOC for MOE = 100	18-Month Mouse Oral
Carcinogenicity (MRID 45408932)

LOAEL = 985 mg/kg/day based on increased skin lesions.

Inhalation Short-Term (1-30 days) and Intermediate-Term (1-6 months)
NOAEL= 100 mg/kg/day

	UFA=10x

UFH=10x	Occupational LOC for MOE = 100	Rat Prenatal Developmental
Toxicity (MRID 45408933)

LOAEL = 1,000 mg/kg based on developmental toxicity findings of
increased incidence of bent ribs.

Inhalation Long-Term (>6 months)	NOAEL= 94.8 mg/kg/day	UFA=10x

UFH=10x	Occupational LOC for MOE = 100	18-Month Mouse Oral
Carcinogenicity (MRID 45408932)

LOAEL = 985 mg/kg/day based on increased skin lesions.

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

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (intraspecies).  UFH =
potential variation in sensitivity among members of the human population
(interspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key date (i.e., lack of a critical study).  MOE =
margin of exposure.  LOC = level of concern.  N/A = not applicable.

Acute Dietary Endpoint: An acute endpoint was not identified for the
general population including infants and children, because no effects
were observed which could be attributed to a single-dose exposure. 
However, for females 13 to 49 years old, the acute RfD of 1.0 mg/kg/day
is derived from the developmental toxicity NOAEL of 100 mg/kg/day based
on increased incidence of bent ribs in fetuses at the developmental
LOAEL of 1,000 mg/kg/day in the rat prenatal developmental toxicity
study.  A 100-fold uncertainty factor (10X inter-species extrapolation
and 10X intra-species variability) is required.  Since the FQPA SF has
been reduced to 1X, the acute PAD is equal to the acute RfD. 

Chronic Dietary Endpoint: The chronic RfD of 0.95 mg/kg/day is derived
from a NOAEL of 94.8 mg/kg/day based on increased incidence of skin
lesions in males at 985 mg/kg/day (LOAEL) in the mouse carcinogenicity
study.  A 100-fold uncertainty factor (10X inter-species extrapolation
and 10X intra-species variability) is required.  Since the FQPA SF has
been reduced to 1X, the chronic PAD is equal to the chronic RfD.

Carcinogenicity: Cyazofamid is characterized as “not likely to be
carcinogenic to humans” based on the lack of increased tumor incidence
in the rat and the mouse carcinogenicity studies.

Incidental Oral (short & intermediate terms) Endpoints and PODs: The
incidental oral toxicity endpoint and point of departure for risk
assessment are derived from evaluating the data from the 90-day oral
toxicity and 28-day oral dose-range-finding in rats. In the 90-day oral
study, increases in urine volume, pH, and urinary protein indicative of
kidney effects were seen in males at the dose of 295 mg/kg.
Microscopically, the affected males also showed bilaterally “increased
number of basophilic tubules” in the kidneys. Similar microscopic
changes were reported in treated males in the 28-day dose range finding
study at a similar dose level (370 mg/kg/day) and these results provided
support for the use of the kidney effects seen in the 90-day study for
short-term exposure assessment. For consideration of the point of
departure for risk assessment, the established NOAELs in both the 90-day
toxicity (30 mg/kg/day) and 28-day dose-range finding (37 mg/kg/day)
studies are in similar dose range and reflect the exposure duration of
concern. A NOAEL of 30 mg/kg is selected as the point of departure for
risk assessment, and it is considered to be protective and conservative.

Dermal Absorption Factor:  There is no available dermal absorption study
and there are no suitable structurally related chemicals to inform or
provide comparative data for dermal absorption.  No effects were seen in
the available 28-day dermal toxicity study up to the limit dose of 1,000
mg/kg/day.  In the 28-day oral rat study that evaluated similar
endpoints, there were an increased number of basophilic kidney tubules
in males at the mid- and high-level doses (370 and 1488 mg/kg/day,
respectively).  The oral toxicity NOAEL and LOAEL are 38.5/370
mg/kg/day.  An approximate (and conservative) dermal absorption factor
may be derived by comparing the LOAELs of both the 28-day dermal and
oral toxicity studies. Since no systemic effects were seen at any dose
in the dermal toxicity study, the dermal LOAEL will be assumed to be the
top dose (1,000 mg/kg/day).  The derived upper-bound dermal absorption
factor is 37%: 

			  370 mg/kg/day   x 100 = 37%

			1,000 mg/kg/day

This estimate of dermal absorption is considered conservative because
the oral bioavailability of the chemical ranges between 5% (at a high
dose of 1,000 mg/kg) and 75% (at 0.5 mg/kg).

Short-Term (1-30 days) and Intermediate-Term (1-6 months) Dermal and
Inhalation Endpoints and PODs:  A prenatal developmental study with rats
was used to select the dose and endpoint for assessing risk due to
short- and intermediate-term dermal and inhalation exposure to
cyazofamid.  For this study, the POD, the developmental toxicity NOAEL
of 100 mg/kg/day, is based on increased incidence of bent ribs at the
LOAEL of 1,000 mg/kg/day.  NOTE that this effect is applicable to adults
only – no dermal hazard was identified for infants and children.

Long-Term (>6 months) Dermal and Inhalation Endpoints and PODs: An
18-month oral carcinogenicity study with mice was used to select the
dose and endpoint for assessing risk due to long-term dermal and
inhalation exposure to cyazofamid.  For this study, the POD, the NOAEL
of 94.8mg/kg/day, is based on increased incidence of skin lesions in
males at the LOAEL of 985 mg/kg/day.  

MOEs for Occupational Risk Assessment: For short-, intermediate-, and
long-term dermal and inhalation exposure risk assessments, an MOE of
greater than or equal to 100 is adequate.  The level of concern (LOC)
for exposure is based on the conventional uncertainty factor of 100X
(10X for interspecies extrapolation and 10X for intraspecies variation).
 Because endpoints are the same for both dermal and inhalation exposure,
the individual dermal and inhalation MOEs should be combined into a
total MOE for comparison to the LOC.

MOE for Residential Risk Assessment:  For all durations and routes of
exposure, an MOE greater than or equal to 100 is adequate.  The LOC is
based on the conventional uncertainty factor of 100X; the FQPA safety
factor was reduced to 1X.

3.3	Endocrine Disruption  TC \l2 "3.3	Endocrine Disruption 

Evidence of endocrine disruption due to cyazofamid was not observed in
the studies reviewed. EPA is required under the Federal Food Drug and
Cosmetic Act (FFDCA), as amended by FQPA, to develop a screening program
to determine whether certain substances (including all pesticide active
and other ingredients) "may have an effect in humans that is similar to
an effect produced by a naturally occurring estrogen, or other such
endocrine effects as the Administrator may designate."  Following the
recommendations of its Endocrine Disruptor Screening and Testing
Advisory Committee (EDSTAC), EPA determined that there were scientific
bases for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA has authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, cyazofamid may be
subjected to additional screening and/or testing in order to better
characterize effects related to endocrine disruption.

4.0	DIETARY EXPOSURE/RISK CHARACTERIZATION  TC \l1 "4.0	DIETARY
EXPOSURE/RISK CHARACTERIZATION  

References:  

Cyazofamid. Amend Section 3 Registration to Add Uses on Fruiting
Vegetables, Okra, Grape (East of the Rocky Mountains), and Greenhouse
Vegetable Transplants.  Summary of Analytical Chemistry and Residue
Data. DP#357042, Amelia Acierto, 03/18/09.  

Cyazofamid: Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure and Risk Assessments for an IR-4 Proposed Section 3
Registration Amendment to Add Uses in/on Fruiting Vegetables, Okra, and
Grapes.  DP#357043, Amelia Acierto, 03/25/09.

The exposure pathways resulting from use of this chemical are dietary
(food and drinking water), residential, and occupational.  The residue
chemistry data submitted in support of the proposed uses and new
tolerances were summarized in the HED memorandum by A. Acierto
(DP#357042, 03/18/09).  The acute and chronic dietary exposure
assessments were completed in a HED memorandum by A. Acierto (DP#357043,
03/25/09).

4.1	Food Residue Profile  TC \l2 "4.1	Food Residue Profile 

References:  

Cyazofamid - Meeting Report of the Metabolism Assessment Review
Committee (MARC).  DP#298915, A. Acierto, 02/18/04.

Permanent tolerances for the combined residues of cyazofamid and its
metabolite CCIM are currently established in/on cucurbits, imported wine
grapes, potatoes, tomatoes, and carrot roots.  The current request for
registration is for a proposed use on fruiting vegetables and okra,
grapes east of the Rocky Mountains, and greenhouse vegetable
transplants.

Nature of the Residue – Plants

The nature of the residue in plants is adequately understood based on
previously submitted metabolism studies on grape, potato, and tomato. 
The HED Metabolism Assessment Review Committee (MARC) concluded in a
meeting on 2/18/04 that, for the risk assessment and tolerance
expression, parent and CCIM are the residues of concern for plant
commodities. 

Nature of the Residue – Livestock

The current uses of cyazofamid fall under 40 CFR §180.6(a)(3) (i.e.,
there is no reasonable expectation of finite residues in livestock
commodities).  Based on the available ruminant metabolism studies in
goats, MARC recommended that for future cattle feeding studies, the
following metabolites should be analyzed: cyazofamid, CCIM, CCBA
(4-(4-chloro-2-cyanoimidazol-5-yl)benzoic acid; see Appendix A),
CCBA-cysteine conjugate.

Residue Analytical Methods – Plants

An adequate data collection method, “Independent Laboratory Validation
of the Residue Method for IKF-916 and CCIM in Tomatoes”, Document
Number 013033-0, Pyxant Labs Inc, with slight modification was used to
determine the residues of cyazofamid and CCIM.  Quantitation was
achieved by liquid chromatography/mass spectrometry/mass spectrometry
(LC/MS/MS). Based on recoveries of samples fortified with cyazofamid at
the lowest level of method validation (LLMV) of 0.01 ppm, the limit of
detection (LOD) and limit of quantitation (LOQ) were calculated to be
0.002 ppm and 0.005 ppm, respectively.  Based on recoveries of samples
fortified with CCIM at the LLMV of 0.01 ppm, the LOD and LOQ were
calculated to be 0.003 ppm and 0.009 ppm, respectively. This method is
deemed acceptable for the determination of residues of cyazofamid and
CCIM in/on fruiting vegetables and okra, and grapes east of the Rocky
Mountains.

Storage Stability

The available storage stability data for tomato may be translated to
support the storage durations and conditions of samples of peppers from
the submitted crop field trial studies.  The available and concurrent
storage stability studies are adequate to support the storage durations
and conditions of samples of tomato and leaf lettuce from the submitted
transplant study.  No corrections for potential decline during storage
are needed for any of the residue studies.

Zero-day data were not provided with the concurrent storage stability
study on leaf lettuce and tomato; IR-4 is reminded that storage
stability studies should always include a 0-day sampling interval to
establish the residue levels present at the time samples are placed into
storage [see OPPTS 860.1380(d)(6)(i)].

Crop Field Trial Data

Grape:  No new grape field trial data were submitted with this petition.
 To support the proposed uses for cyazofamid on grapes in the U.S. east
of the Rocky Mountains, IR-4 is relying on European field trial data
submitted to establish the current import tolerance for cyazofamid
residues in/on wine grapes (PP#1F06305).  ChemSAC considered this
request (see minutes of 8/29/2007 meeting) and concluded that the
European residue data may be used to support application of cyazofamid
to grapes grown east of the Rocky Mountains, provided that the
petitioner addresses the following issues:  (i) the maximum U.S.
application rate should be equal to or less than the rate used in the
European trials; (ii) the U.S. preharvest and reapplication intervals
should match the European trials; and (iii) the petitioner needs to
address any differences in formulation and inert ingredients between the
product(s) used in the European trials and the product(s) proposed for
use in the U.S.

Conclusions.  The available European grape field trial data are adequate
to support the proposed use of the 3.33 lb ai/gal FlC formulation in the
U.S. on grapes grown east of the Rocky Mountains.  The available data
represent application rates >1x the proposed maximum seasonal rate for
use in the U.S., similar retreatment intervals, and a shorter PHI (21/22
days) than the proposed U.S. PHI of 30 days.  In addition, the
formulation used in the European trials and that proposed for use in the
U.S. are comparable (refer to 860.1100).

The available data will support a tolerance with regional registration
for combined residues of cyazofamid and CCIM in/on grapes at 1.5 ppm.  

Vegetable, Fruiting (Crop Group 8) and Okra:  A tolerance is established
for the combined residues of cyazofamid and its metabolite CCIM in/on
tomato at 0.20 ppm [40 CFR §180.601(a)].  To support the proposed use
of cyazofamid on fruiting vegetables, crop group 8, and okra, IR-4 has
submitted field trial data for pepper (bell and non-bell) and referenced
tomato field trials previously submitted by ISK Biosciences in support
of the established tolerance on tomato.  The representative commodities
of the fruiting vegetable group are tomato, bell pepper, and non-bell
pepper.  The results of the pepper field trials are summarized in Table
4.1.  

RAB3 previously concluded that the tomato field trial data were
adequate.  These data are re-evaluated in conjunction with the submitted
pepper field trial data in support of the proposed uses on fruiting
vegetables and okra.  The results of the tomato field trials reflecting
a 0-day PHI are summarized in Table 4.1.

No residue data were submitted to support the proposed use on okra. 
IR-4 is proposing to translate the existing and submitted fruiting
vegetable data (pepper and tomato) to okra.  The proposed use on okra is
identical to the proposed use on the fruiting vegetables crop group. 
HED has approved adding okra to the fruiting vegetable crop group (see
minutes of the ChemSAC meeting of 10/18/06).  Until 40 CFR §180.41 is
updated, a separate tolerance must be established for okra.

Conclusions.  The submitted/available data for bell and non-bell pepper
and tomato are adequate to fulfill data requirements.  

Based on residue data and the Tolerance/MRL Harmonization Spreadsheet,
the recommended tolerances for bell pepper, non-bell pepper, and tomato
would be 0.35, 0.40, and 0.20 ppm, respectively.  Because these values
differ by a factor of <5x, the data suggest that a group tolerance of
0.40 ppm is appropriate for fruiting vegetable group 8.  

The available data for the fruiting vegetable crop group may be used to
support the proposed tolerance for okra.  The tolerance should be
established at the same level as the fruiting vegetable group tolerance,
0.40 ppm. 

Table 4.1.1.  Summary of Residue Data from Fruiting Vegetables Crop
Field Trials with Cyazofamid.

Commodity

(MRID)	Total Applic. Rate1

(lb ai/A)	PHI (days)	Analyte	Residue Levels (ppm)

n	Min.	Max.	HAFT2	Median	Mean	Std. Dev.

Proposed use = 0.429 lb ai/A total application rate, 0-day PHI3

Pepper, bell

(47528401)	0.418-0.429	0	Cyazofamid	12	0.037	0.283	0.224	0.064	0.091
0.071

	CCIM	12	<0.01	0.014	0.012	0.01	0.010	0.001

	Combined	12	<0.047	0.297	<0.236	0.074	0.101	0.072

Pepper, non-bell

(47528401)	0.419-0.426	0	Cyazofamid	6	0.211	0.317	0.307	0.263	0.266
0.038

	CCIM	6	<0.01	0.017	0.014	0.014	0.013	0.003

	Combined	6	<0.221	0.334	0.321	0.277	0.279	0.041

Tomato

(45409031, 45638507, 45638508) 	0.413-0.434	0	Cyazofamid	32	<0.01	0.16
0.145	0.05	0.05	0.03

	CCIM	32	<0.01	0.02	0.015	0.01	0.01	0.01

	Combined	32	<0.02	<0.18	<0.16	0.06	0.06	0.04

1  All pepper field trial data reflect use of a surfactant; the tomato
field trial data include results from 3 trials with surfactant and 10
trials without surfactant; data from the side-by-side trial reflecting
application with and without a surfactant are included.

2  HAFT = Highest Average Field Trial. 

3  Maximum proposed seasonal rate reflects adjustment recommended by HED
(total of the maximum proposed number of applications at the maximum
proposed single application rate).

Vegetable transplants from the greenhouse to the field

Under the current action, IR-4 is proposing use of cyazofamid on
fruiting and cucurbit vegetables that are to be transplanted from the
greenhouse to the field.

IR-4 had originally proposed use of cyazofamid as a single drench
application on all transplants, and ChemSAC approved the protocol for
the study on leaf lettuce and tomato, (see minutes of 2/2/05 meeting),
concluding that if no residues ≥LOQ were found in the 10x study, the
use would be considered non-food.  On examination of the leaf lettuce
and tomato data presented above, ChemSAC concluded (see minutes of
1/16/08 and 3/18/09) that a non-food use classification for tomato is
appropriate; lettuce will not be allowed a nonfood use classification
since there were detectable residues in the 10x study. 

To support transplant use for the remaining fruiting vegetables, okra,
and cucurbit vegetables, the ChemSAC has concluded (see minutes of
3/18/09 meeting) that the petitioner should submit residue data similar
to the lettuce and tomato residue data.  Greenhouse trials using a
single drench application of cyazofamid at 10x the proposed rate are
required for the representative crops:  2 trials each for bell and
non-bell pepper and 4 trials each for cucumber and summer squash.  The
results for peppers and tomatoes can be translated to okra.  If these
data demonstrate that residues are <LOQ following treatment at 10x the
proposed rate, then additional data to support the drench use on
fruiting vegetables, okra, and cucurbit vegetables will not be needed.

A revised label is needed to state that the use on transplants will be
allowed for tomatoes but will not be allowed for any other crops.  The
statement on the label “for use on all transplants” must be deleted.

Processed Food/Feed

Grape:  Grape processing studies were previously submitted in
conjunction with PP#1F06305 in support of the use of cyazofamid on
imported grape wine.  The available processing data indicate that
residues of cyazofamid and CCIM do not concentrate in raisins.    SEQ
CHAPTER \h \r 1 Following processing, the average concentration factor
in must was 1.2x but was reduced by 0.1-0.3x in wine.  Residues of CCIM
were below the LOQ in/on all samples of grapes and grape must
(unfermented or fermented grape juice) but ranged <0.01-0.02 ppm in
wine, indicating processing factors of >1x to >2x.  

Conclusions.  The available grape processing data are adequate to
satisfy data requirements.  The average processing factor for must is
1.2x.  The processing studies on must can be used in place of studies on
grape juice.  Since a processing study is not available for juice, the
processing factor of 1.2x for grape juice will be used in the dietary
exposure assessment.  The proposed tolerance for grapes, 1.5 ppm, is
adequate to cover grape juice.  No additional processing study is
required.

Tomato:  An adequate tomato processing study was previously submitted in
conjunction with PP#1F06305.  Following application of the 3.33 lb
ai/gal FlC formulation of cyazofamid to tomato plants at 0.567 lb ai/A
(1.3x the maximum proposed seasonal application rate), the available
processing data indicated that residues of cyazofamid do not concentrate
in tomato paste and puree (processing factors of <0.3x) and residues of
CCIM do not concentrate in puree but concentrated in paste by a factor
of 4x. 

HED previously concluded that, based on the available field trial data
for tomato reflecting a 7-day PHI, and the respective processing factors
for cyazofamid and CCIM, a tolerance for tomato paste was not required.

A processing factor for combined residues of cyazofamid and CCIM was not
calculated in the original petition review (PP#1F06305).  The data
indicate that the processing factors for combined residues of cyazofamid
and CCIM are 1x for tomato paste and 0.4x for tomato puree.

Conclusions.  The available processing data for tomato are acceptable. 
The data indicate that combined residues of cyazofamid and CCIM are
unlikely to concentrate in the processed commodities of tomato;
therefore, tolerances are not needed.

Confined Accumulation in Rotational Crops

No confined accumulation in rotational crop study was submitted with
this petition.  However, studies were submitted in conjunction with an
earlier petition (PP#1F06305).  The results of these data showed that
cyazofamid and structurally related metabolites are not expected to be
present at a level greater than 0.01 ppm in/on three representative
rotational crop commodities at a plant-back interval of 30 days. 
Therefore, HED has concluded that a rotational crop plant-back interval
(PBI) of 30 days would be appropriate for the cyazofamid end-use labels.
 

Tolerances

The summary of tolerances to be established for the combined residues of
cyazofamid, 4-chloro-2-cyano- N,N
-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonamide, and its
metabolite CCIM,
4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile, expressed as
cyazofamid (PP#8E7427), is listed in Table 4.1.2.

Table 4.1.2.  Tolerance Summary for Cyazofamid

Commodity	Established Tolerance (ppm)

	Proposed Tolerance (ppm)

	Recommended Tolerance (ppm)	Comments; Correct Commodity Definition

Tolerances established or to be listed under 40 CFR §180.601(a)

Vegetable, fruiting, group 8	--	0.80	0.40

	Okra	--	0.80	0.40

	Grape, wine (import)	1.5	1.5	Move to 180.601(c)	Delete here

Tomato	0.20	--	Remove	Covered by tolerance for fruiting vegetable group.

Tolerance to be listed under 40 CFR §180.601(c)

Grape	1.5	1.5	1.5	Because use is to be restricted to areas east of the
Rocky Mountains, the tolerance must be established with regional
registration.

4.2	International Residue Limits TC \l2 "4.2	International Residue
Limits 

Presently, there are no maximum residue levels (MRLs) established by
Codex or Mexico for cyazofamid; therefore, harmonization is not an
issue.  A Canadian MRL has been established for residues of cyazofamid
and CCIM at 0.20 ppm for tomatoes (See Appendix B).  

4.3	Drinking Water Residue Profile  TC \l2 "4.3	Drinking Water Residue
Profile 

References:  

Estimated Drinking Water Concentrations of Parent Cyazofamid and its
Degradates CCIM, CCIM-AM and CTCA for Use in Human Health Risk
Assessment (Use on Fruiting Vegetables, Crop Group 8 + Okra, and Grapes,
East of the Rocky Mountains).  DP#356836, José L. Meléndez, 03/24/09.

The Agency used screening-level water exposure models in the dietary
exposure analysis and risk assessment for cyazofamid in drinking water. 
These simulation models take into account data on the physical,
chemical, and fate/transport characteristics of cyazofamid.  

The Tier 2 linked PRZM/EXAMS models were used in predicting the surface
water concentrations, and the Tier 1 regression model SCI-GROW was used
in predicting groundwater concentrations.  The primary use of these
models by the Agency at this stage is to provide a coarse screen for
determining that pesticide residues (and metabolites) in water are not
of concern.  Further information regarding EPA drinking water models
used in pesticide exposure assessment can be found at:   HYPERLINK
"http://www.epa.gov/oppefed1/models/water/" 
http://www.epa.gov/oppefed1/models/water/ .  

Environmental Profile

Available environmental fate studies suggest cyazofamid is not very
mobile and quickly degrades into a number of degradation products under
different environmental conditions.  The MARC concluded that cyazofamid
and the metabolites designated as CCIM, CCIM-AM
(4-chloro-5-p-tolylimidazole-2-carboxamide; see Appendix A), and CTCA
(4-chloro-5-p-tolylimidazole-2-carboxylic acid; see Appendix A) are
considered to be the major residues in water and should be included in
the drinking water risk assessment.  Among the three major degradates
for cyazofamid (CCIM, CCIM-AM and CTCA), the two terminal ones are CCIM
and CTCA.  CCIM is expected to be the major terminal degradate in water
bodies with low biological activity because it forms as a result of
abiotic hydrolysis of the parent.  In contrast, CTCA is expected to be
the major terminal degradate in biologically active soils and
water/sediment systems.  Both CCIM and CTCA are stable to abiotic
hydrolysis and susceptible to leaching, but only CCIM is highly
susceptible to biodegradation.  Given these fate characteristics,
cyazofamid and/or its degradates could potentially reach surface water
via spray drift or runoff under certain environmental conditions, but
the potential for it to reach groundwater is very low.  CCIM and/or CTCA
could potentially be the terminal degradates in surface water bodies
affected by spray drift and/or runoff depending on the level of
biological activity. However, only CTCA has a high potential to
contaminate ground water due to its high persistence and mobility. 

Estimated Drinking Water Concentrations (EDWCs)

The screening level surface water and ground water concentrations were
estimated using linked PRZM/EXAMS models and the SCI-GROW model,
respectively.  These EDWCs that may occur due to the use of cyazofamid
on turf and ornamentals are presented in Table 4.3 for the following
scenarios:

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

Each of the degradates CCIM, CCIM-AM, and CTCA, assuming application of
the molar equivalent of the parent for each of the degradates by
dividing the rate between the degradates based on molecular ratios and
adjusted maximums found in fate studies; and

The terminal degradate CTCA, assuming application of 100% molar
conversion of the parent into this terminal degradate CTCA.

Table 4.3.  Resulting Maximum Surface/Groundwater EDWCs for Cyazofamid
and each of its Major Degradates (from use on Turf and Ornamentals)

Scenario	Chemical	Surface water EDWCs (ppb)	Ground Water EDWC (ppb)

Acute 

(1-in-10 yr. peak)	Chronic

 (1-in-10 yr. mean)

	1st  Scenario	Parent	14.4	0.38	0.012

2nd  Scenario 	CCIM	17.1	12.1	0.00061

	CCIM-AM	6.7	6.3	0.0027

	CTCA	16.7	11.0	0.52

3rd  Scenario 	CTCA	136	133	2.18

The highest acute (peak) and chronic (mean) EDWCs were estimated for
surface water using the PRZM/EXAMS model.  For the purpose of this Tier
1 dietary assessment, HED used the highest calculated screening EDWCs
for surface water based on the 3rd modeling scenario: 136 ppb for the
acute analysis and 133 ppb for the chronic analysis.  This approach may
significantly overestimate dietary exposure to cyazofamid from drinking
water.  

4.4	Dietary Exposure and Risk  TC \l2 "4.4	Dietary Exposure and Risk 

Reference:  

Cyazofamid: Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure and Risk Assessments for an IR-4 Proposed Section 3
Registration Amendment to Add Uses in/on Fruiting Vegetables, Okra, and
Grapes. DP#357043, Amelia Acierto, 03/25/2009.

Cyazofamid acute and chronic dietary exposure assessments were conducted
using the Dietary Exposure Evaluation Model software with the Food
Commodity Intake Database (DEEM-FCID™, Version 2.03), which
incorporates consumption data from USDA’s Continuing Surveys of Food
Intakes by Individuals (CSFII), 1994-1996 and 1998.  The 1994-96, 98
data are based on the reported consumption of more than 20,000
individuals over two non-consecutive survey days.  Foods “as
consumed” (e.g., apple pie) are linked to EPA-defined food commodities
(e.g. apples, peeled fruit - cooked; fresh or N/S; baked; or wheat flour
- cooked; fresh or N/S, baked) using publicly available recipe
translation files developed jointly by USDA/ARS and EPA.  For chronic
exposure assessment, consumption data are averaged for the entire U.S.
population and within population subgroups, but for acute exposure
assessment are retained as individual consumption events.  Based on
analysis of the 1994-96, 98 CSFII consumption data, which took into
account dietary patterns and survey respondents, HED concluded that it
is most appropriate to report risk for the following population
subgroups: the general U.S. population, all infants (<1 year old),
children 1-2, children 3-5, children 6-12, youth 13-19, adults 20-49,
females 13-49, and adults 50+ years old.

For both the acute and chronic analyses, the drinking water EDWC was
incorporated directly as a point estimate in the DEEM analysis to assess
exposure to cyazofamid from drinking water.

Acute Dietary Exposure and Risk

For acute exposure assessments, individual one-day food consumption data
are used on an individual-by-individual basis.  The reported consumption
amounts of each food item can be multiplied by a residue point estimate
and summed to obtain a total daily pesticide exposure for a
deterministic exposure assessment, or “matched” in multiple random
pairings with residue values and then summed in a probabilistic
assessment.  The resulting distribution of exposures is expressed as a
percentage of the aPAD on both a user (i.e., only those who reported
eating relevant commodities/food forms) and a per-capita (i.e., those
who reported eating the relevant commodities as well as those who did
not) basis.  In accordance with HED policy, per capita exposure and risk
are reported for all tiers of analysis.  However, for Tiers 1 and 2, any
significant differences in user vs. per capita exposure and risk are
specifically identified and noted in the risk assessment.

An acute endpoint was not identified for the general population
including infants and children, because no effects were observed which
could be attributed to a single-dose exposure.  However, for females 13
to 49 years old, the acute RfD of 1.0 mg/kg/day is derived from the
developmental toxicity NOAEL of 100 mg/kg/day based on increased
incidence of bent ribs at the developmental LOAEL of 1,000 mg/kg/day in
the rat prenatal developmental toxicity study.  A 100-fold uncertainty
factor (10X inter-species extrapolation and 10X intra-species
variability) is required.  Since the FQPA SF has been reduced to 1X, the
acute
population-adjusted-dose漠⁲捡瑵⁥䅐⁄獩攠畱污琠⁯桴⁥捡
瑵⁥晒⹄吠敨愠畣整倠䑁眠獡甠敳⁤潦⁲獡敳獳湩⁧捡
瑵⁥楤瑥牡⁹楲歳മ

An unrefined acute dietary exposure analysis (Tier 1 assessment) was
conducted via DEEM-FCID™ for cyazofamid.  Based on the assumptions of
tolerance-level residues (all processing factors set to 1x, based on the
results of processing studies), 100% crop-treated, and screening-level
EDWCs, acute dietary exposure of females 13-49 years old is well below
HED’s level of concern (i.e., <100% of the aPAD of 1.0 mg/kg).  The
combined dietary exposure from food and drinking water is estimated at
0.009409 mg/kg/day (equivalent to <1% of the aPAD) at the 95th
percentile of exposure, the appropriate regulatory statistic for
unrefined dietary assessments.  It is noted that estimated acute dietary
exposure of females 13-49 years old is also well below HED’s level of
concern at the 99th and 99.9th percentiles, as shown in Table 4.4.1.

Table 4.4.1.  Results of Acute Dietary Exposure Analysis for Food and
Drinking Water at the 95th Percentile of Exposure using DEEM FCID

Population Subgroup	aPAD (mg/kg/day)	95th Percentile	99th Percentile
99.9th Percentile

Exposure (mg/kg/day)	% aPAD	Exposure (mg/kg/day)	% aPAD	Exposure
(mg/kg/day)	% aPAD

Females 13-49 years old 	1.0	0.009409	<1	0.015596	1.6	0.022290	2.2

Chronic Dietary Exposure and Risk

For chronic dietary exposure assessments, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form to produce a residue intake
estimate.  The resulting residue intake estimate for each food/food form
is summed with the residue intake estimates for all other food/food
forms on the commodity residue list to arrive at the total average
estimated exposure.  Exposure is expressed in mg/kg body weight/day and
as a percent of the cPAD.  This procedure is performed for each
population subgroup.

The chronic RfD of 0.95 mg/kg/day is derived from a NOAEL of 94.8
mg/kg/day based on increased incidence of skin lesions in males at 985
mg/kg/day (LOAEL) in the mouse carcinogenicity study.  A 100-fold
uncertainty factor (10X inter-species extrapolation and 10X
intra-species variability) is required.  Since the FQPA SF has been
reduced to 1X, the chronic PAD is equal to the chronic RfD.  The chronic
PAD was used for assessing chronic risk.

An unrefined chronic dietary exposure analysis was conducted via
DEEM-FCID™ for cyazofamid.  The assumptions of this dietary exposure
assessment are tolerance-level residues (all processing factors set to
1x, based on the results of processing studies), 100% crop-treated, and
screening-level EDWC.  Cyazofamid chronic dietary (food + drinking
water) exposure estimates are well below HED’s level of concern for
the general U.S. population and each of the population subgroups, as
shown in Table 4.4.2.  Dietary exposure was estimated at 0.003984
mg/kg/day for the general U.S. population (<1% of the cPAD) and 0.010761
mg/kg/day (1.1% of the cPAD) for the most highly exposed population
subgroup (infants <1 year old).  



Table 4.4.2.  Summary of Chronic Dietary Exposure and Risk for
Cyazofamid1

Population Subgroup	Exposure

(mg/kg/day)	% cPAD

General U.S. Population	0.003984	<1

All Infants (< 1 year old)1	0.010761	1

Children 1-2 years old	0.009260	1

Children 3-5 years old	0.007258	<1

Children 6-12 years old	0.004219	<1

Youth 13-19 years old	0.002741	<1

Adults 20-49 years old	0.003461	<1

Adults 50+ years old	0.003659	<1

Females 13-49 years old	0.003472	<1

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

  exposure and  risk is indicated by bold text.

4.5	Cancer Dietary Exposure and Risk  TC \l2 "4.1	Cancer Dietary
Exposure and Risk 

A cancer dietary assessment was not conducted because cyazofamid has
been classified as “not likely to be carcinogenic to humans.”

5.0	NON-OCCUPATIONAL/RESIDENTIAL EXPOSURE/RISK PATHWAY  TC \l1 "5.0
NON-OCCUPATIONAL/RESIDENTIAL EXPOSURE/RISK PATHWAY 

Reference:  

Cyazofamid.  Occupational and Residential Exposure Assessment for
Section 3 Registration of Cyazofamid for Commercial Use on Residential
Turf and Ornamentals. DP#365261, Nancy J. Tsaur, 03/27/2009.

Cyazofamid is proposed for use on residential lawns and ornamentals. 
The proposed label states that application by home-owners to residential
turf is prohibited.  Therefore, non-occupational handler exposure for
residential lawns and ornamentals was not evaluated.  However,
postapplication exposure is possible for adults and children contacting
residential lawns and ornamentals after cyazofamid has been applied. 
The postapplication risk assessment is based on generic assumptions from
the Recommended Revisions to the Residential SOPs, and recommended
approaches by HED’s Science Advisory Council for Exposure (ExpoSAC).

The proposed formulated end use product labeled under the trade name
Cyazofamid 400SC, which contains 34.5% (i.e., 3.33 lbs ai/gallon)
cyazofamid.  The proposed use rates on turf range from 0.51 to 1.02 lb
ai/A, with 14- to 21-day application intervals, and on ornamentals range
from 0.039 to 1.56 lb ai/A, with 14- to 28-day application intervals. 
The maximum number of applications for turf and ornamentals is 3 and 4,
respectively.

Estimated short-/intermediate-term dermal exposures were compared to the
oral NOAEL of 100 mg/kg/day from a rat prenatal developmental toxicity
study in which increased incidence of bent ribs was observed at the
LOAEL of 1000 mg/kg/day.  Because this endpoint is from an oral study,
the estimated dermal exposures were adjusted for 37 percent dermal
absorption. The level of concern (LOC) for non-occupational risk is for
margins of exposure (MOEs) = 100.  

A turf transferrable residue (TTR) study was submitted by the registrant
(MRID#46571104) for use in assessing postapplication exposure
activities.  The results of this study were useful for determining
residue dissipation only.  The actual data from the TTR study were not
appropriate for use in estimating dermal exposure because the method
used to collect the residue is not compatible with the transfer
coefficient data.  Therefore, standard HED SOPs and assumptions were
used to estimate residues.

5.1	Handler Exposure and Risk  TC \l2 "5.1	Handler Exposure and Risk 

Residential handler exposure is not expected for the proposed uses;
therefore, a handler assessment was not conducted.

5.2	Postapplication Exposure and Risk  TC \l2 "5.2	Postapplication
Exposure and Risk 

Possible postapplication exposure for recreational golfers and people
who use college and professional sports fields after cyazofamid has been
applied has already been assessed in a previous memo (K. O’Rourke,
DP#342612, 03/19/08) and is therefore not of concern at this time. 
Post-application MOEs were 14,000 for golfers and 330 for adults using
athletic fields.  Both are above the LOC and, therefore, are not of risk
concern.  It is unlikely for an individual to experience a co-occurrence
of activities within a single day, thus the two scenarios of golfing or
using recreational fields do not need to be aggregated with the
residential lawn postapplication scenario.  Since there is no hazard
identified (no toxicological effect at the highest dose tested, 1000
mg/kg/day) based on the dermal toxicity study, the dermal exposure
scenario for children does not need to be assessed.  However, the adult
dermal scenario must be assessed due to the developmental toxicity
findings of increased incidence of bent ribs.  Based on the frequency of
use and application, both short-term and intermediate-term exposure
scenarios are assessed for postapplication risk estimates.  The PODs
used in the following calculations for postapplication scenarios are
protective for both short- and intermediate-term exposure scenarios. 
The new use sites and scenarios evaluated for commercial use on
residential lawns and ornamental treatments are presented in Table
5.2.1.

Table 5.2.1.  Residential Use Sites and Scenarios

Exposure Scenarios	Turfgrass	Ornamentals

Dermal (adult)	

X	

X

Dermal (child)	

NA	NA

Hand-to-Mouth (child)	

X	NA

Object-to-Mouth (child)	

X	NA

Soil Ingestion (child)	

X	NA

The exposure estimates are based on some upper-percentile (i.e., maximum
application rate, initial amount of TTR, transfer coefficient for
golfer, dermal absorption factor, and duration of exposure) and central
tendency (i.e., transfer coefficient for sports player and body weight)
assumptions and are considered to be representative of high-end
exposure.  The uncertainties associated with this assessment stem from
the use of an assumed amount of pesticide available from turf and
assumptions regarding transfer of chemical residues.  The estimated
exposure is believed to be a reasonable high-end estimate based on
observations from chemical-specific field studies and professional
judgment.

A summary of the estimated exposures and risk estimates, along with the
algorithms used for each turf scenario are presented below in Tables
5.2.2-5.2.5 and the children’s aggregate exposure estimate is
presented in Table 5.2.6.   Table 5.2.2.  Dermal Exposure and Risk for
Adults from Treated Lawns

Subgroup exposed	Application Rate

(lb ai/A)	Fraction of ai Available	Turf Transferrable Residue at Day
“0"

(ug/cm2)1	Dermal Transfer Coefficient

(cm2/hr)	Exposure Time

(hrs/day)	Absorption Factor	Body Weight

(kg)	Daily Dose2

(mg/kg/day)	Short-Term MOE3

Adult	1.02	0.05	0.57	14,500	2	37%	70	0.10	1,100

1 Turf Transferrable Residue (ug/cm2) = Application rate (lb ai/A) x
Fraction of ai Available  x  4.54E+8 ug/lb x 2.47E-8 A/cm2

2  Daily Dose = (Turf Transferrable Residue x  Absorption Factor  x 1E-3
mg/ug  x Dermal Transfer Coefficient x Exposure Time)/Body weight 

3   Short-/Intermediate-Term Dermal MOE = Short-/Intermediate-Term
Dermal  NOAEL (100 mg/kg/day) /Daily Dose

Table 5.2.3.  Oral Hand-to-Mouth Exposure and Risk for Children from
Treated Lawns

Application Rate

(lb ai/A)	Fraction of ai Available	Turf Transferrable Residue at Day
“0"   (ug/cm2)1	Exposure Time

(hrs/day)	Extraction by saliva	Hand Surface Area (cm2/event)	Frequency

(events/ hr)	Body Weight

(kg)	Daily Dose2

(mg/kg/day)	Short-Term MOE3

1.02	0.05	0.57	2	0.5	20	20	15	0.015	2,000

1Turf Transferrable Residue (ug/cm2) = Application rate (lb ai/A) x
Fraction of ai Available  x  4.54E+8 ug/lb x 2.47E-8 A/cm2

2 Daily Dose = (Turf Transferrable Residue (ug/cm2) x Extraction by
Saliva x Hand Surface Area (cm2/event) x Frequency (events/hr) x 1E-3
mg/ ug  x  ET (hrs/day)] / [Body Weight (kg)]

3 Short-/Intermediate-Term Oral MOE = Short-/Intermediate-Term Oral
NOAEL (30 mg/kg/day) /Daily Dose  

Table 5.2.4.  Oral Object-to-Mouth (Turfgrass) Exposure and Risk for
Children from Treated Lawns 

Application Rate

(lb ai/A)	Fraction of ai Available	Grass Residue at Day “0"

(ug/cm2)1	Surface Area Mouthed

(cm2/day)	Body Weight

(kg)	Daily Dose2

(mg/kg/day)	Short-Term MOE3

1.02	0.2	2.29	25	15	0.0038	8,000

1Grass Residue (ug/cm2) = Application rate (lb ai/A) x Fraction of ai
Available  x  4.54E+8 ug/lb x 2.47E-8 A/cm2

2 Daily Dose  = [Grass residue (ug/cm2) x Surface Area Mouthed (cm2/day)
x 1E-3 mg/ug] / [Body Weight (kg)]

3 Short-/Intermediate-Term  Oral MOE = Short-/Intermediate-Term Oral
NOAEL (30 mg/kg/day) /Daily Dose  

Table 5.2.5.  Exposure and Risk for Children from  Ingestion of Soil
from Treated Lawns 

Application Rate

(lb ai/A)	Fraction of ai Available	Soil Residue at Day “0"

(ug/g)1	Ingestion Rate

(mg/day)	Body

Weight

(kg)	Daily Dose2

(mg/kg/day)	Short-Term MOE3

1.02	1	7.66	100	15	0.000051	590,000

1 Soil residue (ug/g) = [Application Rate (lbs ai/A)  x Fraction of ai
Available x  4.54E+8 ug/lb x 2.47E-8 A/cm2 x 0.67 cm3/g soil]

2 Daily Dose  = [Soil residue (ug/g) x Ingestion rate (mg/day) x 1E-6
g/ug] / [Body Weight (kg)]

3 Short-/Intermediate-Term Oral MOE = Short-/Intermediate-Term Oral
NOAEL (30 mg/kg/day) /Daily Dose	Table 5.2.6.  Children’s Aggregate
Exposure and Risk Estimates from Residential Lawns

Children’s Scenarios	TTR/GR/SR0 (ug/cm2 or g) 1	PDR0-norm

(mg/kg/day) 2	Short-Term MOE 3	Total

Short-Term MOE 4

(1) Hand-to-Mouth	0.57	0.015	2,000	1,600

(2) Mouthing Grass	2.29	0.0038	8,000

	(3) Soil Ingestion	7.66	0.000051	590,000

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

2 PDR0norm=potential dose rate on day “0”.

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

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

The MOEs for postapplication exposure to cyazofamid turf products range
from 1,100 to 590,000 and are all above the LOC (i.e., an MOE = 100);
therefore, they do not exceed HED’s level of concern.

5.3	Other Exposure Sources (Spray Drift)  TC \l2 "5.3	Other Exposure
Sources (Spray Drift) 

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for cyazofamid. 
The Agency has been working with the Spray Drift Task Force, EPA
Regional Offices and State Lead Agencies for pesticide regulation and
other parties to develop the best spray drift management practices.  The
Agency is now requiring interim mitigation measures for aerial
applications that must be placed on product labels/labeling.  The Agency
has completed its evaluation of the new data base submitted by the Spray
Drift Task Force, a membership of U.S. pesticide registrants, and is
developing a policy on how to appropriately apply the data and the
AgDRIFT computer model to its risk assessments for pesticides applied by
air, orchard airblast and ground hydraulic methods.  After the policy is
in place, the Agency may impose further refinements in spray drift
management practices to reduce off-target drift and risks associated
with aerial as well as other application types where appropriate.  

Please note that as indicated in this assessment, cyazofamid is directly
applied to residential lawns and ornamentals and does not result in
exposures of concern.  It is unlikely that the potential for risk of
exposure to spray drift from these uses would be higher than that
estimated for contact with treated turf.6.0	AGGREGATE RISK ASSESSMENTS
and RISK CHARACTERIZATION  TC \l1 "6.0	AGGREGATE RISK ASSESSMENTS and
RISK CHARACTERIZATION 

Aggregate exposure risk assessments were performed for the following
scenarios: acute aggregate exposure (food + drinking water),
short-/intermediate-term aggregate exposure (food + residential exposure
+ drinking water), and chronic aggregate exposure (food + drinking
water).  A cancer aggregate risk assessment was not performed because
cyazofamid is classified as “not likely to be carcinogenic to
humans”.  All potential exposure pathways were assessed in the
aggregate risk assessment.  Dietary (food and drinking water) and
residential exposures were considered, as necessary, because there is a
potential for individuals to be exposed concurrently through these
routes.

6.1	Acute Aggregate Risk Assessment (Food and Drinking Water)

  TC \l2 "6.1	Acute Aggregate Risk Assessment (Food and Drinking Water) 

An acute aggregate risk assessment is required for the population
subgroup of concern, females 13-49 years old.  An appropriate endpoint
for the general population was not identified; therefore, a
corresponding assessment is not required.  For the population of
concern, the acute dietary (food and drinking water) risk assessment
reported in Section 4.4 represents acute aggregate risk.  The dietary
route alone is relevant for acute exposure and risk assessment.

6.2	Short- and Intermediate-Term Aggregate Risk Assessment  TC \l2 "6.2 
Short- and Intermediate-Term Aggregate Risk Assessment 

The short-/intermediate-term aggregate risk assessment estimates that
risks are likely to result from exposure to cyazofamid residues from
food, drinking water, and residential pesticide uses.  Short-term and
intermediate-term risks have been assessed together because both
scenarios have the same endpoints and PODs.  High-end estimates of
residential exposure are used, while average values are used for food
and drinking water exposure (i.e. chronic exposures).

≥ 100, and therefore, are not of concern to the Agency.

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

Population	Short- or Intermediate-Term Scenario

	LOC for Aggregate

Risk1	MOE

food & water2	MOE

oral3	MOE

dermal4	MOE inhalation5	Aggregate MOE

(food and residential)6

General U.S. Population	100	25,100	NA	1,100	NA	1,100

Children 3-5 years old

13,800	1,600	NA	NA	1,400

Children 6-12 years old

23,700	1,600	NA	NA	1,500

1 LOC is an MOE = 100.

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

3 MOE oral = [(short- or intermediate-term oral NOAEL)/(hand-to-mouth
residential exposure)] NOAEL = 30 mg/kg/day. (See Table 5.2.6 for
children’s oral exposure).

4 MOE dermal = [(short- or intermediate-term dermal NOAEL)/(high-end
dermal residential exposure)] NOAEL = 100 mg/kg/day.  (See Table 5.2.2
for dermal exposure).

5 MOE inhalation is not applicable for postapplication activities.

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

6.3	Chronic Aggregate Risk Assessment (Food and Drinking Water)

  TC \l2 "6.3	Chronic Aggregate Risk Assessment (Food and Drinking
Water) 

  SEQ CHAPTER \h \r 1 The chronic aggregate risk assessment takes into
account average exposure estimates from dietary consumption of
cyazofamid (food and drinking water) and residential uses.  Based on the
cyazofamid use pattern, no long-term residential exposures are expected.
  Therefore, the chronic aggregate risk assessment is based on exposure
from food and drinking water only, as presented previously in this
memorandum (Section 4.4).  

6.4	Cancer Aggregate Risk Assessment  TC \l2 "6.4	Cancer Aggregate Risk
Assessment 

The HIARC classified cyazofamid as “not likely to be carcinogenic to
humans”.  Thus, an aggregate cancer risk assessment was not performed
for cyazofamid.

7.0	CUMULATIVE RISK  TC \l1 "7.0	CUMULATIVE RISK 

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to cyazofamid and any other
substances and cyazofamid does not appear to produce a toxic metabolite
produced by other substances.  For the purposes of this tolerance
action, therefore, EPA has not assumed that cyazofamid has a common
mechanism of toxicity with other substances.  For information regarding
EPA’s efforts to determine which chemicals have a common mechanism of
toxicity and to evaluate the cumulative effects of such chemicals, see
the policy statements released by EPA’s Office of Pesticide Programs
concerning common mechanism determinations and procedures for cumulating
effects from substances found to have a common mechanism on EPA’s
website at     HYPERLINK "http://www.epa.gov/pesticides/cumulative/." 
http://www.epa.gov/pesticides/cumulative/. 

8.0	OCCUPATIONAL EXPOSURE  TC \l1 "8.0	OCCUPATIONAL EXPOSURE 

Reference:  

Cyazofamid. Occupational and Residential Exposure Assessment for Section
3 Registration of Cyazofamid for Commercial Use on Residential Turf and
Ornamentals. DP#365261, Nancy J. Tsaur, 03/27/2009.

Cyazofamid: Occupational and Residential Exposure Assessment for
Proposed Field Uses on Okra, Fruiting Vegetables, and Grapes, Plus New
Uses on Greenhouse Transplants. DP#357040, Barry O’Keefe, 03/05/2009.

Workers may be exposed to cyazofamid during mixing, loading,
application, and postapplication activities.  Based on the proposed
application regimen, short-/intermediate-term exposure may occur. 
Chronic exposure (greater than or equal to 6 months of continuous
exposure) is not expected.

8.1	Occupational Handler Exposure and Risk  TC \l2 "8.1	Occupational
Handler 

No chemical-specific handler exposure data were submitted in support of
this registration for either the IR-4 petition (Ranman® 400SC) for
tolerances on fruiting vegetables and okra, and grapes east of the Rocky
Mountains, with greenhouse transplanting uses or the ISK proposal
(400SC) for uses on residential turf and ornamentals.  It is the policy
of HED to use data from the PHED Version 1.1 as presented in PHED
Surrogate Exposure Guide (8/98) to assess handler exposures for
regulatory actions when chemical-specific monitoring data are not
available (HED ExpoSAC SOP #7, dated 1/28/99).  The handler exposure
data for the turf handgun sprayer scenario are from ORETF
(MRID#44972201), rather than from PHED.  ORETF data were designed to
replace the present PHED data with higher-confidence, higher quality
data that contain more replicates than PHED data for those scenarios.

Residential Turf/Ornamentals Uses – EPA Registration No. 71512-13

For residential turf and ornamentals, occupational postapplication MOEs
ranged from 340 to 98,000; and therefore, are not of concern to HED. 
The results of the handler occupational exposure and risk assessment for
commercial application to residential turf and ornamentals indicate that
risks are not of concern with baseline clothing or when gloves are worn
(which is required on the proposed label for turf/ornamental uses).  The
total short/intermediate-term MOEs range from 340 to 98,000; which
exceed the LOC of 100, and are not of concern to the Agency.  Exposure
assumptions and MOEs for occupational handlers of cyazofamid 400SC on
residential turf and ornamentals are summarized in Table 9.1.1.

Agricultural Crop Uses – Petition 8E7427 – EPA Registration No.
71512-3

The results of the handler occupational exposure and risk assessment for
the proposed agricultural uses indicate that risks are not of concern
with baseline clothing, or when gloves are worn (which is required on
the proposed label for agricultural uses such as nurseries and
greenhouses).  The total short/intermediate-term MOEs range from 23,000
to 220,000; which exceed the LOC of 100, and are not of concern to the
Agency.  Exposure assumptions and MOEs for occupational handlers of
Ranman® 400SC are summarized in Table 9.1.2.

HED recognizes that it is feasible for the same individual to mix/load
and apply formulations; however, appropriate data are not available in
PHED for which unit exposure values for these combined activities can be
derived.  HED does not recommend simply adding the unit exposure values
for each job function because any extrapolation error (i.e., exposure
from the amount ai handled in the study to that of a real-life
application) would be magnified, leading to greater uncertainty.  For
information and characterization purposes, even with the over-estimation
uncertainty, the MOEs for these combined activities for groundboom and
airblast application of cyazofamid would be above the LOC of 100 (i.e.,
ranging from 23,000 to 220,000). 

The minimum level of PPE for handlers is based on acute toxicity for the
end-use products.  The Registration Division (RD) is responsible for
ensuring that PPE listed on the label is in compliance with the Worker
Protection Standard (WPS).



Table 8.1.1.  Summary of  MOEs for Occupational Handlers of Cyazofamid
400SC.

Exposure Scenario (Scenario #)	Dermal Unit Exposure1 (mg/lb ai) 
Inhalation Unit

Exposure2

(mg/lb ai)	Use Site	Application 

Rate3	Area Treated4	Daily Dose	Short/Intermediate-Term MOE	Total
Short-Term MOE 5

Dermal	Inhalation	Dermal	Inhalation

	Mixer/Loader/Applicator

(1) Mixing/Loading Liquid and Applying with Handgun Sprayer (ORETF,
OMA002) 	0.45

(PPE)	0.0018	Turf	1.02

(lb ai/A)	5

(acres/day)	0.014	0.00015	7,100	650,000	7,000

	Ornamentals	1.56

(lb ai/A)	5

(acres/day)	0.022	0.00023	4,600	427,000	4,600

(2) Mixing/Loading Liquid and Applying with Low-Pressure Handwand (PHED)
100

(baseline)	0.03	Turf	0.012

(lb ai/gal)	40

(gal/day)	0.30	0.00024	340	417,000	340

	0.43

(PPE)	0.03	Turf	0.012

(lb ai/gal)	40

(gal/day)	0.0013	0.00024	78,600	417,000	66,000

(3) Mixing/Loading Liquid and Applying with High-Pressure Handwand
(PHED)	2.5

(PPE)	0.12	Ornamentals	0.0016

(lb ai/gal)	1000

(gal/day)	0.025	0.0032	4,100	31,000	3,600

(4) Mixing/Loading Liquid and Applying with Backpack Sprayer (PHED)	2.5

(PPE)	0.03	Turf	0.012

(lb ai/gal)	40

(gal/day)	0.0074	0.00024	13,500	417,000	13,000

	Ornamentals	0.0016

(lb ai/gal)	40

(gal/day)	0.0010	0.000032	101,400	3,100,000	98,000

1 Baseline dermal unit exposure values represent long pants, long
sleeved shirts, shoes, and socks; PPE values represent the addition of
chemical-resistant gloves for those scenarios in which the MOEs do not
reach 100 at baseline or those for which data are not available without
gloves.  Values are reported in the PHED Surrogate Exposure Guide dated
August 1998, except for the handgun value which was obtained from ORETF.

2 Inhalation unit exposure values represent no respirator.  Values are
reported in the PHED Surrogate Exposure Guide dated August 1998.

3 Application rates are based on maximum values found in label:
Cyazoafamid 400SC (Reg No:  71512-13).

4 Daily area treated is based on the area or gallons that can be
reasonably applied in a single day for each exposure scenario of concern
based on the application method and formulation/packaging type.
(standard EPA/OPP/HED values).

5 Short-/Intermediate-Term MOE = NOAEL (100 mg/kg/day) / Total Daily
Absorbed Dose.  The LOC is 100.

	Total Daily Absorbed Dose (mg/kg/day) = {[(Dermal unit exposure * 37%
Dermal absorption) + (Inhalation unit exposure * 100% absorption)] *
Application rate * Area treated} / 60 kg

Table 8.1.2.  Agricultural Handler Exposure and Risk for Cyazofamid
Ranman® 400SC

Exposure Scenario	Crop or Target	App Ratea

(lb ai/A)	Acres Treated Dailyb	Unit Exposurec	Dose

(mg/kg/day)	MOEs

Baseline Dermal

mg/lb ai	PPE-G

Dermal

mg/lb ai	Baseline Inhalation µg/lb ai	Baseline Dermald,h	PPE-G Dermali
Baseline Inhalatione	Baseline Dermalf	PPE-G

Dermal	Baseline Inhalationg	Combined Baseline Dermal + Inhalationj
Combined PPE-G + Baseline Inhalationk

Mixer/Loader

Mixing/Loading Liquid Concentrates for 

Aerial Applications (PHED)	okra, fruiting vegetables, cucurbit
vegetables, grapes	0.071	350	2.9	0.023	1.2	0.44	0.0035	0.0005	230	28,000
200,000	220	25,000

Mixing/Loading Liquid Concentrates for 

Chemigation Applications (PHED)	okra, fruiting vegetables, cucurbit
vegetables, grapes	0.071	350	2.9	0.023	1.2	0.44	0.0035	0.0005	230	28,000
200,000	220	25,000

Mixing/Loading Liquid Concentrates for 

Groundboom Applications (PHED)	okra, fruiting vegetables, cucurbit
vegetables, grapes	0.071	80	2.9	0.023	1.2	0.1	0.00081	0.00011	980
120,000	880,000	980	106,000

Mixing/Loading Liquids Concentrates for

Airblast Applications (PHED)	grapes	0.071	40	2.9	0.023	1.2	0.051	0.0004
0.000057	2,000	250,000	1,800,000	2,000	220,000

Applicator

Applying Sprays via 

Aerial Equipment (PHED)	okra, fruiting vegetables, cucurbit vegetables,
grapes	0.071	350	0.005 (eng. control)	No Data	0.068

(eng. control)	0.00077 (eng. control)	No Data	0.000028 (eng. control) 
130,000

(eng. control)	No Data	3,600,000

(eng. control)	130,000 (eng. control)	No Data

Applying Sprays via

Groundboom Equipment (PHED)	okra, fruiting vegetables, cucurbit
vegetables, grapes	0.071	80	0.014	0.014	0.74	0.00049	0.00049	0.00007
200,000	200,000	1,400,000	180,000	180,000

Applying Sprays via

Airblast Equipment (PHED)	grapes	0.071	40	0.36	0.24	4.5	0.0063	0.0042
0.00021	16,000	24,000	470,000	15,000	23,000

Flagger

Flagging for

Aerial Sprays Applications (PHED)	okra, fruiting vegetables, cucurbit
vegetables, grapes	0.071	350	0.011	NA	0.35	0.0017	NA	0.00014	59,000	NA
690,000	55,000	NA

Mixer/Loader/Applicator

Mixing/Loading/Applying Liquid Concentrates with 

Low Pressure Handwand – Ground Directed (ORETF)	okra, fruiting
vegetables, cucurbit vegetables for base of plant at transplanting	0.071
5	15	0.33	2.7	0.033	0.00072	0.000016	3,000	140,000	6,300,000	3,000
140,000

	Greenhouse Transplant Production: okra, fruiting vegetables, cucurbit
vegetables	0.078	5	15	0.33	2.7	0.036	0.00079	0.000018	2,800	130,000
5,700,000	2,800	120,000

Mixing/Loading/Applying Liquid Concentrates with 

Low Pressure Handwand – Overhead Directedl (ORETF)	Greenhouse
Transplant Production for okra, fruiting vegetables, cucurbit vegetables
0.078	5	30	Data available	3.8	0.072	Not needed	0.000025	1,400	Not needed
4,000,000	1,400	Not needed

Mixing/Loading/Applying Liquid Concentrates with a Handgun Sprayer (LCO
ORETF data)	okra, fruiting vegetables, cucurbit vegetables for base of
plant at transplanting	0.071	5	No Data	0.45	1.8	No Data	0.00099	0.000011
No Data	100,000	9,400,000	No Data	100,000

	Greenhouse Transplant Production: okra, fruiting vegetables, cucurbit
vegetables	0.078	5	No Data	0.45	1.8	No Data	0.0011	0.000012	No Data
92,000	8,500,000	No Data	91,000

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

b.  Science Advisory Council Policy # 9.1

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

d. Dermal Dose  (mg/kg/day)  = daily unit exposure (mg/lb ai)  x
application rate (lb ai/acre) x acres treated x dermal absorption factor
(37%) / body weight (60 kg adult female).

e. Inhalation Dose (mg/kg/day)  daily unit exposure (μg/lb ai)  x
application rate (lb ai/acre) x acres treated x inhalation absorption
(100%) / body weight (60 kg adult female).  

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

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

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

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

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

k. Combined PPE-G + Baseline Inhalation MOE = 1 / (1/PPE-G Dermal MOE) +
(1/Baseline Inhalation MOE).  Those risks specified as engineering
control represent enclosed cockpit application.  

l. The tree/shrub (“overhead”) directed ORETF data for
Mixing/Loading/Applying Liquid Concentrates with Low Pressure Handwand
was used to assess greenhouse transplant production because seedling
trays are often on benches at waist height or higher.

8.2	Occupational Postapplication Exposure and Risk  TC \l2 "8.2
Occupational Postapplication Exposure and Risk 

Residential Turf/Ornamentals Uses – EPA Registration No. 71512-13

The registration action for cyazofamid application to residential turf
and ornamentals involves various postapplication activities including
lawn mowing and maintenance activities.  Postapplication inhalation
exposure is expected to be negligible, however, dermal exposure is
possible for workers mowing/maintaining the turfgrass, and tending
ornamentals in nurseries and greenhouses.  As mentioned previously, a
TTR study was submitted by the registrant (MRID#46571104) for use in
assessing postapplication activities.  The results of this study were
useful for determining residue dissipation only.  

The actual data from the TTR study were not appropriate for use in
estimating dermal exposure because the study was conducted using a
modified version of the California roller.  In addition, TTR data are
not appropriate for estimating dislodgeable foliar residue (DFR) from
ornamentals.  Therefore, the assessment was conducted with HED’s
standard assumptions for the initial fraction of residue available for
turf and ornamentals.

In addition to TTR and DFR data, transfer coefficients (TC) are used to
relate the residue values to activity patterns, which take place after
application, to estimate potential human exposure.  The transfer
coefficients used in this assessment are from an interim transfer
coefficient guidance document developed by HED’s Science Advisory
Council for Exposure using proprietary data from the Agricultural
Re-entry Task Force (ARTF) database (SOP# 3.1).  

As a screening-level approach, the MOEs were estimated for “Day 0"
exposure (i.e., the day of application).  As shown in Table 9.2.3, the
short-/intermediate-term MOEs are greater than 100 on the day of
application, and therefore, are not of concern.

The cyazofamid technical material has been classified in Toxicity
Category III for acute dermal and primary skin irritation, and Category
IV for primary eye irritation.  Per the Worker Protection Standard
(WPS), a 12-hr restricted entry interval (REI) is required for chemicals
classified under Toxicity Category III/IV.  Based on the postapplication
dermal risk estimates, the labeled 12-hr REI is protective of re-entry
workers.  Cyazofamid is also intended for non-agricultural use sites to
which the WPS does not apply, and correctly contains language cautioning
unprotected persons to keep out of treated areas until sprays have
dried.

Agricultural Crop Uses – Petition 8E7427 – EPA Registration No.
71512-3

Agricultural uses of cyazofamid on fruiting vegetables and okra, grapes
east of the Rocky Mountains, and vegetable greenhouse transplants,
involves various postapplication activities including hand harvesting,
hand pruning, staking, thinning, training, tying, leaf pulling,
girdling, and cane turning.

Inhalation:  HED assumes that inhalation exposures are minimal following
outdoor applications of an active ingredient with low vapor pressure. In
greenhouses, postapplication inhalation exposures are mitigated with the
use of the greenhouse ventilation requirements in the Worker Protection
Standard for Agricultural Pesticides (40 CFR Part 170). Since the
proposed uses of cyazofamid are applied only in outdoor or greenhouse
settings and cyazofamid has a low vapor pressure, postapplication
inhalation exposures and risks were not assessed. 

Dermal:  Chemical-specific dislodgeable foliar residue (DFR) studies on
tomatoes (MRID#: 45409118), grapes (MRID#: 45409118) and squash (MRID#:
45409119) were submitted for a previous action on cyazofamid.  These
studies were reviewed and found to be acceptable for risk assessment
purposes (D285682, K. O’Rourke, 3/23/04).  A summary of each study is
provided below.  In addition to the DFR data, maximum dermal transfer
coefficients from the Science Advisory Council for Exposure Policy
Number 3.1: Agricultural Transfer Coefficients, August 2000, (summarized
in Table 5 below) and the following assumptions were used in the
postapplication assessment:

 			

Max Application Rate	= 	0.078 lb ai/A for okra, fruiting vegetables, and
cucurbit vegetables; 0.071 lb ai/A for grapes,

Exposure Duration	=	8 hours per day,

Body Weight		=	60 kg for adult female, and 		

Dermal Absorption	= 	37%.

Table 8.2.1. Anticipated Postapplication Activities and Dermal Transfer
Coefficients

Proposed Crops	Policy Crop Group Category	Exposure Potentiala	Transfer
Coefficients (cm2/hr)	Activities

Fruiting Vegetables, Okra	  SEQ CHAPTER \h \r 1 Vegetable, fruiting	High
1,000	hand harvest, hand pruning, staking, thinning, training, tying

Cucurbit Vegetables	  SEQ CHAPTER \h \r 1 Vegetable, cucurbit	High	2,500
hand harvest, leaf pulling, hand pruning, thinning, turning

Grapes	Vine/trellis	Very high 	10,000	girdling, cane turning

High	5,000	hand harvest, hand pruning, training, tying, thinning, leaf
pulling

Only worst-case postapplication exposure potential (i.e., very high and
high) was assessed.

The postapplication exposure associated with agricultural crops is
summarized in Table 8.2.2.  All scenarios resulted in MOEs greater than
100 on day 0 (12 hours after application) and therefore are not of
concern to HED.  



Table 8.2.2.  Postapplication Exposure and Risk for Cyazofamid Ranman®
400SC

Crop Grouping/Crop	Activity	Transfer

Coefficient	Days after Treatment	Chemical-specific DFR data	Normalized
DFRa (µg/cm2)	Daily Dermal Doseb (mg/kg/day)	MOEc

Fruiting Vegetables, Okra	hand harvest, hand pruning, staking, thinning,
training, tying	1,000	0

(12 hours)	Tomato DFR 	0.14 	0.00694	14,000

Cucurbit Vegetables	hand harvest, leaf pulling, hand pruning, thinning,
turning	2,500	0

(12 hours)	Squash DFR	0.069	0.00840	12,000

Grapes	girdling, cane turning	10,000	0

(12 hours)	Grape DFR	0.16	0.0787	1,300

	hand harvest, hand pruning, training, tying, thinning, leaf pulling
5,000	0

(12 hours)	Grape DFR	0.16	0.0394	2,500

 a. DFR values were obtained from the DFR studies:  

Tomato DFR:	average measured value from “Day 3" was used as a
surrogate for Day 0 because it was higher than both the predicted and
measured Day 0 values.  The DFR was adjusted for the difference in
application rate used in the study (i.e., 0.071 lb ai/A compared to the
maximum 0.078 lb ai/A rate proposed for fruiting vegetables and okra),

Squash DFR:	average measured Day 0 value from the grape DFR data was
used - with an adjustment for the difference in application rate used in
the study (i.e., 0.071 lb ai/A compared to the maximum 0.078 lb ai/A
rate proposed for cucurbits), and

Grape DFR:	average measured Day 0 value from the grape DFR data was used
- with an adjustment for the difference in application rate used in the
study (i.e., 0.089 lb ai/A compared to the maximum 0.071 lb ai/A rate
proposed for grapes).

b. Daily Dermal Dose = [DFR (µg/cm2) x Tc x 0.001 mg/µg x 8 hrs/day x
DA] ( body weight (60 kg adult female).

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



Table 8.2.3.  Summary of Estimated Post-application MOEs for Cyazofamid
400SC on Turf and Ornamentals

Crop	Application Rate1

(lb ai/A) 	DAT 2	DFR 3

(μg/cm2)	TC 4

(cm2/hr)	Activity 4	

Short-/Int-

Term MOE 5

Turf

Turf	1.02	0	

0.57	

500	

Mowing and other maintenance activities	7,100

0

3400	

Golf course maintenance (mowing, aerating, scouting, fertilizing)	1,000

0

6800	

Sod farm harvesting/transplanting	520

Ornamentals

Nursery Stock	1.56	

0	3.5	

100	

Hand pruning containerized ornamentals	5,800

0

400	

Harvesting, ball/burlap containerized ornamentals	1,400

Cut Flowers

0

2,500	

Irrigation, scouting, thinning, weeding  immature/low foliage plants	230

0

4,000	

Irrigation, scouting mature/high foliage plants	140

0

5,100	

Hand harvesting, pruning, thinning, pinching	110

1 Maximum application rate from proposed label Cyazoafamid 400SC (Reg
No:  71512-13).  The foliar application rate was used for ornamentals.

2 DAT = Days after treatment needed to reach the LOC of 100; DAT 0 = The
day of treatment, after sprays have dried; assumed to be approximately
12 hours.

3 DFR (µg/cm2) = Application rate (lb ai/A) x CF (4.54E+8 µg/lb) x CF
(2.47E-8 A/cm2) x Initial Fraction of ai Retained on the Foliage
(standard assumptions of 5% for turf and 20% for ornamentals)].  

4 TC (cm2/hr) = transfer coefficients and associated activities from
ExpoSAC Policy Memo #003.1 “Agricultural Transfer Coefficients”,
8/7/2000.  

5 MOE = MOE on the corresponding DAT.  MOE = NOAEL / Daily Dose; LOC is
an MOE = 100.

Daily Dose = [(TTR or DFR x  TC x 37% Dermal absorption  x  8-hr
Exposure Time)] / [(CF: 1000 ug/mg) x (60-kg Body Weight)]

Short-/intermediate-term NOAEL = 100 mg/kg/day.9.0	DATA NEEDS AND
LABEL RECOMMENDATIONS  TC \l1 "9.0	DATA NEEDS AND LABEL REQUIREMENTS 

9.1	Chemistry  TC \l2 "9.1	Chemistry 

860.1200 Directions for Use

The maximum seasonal use rates for grapes, okra, fruiting vegetables,
and cucurbits (excluding drench uses) in the Section B/label must be
revised to reflect the total of the maximum number of applications at
the maximum proposed use rate.  This corresponds to 0.43 lb ai/A for all
crop types.  

The Section B/label for cucurbit vegetables, fruiting vegetables, and
okra must be amended: “3 fl oz/100 gallons of water (0.078 lb ai/A)”
should be clarified to indicate that the maximum gal water/A is 100.

.

The Section B/label must be revised to state that applications may be
made to tomatoes in greenhouse transplant production but that no other
greenhouse applications may be made.  The statement on the label “for
use on all transplants” must be deleted.

 860.1550 Proposed Tolerances

The petitioner should submit a revised Section F reflecting the
recommended tolerances and commodity definitions presented in Table
5.1.2.

9.2	Toxicology  TC \l2 "9.2	Toxicology 

The HIARC requested that a 28-day inhalation toxicity study be conducted
for cyazofamid.   However, based on the low volatility and low
inhalation toxicity (Category IV) of cyazofamid and inhalation MOEs
>1,000 for the proposed uses in this risk assessment, cyazofamid
qualifies for a waiver of the 28-day inhalation toxicity study for the
proposed uses [HED Standard Operating Procedure (SOP) 2002.01: Guidance:
Waiver Criteria for Multiple-Exposure Inhalation Toxicity Studies,
08/15/02].  The requirement for the 28-day inhalation toxicity study is
waived for this action only.  If in the future, requests for new uses or
formulations are submitted that may result in a significant change in
either the toxicity profile or exposure scenarios, HED will reconsider
this data requirement.

As part of the new 40CFR §158 Guidelines, a functional immunotoxicity
study in rats and/or mice is required (Guideline 870.7800); see Appendix
D.

As part of the new 40CFR §158 Guidelines, a subchronic neurotoxicity
study is required (Guideline 870.6200); see Appendix E.

 10.0	ATTACHMENTS  TC \l1 "10.0	ATTACHMENTS 

Appendix A: 	Codes, Chemical Names, and Chemical Structures of
Cyazofamid and Identified Metabolites

Appendix B:	International Residue Limit Status (IRLS)

Appendix C:	Toxicological Assessment (Profiles, Doses, and Endpoints) 

Appendix D:	Rationale for Immunotoxicity Data Requirement

Appendix E:	Rationale for Subchronic Neurotoxicity Data Requirement

N. Tsaur: S-10322: Potomac Yard 1 (PY1): (703) 603-8905: 7509P: RAB3 

RDI: RA Team (04/30/09); RAB3 Branch (05/09/09); P. Deschamp (05/15/09).

APPENDIX A.  Codes, Chemical Names, and Chemical Structure of
Cyazofamid and Identified Metabolites.  TC \l2 "Appendix A	ATTACHMENTS 

Identification of Compounds from the Cyazofamid Metabolism Studies.

Common name/ code/matrix	Chemical name		Chemical structure

Cyazofamid/

IKF-916

 

CCIM

 

CCBA

 

CCIM-AM

APPENDIX B: International Residue Limit Status  TC \l2 "Appendix B
International Residue Limit Status 

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name: 
4-Chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonam
ide 	Common Name:

Cyazofamid	X Proposed tolerance

□ Reevaluated tolerance

□ Other	Date: 12/2/08

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

X No Codex proposal step 6 or above

□ No Codex proposal step 6 or above for the crops requested	Petition
Number:  PP#8E7427

DP#:  357042

□ No Limits

□ No Limits for the crops requested	X No Limits

□ No Limits for the crops requested

Residue definition: 
4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonam
ide, including the metabolite
4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile 	Residue
definition:  N/A

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

Tomatoes	0.2

Notes/Special Instructions:

S. Funk, 11/04/2008.

  TC \l2 "Appendix C	Toxicology Assessment APPENDIX C.1.  Toxicity
Profile of Cyazofamid Technical.   TC \l3 "	C.1	Toxicity Profile of
Cyazofamid Technical 

Table C.1.  Toxicity Profile of Cyazofamid [IKF-916] Technical.  TC \f
2 "Table 5.  Toxicity Profile of Cyazofamid [IKF-916] Technical. 

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

870.3100

28-Day dose-range finding study in rats	45408927

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

Male: 0, 3.8, 38.5, 370, & 1488 mg/kg/day

Female: 0, 3.6, 37.1, 389, & 1535 mg/kg/day	NOAEL = 38.5 [M] mg/kg/day

LOAEL = 370 [M] mg/kg/day based on increased number of basophilic
tubules was noted in the kidneys of males.

870.3100

90-Day oral toxicity in rats	45408928 (1999)

Acceptable/guideline

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

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

Females: 0, 50, 500, 5,000, or 20,000 ppm 0, 3.3, 33.3, 337.6, or
1,359.0 mg/kg/day	NOAEL = 29.5 [M] mg/kg/day

LOAEL = 295 [M] mg/kg/day based on increased number of “basophilic
kidney tubules,” and increased urinary volume, pH, and protein.

870.3100

90-Day oral toxicity in mice	Study not available.

	Study not available.

870.3150

90-Day oral toxicity in dogs	45408929 (2001)

Acceptable/guideline

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

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

LOAEL = not observed.

870.3200

28-Day dermal toxicity in rats	45408930 (1997)

Acceptable/guideline

0, 250, 500, or 1,000 mg/kg/day	NOAEL = 1,000 [M/F] mg/kg/day

LOAEL = not observed.

870.3250

90-Day dermal toxicity	Study not available.

	870.3465

90-Day inhalation toxicity	Study not available.

	870.3700a

Prenatal developmental in rats	45430404 (1999)

Acceptable/guideline

0, 30, 100, or 1,000 mg/kg/day	Maternal NOAEL = 1,000 mg/kg/day

LOAEL =  not observed

Developmental NOAEL = 100 mg/kg/day

LOAEL = 1,000 mg/kg/day based on increased incidence of bent ribs.

870.3700b

Prenatal developmental in rabbits	45408934 (1999)

Acceptable/guideline

0, 30, 100, or 1,000 mg/kg/day	Maternal NOAEL = 1,000 mg/kg/day

LOAEL =  not observed

Developmental NOAEL = 1,000 mg/kg/day

LOAEL = not observed

870.3800

Reproduction and fertility effects in rats	45408935 (1998)

Acceptable/guideline

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

F0 M: 11-22, 108-213, and 1114-2185 mg/kg/day

F0 F: 14-21, 137-219, and 1416-2179 mg/kg/day

F1 M: 11-27, 107-267, and 1117-2714 mg/kg/day

F1 F: 14-27, 135-267, and 1451-2678  mg/kg/day	Parental/Systemic NOAEL =
1114/ 1416 [M/F] mg/kg/day

LOAEL = not observed

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

LOAEL = not observed

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

LOAEL = not observed

870.4100a

Chronic toxicity in rats	45408936 (1999)

Acceptable/guideline

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

0, 0.35, 1.7, 17.1, or 171.1 mg/kg/day 

Females: 0, 50, 500, 5,000, or 20,000 ppm 0, 2.0, 20.2, 207.8, or 856.0
mg/kg/day	NOAEL = 171/ 856 [M/F] mg/kg/day

LOAEL = not observed.

870.4100b

Chronic toxicity in dogs	45408931 (2001)

Acceptable/guideline

0, 40, 200, 1,000 mg/kg/day	NOAEL = 200 [M/F] mg/kg/day

LOAEL = 1,000 [M/F] mg/kg/day based on increased cysts in parathyroids
in males.

870.4200

Carcinogenicity rats	45408936 (1999)

Acceptable/guideline

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

LOAEL = not observed.

No evidence of carcinogenicity

870.4300

Carcinogenicity mice	45408932 (1999)

Acceptable/guideline

	NOAEL = 94.8 [M] mg/kg/day

LOAEL = 985 [M] mg/kg/day based on increased incidence of skin lesions
including hair loss, body sores, dermatitis, ulceration, and acanthosis.

No evidence of carcinogenicity

Gene Mutation

870.5100

Bacterial reverse mutation assay	45408937 (1998)

Acceptable/ guideline

cytotoxic but there was precipitation at ≥1,500 μg/plate.

Gene Mutation

870.5300

Mammalian cell culture	45409002 (1998)

Acceptable/ guideline

(ai)	Negative  ± S9 up to cytotoxic and precipitating concentration of
100 µg/mL

Cytogenetics 

870.5375 Chromosomal aberrations	45409003 (1996)

Acceptable/ guideline

(ai)	Negative ± S9 for clastogenic/aneugenic activity up to cytotoxic
and precipitating 200 µg/mL 

Cytogenetics 

870.5395

Micronucleus test on mouse	45409004 (1996)

Acceptable/ guideline

(ai)	Negative  up to the highest dose tested (limit dose) 2,000 mg/kg 

Other Effects 

870.5500

Bacterial DNA repair test (Rec-assay)	45409005 (1998)

Acceptable/ guideline

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

870.6200a

Acute neurotoxicity screening battery	45434601 (2000)

Acceptable/guideline

0, 80, 400, or 2000 mg/kg	NOAEL = 2000 [M/F] mg/kg/day

LOAEL = not observed.

The HIARC concluded that the slight increase (∼45%) in motor activity
at day 14 among the mid- and high-dose males is marginal and should not
be considered an adverse finding.

870.6200b

Subchronic neurotoxicity screening battery	Study not available.

	870.6300

Developmental neurotoxicity	Study not available.

	870.7485

Metabolism  and pharmacokinetics in rats	45409006- 45409009 and 45434602
(1998- 1999)

Acceptable/guideline

Dose: 0.5, 1,000, or 14 day 0.5 mg/kg repeat non-labeled followed by 0.5
mg/kg [phenyl- U-14C]- or [14C-Imidazole] IKF-916.

ose (∼12-39% of the administered low dose) and negligible (<2%) in the
high-dose groups.  Urinary or biliary excretion in the high-dose groups
was low (each ∼2%)  with most of the radioactivity being CCBA. 
Irrespective of the dosing regimen, most of the recovered fecal
radioactivity was unchanged parent compound; the major fecal metabolites
were CCBA and 4-chloro-5-p-tolylimidazole-2-carbonitrile (CCIM) each of
which being less than 5% of the administered dose.  Tissue burdens at
t1/2, tmax, and at 168 hours post dose indicated rapid clearance and low
tissue burdens suggesting little or no bioaccumulation or sequestration.

870.7600

Dermal penetration	Study not available.

	Special study: 

In Vitro Metabolism of IKF-916 and CCIM in Blood and Stomach Contents
MRID 45409010 (1999)

tion to CCIM (∼30%) in blood but was stable in stomach contents while
CCIM was unaffected in either medium.  The results also suggest that
CCIM could be produced in rats following IKF-916 entering the blood
compartment but not necessarily in the stomach compartment.

Special study: 

In Vitro Metabolism of CCIM in S9 Fraction	MRID 45409011 (1999)

Acceptable/non-guideline	The in vitro metabolism of 14C-CCIM was
followed up to five minutes in the presence of rat liver S9.  The
results suggested that CCIM was rapidly and completely metabolized
within 5 minutes to at least three metabolites with the major one being
CHCN (4-chloro-5(4-hydroxymethyl-phenyl)-imidazole-2-carbonitrile) which
accounted for 77-94% of the radioactivity.  Lower concentrations were
found of CCBA (3-13%) and one or more unknown metabolites.  It was
concluded that CCIM produced in the intestines or blood would be rapidly
and completely metabolized by the liver.

Special study:

In Vitro Study to Identify Metabolites Absorbed Through the Intestinal
Mucosa After Incubation with IKF-916 and CCIM	MRID 45409012 (1999)



 

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Special study:

Comparative metabolism of [14C]IKF-916 or [14C]CCIM in rats	MRID
45409013 (1999)

Acceptable/non-guideline	Rats were given a single gavage dose of 0.46
mg/kg of [14C-Bz]IKF-916 or 0.33 mg/kg of [14C-Bz]CCIM and, after 30
minutes, blood, liver, stomach (plus contents), and duodenum (plus
contents) were collected and analyzed for radioactivity and metabolites.
 Following a single gavage dose of CCIM, the metabolites CCBA and CHCN,
in addition to unchanged CCIM, were detected in the plasma and liver. 
The same metabolites, as well as CCIM, were also detected in plasma and
liver following administration of IKF-916. Therefore, orally
administered IKF-916 is converted to CCIM and subsequently to CCBA and
CHCN.

APPENDIX C.2.  Acute Toxicity of Cyazofamid  TC \l3 "	C.2	Acute
Toxicity of Cyazofamid 

Table C.2.  Acute Toxicity of Cyazofamid - Technical  TC \f 2 "Table 4. 
Acute Toxicity of Cyazofamid - Technical. 

Guideline No.	Study Type	MRID No.	Results	Toxicity Category

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

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

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

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

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

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

APPENDIX D:  Rationale for Immunotoxicity Data Requirement   TC \l2
"Appendix D: Rationale for Toxicity Data Requirement 

Guideline Number: 870.7800

Study Title:  Immunotoxicity

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the
data requirements for registration of a pesticide (food and non-food
uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional
immunotoxicity testing and is designed to evaluate the potential of a
repeated chemical exposure to produce adverse effects (i.e.,
suppression) on the immune system. Immunosuppression is a deficit in the
ability of the immune system to respond to a challenge of bacterial or
viral infections such as tuberculosis (TB), Severe Acquired Respiratory
Syndrome (SARS), or neoplasia.  Because the immune system is highly
complex, studies assessing functional immunotoxic endpoints are helpful
in fully characterizing a pesticide’s potential immunotoxicity.  These
data will be used in combination with data from hematology, lymphoid
organ weights, and histopathology in routine chronic or subchronic
toxicity studies to characterize potential immunotoxic effects.  

Practical Utility of the Data

How will the data be used?

These animal studies can be used to select endpoints and doses for use
in risk assessment of all exposure scenarios and are considered a
primary data source for reliable reference dose calculation. For
example, animal studies have demonstrated that immunotoxicity in rodents
is one of the more sensitive manifestations of TCDD
(2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental, reproductive,
and endocrinologic toxicities.  Additionally, the EPA has established an
oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed
immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.

 

If the Agency does not have this data, a 10X database uncertainty factor
may be applied for conducting a risk assessment from the available
studies.

APPENDIX E:  Rationale for Subchronic Toxicity Data Requirement  TC \l2
"Appendix E: Rationale for Toxicity Data Requirement 

Guideline Number: 870.6200

Study Title:  Neurotoxicity Battery (Acute and Subchronic Studies)

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the
data requirements for registration of a pesticide (food and non-food
uses). 

The Neurotoxicity Screening Battery (OPPTS 870.6200) is designed to
evaluate the potential adverse effects on the nervous system from
exposure to pesticide chemicals.  The Agency believes that the guideline
studies are inadequate in their assessment of behavioral effects and do
not use optimal methods to evaluate the potential toxicity to the
nervous tissue structure and function. To detect and characterize these
potential effects more fully, a battery of more sensitive testing is
required. The objective of this neurotoxicity battery testing is to
evaluate the incidence and severity of the functional and/or behavioral
effects, the level of motor activity, and the histopathology of the
nervous system. The acute neurotoxicity study is required to detect
possible effects resulting from a single exposure. The subchronic
neurotoxicity study is intended to detect possible effects resulting
from repeated or long-term exposures.

 

Practical Utility of the Data

How will the data be used?

The acute and subchronic neurotoxicity studies provide critical
scientific information needed to characterize potential hazard to the
human population on the nervous system from pesticide exposure. These
studies can provide data on a wide range of functional tests for
evaluating neurotoxicity including sensory effects, neuromuscular
effects, learning and memory and histopathology of the nervous system 
For example, animal studies with organophosphorous chemicals  have shown
neurotoxicity to be the primary toxic endpoints (e.g., cholinesterase
inhibition) of concern in rodents and non-rodents.    These animal
studies can be used to select endpoints and doses for use in risk
assessment of all exposure scenarios and are considered a primary data
source for reliable reference dose calculation. The Agency has
established an oral reference dose (RfD) for assessing dietary risks for
a number of chemicals (e.g., organophoshates and carbamates) where
neurotoxicity was the most sensitive endpoint of concern.

How could the data impact the Agency's future decision-making? 

If the acute or subchronic neurotoxicity studies show that cyazofamid
poses either a greater or a diminished risk than that given in the
interim decision’s conclusion, the risk assessment for cyazofamid may
need to be revised to reflect the magnitude of potential risk derived
from the new data.

 

If the Agency does not have this data, a 10X database uncertainty factor
may be applied  when conducting a risk assessment using the currently
available studies.

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