Document ID: EPA-HQ-OPP-2007-0872-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-04-23T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

	

OFFICE OF

PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

MEMORANDUM

DATE:		19 March 2008

SUBJECT:	Human Health Risk Assessment to Support the Registration of
Cyazofamid for Use on Carrot (PC Code: 085651, Petition No. 7E7244, DP
#342612).

™ 400SC	EPA Reg No.: 	71512-3

TO:		Susan Stanton/Daniel Rosenblatt, PM Team #05

		Barbara Madden, Team Leader

		Risk Integration, Minor Use and Emergency Response Branch

			and

		Cynthia Giles-Parker, Chief

		Fungicide Branch 

		Registration Division (7505P)

FROM:	Kelly M. O'Rourke, Biologist

		Amelia Acierto, Chemist

		Registration Action Branch 3 (RAB3)

		Health Effects Division (HED) (7509P)

THRU:	Paula Deschamp, Branch Chief

		RAB3/HED (7509P)

The Agriculture and Agri-Food Canada (AAFC) and the Interregional
Research Project No. 4 (IR-4), Rutgers, The State University of New
Jersey, on behalf of the Agricultural Experiment Stations of Florida,
California, Washington, Georgia and New York, have proposed the
establishment of a tolerance for the combined residues of cyazofamid
[4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfona
mide] and its metabolite CCIM
[4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile], expressed as
cyazofamid, in/on carrot, roots at 0.06 ppm (Petition No: 7E7244).  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 use of
cyazofamid. 

	Table of Contents

	Page

  TOC \f  INTRODUCTION	  PAGEREF _Toc148327530 \h  3 

1.0	EXECUTIVE SUMMARY	  PAGEREF _Toc148327531 \h  4 

2.0	PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION	  PAGEREF
_Toc148327532 \h  9 

2.1	Chemical Identity and Structure	  PAGEREF _Toc148327533 \h  9 

2.2	Physical and Chemical Properties of Cyazofamid	  PAGEREF
_Toc148327534 \h  10 

3.0	HAZARD CHARACTERIZATION	  PAGEREF _Toc148327535 \h  10 

3.1	Hazard Profile	  PAGEREF _Toc148327536 \h  10 

3.2	FQPA Considerations	  PAGEREF _Toc148327537 \h  18 

3.3	Dose-Response Assessment	  PAGEREF _Toc148327538 \h  18 

3.4	Endocrine Disruption	  PAGEREF _Toc148327539 \h  21 

4.0	EXPOSURE ASSESSMENT	  PAGEREF _Toc148327540 \h  22 

4.1	Summary of Proposed and Registered Uses	  PAGEREF _Toc148327541 \h 
22 

4.2	Dietary Exposure/Risk Pathway	  PAGEREF _Toc148327542 \h  23 

4.2.1	Residue Profile	  PAGEREF _Toc148327543 \h  23 

4.2.2	Dietary Exposure Analyses	  PAGEREF _Toc148327544 \h  24 

4.2.2.1	Drinking Water Exposure	  PAGEREF _Toc148327545 \h  25 

4.2.2.2	Acute Dietary	  PAGEREF _Toc148327546 \h  27 

4.2.2.3	Chronic Dietary	  PAGEREF _Toc148327547 \h  27 

4.2.2.4	Cancer Dietary	  PAGEREF _Toc148327548 \h  28 

4.3	Residential Exposure/Risk Pathway	  PAGEREF _Toc148327549 \h  28 

4.3.1	Handler Exposure and Risk	  PAGEREF _Toc148327550 \h  29 

4.3.2	Postapplication Exposure and Risk	  PAGEREF _Toc148327551 \h  29 

4.3.3	Other Exposure Sources (Spray Drift)	  PAGEREF _Toc148327552 \h 
30 

5.0	AGGREGATE RISK ASSESSMENTS and RISK CHARACTERIZATION	  PAGEREF
_Toc148327553 \h  30 

5.1	Acute Aggregate Risk Assessment (Food and Drinking Water)	  PAGEREF
_Toc148327554 \h  30 

5.2  Short- and Intermediate-Term Aggregate Risk Assessment	  PAGEREF
_Toc148327555 \h  31 

5.3	Chronic Aggregate Risk Assessment (Food and Drinking Water)	 
PAGEREF _Toc148327556 \h  31 

5.4	Cancer Aggregate Risk Assessment	  PAGEREF _Toc148327557 \h  31 

6.0	CUMULATIVE RISK	  PAGEREF _Toc148327558 \h  32 

7.0	OCCUPATIONAL EXPOSURE	  PAGEREF _Toc148327559 \h  32 

7.1	Occupational Handler	  PAGEREF _Toc148327560 \h  32 

7.2	Occupational Postapplication	  PAGEREF _Toc148327561 \h  34 

8.0	DATA NEEDS/LABEL REQUIREMENTS	  PAGEREF _Toc148327562 \h  35 

8.1	Chemistry	  PAGEREF _Toc148327563 \h  35 

8.2	Toxicology	  PAGEREF _Toc148327564 \h  35 

9.0	REFERENCES	  PAGEREF _Toc148327565 \h  36 

 

INTRODUCTION tc \l1 "INTRODUCTION 

A summary of the findings and an assessment of human risk are provided
in this document.  The hazard characterization, which has not changed
since the previous risk assessment (DP #332426, K. O’Rourke,
10/12/06), was conducted by Ghazi Dannan.  The residue chemistry
evaluation and dietary exposure assessment were provided by Amelia
Acierto, the occupational/residential exposure assessment and the risk
assessment were conducted by Kelly O’Rourke (HED/RAB3), and the
drinking water assessment was prepared by Mohammed Ruhman of the
Environmental Fate and Effects Division (EFED).

Recommendation for Registration

Provided revised Section F and Section B/proposed label are submitted,
this human health risk assessment supports the establishment of a
permanent tolerance for combined residues of cyazofamid
[4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfona
mide] and its metabolite CCIM
[4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile], expressed as
cyazofamid, in or on carrot, roots at 0.09 ppm.

The required revisions to Sections B and F are summarized below and
listed in Section 8.0 (Data Needs/Label Requirements) of this
memorandum.  

As no adjuvants were used in the carrot field trials, a revised Section
B is required to prohibit the use of adjuvants on carrots.  

A revised Section F is required in order to propose a tolerance for the
combined residues of cyazofamid and CCIM at 0.09 ppm in/on carrot,
roots.1.0	EXECUTIVE SUMMARY tc \l1 "1.0	EXECUTIVE SUMMARY 

Cyazofamid, also known as IKF-916, is the common name for 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.  For this action, it is specifically proposed for use
on carrot to control fungal diseases: root dieback (caused by Pythium
violae and P. sulcatum), cavity spot (caused by P. ultimum) and forking
(caused by P. irregulare and P. splendens).   

Background

The most recent Section 3 registration human health risk assessment for
cyazofamid was conducted in October of 2006 for proposed new uses on
non-residential turf and ornamentals (DP #332426, K. O’Rourke,
10/12/06).  There are currently no established Codex, Canadian, or
Mexican maximum residue limits (MRLs) for residues of cyazofamid in/on
plant or livestock commodities. 

Hazard Assessment

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

Following repeated administration in more than one species, cyazofamid
seems to have mild or low toxicity.  The kidney seemed to be a target
organ following 13 weeks of dietary feeding in male rats of the high
dose group which had increased microscopic kidney lesions characterized
as “increased number of basophilic tubules, graded as slight” in
addition to mild increases in urinary output, protein, and pH.  Female
rats of the same study were less sensitive, with the only change being a
marginal increase in urine volume and pH seen only at the highest dose. 
However, there were no adverse kidney effects or any other toxicity
findings following lifetime dietary feeding at concentrations up to
5,000 and 20,000 ppm in male and female rats, respectively.

Skin lesions, likely due to systemic allergy, were observed in the males
of the 18 month carcinogenicity study.  At the high dose, approaching
1,000 mg/kg/day, male mice suffered hair loss due to scratching which
was confirmed at necropsy by increased incidence of body sores (head,
neck, trunk, limb, and/or tail), and was correlated histologically with
increased incidence of acanthosis (hyperplasia), chronic active
dermatitis, ulceration, and premature death.  The sulfonamide moiety in
the cyanoimidazole ring might have rendered cyazofamid allergenic,
albeit a weak one at that.  This is supported by the fact that,
cyazofamid is a slight irritant (Toxicity Category III) in the primary
rabbit skin test and is a positive weak sensitizer in the guinea pig
skin maximization test.  Sulfonamide antimicrobial drugs (e.g.,
sulfamethoxazole) have been known to cause idiosyncratic drug reactions
in some patients with skin reactions (delayed type) ranging from benign
rash to potentially lethal toxidermias.

Cyazofamid’s overall toxicity profile in dogs seems to be limited. 
With the exception of increased parathyroid cysts in the high dose males
of the one year study, there were no major toxicity findings in the
13-week and one-year dog studies up to a dose of 1000 mg/kg/day.

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).
 The HIARC considered this approach conservative because bent ribs are a
reversible developmental anomaly rather than a malformation.  

In the prenatal developmental toxicity study in rabbits, there were no
maternal or developmental effects 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.

In the acute neurotoxicity study, there were no indications of
treatment-related adverse neurotoxicity findings including clinical
signs, qualitative or quantitative neurobehavioral effects, brain
weight, or gross/microscopic pathology.  

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, the HED 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 Food
Quality Protection Act (FQPA) of 1996.  The HIARC concluded there are no
concerns or residual uncertainties for pre- and or postnatal toxicity. 
On this basis, the HIARC concluded that the FQPA safety factor should be
removed (i.e., reduced to 1X) for all potential exposure scenarios to
cyazofamid.  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.  

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 50 years old, the acute reference dose (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 population-adjusted-dose or
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.

Incidental Oral: Because there is no incidental oral exposure scenario
for the population of concern, an endpoint was not selected.

Dermal Absorption Factor: HIARC estimated an upper-bound dermal
absorption factor of 37%.

Short-Term (1-30 days) and Intermediate-Term (1-6 months) Dermal and
Inhalation Endpoints:  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 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.  

Long-Term (>6 months) Dermal and Inhalation Endpoints: 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 NOAEL of 94.8mg/kg/day is based on
increased incidence of skin lesions in males at the LOAEL of 985
mg/kg/day.  

Level of Concern for Occupational/Residential 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) 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.

Exposure Assessment 

RANMAN™ 400SC, which contains 34.5% active ingredient (i.e., 3.33 lbs
ai/gallon) in a soluble concentrate formulation.  The proposed use rate
for carrots is 0.16 lb ai/A, for up to 5 applications, at 14- to 21-day
intervals.  Handlers may apply RANMAN™ 400SC using ground equipment or
overhead irrigation.  

Drinking Water Assessment:  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/ .  

This screening-level analysis provided upper-bound estimated drinking
water concentrations (EDWCs) of the terminal degradate CTCA that might
be found in surface water and groundwater due to the registered use of
cyazofamid on turf and ornamentals.  Although EDWCs were also modeled
for the proposed carrot use pattern, they were not used in this
assessment because they were much lower and would not have been
protective.  The analysis assumed 100% molar conversion of the parent to
CTCA.  Based on the results of the modeling, the surface water acute
EDWC is 136 ppb, and the surface water chronic EDWC is 133 ppb.  For
groundwater, the EDWC is 2.18 ppb. 

Dietary Exposure Estimates:  Tier 1 acute and chronic dietary exposure
assessments for cyazofamid were conducted using the Dietary Exposure
Evaluation Model (DEEM-FCID™), Version 2.03, which uses food
consumption data from the U.S. Department of Agriculture’s Continuing
Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. 
The unrefined analyses assumed that cyazofamid residues are present in
all registered and proposed food commodities at tolerance levels, and
that 100% of all commodities are treated.  All processing factors were
set to 1x, based on the results of processing studies.  Screening-level
EDWCs were incorporated directly into the model as point estimates.

For the acute analysis, dietary 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
0.0092 mg/kg/day, equivalent to <1% of the acute Population Adjusted
Dose (aPAD).

For the chronic analysis, dietary exposure is estimated at 0.0038
mg/kg/day for the general U.S. population (<1% of the chronic Population
Adjusted Dose [cPAD]) and 0.0107 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.

Residential Exposure Estimates:  Cyazofamid is currently registered for
use on professionally managed turf and ornamentals, and this use was
previously assessed (DP #332425, K. O’Rourke, 10/12/06).  The 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
recreational golfers or players of various sports who use a golf course
or athletic field after cyazofamid has been applied.  The
postapplication risk assessment is based on generic assumptions as
specified by the Recommended Revisions to the Residential SOPs and
recommended approaches by HED’s Exposure Science Advisory Committee
(ExpoSAC).  Non-occupational/recreational MOEs were estimated for “Day
0" exposure (i.e., the day of application).  The dermal MOEs range from
330 to 14,000.  These MOEs are greater than 100, and therefore, are not
of concern.

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.  None of the aggregate exposure and risk estimates exceed
HED's level of concern.

Occupational Exposure Estimates

No chemical-specific handler exposure data were submitted in support of
this registration.  In accordance with HED policy, occupational handler
exposures were estimated using the Pesticide Handlers Exposure Database
(PHED) Surrogate Exposure Guide (revised August, 1998).  The results of
the occupational handler exposure and risk assessment indicate that the
Total MOEs range from 100 to 79,000 with baseline clothing, and
therefore, are not of concern.  The minimum level of personal protective
equipment (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).

Chemical-specific dislodgeable foliar residue (DFR) studies on tomatoes,
grapes (MRID#: 45409118) and squash (MRID#: 45409119) were submitted for
a previous action on cyazofamid.  These studies were found to be
acceptable, and the results were considered in this assessment of
carrots.  In addition to these DFR data, the interim transfer
coefficient guidance developed by HED’s Science Advisory Council for
Exposure, which includes proprietary data from the Agricultural Re-entry
Task Force (ARTF) database (SOP # 3.1), was used in estimating
postapplication exposures.

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.  The proposed
supplemental label for RANMAN™ 400SC indicates a 12-hour restricted
entry interval (REI), which is in compliance with the Worker Protection
Standard (WPS), based on the acute toxicity categories for cyazofamid.

Recommendation for Registration

Provided revised Section F and Section B/proposed label are submitted,
this human health risk assessment supports the establishment of a
permanent tolerance for combined residues of cyazofamid
[4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfona
mide] and its metabolite CCIM
[4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile], expressed as
cyazofamid, in or on carrot, roots at 0.09 ppm.

The required revisions to Sections B and F are summarized below and
listed in Section 8.0 (Data Needs/Label Requirements) of this
memorandum.  

As no adjuvants were used in the carrot field trials, a revised Section
B is required to prohibit the use of adjuvants on carrots.  

A revised Section F is required in order to propose a tolerance for the
combined residues of cyazofamid and CCIM at 0.09 ppm in/on carrot,
roots. 



2.0	PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION  TC \l1 "2.0
PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION 

	2.1	Chemical Identity and Structure  TC \l2 "2.1	Chemical Identity and
Structure 

Cyazofamid is a fungicide developed by Ishihara Sangyo Kaisha, Ltd.
(Kusatsu, Shiga, Japan).  The registration of cyazofamid in the U.S. is
held by the ISK Biosciences Corporation (Concord, OH).  The chemical
names and structures of cyazofamid and CCIM (the major metabolite
included in the tolerance expression for plant commodities) are
presented in Tables 1 and 2 below.

 

Table 2.  Identification of Active Ingredient.

Common name	Cyazofamid (provisionally approved by ISO)

Company experimental name	IKF-916

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

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

CAS #	120116-88-3

PC Code	085651

Empirical Formula	C13H13ClN4O2S

Molecular Weight	324.9

Registrant	ISK Biosciences Corporation

End-use product/EP	RANMAN™ 400SC (EPA File Symbol 71512-3)

	2.2	Physical and Chemical Properties of Cyazofamid  TC \l2 "2.2
Physical and Chemical Properties of Cyazofamid 

Table 3.  Physicochemical Properties of Cyazofamid.

Parameter	Value

Melting point	152.7 oC

pH	 4.9 at 25oC

Relative Density (g/mL @ 20oC)	1.446

Water solubility (@ 20oC + 1oC)	0.107 mg/L at pH 7

Solvent solubility (equilibrated @ 21.2 + 1oC)	Organic solvents	  (g/100
mL)

	hexane

methanol

acetonitrile

dichloroethane

toluene

ethyl acetate

acetone

octanol	  0.003

  0.174

  3.095

10.212

  0.600

  1.649

 4.564

 0.004

Vapor pressure 	<1.33 x 10-5 Pa  (@ 25, 30, 35oC)

Dissociation constant, pKa	no pKa evident in pH range 2-12

Octanol/water partition coefficient, Kow	3.2

Half-Lives	Aerobic soil:  5.5 days

Aerobic Aquatic:  16.4 days

Aquatic Photolysis:  0.02 days

3.0	HAZARD CHARACTERIZATION  TC \l1 "3.0	HAZARD CHARACTERIZATION 

Reference:	Cyazofamid [IKF-916] - Report of the Hazard Identification
Assessment Review Committee, G.A.  Dannan, 3/3/2004.

The toxicological database for cyazofamid is complete. 

	3.1	Hazard Profile  TC \l2 "3.1	Hazard Profile 

The acute toxicity and toxicity profile for cyazofamid are summarized in
Tables 4 and 5, respectively.  Cyazofamid has a low order of acute
toxicity based on its classification as Toxicity Category IV via the
oral route, Toxicity Category III by the dermal route, and Toxicity
Category IV by the inhalation route of exposure.  Cyazofamid produces
minimal but reversible eye irritation (Toxicity Category IV), is a
slight dermal irritant (Toxicity Category III), 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.  These findings are consistent with findings of skin lesions,
which may be due to systemic allergy, in the 18 month mouse
carcinogenicity study.  Sulfonamide- containing drugs, for instance, are
known to cause skin and other allergies in some patients.  

Table 4.  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)	-

Subchronic toxicity:  Following repeated administration in more than one
species, cyazofamid seems to have mild or low toxicity.  The kidney
seemed to be a target organ following 13 weeks of dietary feeding in
male rats of the high dose group (5,000 ppm or 295 mg/kg/day) which had
increased microscopic kidney lesions characterized as “increased
number of basophilic tubules, graded as slight” in addition to mild
increases in urinary output, protein, and pH.  Female rats of the same
study were less sensitive; with the only change being a marginal
increase in urine volume and pH seen only at the highest dose of 20,000
ppm (1395 mg/kg/day).  Similar kidney histopathology changes (increased
number of basophilic tubules, graded slight to moderate) were also
evident among the 28-day preliminary study with male rats that were fed
diets containing cyazofamid at concentrations of 5,000 and 20,000 ppm. 
However, there were no adverse kidney effects or any other toxicity
findings following lifetime dietary feeding at concentrations up to
5,000 and 20,000 ppm in male and female rats, respectively.  Not only
did the kidney changes not worsen or progress to a frank or severe
kidney toxicity, but the short-term study findings of basophilic kidney
tubules seem to be reversed after lifetime exposure to cyazofamid.  This
might imply that findings of basophilic kidney tubules are not adverse
and that affected animals can adapt.  However, one should also consider
the fact that the actual daily dose, expressed as mg/kg/day, declines
with age because, after attaining full growth, animals consume less food
on a per kg body weight basis.  For instance, at 5,000 ppm, the mean
daily dose for males of the 28-day, 90-day, and two year studies was
370, 295, and 171 mg/kg/day, respectively.  It is, therefore, to be
expected that a threshold non-adverse change, such as might be the case
with basophilic kidney tubules, will likely be reversed over time.

Chronic toxicity:  Skin lesions, which may be due to systemic allergy,
were observed in the males of the 18 month carcinogenicity study.  At
the high dose, approaching 1,000 mg/kg/day, male mice suffered hair loss
due to scratching which was confirmed at necropsy by increased incidence
of body sores (head, neck, trunk, limb, and/or tail), and was correlated
histologically with increased incidence of acanthosis (hyperplasia),
chronic active dermatitis, ulceration, and premature death.  The
sulfonamide moiety in the cyanoimidazole ring might have rendered
cyazofamid allergenic, albeit a weak one at that. This is supported by
the fact that, cyazofamid is a moderate irritant (III) in the primary
rabbit skin test and is a positive weak sensitizer in the guinea pig
skin maximization test.  Of note, however, is that there were no skin
allergies in the rat feeding study; this is not surprising, however, due
to possible species variation.  Sulfonamide antimicrobial drugs (e.g.,
sulfamethoxazole) have been know to cause idiosyncratic drug reactions
in some patients with skin reactions (delayed type) ranging from benign
rash to potentially lethal toxidermias (see for instance, a research
paper by Choquet-Kastylevsky et. al. [2002] in Current Allergy Asthma
Reports, Vol. 2, pp.16-25).

Cyazofamid’s overall toxicity profile in dogs seems to be limited.  In
both the 13 week and one year dog studies, there were no major toxicity
findings up to a dose of 1,000 mg/kg/day.  The only possible effect was
increased cysts in parathyroids of both sexes and pituitary in females
observed in the high dose groups of the one year study.  In the original
evaluation, these findings were considered treatment-related in the
absence of requested historical control (HC) data.  More recently, the
requested HC data were provided and, with the exception of parathyroid
cysts in the high dose males, the other findings were within the
respective historical control values. Therefore, male dogs had increased
parathyroid cysts at the high dose of 1000 mg/kg/day.

Developmental and reproductive toxicity:  The pre- and post-natal
toxicology database for cyazofamid includes rat and rabbit developmental
toxicity studies and 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.  The
HIARC considered this approach conservative because bent ribs are a
reversible developmental anomaly rather than a malformation.  

In the prenatal developmental toxicity study in rabbits, there were no
maternal or developmental effects 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.

Neurotoxicity:  In the acute neurotoxicity study, there were no
indications of treatment-related adverse neurotoxicity findings
including clinical signs, qualitative or quantitative neurobehavioral
effects, brain weight, or gross/microscopic pathology.  The HIARC
concluded that the slight increase in motor activity at day 14 among the
mid- and high-dose males is marginal and should not be considered an
adverse finding.

Carcinogenicity:  There is no evidence that cyazofamid may be
carcinogenic, as indicated in both the rat and the mouse carcinogenicity
studies.  It 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.

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

Metabolism:  Pharmacokinetics and metabolism studies in rats following
administration of a single low (0.5 mg/kg) or high (1,000 mg/kg) dose,
showed relatively rapid absorption (irrespective of dose tcmax =
0.25-0.5 hrs) and elimination (t1/2 4.4-5.8 hrs) at the low dose and
saturated absorption with prolonged elimination (t1/2 of 7.6-11.6 hrs)
at the high-dose.  The extent of absorption (expressed as per cent of
administered dose) was highly dose-dependent, being nearly 75% at the
low dose and only about 5% at the high dose.  Both the urine and feces
were major routes of excretion at the low dose with most of the urinary
radioactivity being a metabolite named CCBA
(4-(4-chloro-2-cyanoimidazol-5-yl)benzoic acid).  Results of biliary
excretion experiments showed biliary elimination of radiolabel to be
highly variable at the low dose (~12-39% of the administered low dose)
and negligible (<2%) in the high-dose groups.  Urinary or biliary
excretion in rats of the high-dose groups was low (each ~2%) with most
of the radioactivity being CCBA.  Irrespective of the dosing regimen,
most of the recovered fecal radioactivity was unchanged parent compound;
the major fecal metabolites were CCBA and
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 were indicative of rapid clearance and low
tissue burdens suggesting little or no bioaccumulation or sequestration.

Metabolite Toxicity:  Acute oral toxicity studies were submitted for
cyazofamid metabolites CCIM, and CCIM-AM.  CCIM is a major metabolite in
some plant commodities (wine), while CCIM-AM is a minor metabolite. 
CCIM appears to be more acutely toxic (Toxicity Category III) than
cyazofamid (Toxicity Category IV).  However, CCIM is not a terminal
metabolite and continues to degrade in plants, livestock and the
environment.  Metabolism and pharmacokinetics studies indicate that
cyazofamid uptake is saturable with 75% being absorbed following a
single dose of 0.5 mg/kg and 5% at the much higher does of 1000 mg/kg. 
In vitro uptake studies indicate that CCIM is absorbed more readily than
cyazofamid.  Thus, the difference in acute oral toxicity probably
reflects poor uptake of cyazofamid at high doses and is not likely to be
relevant to the lower doses expected from dietary exposure where
cyazofamid is absorbed readily.  

Table 5.  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

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

(ai)	Negative  ± S9 up to 5,000 µg/plate by standard plate and tube
preincubation (not cytotoxic but there was precipitation at ≥1,500
μg/plate.

Gene Mutation

870.5300

Mammalian cell culture	45409002 (1998)

Acceptable/ guideline

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

Cytogenetics 

870.5375 Chromosomal aberrations	45409003 (1996)

Acceptable/ guideline

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

Cytogenetics 

870.5395

Micronucleus test on mouse	45409004 (1996)

Acceptable/ guideline

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

Other Effects 

870.5500

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

Acceptable/ guideline

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

870.6200a

Acute neurotoxicity screening battery	45434601 (2000)

Acceptable/guideline

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

LOAEL = not observed.

The HIARC concluded that the slight increase (∼45%) in motor activity
at day 14 among the mid- and 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.

Biliary excretion study: 0.5 or 1,000 mg/kg [phenyl- U-14C]- or
[14C-Imidazole] IKF-916. 	There was rapid absorption (irrespective of
dose tcmax = 0.25-0.5 hrs) and rapid elimination at the low dose (t1/2
4.4-5.8 hrs) while there was saturated absorption with prolonged
elimination (t1/2 of 7.6-11.6 hrs) at the high-dose.  The extent of
absorption (as per cent of administered dose) was highly dose-dependent
being nearly 75% at the low dose and only about 5% at the high dose. 
Both the urine and feces were major routes of excretion at the low dose
with most of the urinary radioactivity being a metabolite named CCBA
(4-(4-chloro-2-cyanoimidazol-5-yl)benzoic acid).  The biliary
elimination was highly variable at the low dose (∼12-39% of the
administered low dose) and negligible (<2%) in the high-dose groups. 
Urinary or biliary excretion in the high-dose groups was low (each
∼2%)  with most of the radioactivity being CCBA.  Irrespective of the
dosing regimen, most of the recovered fecal radioactivity was unchanged
parent compound; the major fecal metabolites were CCBA and
4-chloro-5-p-tolylimidazole-2-carbonitrile (CCIM) each of which being
less than 5% of the administered dose.  Tissue burdens at t1/2, tmax,
and at 168 hours post dose indicated rapid clearance and low tissue
burdens suggesting little or no bioaccumulation or sequestration.

870.7600

Dermal penetration	Study not available.

	Special study: 

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

Acceptable/non-guideline	The in vitro biodegradation of [14C-Bz]IKF-916
or [14C-Bz)CCIM by rat blood or rat stomach contents was examined.  The
results indicated that, during the 60-minute incubation period, IKF-916
underwent degradation to CCIM (∼30%) in blood but was stable in
stomach contents while CCIM was unaffected in either medium.  The
results also suggest that CCIM could be produced in rats following
IKF-916 entering the blood compartment but not necessarily in the
stomach compartment.

Special study: 

In Vitro Metabolism of CCIM in S9 Fraction	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)

Acceptable/non-guideline	Using in vitro isolated rat intestinal segments
containing [14C]IKF-916 or [14C]CCIM, 2.6% of IKF-916 and 10.4% of CCIM
was transferred from the lumen (mucosal side) to the exterior (serosal
side) of the gut segment.  Of the IKF-916 that was absorbed and
transferred to the buffer solution, approximately 60% had undergone
biotransformation/degradation to CCIM, CCBA and three additional
products.  Also, CCIM appeared to be degraded to two metabolites not
observed for intestine preparations containing IKF-916.  Based on the
findings of this study, cyazofamid seems to be poorly absorbed from the
intestinal lumen although its conversion to CCIM or other metabolites
may increase overall transfer across the gut wall.

Special study:

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

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

	3.2	FQPA Considerations  TC \l2 "3.2	FQPA Considerations 

On February 10, 2004, the HED HIARC evaluated the potential for
increased susceptibility of infants and children from exposure to
cyazofamid according to the February 2002 OPP 10X guidance document. 
There are no concerns or residual uncertainties for pre- and or
postnatal toxicity.  On this basis, the HIARC concluded that the FQPA
safety factor (SF) should be removed (i.e., reduced to 1X) for all
potential exposure scenarios to cyazofamid.  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.  The recommendation is based on the following:

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 Tier 1, conservative, high-end assessments
and will not underestimate the potential dietary (food and water)
exposures.

	3.3	Dose-Response Assessment  TC \l2 "3.3	Dose-Response Assessment 

On February 10, 2004, the HIARC evaluated the toxicology database for
cyazofamid with regard to the acute and chronic reference doses (RfDs)
and the toxicological endpoint selection for use as appropriate in
occupational exposure/risk assessments.  The doses and toxicological
endpoints selected for various exposure scenarios are discussed below
and summarized in Table 6.  The HIARC requested that a 28-day inhalation
toxicity study be conducted. 

Table 6.  Summary of Toxicological Dose and Endpoints for Cyazofamid.

Exposure

Scenario	Dose Used in Risk Assessment, UF 	FQPA SF and Level of Concern
for Risk Assessment	Study and Toxicological Effects

Acute Dietary

(Females 13-50 years of age)	NOAEL = 100 mg/kg

UF = 100

Acute RfD = 1.0 mg/kg	FQPA SF = 1X

aPAD = acute RfD

              FQPA SF

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

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

Acute Dietary

(General population including infants and children)	NOAEL = NA

UF = NA

Acute RfD = NA 	FQPA SF =  NA

aPAD = acute RfD

              FQPA SF

= NA	No adverse effects were observed which could be attributed to a
single-dose exposure.

Chronic Dietary

(All populations)	NOAEL= 94.8 mg/kg/day

UF = 100

Chronic RfD = 0.95

 mg/kg/day	FQPA SF = 1X

cPAD = chronic RfD

               FQPA SF

= 0.95 mg/kg/day	18-Month Mouse Oral Carcinogenicity (MRID 45408932)

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

Short- (1-30 days) and Intermediate-Term (1 to 6 months) Incidental Oral

	NOAEL= NA 

No Residential Uses	Residential LOC for MOE = NA 

Occupational = NA	Because there is no incidental oral exposure scenario
for the population of concern, an endpoint was not selected.

Short- (1-30 days) and Intermediate-Term (1 to 6 months) Dermal 	Oral
study NOAEL = 100 mg/kg/day

(dermal absorption rate = 37 %)	Residential LOC for MOE = NA

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.

Long-Term Dermal (>6 months)

	Oral study NOAEL = 94.8 mg/kg/day

(dermal absorption rate = 37 %)	Residential LOC for MOE = NA

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

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

Short- (1-30 days) and Intermediate-Term (1 to 6 months) Inhalation 

	Oral study NOAEL = 100 mg/kg/day

	Residential LOC for MOE = NA

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.

Long-Term Inhalation (>6 months)

	Oral study NOAEL = 94.8 mg/kg/day

	Residential LOC for MOE = NA

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)	Not Applicable	NA	NA

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL =
no-observed-adverse-effect-level, LOAEL =
lowest-observed-adverse-effect-level, PAD = population adjusted dose (a
= acute, c = chronic) RfD = reference dose, MOE = margin of exposure,
LOC = level of concern, NA = 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 50
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:  Because there is no incidental oral exposure scenario
for the population of concern, an endpoint was not selected.

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 doses (370 and 1488 mg/kg/day,
respectively).  The oral toxicity NOAEL/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:  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 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.  

Long-Term (>6 months) Dermal and Inhalation Endpoints: 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 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, and MOE of 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.  As with occupational exposure, route specific
MOEs should be combined into a total MOE for comparison to the LOC.

	3.4	Endocrine Disruption  TC \l2 "3.4	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	EXPOSURE ASSESSMENT  TC \l1 "4.0	EXPOSURE ASSESSMENT 

Reference:	Cyazofamid.  P#7E7244:  Petition for the Establishment of a
Tolerance for the Combined Residues of Cyazofamid and its Metabolite
CCIM , in/on Carrot, Roots.  Summary of Analytical Chemistry and Residue
Data, DP #343419. A. Acierto, 3/6/2008.

Cyazofamid - Meeting Report of the Metabolism Assessment Review
Committee (MARC), A. Acierto, et. al., 2/13/2004.

Cyazofamid: Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure and Risk Assessments for a PMRA and IR-4 Proposed
Section 3 Registration in/on Carrot Roots, DP #343442, A. Acierto,
3/5/2008.

RANMAN™ 400SC, which is proposed for use on carrot to control fungal
diseases: root dieback (caused by Pythium violae and P. sulcatum),
cavity spot (caused by P. ultimum) and forking (caused by P. irregulare
and P. splendens).  The proposed use rates and application methods are
summarized in Table 7.

Table 7.  Summary of Directions for Use of Cyazofamid on Carrot

Application Timing, Type, Equipment	Formulation  (EPA Reg No)	Appli Rate

g a.i./ha

[lb. a.i./A]	Max. No. Appl. per season	Total Rate

g a.i./ha

[lb. a.i./A]	PHI

(days)	

Use Directions & Limitations

Broadcast or band:

 

Soil:

   -Pre-emergent  

 

Foliar:

   - 0.5 -1” seedling

   - 2-6” vegetative

   - 6” vegetative, true

      leaves

   -18-26” vegetative

	

RANMAN 

400SC

Reg. No.

71512-3	

176.5

[0.156]	

5	

865.2 -880

[0.77 - 0.79]

	

14	1) For pre-plant incorporated (broadcast or band) applications: Apply
in sufficient water to obtain adequate coverage within 3 days of
planting and mechanically incorporate into the soil or incorporate with
at least 1/4 inch of water.

2) Surface applications (Broadcast or band) may be made 14 days after
plant emergence and continue on a 14-21-day schedule. Incorporate into
the soil with ½ - 1 inch of water.

3) May be applied via an overhead irrigation system using calibration
technique directions. Apply near last 2 hours of cycle. 

4) For banded applications, a 6 to 8-inch band is recommended. Use
formula to calculate amount required in the band.

HED has requested a change to the proposed use directions.  The crop
field trial data submitted with this petition reflect the use of
cyazofamid only.  As no adjuvants were used in the carrot field trials,
a revised label is required to prohibit the use of adjuvants on carrots.
 This requested change is reiterated in Section 8.0 Data Needs/Label
Requirements, and should be made a condition of registration.  	4.2 
Dietary Exposure/Risk Pathway  TC \l2 "4.2	Dietary Exposure/Risk Pathway

		4.2.1	Residue Profile  TC \l3 "4.2.1	Residue Profile 

Permanent tolerances for the combined residues of cyazofamid and its
metabolite CCIM are currently established in/on cucurbits, imported wine
grapes, potatoes, and tomatoes.  The current request for registration is
for a proposed food use on carrot, roots.

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 2/18/2004 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 for: cyazofamid, CCIM, CCBA, 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 carrots.

Storage Stability: Harvested carrot samples from the field trials were
stored frozen for a maximum of 373 days prior to extraction and
analysis.  Untreated control field samples were fortified with
cyazofamid (0.10 ppm) and CCIM (0.10 ppm) and stored frozen (<-20 °C)
for 374 days. Mean recoveries of 70 – 120 % (±20 % SD) indicated that
residues of cyazofamid remained stable throughout the storage period. 
However, mean recoveries of 42 ± 2 % indicated that residues of CCIM
were not stable during the storage period; thus, a correction was
applied to residue values determined in the field trial studies.

Processed Food/Feed:  No processed commodities are associated with
carrots.

Crop Field Trial Data:  The field trial data on carrots are summarized
in Table 8.  These data support the use of cyazofamid (formulated as a
soluble concentrate) on carrots for up to five applications at 0.156 lb
ai/A (seasonal maximum of 0.78 lb ai/A), at 14- to 21-day intervals, and
a PHI of 14 days.  Based on the tolerance calculation, the available
field trial data will support a tolerance of 0.09 ppm for the combined
residues of cyazofamid and CCIM in/on carrots.  

Table 8.  Summary of Residue Data from Crop Field Trials with
Cyazofamid.

Commodity	Total Applic. Rate

g a.i./ha

[lb. a.i./A]	PHI (days)	Residue Levels

(ppm)

	n	Min.	Max.	HAFT1	Median

(STMdR)	Mean

(STMR)	Std. Dev.

Cyazofamid

Carrot	852.9 - 904.6

[0.799-0.807]	13-16	36	<0.01	0.045	0.039	0.01	0.018	0.010

CCIM

Carrot	852.9 – 904.6

[0.799-0.807]	13-16	36	<0.022	<0.02 2	<0.02 2	<0.02 2	<0.02 2	0

1HAFT = Highest Average Field Trial.

2Values were corrected to account for residue decline (58%) due to
storage.

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.  

International Harmonization: Presently, there are no maximum residue
limits (MRL) established by Codex, Canada or Mexico for cyazofamid. 
Therefore, international harmonization is not an issue for this
petition.

Drinking Water Residues of Concern:  The MARC concluded that cyazofamid
and the metabolites designated as CCIM, CCIM-AM and CTCA are considered
to be the major residues in water and should be included in the drinking
water risk assessment.  

		4.2.2	Dietary Exposure Analyses  TC \l3 "4.2.2	Dietary Exposure
Analyses 

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 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.

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.

			4.2.2.1  Drinking Water Exposure  TC \l4 "4.2.2.1	Drinking Water
Exposure 

Reference:	Estimated Drinking Water Concentrations of Parent Cyazofamid
and its Degradates CCIM, CCIM-AM and CTCA for Use in Human Health Risk
Assessment (Turf and ornamentals use pattern).  M. A. Ruhman, DP
#319466, 9/6/2006.

		Estimated Drinking Water Concentrations of Parent Cyazofamid and its
Degradates CCIM, CCIM-AM and CTCA for Use in Human Health Risk
Assessment (Carrot use pattern).  M. A. Ruhman, DP #342613, 3/5/2008.

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.  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 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 groundwater due to its
high persistence and mobility. 

Estimated Drinking Water Concentrations (EDWCs):  

The screening-level surface water and groundwater concentrations were
estimated using linked PRZM/EXAMS models and the SCI-GROW model,
respectively.  It was determined that the EWDCs based on the carrot use
pattern are much lower than those previously modeled for the turf and
ornamentals use pattern.  Therefore, the EDWCs that may occur due to the
registered use of cyazofamid on turf and ornamentals were retained for
the dietary exposure assessment; they are presented in Table 9 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 degradate 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 9.  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)	Groundwater EDWC (ppb)

Acute 

(1-in-10 yr. peak)	Chronic

 (1-in-10 yr. mean)

	1st  Scenario	Parent	14.362	0.377	0.01180

2nd  Scenario 	CCIM	17.106	12.094	0.00061

	CCIM-AM	6.699	6.312	0.00270

	CTCA	16.716	11.993	0.52300

3rd  Scenario 	CTCA	136.242	133.458	2.18000

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; however, since estimated aggregate food and drinking water
exposures using this approach are well below the acute and chronic
levels of concern, additional refinements were not necessary.  

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.

			4.2.2.2	 Acute Dietary  TC \l4 "4.2.2.2	Acute Dietary 

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

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
EDWC, 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
0.009153 mg/kg/day (equivalent to <1% of the aPAD) at the 95th
percentile of exposure, the appropriate regulatory statistic for Tier 1
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 10.

Table 10.  Acute Dietary Exposure Analysis for Food and Drinking Water
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	0.009153	<1	0.015222	1.52	0.022308	2.2

			4.2.2.3	 Chronic Dietary  TC \l4 "4.2.2.3	Chronic Dietary 

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.

as 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 11.  Dietary exposure was estimated at
0.003797 mg/kg/day for the general U.S. population (<1% of the cPAD) and
0.010691 mg/kg/day (1.1% of the cPAD) for the most highly exposed
population subgroup (infants <1 year old).  

Table 11.  Summary of Chronic Dietary Exposure and Risk for Cyazofamid1

Population Subgroup	    Exposure

(mg/kg/day)	% cPAD

General U.S. Population	0.003797	<1

All Infants (< 1 year old)	0.010691	1.1

Children 1-2 years old	0.008923	<1

Children 3-5 years old	0.006946	<1

Children 6-12 years old	0.003992	<1

Youth 13-19 years old	0.002571	<1

Adults 20-49 years old	0.003284	<1

Adults 50+ years old	0.003500	<1

Females 13-49 years old	0.003307	<1

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

  exposure and  risk is indicated by bold text.

			4.2.2.4	 Cancer Dietary  TC \l4 "4.2.2.4	Cancer Dietary 

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

4.3	Residential Exposure/Risk Pathway  TC \l2 "4.3	Residential
Exposure/Risk Pathway 

Reference:	Occupational and Residential Risk Assessment to Support
Request for Registration of Cyazofamid on Non-Residential Turf and
Ornamentals, K. O’Rourke, DP #332425, 10/12/06

A residential exposure and risk assessment was previously conducted (DP
#332425, K. O’Rourke, 10/12/06) for a product containing cyazofamid
(i.e., Cyazofamid 400SC) which is registered for use on professionally
managed turf areas such as golf courses and athletic fields.  The
exposure scenarios and risks are summarized in the following sections.

Cyazofamid 400SC may be applied to turf at rates ranging from 0.51 to
1.02 lb ai/A at intervals of 14 to 21 days.  The label states that
application by home-owners to residential turf is prohibited. 
Therefore, non-occupational handler exposure was not evaluated. 
However, postapplication exposure is possible for recreational golfers
or players of various sports who use a golf course or athletic field
after cyazofamid has been applied.

		4.3.1	Handler Exposure and Risk  TC \l3 "4.3.1	Handler Exposure and
Risk 

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

		4.3.2	Postapplication Exposure and Risk  TC \l3 "4.3.2	Postapplication
Exposure and Risk 

Postapplication exposure scenarios were assessed for recreational
golfers and players of various sports who use a golf course or athletic
field 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).

A TTR study was previously submitted by the registrant (MRID#: 46571104)
for use in assessing postapplication activities.  The 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 assumptions were used to
estimate residues.  

The MOEs were estimated for “Day 0" exposure (i.e., the day of
application) because it is assumed that individuals could enter the
course or athletic field immediately after application.  As shown in
Table 12, the MOEs are greater than 100 on the day of application, and
therefore, are not of concern.

Table 12.  Recreational Post-application MOEs

Subgroup

Exposed	Application Rate 

(AR)

(lbs ai/A) 1	TTR (µg/cm2) 2	Transfer Coefficient (TC)

(cm2/hr)	Exposure Time (ET) (hrs/day)	Short-/Intermediate-Term Dermal

	ADD (mg/kg/day) 3	MOE 4

Golfers	1.02	0.57	500	4	0.0070	14,000

Sports Players

	43,000	2	0.30	330

1 Maximum application rate from label: Cyazofamid 400SC

2 TTR (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 transferrable from the foliage
(standard assumption of 5%) 

3 Average daily dose (mg/kg/day) = [(TTR (µg/cm2) * TC (cm2/hr) * 37%
dermal absorption * mg/1,000 µg * ET ( hrs/day)] / [60-kg BW]	

4 Short-/Intermediate Term MOE = NOAEL / ADD; Short-/Intermediate-Term 
NOAEL = 100 mg/kg/day.  The LOC is 100.

	

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.  [Note: child golfer’s exposure is likely to be similar to
that of an adult golfer because the child’s shorter duration on the
course (i.e., 2 hours rather than 4) offsets the higher ratio of surface
area to body weight.]

		4.3.3	Other Exposure Sources (Spray Drift)  TC \l3 "4.3.3	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 golf course turf and athletic fields 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.

5.0	AGGREGATE RISK ASSESSMENTS and RISK CHARACTERIZATION  TC \l1 "5.0
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.

5.1	Acute Aggregate Risk Assessment (Food and Drinking Water)

  TC \l2 "5.1	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.  Refer to Section 4.2.2.2,
which discusses acute dietary exposure (food and drinking water) in
detail.  The dietary route alone is relevant for acute exposure and risk
assessment.

	5.2	Short- and Intermediate-Term Aggregate Risk Assessment  TC \l2 "5.2
 Short- and Intermediate-Term Aggregate Risk Assessment 

The short-/intermediate-term aggregate risk assessment estimates risks
likely to result from exposure to cyazofamid residues from food,
drinking water, and pesticide uses on residential/recreational sites. 
High-end estimates of residential exposure are used, while average
values are used for food and drinking water exposure (i.e. chronic
exposures).

A short-/intermediate-term risk assessment is required because there are
potential postapplication exposures from registered uses on golf courses
(adults and children 3-5 and 6-12 years old) and college/professional
athletic fields (adults only).  The results of the
short/intermediate-term aggregate assessments are presented in Table 13.
 HED is generally not concerned if the MOEs remain above the LOC, which
for this assessment, is 100.  The MOEs for all scenarios are greater
than 100, and therefore, are not of concern.

	Table 13.  Short-/Intermediate-Term Aggregate Risk Assessment for
Cyazofamid

Population	Food + Water Exposure

(mg/kg/day)	Residential Exposure, (mg/kg/day) 1	Combined Exposure,
(mg/kg/day)	MOE 

Food + Water + Residential 2

General U.S. Population	0.003797	0.30	0.30	330

Children 3-5 years old	0.006946	0.0070	0.014	7,100

Children 6-12 years old	0.003992	0.0070	0.011	9,100

1 Adult exposure is based on athletic field use; adult exposure from
golf course use is used as a high-end surrogate for children.

2 MOE = NOAEL/Combined Exposure, where the short-/intermediate-term
NOAEL is 100 mg/kg/day.

	5.3	Chronic Aggregate Risk Assessment (Food and Drinking Water)

  TC \l2 "5.3	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.  Refer to Section 4.2.2.3, which
discusses chronic dietary exposure in detail.  

	5.4	Cancer Aggregate Risk Assessment  TC \l2 "5.4	Cancer Aggregate Risk
Assessment 

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

6.0	CUMULATIVE RISK  TC \l1 "6.0	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/. 

7.0	OCCUPATIONAL EXPOSURE  TC \l1 "7.0	OCCUPATIONAL EXPOSURE 

Reference:	Occupational and Residential Risk Assessment to Support
Request for Registration of Cyazofamid on Carrots, K. O’Rourke, DP
#343443, 3/18/08.

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.

	7.1	Occupational Handler  TC \l2 "7.1	Occupational Handler 

No chemical-specific handler exposure data were submitted in support of
this registration.  It is the policy of the HED to use data from the
Pesticide Handlers Exposure Database (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 Science Advisory Council for Exposure Standard Operating
Procedure #7, dated 1/28/99).

The results of the occupational handler exposure and risk assessment
indicate that risks are not of concern with baseline clothing.  The
Total Short/Intermediate-Term MOEs range from 100 to 79,000; which reach
or exceed the LOC of 100, and are not of concern.  Exposure assumptions
and MOEs for occupational handlers are summarized in Table 14.

HED recognizes that it is feasible for the same individual to mix/load
and apply formulations with the groundboom sprayer, 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 MOE for these combined
activities for groundboom application of cyazofamid would be above the
LOC of 100 (i.e., 440). 

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 14.  Summary of  MOEs for Occupational Handlers of Cyazofamid

Exposure Scenario (Scenario #)	Dermal Unit Exposure (mg/lb ai) 1
Inhalation

Unit

Exposure

(mg/lb ai)2	Use Site	Application 

Rate 

(lb ai/A)3	Area Treated

(A/day) 4	Daily Dose

(mg/kg/day) 5	Total 

Short-/Int-term MOE 6

Dermal	Inhalation

	Mixer/Loader

(1) Mixing/Loading Liquid for Chemigation	2.9	0.0012	Carrots	0.16	350
1.0	0.0011	100

(2) Mixing/Loading Liquid for Groundboom Application	2.9	0.0012	Carrots
0.16	80	0.23	0.00026	440

Applicator

(3) Applying Sprays with Open Cab Groundboom	0.014	0.00074	Carrots	0.16
80	0.0011	0.00016	79,000

1 Baseline dermal unit exposure values represent long pants, long
sleeved shirts, shoes, and socks.  Values are reported in the PHED
Surrogate Exposure Guide dated August 1998.

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

RANMAN™ 400SC (Reg No:  71512-3).

4 Daily area treated is based on the area 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 Daily Dose (mg/kg/day) = Unit Exposure * % Absorption * Application
rate * Area treated} / 60 kg; where dermal absorption is 37% and
inhalation absorption is assumed to be 100%.

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

	

	7.2	Occupational Postapplication  TC \l2 "7.2	Occupational
Postapplication 

Postapplication exposure is possible for workers entering treated fields
to tend or harvest carrots.  Chemical-specific dislodgeable foliar
residue (DFR) studies on tomatoes, 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.  The results, which were summarized in an earlier
assessment (D285682, K. O’Rourke, 3/23/04), were considered in this
evaluation of carrots.  

The data for grapes, which resulted from a seasonal application rate
closest to that of carrots (0.71 lb ai/A/season compared to 0.78 lb
ai/A/season for carrots) and had the highest residue measurements
relative to the application rate, were used to estimate surrogate DFR
values for carrots.  These data indicated that the initial (i.e., “Day
0”) DFR was 20% of the application rate.  

In addition to DFR data, transfer coefficients (TC) were used to relate
the residue values to activity patterns, which take place after
application, to estimate potential human exposure.  The transfer
coefficients 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).  The application rate, DFR estimates, and transfer
coefficients used in this assessment are central tendency to
upper-percentile values.  Therefore, the estimated daily dose is
characterized as mid- to high-end.

Inputs and calculated postapplication risk estimates can be seen in
Table 15.  Risk calculations for postapplication workers result in MOEs
ranging from 2,300 to 19,000 on the day of application.  These MOEs are
greater than 100 on the day of application and, therefore, are not of
concern.

r RANMAN™ 400SC indicates a 12-hour REI, which is in compliance with
the WPS.

Table 15.  Summary of Estimated Post-application MOEs

Crop	Application Rate

(lb ai/A) 1	DAT 2	DFR 3

(μg/cm2)	TC 4

(cm2/hr)	Activity 4	

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1 Maximum application rate from proposed supplemental label RANMAN™
400SC (Reg No:  71512-3).  

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 Dislodgeable from the Foliage
(20%, based on DFR data on grapes).  

4 TC (cm2/hr) = transfer coefficients and associated activities from
ExpoSAC Policy Memo #003.1 “Agricultural Transfer Coefficients”,
8/17/2000.

5 MOE = MOE on the corresponding DAT.  MOE = NOAEL / Daily Dose. 

Daily Dose = [(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.  The LOC is 100.8.0
DATA NEEDS/LABEL REQUIREMENTS  TC \l1 "8.0	DATA NEEDS/LABEL REQUIREMENTS

	8.1	Chemistry  TC \l2 "8.1	Chemistry 

The crop field trial data submitted with this petition reflect the use
of cyazofamid only.  As no adjuvants were used in the carrot field
trials, a revised Section B/label is required to prohibit the use of
adjuvants on carrots.

Based on the tolerance calculation for carrot, the available field trial
data will support a tolerance of 0.09 ppm for the combined residues of
cyazofamid and CCIM in/on carrots.  A revised Section F is required in
order to propose a tolerance for the combined residues of cyazofamid and
CCIM at 0.09 ppm in/on carrot, roots.

	8.2	Toxicology  TC \l2 "8.2	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 use [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 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.

9.0	REFERENCES  TC \l1 "9.0	REFERENCES 

Cyazofamid [IKF-916] - Report of the Hazard Identification Assessment
Review Committee, G.A.  Dannan, 3/3/2004.

Cyazofamid.  P#7E7244:  Petition for the Establishment of a Tolerance
for the Combined Residues of Cyazofamid and its Metabolite CCIM , in/on
Carrot, Roots.  Summary of Analytical Chemistry and Residue Data, A.
Acierto, DP #343419, 3/6/2008.

Cyazofamid - Meeting Report of the Metabolism Assessment Review
Committee (MARC), A. Acierto, et. al., 2/13/2004.

Cyazofamid: Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure and Risk Assessments for a PMRA and IR-4 Proposed
Section 3 Registration in/on Carrot Roots, A. Acierto, DP #343442,
3/5/2008.

Estimated Drinking Water Concentrations of Parent Cyazofamid and its
Degradates CCIM, CCIM-AM and CTCA for Use in Human Health Risk
Assessment (Turf and ornamentals use pattern).  M. A. Ruhman, DP
#319466, 9/6/2006.

Estimated Drinking Water Concentrations of Parent Cyazofamid and its
Degradates CCIM, CCIM-AM and CTCA for Use in Human Health Risk
Assessment (Carrot use pattern).  M. A. Ruhman, DP #342613, 3/5/2008.

Occupational and Residential Risk Assessment to Support Request for
Registration of Cyazofamid on Non-Residential Turf and Ornamentals, K.
O’Rourke, DP #332425, 10/12/06. 

Occupational and Residential Risk Assessment to Support Request for
Registration of Cyazofamid on Carrots, K. O’Rourke, DP #343443,
3/18/08.

Figure 1.  Codes, Chemical Names and Chemical Structure of Cyazofamid

and Identified Metabolites. 

Identification of Compounds from the Cyazofamid Metabolism Studies.

Common name/ code/matrix	Chemical name		Chemical structure

Cyazofamid/

IKF-916

 

CCIM

 

CCBA

 

CCIM-AM

 

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