Document ID: EPA-HQ-OPP-2007-0872-0006
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:		6 March 2008

	Subject:	Cyazofamid. PP# 7E7244:  Petition for the Establishment of a
Tolerance for the Combined Residues of Cyazofamid and its Metabolite
CCIM, in/on Carrot, Roots.  Summary of Analytical Chemistry and Residue
Data.

             DP Number :	343419	

 Decision No.  	381623

PC Code:	

085651	Submission:

	

40 CFR §180	

601	

MRID/PMRA No.      	

47186801/1460112

	From:	Amelia Acierto, Chemist

		Registration Action Branch 3

		Health Effects Division (7509P)

	Through:	Paula Deschamp, Branch Chief

		Registration Action Branch 3

		Health Effects Division (7509P)

	To:	Barbara Madden, Team Leader

		Minor Use, Inerts and Emergency Response Branch (MUIERB)

       Registration Division (7505P)

	

			and

		Cynthia Giles-Parker, Chief

	      Fungicide Branch

      Registration Division (7505P)

Executive Summary

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, root at 0.06 ppm.

Permanent tolerances are currently established (40 CFR §180.601) for
the combined residues of cyazofamid and its metabolite CCIM at 0.02 ppm
in/on potato, 0.10 ppm in/on cucurbits, 0.20 ppm in/on tomato, and 1.5
ppm in/on grape, wine.   

The nature of the residue in plants is adequately understood based on
previously submitted metabolism studies on grape, potato, tomato, goat
and hen as well as a confined metabolism studies using   SEQ CHAPTER \h
\r 1  [benzene-14C]cyazofamid and [imidazole-14C]cyazofamid as test
substances.  The plant and livestock metabolism studies indicated that
several of the metabolites resulting from the cyazofamid metabolism are
common to both plants and livestock.  The proposed metabolic pathways in
the plants (tomato, potato and grape) were identical.  The studies have
been reviewed and deemed acceptable by the Agency.  (D285650, A.
Acierto, 2/20/04). 

In support of the current petition for a minor use of cyazofamid in/on
carrots, the AAFC and the IR-4 have submitted residue data from crop
field studies conducted during the 2004-2005 growing season in Canada at
Zone 1A (1 trial in Prince Edward Island), Zone 5 (2 trials in
Manitoba), Zone 5B (2 trials in Quebec), and in the US at field sites
located in Region 2 (1 in Georgia), Region 3 (1 in Florida), Region 5 (1
in Michigan), Region 6 (1 in Texas), Region 10 (4 in California), and
Region 11 (1 in Washington).  The formulation used in the studies is the
3.33 lb ai/gal suspension concentrate (Ranman™ 400SC, EPA Reg, No.
71512-3, registered to ISK Biosciences Corporation).  The application
parameters consisted of one pre-emergent broadcast application directly
to the soil, followed by 4 foliar applications at the seedling to the
vegetative stage with retreatment intervals (RTI) from 12 to 92 days. 
The treatment rate ranged from 163 – 186 g a.i./ha/application [0.146
– 0.166 lb ai/A/application] for a total seasonal rate ranging from
853 – 905 g a.i./ha [0.799 – 0.807 lb. a.i./A].  The preharvest
interval (PHI) ranged from 14 - 16 days.  Two decline studies were
included with PHIs at 0, 7-8, 14-15, 20-21 and 28-29 days.   The field
trials were designated either as Treatment 2 or Treatment 3. 
Applications of cyazofamid in Treatment 2 was followed by sprinkler
irrigation within 6 hours.  In Treatment 3, the first 2 applications
were followed by sprinkler irrigation to ensure germination, but after
the third, fourth and fifth applications, sprinkler irrigation was not
permitted until after 24 hours  This study was added to determine the
worst case situation (i.e., 24 hour delayed irrigation after the third,
fourth and fifth treatments) as recommended by HED’s ChemSAC
(2/4/2004). 

In a meeting of 2/18/04, the HED MARC concluded that for risk assessment
and tolerance expression, the parent, cyazofamid and CCIM metabolite are
the residues of concern in plants (grape, potato and tomato) and
livestock.  The parent is the residue of concern in rotational crops. 

Adequate enforcement methodology is available to enforce the proposed
tolerances.  Cyazofamid and the metabolite CCIM are completely recovered
(>80% recovery) using FDA’s Multi-Residue Protocol D (without
cleanup).  In addition, the petitioner has submitted the results of an
Independent Laboratory validation (ILV) for a HPLC/UV method (high
performance liquid chromatography method using an ultra violet detector)
which can be used as a single analyte confirmatory method.  

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.

Harvested carrot samples from these field trials were stored frozen for
a maximum of 373 days prior to extraction and analysis. A freezer
storage stability study was conducted in conjunction with the residue
study to determine the stability of cyazofamid residues in the field
trial samples under frozen conditions.  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.  Mean recoveries of 42 ± 2 % indicated that residues of

CCIM were not stable during the storage period. 

Residues of cyazofamid in treated carrot field samples ranged from <
0.01 ppm to 0.045 ppm and residues of CCIM (corrected for storage
dissipation) were all < 0.02 ppm (i.e., the combined residues were 0.03
ppm to 0.065 ppm) at the target PHI of 14 days (13 – 16 days).  Two
residue decline trials indicate that the residues of cyazofamid and CCIM
did not decline with increasing PHI.  

Regulatory Recommendations and Residue Chemistry Deficiencies 

Pending the resolution of the deficiencies noted below, there are no
residue chemistry issues that would preclude granting the use of
cyazofamid on the requested crop.   Sufficient data are available to
support the establishment of a permanent tolerance for the combined
residues of cyazofamid and CCIM in/on carrots.

Provided the forthcoming Human Health Risk Assessment does not identify
any risks of concern, HED recommends establishment of the tolerance as
follows:

	Carrot, root …………………………………………… 0.09
ppm

 

860.1200 Directions for Use

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

860.1550   Proposed Tolerances

2)	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,
root.

Background

Cyazofamid, a fungicide which belongs to a novel  chemical class based
on the cyanoimidazole moiety, is a broad spectrum fungicide active
against oomycete fungi (such as Phytophthora, Plasmopara,
Pseudoperonospora, and Pythium) and Plasmodiophoromycetes
(Plasmodiospora brassicae).  It inhibits all stages of fungal
development in the life cycle of Phythophthora infestans which causes
late blight disease on potatoes and tomatoes,  and inhibits the
germination and formation of zoosporangia, germination of cytospores, 
zoospore mobility and mycelial growth.  It controls downy mildew on
cucurbit vegetables and grapes. 

Cyazofamid 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).   Permanent tolerances are established for the combined
residues of cyazofamid and CCIM in cucurbit vegetables, group 9; grape,
wine; potato; and tomato under 40 CFR §180.601.

The chemical names and structures of cyazofamid and its major
metabolite, CCIM, are shown in Table A.1., and the physicochemical
properties of the parent are summarized in Table A.2.

Table  A.1.  Chemical Names and Structures of Cyazofamid and CCIM.

cyazofamid	Chemical Structure

 

Common name	Cyazofamid

Company experimental name	N/A

IUPAC name	  SEQ CHAPTER \h \r 1 4-chloro-2-cyano-N,
N-dimethyl-5-p-tolylimidazole-1-sulfonamide

CAS name	  SEQ CHAPTER \h \r 1
4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonam
ide

CAS #	120116-88-3

End-use product/(EP)	RANMAN 400SC Agricultural Fungicide

CCIM	Chemical Structure

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

CAS name	

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

TABLE A.2.	Physicochemical Properties of the Technical Grade Cyazofamid.

Parameter	Value	Reference

Melting point (°C)	152.7	REG2006-05

pH	4.9	e-Pesticide Manual, 

13th Edition

Density at 20 °C (g/mL)	1.446

	Water solubility (at 20 °C)	pH	Solubility (mg/L)	REG2006-05

*MRID 45408907

	5

7

9	0.121

0.107

0.109

	Solvent solubility (at 21.2°C)	Solvent	Solubility (g/L)

Acetone

Ethyl acetate

Methanol

Dichloromethane

Toluene

Hexane

n-Octanol

Acetaonitrile

2-Propanol	43.1

16.19

1.74

94.82

6.0

0.03

0.04

29.446

0.43

	Vapour pressure at 25°C	<1.33 x 10-5 Pa

	Dissociation constant (pKa)	Does not dissociate in water. No pKa in the
pH range of 2-12.

	Octanol/water partition coefficient 	LogKOW = 3.2

KOW = 1.585 X 103

	UV/visible absorption spectrum	pH	Λmax (nm)

2

7

10	285

279

287

	*Reviewed by RD (Dr. Shyam Mathur D295479).

860.1200  Directions for Use

The petitioners, Agriculture and Agri-Food Canada (AAFC) and the
Interregional Research Project No. 4 (IR-4), submitted a copy of a
supplemental label for the use of Ranman( 400SC (EPA Reg. No 71512-3)
in/on carrot.  The proposed use directions are summarized in Table A.3. 

Table A.3.  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.

      1EP = End-use Product

Conclusions.      The submitted proposed use directions are adequate to
allow evaluation of the submitted residue data for carrots.   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.
 

   

860.1300  Nature of the Residue - Plants     

No new plant metabolism studies were submitted with this petition. 
Adequate plant metabolism studies with cyazofamid on grape, potato and
tomato were submitted in conjunction with PP# 1F06305.  In each study,
the cyazofamid test substances were radiolabeled in either the phenyl
ring ([benzene-14C]cyazofamid) or in the 4th position of the imidazole
ring ([imidazole-14C]cyazofamid).  The principal residue component
identified in whole grapes, potatoes and tomatoes was the unchanged
parent cyazofamid and the metabolite CCIM was identified at much lower
levels.  Comparison of the metabolic profile of the initial extract with
that of the stored sample demonstrates that cyazofamid changed (degraded
by ~24%) over the 6 month storage period, with a corresponding increase
in the metabolite CCIM in  potato but remained relatively unchanged for
9 – 9.5 months in tomato under frozen conditions.

The nature of the residue in plants is adequately understood for the
purposes of this petition.

860.1300 Nature of the Residue - Livestock

No new livestock metabolism studies were submitted with this petition. 
Metabolism studies with goat and hen were submitted previously (PP#
1F06305, DP# 285650, A. Acierto, 2/20/2004).  The studies were conducted
on goat (MRID 45409018) and hen (MRID 45409019).  The studies have been
reviewed and deemed acceptable.  It was concluded by the HED’s MARC
that although potatoes constitute a significant feed item for cattle,
the proposed uses fall under 40 CFR § 180.6(a)(3).  

As in the previous petition, there are no poultry feed items associated
with the uses of cyazofamid.

860.1340 Residue Analytical Methods

Enforcement Method:  Adequate enforcement methodology is available to
enforce the proposed tolerances.  Cyazofamid and the metabolite CCIM are
completely recovered (>80% recovery) using FDA’s Multi-Residue
Protocol D (without cleanup).  In addition, the petitioner has submitted
the results of an Independent Laboratory validation (ILV) for a HPLC/UV
method (high performance liquid chromatography method using an ultra
violet detector) which can be used as a single analyte confirmatory
method.  ((DP# 285650, 2/20/2004, A. Acierto).

Data Collection Method:  The petitioners used the analytical method,
“Independent Laboratory Validation of the Residue Method for IKF-916
and CCIM in Tomatoes”, Document Number 013033-0, Pyxant Labs Inc”,
with slight modifications.  Quantitation was by LC/MS/MS.  Briefly,
residues of cyazofamid and CCIM were extracted from 20 grams of carrot
with acetonitrile (ACN).  After filtration, the extract was transferred
to a separatory funnel, washed with hexane, cleaned up on a Nexus SPE
column, and the eluate was concentrated by using a TurboVap LV
workstation.  After reconstitution in 50:50 ACN:H2O, quantitation was
achieved by liquid chromatography/mass spectrometry/mass spectrometry
(LC/MS/MS).  With the exception of mean method validation and concurrent
recovery values of 64 ± 5 % and 64 ± 6 %, respectively, for samples
spiked with 0.010 ppm cyazofamid, acceptability of the method was
confirmed by method validation and concurrent recoveries of 70 – 120 %
(± 20 % standard deviation (SD) for both cyazofamid and CCIM.  Based on
recoveries of samples fortified with cyazofamid at the lowest level of
method validation (LLMV) of 0.01 ppm, the LOD and 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.

860.1360 Multiresidue Methods

Adequate multiresidue method data for cyazofamid and its metabolites
were submitted previously in conjunction with PP# 1F06305.   Cyazofamid
and its metabolite CCIM were analyzed according to the FDA Multi-Residue
Method (MRM) Test guidelines in PAM, Volume I Appendix II (1/94). 
Testing using Protocols A and B is not required because cyazofamid and
CCIM do not have an N-methylcarbamate structure and are not acid or
phenol compounds.  Using Protocol C, injections of cyazofamid and CCIM
yielded adequate responses to several of the Section 302 GLC systems. 
Cyazofamid and CCIM were completely recovered (>80% recovery) using
Protocol D (without cleanup).  Cyazofamid was partially recovered
(50-80% recovery) using Protocols E and F.  CCIM was not further tested
with Protocols E and F, because <30% of CCIM was recovered from the
Florisil column cleanup tests.  

Conclusions.  The Agency found that the FDA Multi-Residue Method,
Protocol D (without cleanup) met the requirement of the Residue
Chemistry Test Guideline 860.1360 to enforce tolerances for non-fatty
commodities and recommended its use as the enforcement method to enforce
the tolerances for residues of cyazofamid and CCIM in potato, tomato,
vegetable cucurbit group 9, and grapes.  The data collection method have
been reviewed previously by the Agency’s Analytical Chemistry Branch
(ACB) and concluded that the submitted method was sufficiently validated
by an independent laboratory and that the method met the OPPTS 860.1340
Residue Chemistry Test Guidelines. 

860.1380 Storage Stability

Storage stability data submitted previously (PP# 1F06305, DP# 285650,
2/20/2004, A. Acierto) demonstrated that the stability of cyazofamid and
its metabolite CCIM in grape juice, raisins, potato chips, potato
granules, potato wet peel, and tomato puree yielded variable results
when stored at -25 to 0oC for up to ~3 years.  Cyazofamid was found
stable in grape fruit up to 12 months but declined by ~50% after 24
months of storage.   Metabolite CCIM was reasonably stable for up to 6
months but declined by an average of ~50% after 24 months of storage. 
Cyazofamid was relatively stable in potatoes for up ~8 months but
declined by an average of 35% after 12-36 months.  CCIM was relatively
stable for ~26 months.  In tomatoes, cyazofamid and CCIM were reasonably
stable for up to ~36 months.

In the current petition, a freezer storage stability study was conducted
in conjunction with the residue study to determine the stability of
cyazofamid residues in carrots under frozen conditions.  Untreated
control field samples were fortified with cyazofamid (0.10 ppm) and CCIM
(0.10 ppm) and stored frozen (<-20 °C) for 374 days (~12.5 months). 
Mean recoveries of 70 – 120 % (±20 % SD) indicated that residues of
cyazofamid remained stable throughout the storage period.  Mean
recoveries of 42 ± 2 % which indicated that residues of CCIM were not
stable during the storage period. 

	Conclusion:  The storage stability data are acceptable and are
consistent with the results observed in the other plant commodities
reported in the previous petition (PP1F06305).

860.1400 Water, Fish, and Irrigated Crops

There are no proposed uses that are relevant to this guideline topic.

860.1460 Food Handling

Cyazofamid is presently not registered or proposed for use in
food-handling establishments.

860.1480 Meat, Milk, Poultry, and Eggs

No feeding studies were submitted with this petition.  In conjunction
with the previous petition (PP# 1F06305), examination of the uses of
cyazofamid on cucurbits, potatoes, tomatoes, and imported grape, wine
indicated that potato culls and processed potato waste are the only
relevant feed items which may be fed to beef and dairy cattle.  The
contribution of potato culls and processed waste to the maximum
theoretical dietary burdens (MTDB) of cyazofamid to beef and dairy
cattle were 0.108 ppm and 0.093 ppm, respectively. 

Based on the inclusion of the proposed use on carrots in this petition,
and the most recent guidance from HED concerning revisions of feedstuffs
percentages in Table 1, and constructing reasonably balanced livestock
diets (RBDs), a lower dietary burden has been estimated in Table C.1.
below (E-mail, J. Stokes, 3/17/08).

Table C.1.    Livestock dietary burdens for (cyazofamid) a      (Maximum
Reasonably Balanced Diet)

	%  Diet b	Residue (ppm)

Feedstuff	Type	Tolerance ppm	% Dry Matter	Beef	Dairy	Poultry	Swine	Beef 
Diary 	Poultry 	Swine 

Grass /nongrass/ cereal grain,  orage/silage/hay, untreated	R	--	--	15
45	--	--	--	--	--	--

Potato, processed waste	CC	0.02	15	30	10	Nu	Nu	0.04	0.013	--	--

carrot, culls	CC	0.09	12	Nu	10	Nu	Nu	--	0.075	--	--

Corn, field, grain/other grains/grain milled byproducts) , untreated	CC
--	--	50	25	--	--	--	--	--	--

Soybean, meal/other oilseed meals or seeds, untreated	PC	--	--	5	10	--
--	--	--	--	--

Totals

100	100	--	--	0.04	0.09	--	--

a    Residue levels for beef and dairy are corrected for moisture
content and are determined by formula: tolerance / %DM  x  % in diet. 
Residue levels for poultry and swine are considered “as-is” and are
determined by formula: tolerance  x   % in diet.

Two feedstuffs, i.e., processed potato waste and carrot culls, can
contribute to estimate a maximum reasonably balanced diet.   Feedlot
beef will be fed processed potato waste (Note:  Cull potatoes are
usually added to the processing waste; therefore 30% is maximum for
potato feedstuffs).  Carrot culls will not be available for feeding
feedlot beef.  Dairy cows can be fed both.  However, HED has decided
that only one alternative type feedstuffs should be included in any
theoretical livestock diet.  For the dairy cow, of the two feedstuffs,
the carrot culls would be the major contributor to the dietary burden.

The results of the goat metabolism study (200x) relative to this revised
dietary burden (0.09 ppm, dairy) indicates that tolerances for residues
of cyazofamid in ruminants are not required for the purpose of petition,
PP# 1F06305 [40 CFR §180.6(a)(3)]. 

Tolerances for residues of cyazofamid in poultry commodities are not
required since there are no poultry feed items associated with the
proposed uses.  For poultry, the proposed uses also fall under 40 CFR
§180.6(a)(3).

860.1500 Crop Field Trials

47186801.DER

Residue data were submitted by AAFC (Agriculture and Agri-Food Canada)
and IR-4 (Interregional Research Project Number 4) to support the
establishment of an MRL/tolerance for the combined residues of
cyazofamid and its metabolite, CCIM in/on carrots for the control of
Pythium root dieback, cavity spot, and forking diseases.  Fourteen
residue trials were conducted in Canada and in the US in the 2004-2005
growing season in Zone 1A (1 in Prince Edward Island), Zone 2 (1 in
Georgia), Zone 3 (1 in Florida), Zone 5 (1 in Michigan, 2 in Manitoba),
Zone 5B (2 in Quebec), Zone 6 (1 in Texas), Zone 10 (4 in California),
and Zone 11 (1 in Washington).

Cyazofamid, formulated as a soluble concentrate, was applied as one
broadcast application to the soil and as four foliar treatments to
carrots, at rates ranging from 163.2 – 186.1 g a.i./ha [0.146 0.1660
lb. a.i./A/application], with a re-treatment interval of 12 – 92 days,
for total seasonal rates ranging from 852.9 – 904.6 g a.i./ha [0.80
– 0.81 lb. a.i./A].  An adjuvant was not added to the spray mixture in
any of the applications. There were one or two treated plots at each
site, with applications timed to harvest at a 14-day PHI.

Residues of cyazofamid in treated carrot samples ranged from < 0.01 ppm
to 0.045 ppm and residues of CCIM (corrected for storage dissipation)
were all < 0.02 ppm (i.e. combined residues of cyazofamid and CCIM
ranged from 0.03 ppm to 0.065 ppm) at the target PHI of 14 days (13 –
16 days) as summarized in Table C.2.   Two residue decline trials did
not indicate residues declined with increasing PHI.

TABLE C.2.	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

[0.7992-0.8070]	13-16	36	<0.01	0.045	0.039 	0.01	0.018 	0.010

CCIM

Carrot	852.9 – 904.6

[0.7992-0.8070]	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.

Conclusion:  The crop field trials for cyazofamid in/on carrots are
considered scientifically valid.  The number and locations of  the field
trials are in accordance OPPTS Guideline 860.1500.  The results did not
differ when crops were irrigated immediately after treatment (Treatment
2) or under the worst case scenario where irrigation was delayed for 24
hour after the third, fourth and fifth treatments (Treatment 3).   The
use pattern of the field trials reflect the use pattern proposed for
carrots.  Two residue decline trials did not indicate that the residues
declined with increasing PHI.  Based on the tolerance calculation for
carrot (see Appendix II) the available field trial data will support a
tolerance of 0.09 ppm for the combined residues of cyazofamid and CCIM
in/on carrots.

860.1520 Processed Food and Feed

No processed commodities are associated with carrots.

860.1850 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) using test substances that were
radiolabeled in either the phenyl ring ([benzene-14C]cyazofamid) or in
the 4th position of the imidazole ring ([imidazole-14C]cyazofamid).  
Loamy sand soil were treated separately with the test substances at the
maximum seasonal rate of 0.445 lb ai/A and aged for 31, 119, and 360
days prior to seeding with lettuce (a leafy vegetable), carrot (a root
vegetable), and wheat (a cereal grain).   The total radioactive residues
(TRR) were determined in mature and immature crop commodities.  The
results showed that the TRR in the [imidazole-14C] cyazofamid treated
samples were, overall, higher than the [benzene-14C]cyazofamid treated
samples and that residues were generally highest in samples from the 31
plant-back interval (PBI), and decreased to <0.01 ppm in the mature
lettuce, carrot root, and wheat grain sample at the 360-day PBI. 
Residue characterization from the 31-day PBI with TRR >0.01 ppm
identified cyazofamid (0.2-0.6% TRR) as a minor residue component along
with the following metabolites: CCIM (0.2-0.9% TRR), CCIM-AM (0.1-0.9%
TRR), and CCBA (0.1-1.3% TRR).  The majority of radioactivity eluted at
the solvent front suggested that much of the bound residue was due to
incorporation of the label into biomolecules, consistent with the
results from the plant metabolism studies conducted on potatoes,
tomatoes and grapes.

860.1900 Field Accumulation in Rotational Crops

No data was submitted in support of this petition on carrots.  Based on
the confined rotational crop studies in PP# 1F06305 (see 45409036.DER), 
HED did not require a field accumulation study in rotational crops
(OPPTS 860.1900) and did not require tolerances for rotational crop
commodities to be established.  These determinations were based on the
results of the study which 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.

Proposed Tolerance 

The petitioners proposed the establishment of a permanent tolerance for
the combined residues of cyazofamid and CCIM in/on carrot, root at 0.06
ppm.   The Agency’s Guidance for Setting Pesticide Tolerances Based on
Field Trial Data was utilized for determining the appropriate tolerance
levels for carrot root (Appendix II).  The available field trial data
indicate that the proposed tolerance for carrot needs to be increased to
0.09 ppm.  The Section F should be revised to reflect the recommended
tolerance level as specified in Table D.

Presently, there are no maximum residue limits (MRL) established by
Codex, Canada or Mexico for cyazofamid.  Therefore, harmonization is not
an issue (Appendix I).

Table D.  Tolerance Summary of the Proposed and Recommended Tolerance
for the Combined Residues of Cyazofamid and CCIM.

Commodity	Proposed Tolerance

(ppm)	Recommended Tolerance

(ppm)	Residue Definition

Carrot, root	          0.06	              0.09	Combined Residues of
Cyazofamid,
4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonam
ide and its metabolite, CCIM, 
4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile

E.	REFERENCES

MRID No. 47186801/PMRA No. 1460112. Barney, W.P. (2007) Cyazofamid:
Magnitude of the Residue on Carrot: Lab Project Number: 08522. Study No.
08522.04-CAR05 Unpublished study prepared by Interregional Research
Project #4, Rutgers, The State University of New Jersey, Princeton, New
Jersey. 341 pages. 

PMRA No. 1460007. Kane, S. (2001) Independent Laboratory Validation of
the Residue Method for IKF-916 and CCIM in tomatoes, Document Number
013033-0, Unpublished study prepared by Pyxant Labs Inc. Colorado
Springs, Colorado. 34 pages.

DP#:	285650

Subject:	PP# 1F06305.  Cyazofamid. Petition for the Establishment of
Permanent Tolerances for use on Cucurbits, Potatoes, Tomatoes, and
Imported Wine Grapes.  Summary of Analytical Chemistry and Residue Data.

From:	Amelia M. Acierto

To:	Janet Whitehurst/Cynthia Giles-Parker, PM Team #22

Date:	2/20/2004

MRID Nos:	45638502–45638510, 45409014-45409020, 45409022-45409036.

F.	DOCUMENT TRACKING

Petition Number:      7F7244

DP #:	343419

PC Code:	         085651

								

ATTACHMENTS:

APPENDIX I:		INTERNATIONAL RESIDUE LIMIT STATUS

APPENDIX II:	TOLERANCE ASSESSMENT CALCULATION

Template Version June 2005.

APPENDIX  I

										

  SEQ CHAPTER \h \r 1  INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name: 

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

	Common Name:  Cyazofamid

☐  Proposed tolerance

☐ Reevaluated tolerance

x Other  (updated)	Date:  02/28/2008

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

X  No Codex proposal step 6 or above

☐  No Codex proposal step 6 or above for the crops

      Requested	Petition Number:  PP# 7F7244

DP Barcode:  D343419

Other Identifier: IKF-916

Residue definition (step 8/CXL): N/A	Reviewer/Branch:  A. Acierto/RAB3

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

Residue definition:    Combined Residues of Cyazofamid,
4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonam
ide and its Metabolite, CCIM, 
4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile

Carrot, root	0.09

Cucurbit vegetables, Group 9	0.10

Potatoes	0.02

Residue definition:  Combined Residues of Cyazofamid,
4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonam
ide and its Metabolite, CCIM, 
4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile

Tomato	0.20

Grape, wine *import	1.5

Limits for Canada	Limits for Mexi潣܇⁘丠⁯楌業獴

☐  No Limits for the crops requested	X  No Limits

☐  No Limits for the crops requested

Residue definition: N/A	Residue definition: N/A

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

Notes/Special Instructions:  

S.Funk, 03/11/2008

APPENDIX  II.  TOLERANCE ASSESSMENT CALCULATION.

For each of the crops listed below, the Guidance for Setting Pesticide
Tolerances Based on Field Trial Data SOP, along with the tolerance
spreadsheet, was used for calculating recommended tolerances.  As
specified in the SOP, the minimum of the 95% upper confidence limit
(UCL) on the 95th percentile and the point estimate of the 99th
percentile was selected as the tolerance value in cases when the dataset
was large (greater than 15 samples) and reasonably lognormal.  For
datasets that were small (≤15 samples) and reasonably lognormal, the
upper bound estimate of the 95th percentile based on the median residue
value was compared to the minimum of the 95% UCL on the 95th percentile
and the point estimate of the 99th percentile, and the minimum value was
selected as the tolerance value.  For datasets that were not lognormal,
the upper bound on the 89th percentile was selected as the tolerance
value (distribution-free method).  The rounding procedures specified in
the SOP were also used.

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ranged from <LOQ (<0.01 ppm) to 0.045 ppm and and CCIM were <LOQ.   
Values below the LOQ are generally referred to as censored data.   The
use of maximum likelihood estimation (MLE) techniques to estimate the
mean and standard deviation of dataset is normally recommended if more
than 10-15% of the dataset is censored but not for datasets with large
degree of censoring (i.e., >60%) since the technique becomes unreliable.
 

Since >50% of the field trial samples were below the LOQ, the MLE
procedure was used to impute censored values.  The residue data were
first entered into the MLE spreadsheet to obtain the estimated values
and the cyazofamid MLE and CCIM MLE data set were then entered into the
tolerance spreadsheet.  After entering the MLE dataset into the
spreadsheet, visual inspection of the lognormal probability plot  (Fig.
1) indicates that the dataset is reasonably lognormal.  The result from
the S-F test statistic (Fig. 2) confirmed that the assumption of
lognormality should not be rejected.

The petitioners have proposed a tolerance of 0.06 ppm. The available
data indicate that 0.09 ppm is an appropriate value for the tolerance
for carrot, root.

 

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