Document ID: EPA-HQ-OPP-2008-0042-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-10-15T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		28-MAY-2008

Subject:		Cyprosulfamide.  Request to Register Uses on Field Corn, Pop
Corn, Sweet Corn and Sorghum (Seed Treatment).  Summary of Analytical
Chemistry and Residue Data.  

PC Code:  877400	DP Barcode:  341999

Decision No.:  378533	Registration No.: NA

Petition No.:  7E7206	Regulatory Action: Section 3 Registration

Risk Assessment Type: Residue Chemistry	Case No.: NA

TXR No.:  NA	CAS No.: 221667-31-8

MRID No.:  47069724-47069739;

47069744-47069750	40 CFR:  180.xxx

		              									Ver.Apr.08

	From:	William H. Donovan, Ph.D., Chemist

		Reregistration Branch 3

		Health Effects Division (7509P)

	Through:	Catherine Eiden, Branch Chief

		Reregistration Branch 3

		Health Effects Division (7509P)

		

	To:	Karen Angulo, RM Team 08

		Inerts Branch

		Registration Division (7505P)

This document was originally prepared under contract by Dynamac
Corporation (2275 Research Blvd, Suite 300; Rockville, MD 20850;
submitted 11/14/2007).  The document has been reviewed by the Health
Effects Division (HED) and revised to reflect current Office of
Pesticide Programs (OPP) policies.

Executive Summary

Bayer CropScience has submitted a petition, PP#7F7206, proposing the
establishment of tolerances for residues of cyprosulfamide
[N-[[4-[(cyclopropylamino)carbonyl]phenyl]sulfonyl]-2-methoxybenzamide]
in/on the following raw agricultural commodities (RACs):

Corn (maize) kernel	0.01 ppm

Corn, immature kernel	0.01 ppm

Bayer has also proposed the establishment of tolerances for the combined
residues of cyprosulfamide and its metabolites AE
0001789-sulfonamide-lactate [3-[({4-[(cyclopropylamino)carbonyl]phenyl}
sulfonyl)amino]-2-hydroxypropanoic acid], AE 0001789-sulfonamide-alanine
[3-[({4-[(cyclopropylamino)carbonyl]phenyl}sulfonyl)amino]alanine], and
AE 0001789-N-cyclopropyl-4-sulfamoylbenzamide
[4-(aminosulfonyl)-N-cyclopropylbenzamide] in/on the following RACs:

Field Corn Forage	0.15 ppm

Sweet Corn Forage	0.40 ppm

Stover	0.60 ppm

In addition, Bayer has proposed tolerances for the combined residues of
cyprosulfamide and its metabolite AE
0001789-N-cyclopropyl-4-sulfamoylbenzamide in/on the following livestock
commodities:

Milk	0.01 ppm

Meat	0.01 ppm

Fat	0.01 ppm

Liver	0.02 ppm

Kidney	0.05 ppm

Cyprosulfamide is a new herbicide safener developed by Bayer CropScience
for use on corn and sorghum.  Review of the submitted petition is being
conducted as a Tri-lateral Review work-share effort which will be
carried out in part with Canada (PMRA) and the United Kingdom (PSD). 
All tolerances are proposed as harmonized MRLs (maximum residue limits),
with the exception of tolerances for livestock feed items.  Tolerances
for livestock feed items are proposed for the U.S. only.

In conjunction with this petition, Bayer is requesting registration of
four new products containing cyprosulfamide:  (1) SC 450 Herbicide (EPA
File Symbol No. 264-RNAR), a 1.88 lb/gal suspension concentrate
(equivalent to a flowable concentrate, FlC) formulation also containing
the herbicide thiencarbazone-methyl at 1.88 lb/gal; (2) SC 465 Herbicide
(EPA File Symbol No. 264-RNAA), a 1.25 lb/gal FlC formulation also
containing the herbicides thiencarbazone-methyl at 0.75 lb/gal and
isoxaflutole at 1.88 lb/gal; (3) SC 480 Herbicide (EPA File Symbol No.
264-RNAT), a 2.0 lb/gal FlC formulation also containing the herbicide
isoxaflutole at 2.0 lb/gal; and (4) FS 500 Sorghum Seed Protectant, a
4.17 lb/gal FlC formulation.  The first three products are proposed for
application to corn as preplant, preemergence, or postemergence
applications at maximum total seasonal rates of 0.20 lb safener/A, with
a 45-day preharvest interval (PHI) and a 14-day retreatment interval
(RTI).  The fourth product is proposed for seed treatment of sorghum at
0.052 lb safener per 100 lb seed.

The nature of the residue in corn is adequately understood based on
metabolism studies reflecting seed treatment, preemergence application,
and postemergence application.  The metabolic profile observed in the
seed treatment and preemergence studies is consistent with the rapid
degradation of cyprosulfamide in the soil via cleavage of the
carboxamide bond in the sulfonylbenzamide moiety to produce AE
0001789-N-cyclopropyl-4-sulfamoylbenzamide (AE 0852999) followed by crop
uptake.  Once AE 0852999 is taken up by the plant, it is further
conjugated to produce the AE 0001789-sulfonamide acetate, AE
0001789-sulphonamide aspartate, and AE 0001789-sulfonamide-alanine (AE
2300003).  AE 2300003 can be conjugated further to form the AE
0001789-sulfonamide-alanine-conjugate or deaminated to produce the AE
0001789-sulfonamide lactate (AE 2300002) which in turn can be
decarboxylated to produce the AE 0001789-sulfonamide-glycine metabolite.
 The metabolism of cyprosulfamide in leaves, following postemergence
application, involves hydroxylation of the methoxybenzoyl ring and the
subsequent conjugation to glucose or the loss of the cyclopropyl moiety
to produce the AE 0001789-descyclopropyl metabolite.  The identification
of minor amounts of AE 0852999 and AE 2300002 indicates that there may
be some uptake from the soil for postemergence application.  

For all corn RACs, HED has determined that the residue of concern for
risk assessment and tolerance enforcement is cyprosulfamide per se
(D351495, G. Kramer, 18-APR-2008).

Based on a radiotracer study, the proposed seed treatment use of
cyprosulfamide on sorghum may be considered a nonfood use.  

The nature of the residue in livestock is adequately understood based on
metabolism studies with goats and hens.  The major metabolic pathway for
cyprosulfamide in livestock involved hydrolysis of the amide bond of the
sulfonylbenzamide moiety to produce AE 0852999 and AE 0001789-anisic
acid, followed by conjugation to form methoxyhippuric acid and the
N-acetyl and N-pyruvyl derivatives of AE 0852999.  Demethylation of the
parent compound was a minor metabolic pathway.  For livestock
commodities, HED has determined that the residues of concern for
tolerance expression and risk assessment are cyprosulfamide and its
metabolite AE 0852999 (M02) (D351495, G. Kramer, 18-APR-2008).

Adequate HPLC-MS/MS methods have been submitted for the enforcement of
tolerances for cyprosulfamide residues in/on crop commodities (Method
UB-008-P06-01) and livestock commodities (Method UB-006-A06-01).  Method
UB-008-P06-01 determines residues of cyprosulfamide, AE 2300002, AE
2300003, and AE 0852999 in/on crop commodities, and Method UB-006-A06-01
determines residues of cyprosulfamide and AE 0852999 in livestock
commodities.  The validated limit of quantitation (LOQ) is 0.01 ppm for
each analyte in each matrix.  The proposed enforcement methods have been
forwarded to the Analytical Chemistry Branch of the Biological and
Economic Analysis Division (ACB) for petition method validation.   The
FDA multiresidue methods of the Pesticide Analytical Manual (PAM) Vol.
I. are not suitable for the determination of residues of cyprosulfamide
and its metabolites.

Interim storage stability data have been submitted for residues of
cyprosulfamide and metabolites AE 2300002, AE 2300003, and AE 0852999
in/on corn kernel (see requirements under Storage Stability), corn
forage, corn stover, soybean seed, lettuce, potato tuber, and tomato
fruit.  These data indicate that residues of cyprosulfamide are stable
in/on tomato fruit for at least 6 months and in/on corn kernel, corn
forage, corn stover, lettuce, and potato tuber for at least 12 months of
frozen storage.  Residues of metabolites AE 2300002, AE 2300003, and AE
0852999 are stable in/on corn kernel, corn forage, corn stover, lettuce,
potato tuber, and tomato fruit for at least 12 months of frozen storage.
 Residues of metabolite AE 0852999 were found to be stable in/on soybean
seed during 12 months of frozen storage; residues of AE 2300002 and AE
2300003 were found to be stable in/on soybean seed for at least 6
months, with some slight degradation observed after 12 months of frozen
storage.  The submitted storage stability data are not adequate to
support the storage durations and conditions of all crop samples from
the crop field trial, processing, and field rotational crop studies
associated with this petition, as some samples were stored up to 17
months prior to analysis.  The storage stability study is ongoing and
intended to include storage intervals of up to 18 months.  When the
final report of the study is submitted, the adequacy of the data to
support all sample storage conditions and durations will be assessed.  

An adequate cattle feeding study has been submitted.  The data indicate
that no quantifiable residues of cyprosulfamide or its metabolite AE
0852999 are expected in milk, muscle, or fat at 10x the dietary burden
to dairy cattle.  Therefore, no tolerances for cyprosulfamide residues
in milk, meat, or fat are required to support the proposed uses on corn.
 Quantifiable residues were observed in kidney and liver; the data
indicate that tolerances are needed for the combined residues of
cyprosulfamide and AE 0852999 in the meat byproducts of cattle, goat,
horse, and sheep at the combined LOQ for the two analytes (0.02 ppm). 
No tolerances are needed for swine or poultry commodities.  

Pending submission of the final report of the storage stability study,
the submitted crop field trial data for field, sweet, and pop corn are
adequate.  The trials reflected postemergence treatment at 1x the
proposed maximum seasonal rate.  The proposed PHI is adequate for corn
forage and sweet corn ears (kernel plus cob with husks removed). 
However, the proposed PHI for grain and stover must be removed from the
product labels as it is not supported by the field trial data; based on
the proposed use pattern, a PHI is not needed for corn grain and stover.
 No quantifiable residues of cyprosulfamide, AE 2300002, AE 2300003, or
AE 0852999 were found in/on any sample of field corn grain, sweet corn
ears (collected at or near the proposed PHI), or pop corn grain. 
Quantifiable residues of cyprosulfamide and/or its metabolites were
found in some samples of corn forage and stover.  The available data
support tolerances at the LOQ for residues of cyprosulfamide per se
in/on field corn grain, pop corn grain, and sweet corn ears.  The data
also support tolerances for residues of cyprosulfamide per se in/on
field corn forage at 0.20 ppm, in/on sweet corn forage at 0.40 ppm,
in/on field corn stover and pop corn stover at 0.20 ppm, and in/on sweet
corn stover at 0.35 ppm.

No quantifiable residues of cyprosulfamide or metabolites were observed
in/on field corn grain following treatment at 5x; therefore, no
processing study or tolerances for processed commodities are required.

The nature of the residue in rotational crops is adequately understood;
the residues of concern in rotational crop commodities are
cyprosulfamide and its metabolite AE 0852999 (M02) (D351495, G. Kramer,
18-APR-2008).  Adequate limited field rotational crop studies have been
submitted which indicate that a 2-month plantback interval is needed for
all rotational crops other than corn.  The proposed plantback intervals
on the product labels are adequate.

HED notes that three of the four the cyprosulfamide products proposed
for registration contain active ingredients in addition to
cyprosulfamide.  The adequacy of available data to support the requested
uses of those pesticides, thiencarbazone-methyl and isoxaflutole, are
addressed in separate reviews (see DP#s 339779 and 340598/340678,
respectively).

  SEQ CHAPTER \h \r 1 Regulatory Recommendations and Residue Chemistry
Deficiencies

Pending submission of revised product labels (see requirements under
Directions for Use), submission of a complete description of the
livestock enforcement method (see requirements under Residue Analytical
Methods), submission of additional reference standards (see requirements
under Submittal of Analytical Reference Standards), and submission of a
revised Section F (see requirement under Proposed Tolerances), there are
no residue chemistry issues that would preclude granting a conditional
registration for the requested uses of cyprosulfamide, or establishment
of permanent tolerances for cyprosulfamide residues as follows:

Tolerances for residues of the herbicide safener cyprosulfamide
(N-[[4-[(cyclopropylamino)carbonyl]phenyl]sulfonyl]-2-methoxybenzamide):

Corn, field, grain	0.01 ppm

Corn, pop, grain	0.01 ppm

Corn, sweet, kernel plus cob with husks removed	0.01 ppm

Corn, field, forage	0.20 ppm

Corn, field, stover	0.20 ppm

Corn, pop, stover	0.20 ppm

Corn, sweet, forage	0.40 ppm

Corn, sweet, stover	0.35 ppm

Tolerances for combined residues of the herbicide safener cyprosulfamide
(N-[[4-[(cyclopropylamino)carbonyl]phenyl]sulfonyl]-2-methoxybenzamide)
and its metabolite 4-(aminosulfonyl)-N-cyclopropylbenzamide, calculated
as cyprosulfamide:

Cattle, meat byproducts	0.02 ppm

Goat, meat byproducts	0.02 ppm

Horse, meat byproducts	0.02 ppm

Sheep, meat byproducts	0.02 ppm

The data requirements pertaining to storage stability (see requirements
under Storage Stability) must be fulfilled as a condition of
registration.

A human-health risk assessment is forthcoming in a separate document.

860.1200 Directions for Use

The proposed PHI of 45 days for grain and stover is not supported by the
field trial data, which reflect longer PHIs than 45 days.  The
petitioner should modify the labels to clarify that the 45-day PHI
pertains only to corn forage (field and sweet) and sweet corn ears. 
Because the product labels specify that applications may not be made
after the V12 growth stage of corn, a PHI is not required for corn RACs.

The label for the SC 480 Herbicide should be modified to clarify a
contradiction in the “Preplant Surface-Applied” application
directions and the “Restrictions and Precautions for Use” section. 
The Restrictions section specifies that only one application may be made
to corn per season.  The instructions for Preplant surface-applied
application specify that the application may be split, with 60% of the
recommended rate applied prior to planting and the remaining 40% applied
at planting.  If the petitioner wishes to allow split
preplant/at-planting applications, the Restrictions section should be
modified accordingly.

The labels for the SC 465 and SC 480 Herbicides include instructions for
“Post-Harvest Non-crop” application but do not include any
application rates for this type of application.  The labels should be
modified to either propose application rates or to remove the
instructions for this type of application.

The label for SC 450 Herbicide requires a minor correction to Table 2
(second table of rotational crop restrictions); in the row for the
17-month plantback interval, the footnote “3” on “All other
crops” should be modified to “4”.

860.1340 Residue Analytical Methods

The registrant should submit a copy of the complete, detailed livestock
method (UB-006-A06-01) with corresponding validation data as an
independent method document.  Currently, only a synopsis of the
livestock method is available (MRID 47069738).  

860.1380 Storage Stability

The final report of the storage stability studies, which are to include
storage intervals up to 18 months, must be submitted.

860.1650 Submittal of Analytical Reference Standards

Analytical reference standards of cyprosulfamide metabolite AE 0852999
(M02) and isotopically-labeled standards of both parent and M02 to be
used as internal standards must be supplied to the EPA National
Pesticide Standards Repository.  

860.1560 Proposed Tolerances

The proposed tolerances should be revised to reflect the recommended
tolerance levels and correct commodity definitions as specified above
and in Table 11.  

Background

The chemical structure and nomenclature of cyprosulfamide and its key
metabolites are presented in Table 1.  The physicochemical properties of
the technical grade of cyprosulfamide are presented in Table 2.

The chemical names and structures of cyprosulfamide and its
transformation products are presented in Appendix 1.  

Table 1.		Cyprosulfamide Nomenclature.

Chemical structure	

Common name	Cyprosulfamide

Company experimental name	AE 0001789

IUPAC name	N-cyclopropyl-4-[(2-methoxybenzoyl)sulfamoyl]-benzamide

CAS name
N-[[4-[(cyclopropylamino)carbonyl]phenyl]sulfonyl]-2-methoxybenzamide
(9CI)

CAS registry number	221667-31-8

End-use product (EP)	SC 450 Herbicide (EPA File Symbol No. 264-RNAR),
1.88 lb/gal FlC formulation;

SC 465 Herbicide (EPA File Symbol No. 264-RNAA), 1.25 lb/gal FlC
formulation;

SC 480 Herbicide (EPA File Symbol No. 264-RNAT), 2.0 lb/gal FlC
formulation;

FS 500 Sorghum Seed Protectant, 4.17 lb/gal FlC formulation 

Chemical structure of cyprosulfamide metabolite AE
0001789-sulfonamide-lactate (M10; AE 2300002)	

3-[({4-[(cyclopropylamino)carbonyl]phenyl}sulfonyl)amino]-

2-hydroxypropanoic acid (IUPAC)

Chemical structure of cyprosulfamide metabolite AE
0001789-sulfonamide-alanine (M11; AE 2300003)	

3-[({4-[(cyclopropylamino)carbonyl]phenyl}sulfonyl)amino]alanine (IUPAC)

Chemical structure of cyprosulfamide metabolite AE
0001789-N-cyclopropyl-4-sulfamoylbenzamide (M02; AE 0852999)	

4-(aminosulfonyl)-N-cyclopropylbenzamide (CAS)

Table 2.		Physicochemical Properties of Cyprosulfamide.

Parameter	Value	Reference

Melting point/range	218 C	MRID 47069746

pH	3.99 at 23 C

	Density	Pure cyprosulfamide:  1.64 g/mL, at 20 C

Technical cyprosulfamide:  1.51 g/mL, at 20 C

	Water solubility	0.0034 g/L, at pH 4, 20 C

1.09 g/L, at pH 7, 20 C

26.1 g/L, at pH 9 (nominal pH = 8.1), 20 C

0.0125 g/L, in bidistilled water (pH = 5.1), 20 C

	Solvent solubility		g/L at 20 C

Ethanol	0.47

n-Hexane	<0.001

Toluene	0.047

Dichloromethane	3.5

Acetone	3.1

Ethyl acetate	0.51

Dimethyl sulfoxide	200 – 300

	Vapor pressure	p << 10-5 Pa at 20-50 C

	Dissociation constant, pKa	pKa = 4.2

	Octanol/water partition coefficient, Log(KOW)	1.77, at pH 4, 23 C

-0.80, at pH 7, 23 C

λ1 = 202 nm

λ2 = 241 nm

	

860.1200  Directions for Use

Bayer has submitted proposed labels for four products containing
cyprosulfamide.  Information pertaining to the proposed end-use products
is presented in Table 3.  A summary of the proposed use patterns is
presented in Table 4.  The proposed rotational crop restrictions are
listed in Table 5.



Table 3.		Summary of  Proposed End-Use Products.

Trade Name	EPA File Symbol No.	Cyprosulfamide Concentration	Formulation
Type	Target Crops	Target Pests	Label Date

SC 450 Herbicide	264-RNAR	1.88 lb/gal1	FlC	Field corn, sweet corn,
popcorn, and corn grown for silage, grain or seed	Safener	4/16/07

SC 465 Herbicide	264-RNAA	1.25 lb/gal2	FlC	Field corn and corn grown for
silage	Safener	4/16/07

SC 480 Herbicide	264-RNAT	2.0 lb/gal3	FlC	Field corn and corn grown for
silage	Safener	4/16/07

FS 500 Sorghum Seed Protectant	None provided	4.17 lb/gal	FlC	Sorghum
Safener; to protect against injury from S-metolachlor	4/16/07

1  SC 450 Herbicide also contains the herbicide thiencarbazone-methyl at
1.88 lb/gal.

2  SC 465 Herbicide also contains the herbicides isoxaflutole at 1.88
lb/gal and thiencarbazone-methyl at 0.75 lb/gal.

3  SC 480 Herbicide also contains the herbicide isoxaflutole at 2.0
lb/gal.

Table 4.		Summary of Directions for Use of Cyprosulfamide.1

Applic. Timing,

Type, and

Equipment	Trade Name; Formulation

[EPA Reg. No.]	Applic. Rate 

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

(lb safener/A)	PHI

(days)

Corn (including field corn, sweet corn, popcorn, and corn grown for
silage, grain, or seed)

Preplant

Surface-applied or incorporated

Ground and aerial	SC 450 Herbicide;

1.88 lb/gal FlC

[264-RNAR]

ai = thiencarbazone-methyl 1.88 lb/gal

safener = cyprosulfamide 1.88 lb/gal	0.020 (coarse soils with ≤2.0%
OM)

0.026-0.033 (coarse soils with >2.0% OM, medium, and  fine soils)	2
0.040 (from 1.88 lb/gal FlC formulation) 

0.201 (from all sources)	NS

Preplant/preemergence burndown

Ground and aerial 

	NS

Preemergence

During or after planting

Ground and aerial

	NS

Early postemergence

Ground and aerial

	45

Postemergence

Broadcast or directed spray

Ground and aerial

0.013

	45

Use Directions and Limitations:  Preplant application may be made up to
21 days prior to planting.  Preemergence application may be made during
planting (behind the planter after furrow closure) or after planting. 
Early postemergence application may be made to corn from spiking through
2-leaf collar growth stage (V2, the first leaf has a rounded tip). 
Postemergence applications may be made as a broadcast spray from spike
to 6-leaf collar stage (V6, first leaf has a rounded tip), or as a
directed spray from 6 to 12-leaf collar stages of corn (V6-V12). 
Application to corn that is more than the V12 stage is prohibited. 
Applications are to be made in a minimum of 10 gal/A for ground
equipment or a minimum of 5 gal/A for aerial equipment.  Up to two
applications of the FlC formulation may be made in one growing season
with a minimum retreatment interval of 14 days.  The label specifies a
maximum rate of 0.141 lb/A of cyprosulfamide for a single application. 
The FlC formulation requires the use of an external adjuvant [such as a
crop oil concentrate (COC)] and a nitrogen fertilizer source to achieve
optimum weed control.  

Field corn and corn grown for silage

Preplant

Surface-applied or incorporated

Ground)	SC 465 Herbicide

1.25 lb/gal FlC

[264-RNAA]

ai = thiencarbazone-methyl 0.75 lb/gal

ai = isoxaflutole  1.88 lb/gal

safener = cyprosulfamide 1.25 lb/gal	0.033 (coarse soils with ≤2.0%
OM)

0.044-0.055 (coarse soils with >2.0% OM, medium, and  fine soils)	1	

0.055 from 1.25 lb/gal FlC formulation

0.201 (from all sources)	NS

Preplant/preemergence burndown

Ground 

	NS

Preemergence during or after planting

Ground

	NS

Early postemergence

Ground

	45

Use Directions and Limitations:  Use on popcorn and sweet corn is
prohibited.  Use limited to field corn and corn grown for silage in the
states of AR, CO, IL, IN, IA, KS, KY, MO, MT, NE, ND, OH, OK, PA, SD,
TN, TX, and WY.  Preplant application may be made up to 21 days prior to
planting.  Preemergence application may be made during planting or after
planting.  Early postemergence application may be made to corn from
spiking through 2-leaf collar growth stage (V2, the first leaf has a
rounded tip).  Applications are to be made in a minimum of 10 gal/A
using ground equipment; aerial application is prohibited.  The use of
spray adjuvants (COC, methylated seed oil, non-ionic surfactant) is
recommended for preplant/preemergence burndown and early postemergence
applications.

Field corn and corn grown for silage

Preplant

Surface-applied or incorporated

Ground)	SC 480 Herbicide

2.0 lb/gal FlC

[264-RNAT]

ai = isoxaflutole  2.0 lb/gal

safener = cyprosulfamide 2.0 lb/gal	0.047-0.141 (application rate is
dependent on soil texture, %OM, and timing of application)	1	0.141 (from
2.0 lb/gal FlC formulation)

0.201 (from all sources)	NS

Preplant/

Preemergence burndown

Ground 

	NS

Preemergence during or after planting

Ground

	NS

Early postemergence

Ground

	45

Use Directions and Limitations:  Use limited to field corn and corn
grown for silage in the states of AR, CO, IL, IN, IA, KS, KY, MO, MT,
NE, ND, OH, OK, PA, SD, TN, TX, and WY.  Preplant application may be
made up to 21 days prior to planting; application may be split with 60%
applied preplant and 40% applied at planting.  Preemergence application
may be made during planting (behind the planter after furrow closure) or
after planting.  Early postemergence application may be made to corn
from spiking through 2-leaf collar growth stage (V2, the first leaf has
a rounded tip).  Applications are to be made in a minimum of 10 gal/A
using ground equipment; aerial application is prohibited.  The use of
spray adjuvants (COC, methylated seed oil, non-ionic surfactant) is
recommended for preplant/preemergence burndown application. 

Sorghum

Seed treatment

Mist type or slurry seed treatment equipment	FS 500 Sorghum Seed
Protectant

4.17 lb/gal FlC	0.052 lb safener/

100 lb of seed	1	0.052 lb safener/

100 lb of seed	NA

Use Directions and Limitations:  Use of treated seed for food, feed, or
oil purposes is prohibited.  

1  NS = Not specified.  NA = Not applicable.

For the 1.88, 1.25, and 2.0 lb/gal FlC formulations, the use directions
specify:  (1) the products may be used in either conventional,
conservation tillage, or no-till crop management systems; (2)
applications may be made alone or as a tank mix with other herbicides;
with all tank mix partners, directions for use, precautionary
statements, geographic restrictions, and other restrictions on the tank
mix partner label must be followed; and (3) application through any type
of irrigation system is prohibited.

A restricted entry interval (REI) of 4 hours is proposed for the 1.88
lb/gal FlC formulation.  A REI of 12 hours is proposed for the 1.25
lb/gal and 2.0 lb/gal FlC formulations.

Table 5.		Summary of Rotational Crop Restrictions on Proposed Product
Labels.

Trade Name; Formulation

[EPA Reg. No.]	Plantback Interval	Crop 	Precipitation requirement1

SC 450 Herbicide;

1.88 lb/gal FlC

[264-RNAR];

application rates >0.013 lb/A	0 months	Yellow field corn2 	None 

	3 months	Wheat 	None 

	9 months	Barley, cotton, soybean,2 sweet corn,2,3 popcorn,2,3 white
field corn2,3 	15 inches of cumulative precipitation from application to
planting of rotational crop 

	17 months	Alfalfa,3 green and dry beans, sorghum, oats, sunflower,
canola, potato, sugar beet, and all other crops3 	30 inches of
cumulative precipitation from application to planting of rotational crop

SC 450 Herbicide;

1.88 lb/gal FlC

[264-RNAR];

 rates ≤0.013 lb/A	0 months	Yellow field corn2 	None 

	2 months	Soybean2,4 	None 

	3 months	Wheat 	None 

	9 months	Barley, cotton, sorghum, sweet corn,2,3 popcorn,2,3 white
field corn2,3 	15 inches of cumulative precipitation from application to
planting of rotational crop 

	17 months	Alfalfa,3 green and dry beans, oats, sunflower, canola,
potato, sugar beet, and all other crops3	30 inches of cumulative
precipitation from application to planting of rotational crop 

SC 465 Herbicide

1.25 lb/gal FlC

[264-RNAA]5	0 months	Field corn2 	None 

	4 months	Wheat 	None 

	9 months	Barley, soybean,2 sweet corn,2,3 popcorn2,3 	15 inches of
cumulative precipitation from application to planting of rotational crop

	17 months	Alfalfa,3 green and dry beans,3 oats,3 sorghum,6 sunflower,3
canola,3 potato,3 sugar beet,3 and all other crops3 	30 inches of
cumulative precipitation from application to planting of rotational crop

SC 480 Herbicide

2.0 lb/gal FlC

[264-RNAT]	0 months	Corn (field) 	None 

	4 months	Wheat 	None 

	6 months	Soybeans, barley, sweet corn, popcorn, potato, grain sorghum,
and sunflower 	None 

	10 months	Alfalfa	15 inches of cumulative precipitation from
application to planting of rotational crop. 

	10 months	Dry beans and sugar beets; east of the Mississippi river 

18 months	Dry beans and sugar beets; west of the Mississippi river 

18 months	All other crops 

	FS 500 Sorghum Seed Protectant

4.17 lb/gal FlC	Immediately	Corn (all types), sorghum 	None

	2 months	All other crops 

	1  The amount of cumulative precipitation required before planting a
rotational crop is in addition to the required rotational interval given
in months.  Furrow or flood irrigation not to be included in total.  No
more than 7 inches of overhead irrigation included in total.

2  Crops planted back at intervals of one year or less should not have
known acute sensitivity to ALS-inhibiting and/or SU herbicides.

3  When soil pH is 7.5 or above, crop plant back should be delayed to
the next interval, and to 24 months for crops listed in the 17-month
interval above.

4  When soil pH is 7.5 or above, soybean plant back should be delayed to
the 9-month interval.

5  For SC 465 Herbicide used at rates greater than 0.022 lb safener/A. 
If the corn crop treated with SC 465 Herbicide is lost, only field corn
may be replanted immediately; a second application of SC 465 Herbicide
should not be made.

6  If SC 465 Herbicide was used at ≤0.022 lb safener/A or less and the
total of thiencarbazone-methyl from all sources is ≤0.0134 lb ai/A,
sorghum may be planted at the 9-month or more interval.

Conclusions.  The submitted labels are adequate to allow evaluation of
the residue data relative to the proposed use.  The available corn field
trial data represent two use patterns:  1) SF, which consisted of a
postemergence broadcast application at the V2 growth stage at ~0.15 lb
ai/A , grown from seeds treated with cyprosulfamide, for a total rate of
~0.17 lb ai/A/season and 2) FF, which consisted of an early-season
broadcast application at the V6 growth stage at ~0.1 lb ai/A, followed
by a basal-directed application at the V12 growth stage at up to ~0.1 lb
ai/A, for a total rate of ~0.20 lb ai/A/season.  The harvest intervals
in the current field trials were variable, but generally support a
minimum PHI of 45 days for forage (field and sweet) and sweet corn ears.
  

Because the product labels specify that applications may not be made
after the V12 growth stage of corn and the crop field trials generally
reflected final application at the V12 growth stage, a PHI is not
required for corn RACs.  The petitioner should modify the labels to
clarify that the 45-day PHI pertains only to corn forage (field and
sweet) and sweet corn ears.  

The RTIs in the crop field trials ranged from 13-46 days, with an
average of 21 days.  The petitioner has proposed a minimum RTI of 14
days.  Although the crop field trial data did not all reflect the
minimum proposed RTI, the length of the RTI did not seem to affect the
residue results.  Therefore, HED concludes that the proposed minimum RTI
is appropriate.

The labels for the SC 450, SC 465, and SC 480 Herbicides include
instructions for “Post-Harvest Non-crop” application, to be made in
the fall or early spring for burndown/control of certain weeds; crops
may be planted after application at intervals in the rotational crop
restrictions for the product.  For the SC 450 Herbicide, application is
to be made at 0.013-0.033 lb safener/A; the labels for the SC 465 and SC
480 Herbicides do not include any application rates for this type of
application.  The labels for SC 465 and SC 480 Herbicides should be
modified to either propose application rates or to remove the
instructions for this type of application.

The label for the SC 480 Herbicide should be modified to clarify an
apparent contradiction in the “Preplant Surface-Applied” application
directions and the “Restrictions and Precautions for Use” section. 
The Restrictions section specifies that only one application may be made
to corn per season.  The instructions for Preplant surface-applied
application specify that the application may be split, with 60% of the
recommended rate applied prior to planting and the remaining 40% applied
at planting.  If the petitioner wishes to allow split
preplant/at-planting applications, the Restrictions section should be
modified accordingly.

The label for SC 450 Herbicide requires a minor correction to Table 2
(second table of rotational crop restrictions); in the row for the
17-month plantback interval, the footnote “3” on “All other
crops” should be modified to “4”.

860.1300 Nature of the Residue - Plants

The information below was obtained from Section IIA 6.2.1 of “Tier 2
Summary of the Metabolism and Residues Data for Cyprosulfamide (AE
0001789),” which was prepared by Bayer CropScience.  The referenced
studies were submitted to EPA under MRIDs 47069724 (corn postemergence
application, sulfonylbenzamide label), 47069725 (corn postemergence
application, methoxybenzoyl label), 47069726 (corn preemergence
application, both labels), 47069727 (corn seed treatment, both labels),
and 47069728 (sorghum seed treatment).

Cyprosulfamide is a maize/corn safener and plant growth regulator which
has been shown to exhibit these properties only in maize/corn and
sorghum. Therefore plant metabolism studies only in maize/corn and
sorghum have been conducted. Studies have been conducted with the parent
substance firstly uniformly 14C-labeled in the sulfonylbenzamide ring
and secondly uniformly 14C-labeled in the methoxybenzoyl ring.  The
label positions in the molecular structure of the active substance are
shown in the following figure. The asterisk denotes the uniform 14C
labeling within the phenyl ring. 

	

sulfonylbenzamide-ring-UL-14C (S)	methoxybenzoyl-ring-UL-14C (M)

The metabolism of cyprosulfamide was determined in three separate use
patterns, seed treatment (maize/corn and sorghum), preemergence
application (maize/corn), and postemergence application (maize/corn). 
Cyprosulfamide labeled in either the sulfonylbenzamide ring
([sulfonylbenzamide-UL-14C], S-label) or the methoxybenzoyl ring
([methoxybenzoyl-UL 14C], M-label) was used in each scenario, with the
exception of sorghum seed treatment (S-label only).

For the seed treatments, cyprosulfamide was applied at approximately 3x
the nominal rate of 1.0 g safener/kg seed (2.92 g safener/kg S-label,
2.85 g safener/kg M-label) for maize/corn and 1-1.5x the nominal rate of
0.5 g safener/kg seed (0.50 g safener/kg S-label, 0.76 g safener/kg
M-label) for sorghum.  HED notes that Bayer is not proposing seed
treatment uses of cyprosulfamide for corn in the U.S. at this time.

The maize/corn samples were separated into corn forage, sweet corn cobs,
sweet corn kernels, stover, and grain (raw agricultural commodities,
RACs) for metabolic determination, with total radioactive residues (TRR)
all being <0.3 ppm.  The highest TRR were found in the corn stover with
each label (0.207 ppm S-label, 0.016 ppm M-label). For all RACs, the TRR
were much lower for the M-label than for the corresponding S-label.  The
lowest TRR were found in the sweet corn kernels for each label (0.006
ppm S-label, 0.004 ppm M-label).

Generally, it was difficult to determine the identification of the
metabolites in the raw agricultural commodities for the M-label samples
due to the low TRR found.  However, it was possible to determine the
nature of the residues for the S-label samples.  The main metabolites
found in both the stover and forage were AE 2300003 (61% of the TRR,
0.064 ppm; 57% of the TRR, 0.056 ppm, respectively), AE 2300002 (18% of
the TRR, 0.038 ppm; 19% of the TRR, 0.019 ppm, respectively), and AE
0852999 (4% of the TRR, 0.008 ppm; 3% of the TRR, 0.002 ppm,
respectively).  The residues in the remaining raw agricultural
commodities were characterized by solvent extraction for both the
M-label and S-label where possible.

For sorghum, RACs of forage, grain, and stover were harvested at
maturity. The TRR in forage, grain, and stover at both the 1 and 1.5x
treatment rates were <0.005 ppm.  Consequently, there is no uptake of
cyprosulfamide into the sorghum plant (both human and animal consumable
agricultural commodities) grown from cyprosulfamide-treated seed.

The treatment rates for the preemergence maize/corn metabolism study
were 766 g safener/ha (S-label) and 754 g safener/ha (M-label).  These
treatment rates are approximately 3.4 times the proposed US maximum
seasonal application rate of 225 g safener/ha [0.201 lb safener/A];
approximately 7.6 times the proposed EU maximum seasonal rate of 100 g
safener/ha; and approximately 7.3 times the proposed Canadian maximum
seasonal rate of 105 g safener/ha.   

As with the seed treatment, the maize/corn samples were separated into
corn forage, sweet corn cobs, sweet corn kernels, stover, and grain for
metabolic determination, with TRR all being <0.3 ppm.  The highest TRR
were found in the corn stover with each label (0.258 ppm S-label, 0.019
ppm M-label).  For all RACs, the TRR were much lower for the M-label
than for the corresponding S-label.  The lowest TRR were found in the
sweet corn kernels and sweet corn cobs (0.007 ppm S-label, 0.003 ppm
M-label, respectively).

As with the seed treatment, the nature of the residues for the M-label
and low level S-label was generally characterized by extraction.  For
the S-label, the main metabolites found in the forage and stover were AE
2300003 (25% of the TRR, 0.033 ppm; 26% of the TRR, 0.066 ppm,
respectively), AE 0001789-alanine-conjugate (M15; 23% of the TRR, 0.031
ppm; 11% of the TRR, 0.028 ppm, respectively), and AE 2300002 (13% of
the TRR, 0.017 ppm; 13% of the TRR, 0.033 ppm, respectively).

Maize/corn was treated postemergence at growth stage V9 (BBCH 19),
covering the proposed application growth stage for U.S. (V6/BBCH 16-36
and V12/BBCH 19-69) and slightly later than the proposed application for
EU and Canadian growth stage.  The treatment rates were 812 g safener/ha
(S-label) and 793 g safener/ha (M-label).  These treatment rates are
approximately 3.6 times the proposed U.S. maximum seasonal application
rate of 225 g safener/ha and approximately 8 times the proposed EU and
Canadian maximum seasonal rate. 

The maize/corn was divided into the same RACs as for the seed treatment
and preemergence application.  Unlike the seed treatment and
preemergence applications, the TRR found in the RACs for the M-label and
the S-label were similar.  The highest TRR were found in the stover and
forage (2.829 ppm M-label, 3.035 ppm S-label and 2.878 ppm M-label,
2.441 ppm S-label respectively).  The lowest residues were found in the
sweet corn cob (0.0019 ppm M and S-label).

As with the preemergence and seed treatments, the nature of the
metabolites found in the low level residues was characterized by solvent
extraction.  The principal residues were identified as parent
cyprosulfamide, with lesser amounts of AE 1272799 (M05, AE
0001789-descyclopropyl) and AE 0001789 O-glucoside (M16).  Parent
cyprosulfamide was the main residue for both the stover and the forage
(48.3% of the TRR, 1.468 ppm S-label, 66.3% of the TRR, 1.874 ppm
M-label and 71.1% of the TRR, 1.736 ppm S-label, 81.7% of the TRR, 2.35
ppm M-label, respectively).  Conversely, for the grain AE 1272799 (M05,
AE 0001789-descyclopropyl) was the main residue found (10% of the TRR,
0.005 ppm S- and M-label).

If it is considered that the three scenarios for maize/corn are a
progression of the various types of application from seed to
preemergence to post emergence, then it is possible to determine the
metabolic pathway for cyprosulfamide.  For the seed treatment, the
cyprosulfamide is surrounded by soil.  For the preemergence application
the cyprosulfamide is sprayed directly onto bare soil and for the
postemergence, an increasing proportion of the spray would be
intercepted by the plants as they matured. 

The metabolic profile observed in the seed treatment and preemergence
studies is consistent with the rapid degradation of cyprosulfamide in
the soil via cleavage of the carboxamide bond in the sulfonylbenzamide
moiety to produce AE 0852999 followed by crop uptake.  Once AE 0852999
is taken up by the plant, it is further conjugated to produce the AE
0001789-sulfonamide acetate (M12), AE 0001789-sulphonamide aspartate
(M13), and AE 2300003.  The AE 2300003 can be conjugated further to form
the AE 0001789-sulfonamide-alanine-conjugate (M15) or deaminated to
produce the AE 2300002 which in turn can be decarboxylated to produce
the AE 0001789-sulfonamide-glycine (M18) metabolite.  The uptake of the
soil metabolite AE 0852999 by the crop is consistent with the higher
residues observed in the S-labeled studies vs. the M-labeled studies.

However, for the postemergence application, although there may well be
some uptake from the soil as evidenced by the identification of minor
amounts of AE 0852999 and AE 2300002, the majority of the cyprosulfamide
residues would be absorbed through the leaves.  The metabolism of
cyprosulfamide in leaves involves hydroxylation of the methoxybenzoyl
ring and the subsequent conjugation to glucose or the loss of the
cyclopropyl moiety to produce the AE 0001789-descyclopropyl (M05)
metabolite.

During the course of the analysis of the metabolism samples, an
exhaustive extraction regime was under taken in order to hydrolyze the
conjugates (alanine, lactate and glucoside) to give the “free”
metabolites.  In all cases this was found to be unsuccessful.  Further
treatment with enzyme digestion was also unsuccessful.  Therefore the
conjugates were included in the data gathering methods and subsequent
residue trial analysis.

A summary metabolic pathway encompassing all application scenarios is
given below.

Conclusions.  The submitted plant metabolism data are adequate to
satisfy data requirements for the purposes of this petition.  The data
for sorghum indicate that the proposed seed treatment of sorghum with
cyprosulfamide at 0.052 lb safener/100 lb of seed may be considered a
nonfood use (Classification of Seed Treatments as Food or Nonfood Uses,
ChemSAC memo dated 10/28/1999).  No further residue data are required to
support this use.  For all corn RACs, HED has determined that the
residue of concern for risk assessment is cyprosulfamide per se
(D351495, G. Kramer, 18-APR-2008).  

860.1300 Nature of the Residue - Livestock

The information below was obtained from Sections IIA 6.2.2 and 6.2.3 of
“Tier 2 Summary of the Metabolism and Residues Data for Cyprosulfamide
(AE 0001789),” which was prepared by Bayer CropScience  The referenced
studies were submitted to EPA under MRIDs 47069731 (goat,
sulfonylbenzamide label), 47069732 (goat, methoxybenzoyl label),
47069729 (hen, sulfonylbenzamide label), and 47069730 (hen,
methoxybenzoyl label).

Metabolism studies with lactating goats and laying hens were conducted
with cyprosulfamide separately labeled in the sulfonylbenzamide ring and
in the methoxybenzoyl ring.  

Goats

Sulfonylbenzamide ring label:  Lactating goats were orally dosed with
[sulfonylbenzamide-UL-14C]cyprosulfamide at a rate of 1.34 mg safener/kg
body weight (22.9 ppm cyprosulfamide equivalents in the diet, based on
dry weight of feed) once daily for five consecutive days.  The dose rate
is ~140x the dietary burden of cyprosulfamide to dairy cattle (see Table
7).  

Milk was collected twice daily and feces and urine were collected once
daily during the treatment period.  Approximately 5½ hours after the
last dose, the goats were sacrificed, and edible tissues (composite fat,
kidney, liver, and composite muscle) were collected for analysis.

The TRR (expressed as cyprosulfamide equivalents) were 0.006 ppm in
day-1 milk; 0.010 ppm in day-2 milk, day-3 milk, and day-4 milk;  0.012
ppm in day-5 milk; 0.016 ppm in fat; 0.327 ppm in kidney; 0.078 ppm in
liver; and 0.024 ppm in muscle.  Approximately 43.2% (9.38 mCi) of the
administered dose (total of 21.73 mCi) was found in the combined feces
and an additional 28.3% (6.15 mCi) of the administered dose was found in
the combined urine.  However, the extent of absorption of the
administered dose by the lactating goats could not be determined because
radioactivity in the bile was not monitored during the 5-day dosing
period to determine how much of the radioactivity found in the feces was
absorbed prior to excretion.

Extraction of milk, kidney, liver, and muscle with acetonitrile and
acetonitrile/water and extraction of fat with acetonitrile and hexane
solubilized 97.4% to 99.4% of the TRR in milk and 95.1%, 99.7%, 96.3%,
and 98.4% of the TRR in fat, kidney, liver, and muscle, respectively. 
The nonextractable residues represented only 0.6% to 2.6% (<0.001 ppm),
4.9% (0.001 ppm), 0.3% (0.001 ppm), 3.7% (0.003 ppm), and 1.6% (<0.001
ppm) of the TRR in milk, fat, kidney, liver, and muscle, respectively.

The major residues found in the milk and tissues were the unchanged
parent, cyprosulfamide (22.6% to 79.9% of the TRR in all matrices; 0.002
ppm to 0.248 ppm), AE 0852999 (5.7% to 38.3% of the TRR in all matrices;
0.001 ppm to 0.055 ppm), and AE 0001789 N-acetylsulfonamide (M12, 13.9%
to 20.2% of the TRR in milk; 0.002 ppm).  Minor residues representing
0.8% to 7% (<0.001 ppm to 0.005 ppm) of the TRR in the milk and tissues
were AE 0001789-sulfonamide-pyruvate (M17) and AE 0001789-desmethyl
(M04, AE 1448796).  The majority of the residues (85.8% to 94.0% of TRR)
in all matrices were identified.

The major metabolic pathway for [sulfonylbenzamide-UL-14C]cyprosulfamide
in lactating goats involved hydrolysis of the amide bond of the
sulfonylbenzamide moiety followed by conjugation to form the N-acetyl
and N-pyruvyl derivatives of the sulfonamide.  Demethylation of the
parent compound was a minor metabolic pathway.  The major metabolic
pathway found in this goat metabolism study was consistent with the
pathway found in the [sulfonylbenzamide-UL-14C]cyprosulfamide poultry
metabolism study.

Methoxybenzoyl ring label:  A lactating goat was dosed orally with
[methoxybenzoyl-UL-14C]cyprosulfamide at a dose rate of 1.4 mg
safener/kg body weight (25.3 ppm cyprosulfamide residues in ruminant
diet, based on dry weight of feed) once daily for five consecutive days.
 The dose rate is ~160x the dietary burden of cyprosulfamide to dairy
cattle (see Table 7).  

Milk was collected twice daily and feces and urine were collected once
daily during the treatment period.  Approximately 6 hours after the last
dose, the goat was sacrificed, and the edible tissues (composite fat,
kidney, liver, and composite muscle) were collected for analysis.

The TRR found in the milk and edible tissues were 0.005 to 0.013 ppm in
the milk, 0.016 ppm in fat, 0.497 ppm in kidney, 0.116 ppm in liver, and
0.044 ppm in muscle.  Approximately 39.1% (6.58 mCi) of the administered
dose (total of 20.21 mCi) was found in the combined feces and an
additional 43.1% (7.26 mCi) of the administered dose was found in the
combined urine.  However, the extent of absorption of the administered
dose by the lactating goat could not be determined because radioactivity
in the bile was not monitored during the 5-day dosing period.

Extraction of milk, kidney, liver, and muscle with acetonitrile and
acetonitrile/water, and extraction of fat with acetonitrile and hexane
solubilized 82.5% to 82.8% of the TRR in milk, 93.3% of the TRR in fat,
99.6% of the TRR in kidney, 94.8% of the TRR in liver, and 99.6% of the
TRR in muscle.  The nonextractable residues represented 17.2% to 17.5%
(≤0.002 ppm), 6.7% (0.001 ppm), 0.4% (0.002 ppm), 5.2% (0.006 ppm),
and 0.4% (<0.001 ppm) of the TRR in milk, fat, kidney, liver, and
muscle, respectively.

The major residues found in the milk and tissues were the unchanged
parent, cyprosulfamide (53.4% to 93.6% of the TRR in all matrices; 0.003
ppm to 0.448 ppm), AE 0001789-methoxyhippuric acid (M18, 1.5% to 14.6%
of the TRR in all matrices; <0.001 ppm to 0.011 ppm), and AE
0001789-anisic acid (M07, 1.3% to 12.8% of the TRR in all matrices;
<0.001 ppm to 0.018 ppm).  AE 0001789-desmethyl (M04) was found as a
minor metabolite (0.6% to 8.2% of the TRR in all matrices; <0.001 ppm to
0.010 ppm).  The majority of the residues (76.2% to 97.9% of TRR) in all
matrices were identified.

The major metabolic pathway for [methoxybenzoyl-UL-14C]cyprosulfamide in
a lactating goat involved hydrolysis of the amide bond of the
sulfonylbenzamide moiety followed by conjugation of the resulting anisic
acid with glycine to form methoxyhippuric acid (M18).  Demethylation of
the parent compound was a minor metabolic pathway.  The major metabolic
pathway found in this goat metabolism study was consistent with the
pathway found in the [methoxybenzoyl-UL-14C]cyprosulfamide poultry
metabolism study.

The proposed metabolic pathway for cyprosulfamide in lactating goats is
presented in the figure below, which was copied without alteration from
the Tier II Summary.

*Methoxybenzoyl label-specific metabolite

**Sulfonylbenzamide label-specific metabolite

Poultry

Sulfonylbenzamide ring label:  The metabolism and distribution of
[sulfonylbenzamide-UL-14C]cyprosulfamide was studied in laying hens. 
Six laying hens were dosed orally, via capsule, with
[sulfonylbenzamide-UL-14C]cyprosulfamide at a rate of 2.1 mg safener/kg
body weight (33.5 ppm cyprosulfamide equivalents in poultry diet) once
daily for 14 consecutive days.  The dose rate is ~4,200x the dietary
burden of cyprosulfamide to poultry (see Table 7).  

Eggs were collected twice daily and excreta was collected once daily
during the treatment period.  Approximately 6 hours after the last dose,
the hens were sacrificed, and edible tissues (fat, liver, and composite
muscle) were collected for analysis.

The TRR (expressed as cyprosulfamide equivalents) ranged from 0.002 to
0.044 ppm in day-1 to day-14 in eggs, reaching a plateau level by day-4,
and was 0.044 ppm in fat, 0.762 ppm in liver, and 0.122 ppm in muscle. 
Approximately 92% of the administered dose (13.8 mCi) was found in the
excreta collected up to the time of sacrifice.

Extraction of eggs, liver, and muscle with acetonitrile and
acetonitrile/water, and extraction of fat with heptane and
acetonitrile/water solubilized 95.9% to 97.0% of the TRR in eggs, 98.6%
of the TRR in fat, 98.9% of the TRR in liver, and 99.4% of the TRR in
muscle.  The nonextractable residues represented only 3.0% to 4.1%
(0.001 ppm to 0.002 ppm), 0.7% (<0.001 ppm), 1.1% (0.008 ppm), and 0.6%
(0.001 ppm) of the TRR in eggs, fat, liver, and muscle, respectively.

The major residues found in the eggs and tissues were AE 0852999 (81.4%
to 93.5% of the TRR in all matrices; 0.034 ppm to 0.712 ppm) and the
unchanged parent, cyprosulfamide, (0.3% to 15.5% of the TRR in all
matrices; 0.002 ppm to 0.007 ppm).  The majority of the residues (93.6%
to 96.9% of TRR) were identified in all matrices.

The major metabolic pathway for [sulfonylbenzamide-UL-14C]cyprosulfamide
in laying hens involved hydrolysis of the amide bond of the
sulfonylbenzamide moiety to produce AE 0852999.  

Methoxybenzoyl ring label:  A study was conducted to investigate the
metabolism and distribution of [methoxybenzoyl-UL-14C]cyprosulfamide in
laying hens.  Six laying hens were dosed orally, via capsule, with
[methoxybenzoyl-UL-14C]cyprosulfamide at a rate of 2.4 mg safener/kg
body weight (30.5 ppm cyprosulfamide residues in poultry diet) once
daily for 14 consecutive days.  The dose rate is ~3,800x the dietary
burden of cyprosulfamide to poultry (see Table 7).  

Eggs were collected twice daily and excreta was collected once daily
during the treatment period.  Approximately 6 hours after the last dose,
the hens were sacrificed, and composite fat, liver, and composite muscle
were collected for analysis.

The TRR found in the eggs were 0.004 ppm on day 1 and quickly reached a
plateau between 0.008 ppm and 0.011 ppm on days 2 to 14 of the dosing
period.  The TRR found in the edible tissues were 0.009 ppm in fat,
0.027 ppm in liver, and 0.006 ppm in muscle.  Approximately 83.6% of the
administered dose (13.37 mCi) was found in the excreta collected up to
the time of sacrifice.

Since the TRR in fat and muscle were very low (0.006 ppm to 0.009 ppm),
these two matrices were not extracted for further analysis.

Extraction of eggs and liver with acetonitrile and acetonitrile/water
solubilized 89.2% and 64.1% of the TRR in eggs and liver, respectively. 
Reflux of the acetonitrile/water-extracted liver solids with 2% formic
acid solution in acetonitrile/water extracted an additional 7.4% of the
TRR in the liver.  The nonextractable residues represented 10.8% to
28.4% (0.001 ppm to 0.008 ppm) of the residues in eggs and liver.

The only residues identified in the eggs and liver were the unchanged
parent, cyprosulfamide (13.6% to 42.1% of the TRR in eggs and liver;
0.004 ppm) and AE 0001789-anisic acid (M07, AE 0854787, 32.4% to 47.1%
of the TRR in eggs and liver; 0.005 ppm to 0.009 ppm).

The metabolism of [methoxybenzoyl-ring-UL-14C]cyprosulfamide in poultry
was very simple and involved hydrolysis of the amide bond of the
sulfonylbenzamide moiety to form AE 0001789-anisic acid.  This pathway
was consistent with the metabolic pathway found in the
[methoxybenzoyl-UL-14C]cyprosulfamide goat metabolism study.

The proposed metabolic pathway for cyprosulfamide in poultry is
presented in the figure below, which was copied without alteration from
the Tier II Summary.

*Methoxybenzoyl label-specific metabolite

**Sulfonylbenzamide label-specific metabolite

Conclusions.  The submitted livestock metabolism data are adequate to
satisfy data requirements for the purposes of this petition.  For
livestock, HED has determined that the residues of concern for tolerance
expression and risk assessment are cyprosulfamide and its metabolite AE
0001789-N-cyclopropyl-4-sulfamoylbenzamide (M02) (D351495, G. Kramer,
18-APR-2008).

860.1340 Residue Analytical Methods

The information below was obtained from Section IIA 4.3 of “Tier 2
Summary of the Analytical Methods and Validation for the Active
Substance Cyprosulfamide (AE 0001789),” which was prepared by Bayer
CropScience.  The referenced studies were submitted to EPA under MRIDs
47069733 (Method UB-008-P06-01), 47069734 (ILV Method UB-008-P06-01),
47069735 (Method 00961), 47069736 (extraction efficiency plant commodity
methods), 47069738 (ILV Method UB-006-A06-01), and 47069739 (extraction
efficiency UB-006-A06-01).  

Several methods were developed for the determination of residues of
cyprosulfamide in plant and animal matrices.  A summary of the methods
described in this section is given in Table 6.

Plant matrices 

For the determination of the relevant residues of cyprosulfamide in
plant matrices, four methods were developed. 

Method 00964:  The analytical Method 00964 was developed as a data
collection and enforcement method.  The method determines residues of
cyprosulfamide in/on plant materials.  Cyprosulfamide is extracted from
field corn (kernel), field corn (forage), field corn (stover), sweet
corn (cob with kernel but without husks), wheat (grain), soybean (seed),
lemon (fruit) and potato (tuber) with acetonitrile:water (4:1, v:v)
using a microwave.  An aliquot of the raw extract is evaporated to
dryness and redissolved in a solution containing the stable isotopically
labeled analyte as internal standard.  After filtration the solution is
analyzed by HPLC-MS/MS without further clean-up.  Residues are
quantified against both external solvent standards (stated to be typical
for U.S. enforcement purposes) and matrix-matched standards (stated to
be typical for EU enforcement purposes).  The LOQ is 0.01 ppm in all
matrices.  The calculated limit of detection (LOD) ranged from 0.001 to
0.004 ppm.  

Method validation was conducted using samples of field corn kernel,
field corn forage, field corn stover, sweet corn cob with kernel but
without husks, wheat grain, soybean seed, lemon fruit, and potato tuber.
 Samples were fortified with cyprosulfamide at 0.01 and 0.10 ppm; field
corn forage samples were additionally fortified at 1 and 10 ppm.  Mean
recoveries for all matrices were within the 70-110% range and RSDs were
<11%.  An adequate ILV was conducted for Method 00964 using tomato,
whole orange, corn kernel and forage, and soybean seed.

For Method 00964, two MRM (multiple reaction monitoring) transitions are
to be monitored in each matrix tested, m/z 373 → 176 for quantitation
and m/z 373 → 93 for confirmation of cyprosulfamide.  In the case of
corn stover (straw) the MRM assignment was exchanged and m/z 93 was used
for quantitation due to interferences observed at m/z 176.  Because two
transitions are monitored, an additional confirmatory method is not
necessary.  The petitioner noted that the confirmatory method was fully
validated, and therefore, the quantitation and confirmation method can
be exchanged (e.g., if the quantitation peak is superimposed by
interferences).  

Method 00962:  A second method, Method 00962, was developed for data
collection purposes.  Method 00962 allows determination of residues of
thiencarbazone-methyl and its metabolites in addition to residues of
cyprosulfamide.  The extraction/analysis procedures in Method 00962 for
cyprosulfamide determination are identical to those of Method 00964.  

Method 00961:  The analytical Method 00961 was developed for the
determination of cyprosulfamide and its metabolites AE 2300003, AE
2300002, and AE 0852999 in crop matrices.  Residues are extracted from
plant material by microwave extraction with an acetonitrile:water
mixture (8:2, v:v).  Extracted residues are made up to volume and
subjected to HPLC-MS/MS without any further clean-up step.  For
quantification, external calibration with standard solutions quoting the
peak area ratio of the analytes and the corresponding stable
isotopically labeled internal standards is used.  For confirmation of
results, a second MRM transition is recorded for each individual analyte
in each investigated matrix.  Fortification levels and residues are
calculated and expressed as parent equivalents using molecular weight
conversion factors.  The LOQ is 0.01 ppm for each analyte in each
matrix.  The LOD for each analyte was set to be approximately 3 times
lower than the corresponding LOQ.

Method validation was conducted using samples of citrus fruit, potato
tuber, field corn stover, field corn forage, field corn and sweet corn
kernels, wheat grain, tomato fruit, soybean seed, and head lettuce
fortified at 0.01 and 0.1 ppm with cyprosulfamide and each of the
metabolites. Recovery results obtained (expressed as parent equivalents)
were within guideline requirements (70-110%, RSD <20%).  An adequate ILV
was conducted for a modification of Method 00961 using corn/maize
fortified with each analyte.

Method UB-008-P06-01:  An analytical method, UB-008-P06-01, was
developed to determine the residues of cyprosulfamide and its
metabolites AE 2300003, AE 2300002, and AE 0852999 in/on corn raw
agricultural commodities.  The method was reported to be a modification
of Method 00961 to accommodate local equipment and practices.  Crop
matrices are extracted by heating the sample in a mixture of
acetonitrile:water (4:1, v:v) in a microwave.  The mixture is filtered
and the extraction is repeated.  The combined filtrates are amended with
a mixture of isotopic internal standards and passed through a small C18
solid-phase extraction (SPE) cartridge.  The eluate is evaporated to
near dryness and reconstituted for analysis by HPLC-MS/MS.  For
quantification, the ratio of the analyte response and the corresponding
stable isotopically labeled internal standard response was used.  For
confirmation of results, a second MRM transition was recorded for each
individual analyte in each investigated matrix.  Fortification levels
and residues are calculated and expressed as parent equivalents using
molecular weight conversion factors.  The method LOQ is 0.010 ppm for
all analytes in crop matrices; the calculated LODs ranged 0.0009-0.0050
ppm.  

Method validation was conducted using samples of sweet corn kernels,
field corn grain, corn forage, and corn stover fortified at 0.01 ppm
with cyprosulfamide and each metabolite.  Additional fortifications with
cyprosulfamide and each metabolite were made at 0.02 ppm for stover,
0.10 ppm for kernels, grain and forage, 0.50 ppm for forage, and 1.2 ppm
for stover.  Recovery results obtained (expressed as parent equivalents)
were within guideline requirements (70-120%, RSD <20%).  An adequate ILV
was conducted for Method UB-008-P06-01 using corn stover.  

Radiovalidation:  The extraction efficiency of the residue methods
00964, 00962, 00961, and UB-008-P06-01/02 was tested using aged
radioactive residues in corn forage and stover from corn treated with a
foliar postemergence application, and corn forage and stover from corn
treated with a preemergence application of
[sulfonylbenzamide-ring-UL-14C]cyprosulfamide.  Extraction efficiency
was tested for the determination of the total residue of cyprosulfamide,
consisting of the parent compound and the metabolites AE 2300003, AE
2300002, and AE 0852999.  The recoveries of the extracted total residue
of cyprosulfamide in each matrix were determined with an extraction
procedure common to each method and were compared with the results
obtained in the metabolism studies.  The extraction procedure
effectively extracted and measured 80%, 95%, 108%, and 84% of the aged
radioactive total cyprosulfamide residue from corn forage following the
postemergence treatment, corn forage following preemergence treatment,
corn stover following postemergence treatment and corn stover following
preemergence treatment, respectively.  These results clearly demonstrate
that the residue methods are efficient for extracting the residues
cyprosulfamide, AE 2300003, AE 2300002, and AE 0852999 from plant
matrices.  

Data collection:  Samples of crop commodities from the storage stability
studies associated with this petition were analyzed for residues of
cyprosulfamide and its metabolites (AE 2300003, AE 2300002, and AE
0852999) using HPLC-MS/MS methods 00964 and 00961, respectively. 
Samples of corn commodities from the crop field and processing studies
and samples of rotational crop commodities from the field rotational
crop studies associated with this petition were analyzed for residues of
cyprosulfamide and its metabolites using HPLC-MS/MS Method UB-008-P06-01
or UB-008-P06-02.  

The European multi-residue method DFG S 19 was shown to be unsuitable
for the determination of cyprosulfamide.

Table 6.		Summary of Residue Analytical Methods.

Matrix	Analyte	Method No.	Method principle	LOQ 

Plant	Cyprosulfamide	00964	HPLC-MS/MS	0.01 ppm:  Field corn, sweet corn,
wheat grain, soybean seed, lemon, tomato, orange and potato 

Plant	Cyprosulfamide

thiencarbazone-methyl

thiencarbazone-methyl metabolites	00962	HPLC-MS/MS	0.01 ppm:  Field corn

Plant	Cyprosulfamide

AE 2300002

AE 2300003

AE 0852999	00961	HPLC-MS/MS	0.01 ppm:  Field corn, sweet corn, lettuce,
wheat grain, tomato, potato and soybean seed

Plant	Cyprosulfamide

AE 2300002

AE 2300003

AE 0852999	UB-008-P06-01	HPLC-MS/MS	0.01 ppm:  Field Corn, sweet corn,
pop corn commodities

Plant	Cyprosulfamide	DFG Method S 19	GC	DFG method S19 not applicable
for determination of cyprosulfamide

Plant	Cyprosulfamide

AE 2300002

AE 2300003

AE 0852999	FDA PAM Multiresidue (MRM)	GC	PAM not applicable for
determination of cyprosulfamide and metabolites

Livestock	Cyprosulfamide

AE 0852999	UB-006-A06-01	HPLC-MS/MS	0.01 ppm:  Livestock tissues;

0.005 ppm:  Milk

Livestock	Cyprosulfamide	UB-007-A06-01	HPLC-MS/MS

	

Livestock matrices

For the determination of the relevant cyprosulfamide residues in
livestock matrices, two methods were developed. 

Method UB-006-A06-01:  The analytical method UB-006-A06-01 was developed
to determine residues of cyprosulfamide and AE 0852999 in cattle milk
(whole milk, skim milk, and cream), cattle tissues, and chicken muscle. 
Tissues are extracted with acetonitrile:water (4:1 v:v) and heated in a
water bath at 60 ºC for approximately 30 minutes. The extraction is
repeated, the extracts are combined, and isotopic internal standards are
added.  An aliquot of the extract is cleaned up by C18 SPE and the
eluate is concentrated and reconstituted in 0.1% aqueous acetic
acid:acetonitrile (90:10, v:v) for analysis by HPLC-MS/MS.  Samples of
milk are extracted by accelerated solvent extraction, using water at 90
ºC, and isotopic internal standards are added to the extract.  An
aliquot of the extract is cleaned up by C18 SPE and the eluate is
concentrated and reconstituted in 0.1% aqueous acetic acid:acetonitrile
(90:10, v:v) for analysis by HPLC-MS/MS.  For determination of
cyprosulfamide, two negative ionization MRM transitions for each matrix
(373 to 176 and 373 to 93) are monitored; the former is used for
estimation of residues and the other for confirmation.  For AE 0852999,
the method uses two MRM transitions for each matrix, either positive
ionization with the transition 241 to 184 or negative ionization with
the transition 239 to 175; the former is used for estimation of residues
and the other for confirmation.  The LOQ is 0.01 ppm for tissues and
0.005 ppm for milk.  The calculated LODs ranged 0.0004-0.004 ppm.  

Method validation was conducted using samples of cattle fat, cattle
kidney, cattle liver, cattle muscle, chicken muscle, skim milk, whole
milk, and cream fortified with cyprosulfamide at the LOQ and 10xLOQ. 
Mean recoveries for all matrices ranged 75-127% and RSDs were <15%.  An
adequate ILV was conducted for Method UB-006-A06-01 using cattle milk
and liver.

 each matrix tested, m/z 373 → 176 and m/z 373 → 93; one transition
is used for quantification and one is used for confirmation.  The LOQ is
0.01 ppm for tissues and 0.005 ppm for milk.  The calculated LODs ranged
0.002-0.003 ppm.  

Method validation was conducted using samples of cattle milk, fat,
kidney, liver, and muscle fortified at the LOQ and 10xLOQ.  Mean
recoveries for all matrices were within the 70-120% range and RSDs were
<15%.  An adequate ILV was conducted for Method UB-007-A06-01 using
cattle milk, fat, kidney, liver, and muscle.

Radiovalidation:  The extraction efficiency of methods UB-007-A06-01 and
UB-006-A06-01, which share a common extraction procedure, was determined
for the extraction of aged radioactive residues of cyprosulfamide and AE
0852999 from goat liver, kidney and milk from goats treated with
[sulfonylbenzamide-ring-UL-14C]cyprosulfamide.  The extracted residues
of cyprosulfamide and AE 0852999 in each matrix were compared with the
results obtained in the metabolism studies.  The residue analytical
methods UB-006-A06-01 and UB-007-A06-01 have been shown to effectively
extract incurred radioactive residues of cyprosulfamide from goat
kidney, liver and milk, collecting 105.5%, 107.6%, and 81.2%
respectively, of the TRR.

Data collection:  Samples of livestock commodities from the cattle
feeding study associated with this petition were analyzed for residues
of cyprosulfamide and AE 0852999 using HPLC-MS/MS Method UB-006-A06-01.

Conclusions.  Adequate methods were used for data collection in the
storage stability, livestock feeding, crop field trial, processing, and
field rotational crop studies associated with this petition.  The
following proposed enforcement methods were forwarded to BEAD/ACL for
petition method validation:  Method UB-008-P06-01 (plant commodities)
and Method UB-006-A06-01 (livestock commodities) (D345603, W. Donovan,
23-OCT-2007).  Based upon BEAD/ACL review without laboratory trials,
Method UB-008-P06-01 for plant commodities and Method UB-006-A06-01 for
livestock commodities both appear to meet the OPPTS 860.1340 Residue
Chemistry Test Guidelines for acceptable tolerance methods (D345604, C.
Stafford, 27-MAY-2008).  However, the registrant should submit a copy of
the complete, detailed livestock method (UB-006-A06-01) with
corresponding validation data as an independent method document. 
Currently, only a synopsis of the method is available (MRID 47069738).  

860.1360 Multiresidue Methods

The information below was obtained from Section IIA 4.3 of “Tier 2
Summary of the Analytical Methods and Validation for the Active
Substance Cyprosulfamide (AE 0001789),” which was prepared by Bayer
CropScience.  The referenced study was submitted to EPA under MRID
47069744.  

The suitability of the FDA MRM protocols to analyze for residues of
cyprosulfamide and three metabolites in non-fatty and fatty foods was
evaluated.  The study specifically evaluated the usefulness of the MRM
described in the FDA Pesticide Analytical Manual (PAM) – Volume I,
Appendix II, Third Edition, Jan. 1994: Multiresidue Protocols A, B, C, D
and F only for measuring residues of cyprosulfamide and its three
metabolites.

A review of the FDA PESTDATA table and the PAM I Index to Methods
indicates that no data exist for cyprosulfamide, AE 0852999, AE 2300002,
or AE 2300003; therefore, testing through the MRM protocols is required.
 Initial evaluation of the structures and characteristics of these
compounds indicate that they are not N-methylcarbamates; their natural
fluorescence is unknown; they are not phenols; and they are not
substituted ureas.  Metabolites AE 2300002 and AE 2300003 have an acid
component.  AE 2300003 was not soluble in either acetone or methanol
therefore the compound was deemed unsuitable for these methods and
testing was suspended.  Cyprosulfamide, AE 0852999, and AE 2300002 were
tested through Protocols A and C to provide fluorescence detection and
GC chromatography column and detection information.

Only cyprosulfamide was found to be naturally fluorescent in the initial
screen through Protocol A.  However, the response for cyprosulfamide as
seen during Protocol A testing was not sufficient for an enforcement
method; therefore, further testing was terminated.  Methylated AE
2300002 did not chromatograph under the conditions required for Protocol
B; therefore, further testing was terminated. Only AE 0852999 was deemed
suitable for GC analysis though Protocol C and therefore testing though
Protocols D and F was conducted.  AE 0852999 was not recovered through
Florisil in either Protocols D or F; therefore further testing was
terminated.  Protocol G was not conducted because the compounds are not
a substituted urea.

Conclusions.  The submitted data are adequate to satisfy data
requirements.  The FDA multi-residue methods are not suitable for
residue analysis and enforcement purposes of cyprosulfamide and its
metabolites.  The data will be forwarded to FDA for further evaluation.

860.1380 Storage Stability

Plant commodities

The information below was obtained from Section IIA 6.1.1 of “Tier 2
Summary of the Metabolism and Residues Data for Cyprosulfamide (AE
0001789),” which was prepared by Bayer CropScience.  The study with
cyprosulfamide metabolites was submitted to EPA under MRID 47069737; the
study with cyprosulfamide per se was not submitted to EPA.  

Cyprosulfamide:  A study was completed to determine the stability of
residues of cyprosulfamide in fortified control samples corn kernel,
corn forage, corn stover, soybean seed, lettuce, potato tuber, and
tomato fruit during freezer storage for 0 to 12 months (0 to 6 months
for tomato fruit).  Results for freezer storage up to 18 months (12 to
18 months for tomato fruit) will be reported separately in a subsequent
report.  

The samples were fortified at nominal levels of cyprosulfamide between
163 and 262 µg/kg.  The whole sample material was spiked as one batch
with separate batches for each matrix.  The samples were stored in
polyethylene storage boxes at -18 C or below and were analyzed at
nominal intervals of 0, 30, 90, 180 and 360 days.  Results for tomato
fruit were limited to nominal intervals between 0 and 180 days. 

The spiking procedure had to be repeated for tomato fruit due to
implausible results (apparent increase of residues during storage period
of 183 days) which were probably caused by the bulk spiking procedure. 
The original study was continued but a satellite group with tomato fruit
was started in parallel for total storage duration of 18 months.  For
this satellite group, separate subsamples of the homogenized material
were fortified and stored in brown glass bottles at -18 C or below.

Residues of cyprosulfamide in/on plant material were determined by
HPLC-MS/MS according to Method 00964.  Two calculations were carried
out: with and without correction for the concurrent recoveries.  For
normalization to day 0, the average recovery found in the spiked samples
on day 0 was defined as 100% for each sample material, and the
recoveries from the other storage intervals were calculated as
normalized recoveries of that value. For correction for the concurrent
recoveries, the measured recoveries at a particular time point were
corrected for the corresponding concurrent recoveries for that day. 
Afterwards, these values were normalized to the residues determined on
day 0.  Due to the modified spiking procedure for tomato fruit, the
fortification level was known (0.2 ppm), for this procedure normalizing
to Day 0 after correction for concurrent recoveries was not required.

For both evaluations, the residues of cyprosulfamide in all matrices
spiked with cyprosulfamide were stable (< 30% decomposition) during
frozen storage for at least 6 months (tomato fruit) and 12 months (corn
kernel, corn forage, corn stover, soybean seed, lettuce, potato tuber). 
Mean recovery rates for cyprosulfamide were 90-140% when normalized to
day 0, and 88-116% when corrected for concurrent recoveries.  

Cyprosulfamide metabolites:  A study was completed to determine the
stability of residues of AE 0852999, AE 2300002, and AE 2300003 in
fortified control samples of corn kernel, corn forage, corn stover,
soybean seed, lettuce, potato tuber, tomato fruit during freezer storage
for 0 to 12 months; results for 18 months freezer storage will be
reported separately.  

The samples were fortified at levels between 0.21 and 0.52 ppm for all
compounds (calculated and expressed as cyprosulfamide equivalents).  The
samples were stored in polyethylene storage boxes at -18 C or below and
were analyzed at nominal intervals of 0, 30, 90, 180 and 360 days. 

Residues of AE 0852999, AE 2300002, and AE 2300003 in/on plant material
were determined by HPLC-MS/MS according to Method 00961.  Two
calculations were carried out: with and without correction for the
concurrent recoveries.  For normalization to day 0, the average
recoveries found in the spiked samples on day 0 was defined as 100% for
each sample material, and the recoveries from the other storage
intervals were calculated as normalized recoveries of that value.  For
correction for the concurrent recoveries, the measured recoveries at a
particular time point were corrected for the corresponding concurrent
recoveries for that day.  Afterwards, these values were normalized to
the residues determined on day 0. 

No degradation during the deep-freezer storage of 12 months was
observed, with the exception of soybean seed, where recoveries for AE
2300002 and AE 2300003 were just below 70% (corrected for concurrent
recoveries) after 12 months.  Mean recovery rates for AE 2300003, AE
2300002, and AE 0852999 were between 74-107% when normalized to day 0,
and 67-109% when corrected for concurrent recoveries at the 12-month
storage interval.  Mean recovery rates for AE 2300003 (69%) and AE
2300002 (67%) measured in soybean seed and corrected for concurrent
recoveries were the only recoveries below 70%; the corresponding
normalization of the values to day 0 resulted in recoveries of 74% and
76%, respectively.  No degradation of these analytes was observed in
soybean seed after a storage interval of six months.

Therefore, residues of AE 0852999, AE 2300002, and AE 2300003 were
stable (< 30% decomposition) during frozen storage for at least 6 months
in/on soybean seed and for at least 12 months in/on corn kernel, corn
forage, corn stover, lettuce, potato tuber, and tomato fruit.

Samples of corn commodities from the crop field trials associated with
this petition were stored frozen (<-15 ºC) for a maximum of 12.8 months
for forage, 12.1 months for sweet corn ears, 12.0 months for grain, and
15.0 months for stover prior to analysis.  Samples of field corn grain
samples from the exaggerated rate field trials were held in frozen
storage for a maximum of 14.5 months prior to analysis.  

The storage durations and conditions of samples of rotational crop
commodities from the field rotational crop studies submitted with this
petition were not reported in the Tier II Summary of results for these
studies.  Based on information reported in the MRIDs for these studies,
samples of rotational crop commodities were stored frozen (<-15 ºC) for
a maximum of 13.9 months for turnip roots and tops, 14.9 months for
soybean seed, 17.3 months for soybean forage and hay, 5.3 months for
wheat grain, and 11.2 months for wheat forage, hay, and straw.  

Conclusions.  The submitted storage stability data are not adequate to
support the storage conditions and durations of samples from the studies
submitted to support this petition.  The storage stability data
represent a maximum storage interval of 12 months.  The maximum storage
duration for corn commodity samples was 15 months.  The final report of
the storage stability studies, which are to include storage intervals up
to 18 months, must be submitted.

For the field rotational crop commodity samples, the storage stability
data for corn forage, corn stover, lettuce, soybean seed, and potato
tuber will be adequate to support all rotational crop commodities
(turnip root and top; soybean forage, hay, and seed; and wheat forage,
hay, straw, and grain) provided the final report of the studies are
submitted; the maximum storage interval for rotational crop commodities
was 17 months.    

860.1400 Water, Fish, and Irrigated Crops

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

860.1460 Food Handling

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

860.1480 Meat, Milk, Poultry, and Eggs

The information below was obtained from Section IIA 6.4 of “Tier 2
Summary of the Metabolism and Residues Data for Cyprosulfamide (AE
0001789),” which was prepared by Bayer CropScience.  The referenced
study was submitted to EPA under MRID 47069745.  

Livestock dietary burdens

There are several livestock feed items associated with the proposed uses
on corn.  The calculations of the livestock dietary burdens for
cyprosulfamide are presented in Table 7.  The calculation reflects the
most recent guidance from HED (email, J. Stokes, 2/27/08) concerning
revisions of feedstuff percentages in Table 1 and constructing
reasonably balanced dietary burdens (RBDBs).  The calculated dietary
burdens of cyprosulfamide (based on tolerance-level residues) are 0.09
ppm for beef cattle, 0.16 ppm for dairy cattle, 0.008 ppm for poultry,
and 0.008 ppm for swine.

Table 7.		Calculations of Dietary Burdens of Cyprosulfamide Residues to
Livestock.

Feedstuff	Type1	% Dry Matter2	% Diet2	Recommended Tolerance (ppm)
Dietary Contribution (ppm)3

Beef Cattle

Corn, field, silage	R	40	15	0.20	0.075

Corn, field, grain/milled byproducts	CC	88/85	80	0.01	0.0094

Untreated	PC	--	5	--	--

TOTAL BURDEN	--	--	100	--	0.09

Dairy Cattle

Corn, field, silage	R	40	30	0.20	0.150

Untreated  	R	--	15	--

	--

Corn, field, grain/milled byproducts	CC	88/85	45	0.01	0.0053

Untreated	PC	--	10	--	--

TOTAL BURDEN	--	--	100	--	0.16

Poultry

Corn, field, grain/milled byproducts	CC	88/85	80	0.01	0.008

Untreated	PC	--	20	--	--

TOTAL BURDEN	--	--	100	--	0.008

Swine

Corn, field, grain/milled byproducts	CC	88/85	80	0.01	0.008

Untreated	PC	--	20	--	--

TOTAL BURDEN	--	--	100	--	0.008

1  R:  Roughage; CC:  Carbohydrate concentrate; PC:  Protein
concentrate.

2  OPPTS 860.1000 Table 1 Feedstuffs (October 2006).  

3  Contribution = ([tolerance /% DM] X % diet) for beef and dairy
cattle; contribution = ([tolerance] X % diet) for poultry and swine. 

Dairy Cattle Feeding Study

The magnitude of the residue of cyprosulfamide was studied in lactating
dairy cows.  Thirteen lactating Holstein dairy cows (Bos taurus; three
cows/treatment group and one control cow) were dosed orally, via
capsule, for 29 consecutive days with cyprosulfamide at target dose
rates (based on feed dry weight) of either 0 mg/kg feed/day (control),
0.1 mg/kg feed/day (EU guideline limit), 1.0 mg/kg feed/day, 3.0 mg/kg
feed/day or 10 mg/kg feed/day.  The petitioner concluded that levels
were approximately 0.1x, 1x, 3x and 10x the anticipated maximum dietary
burden, based on an dietary burden of 1.0 ppm (from a diet consisting of
sweet corn cannery waste and field and sweet corn forage).  The dosing
levels represent ~0.63x, 6.3x, 19x, and 63x the HED-calculated dietary
burden to dairy cattle of 0.16 ppm.  

Milk was collected twice daily during the dosing period.  Milk samples
from the highest dose group on study days 0, 1, 3, 7, 10, 14, 17, 21,
24, 26, and 28 were reserved for analysis.  Additionally, a portion of
the 28-day milk from the highest dose group (and the control group) was
separated into milk fat (cream) and skim milk (whey).  On day 29, the
animals were sacrificed and liver, kidney, composite muscle, and
composite fat were collected for analysis.

Samples were analyzed for residues of cyprosulfamide and AE 0852999
using an HPLC-MS/MS method, UB-006-A06-01.  The LOQ was 0.005 ppm for
each analyte in milk matrices and 0.010 ppm for each analyte in the
tissue matrices.  The individual analyte residues of cyprosulfamide
(parent) and its metabolite AE 0852999 were summed to give a total
cyprosulfamide residue in parent equivalents.  Method validation was
performed prior to sample analysis and concurrent recoveries were
performed during sample analysis to demonstrate acceptable method
performance.  The tissue and milk samples in this study were analyzed
within 17 days of collection; therefore, freezer storage stability
studies on beef tissue and milk matrices are not required.

Residues of cyprosulfamide and AE 0852999 were below the LOQ in the milk
samples from the highest feeding level throughout the entire study.  No
concentration factors for total cyprosulfamide residue in skim milk or
milk fat separated from whole milk could be determined since residues of
both analytes were below the LOQ in all three matrices.  

The highest total cyprosulfamide residues were found in the kidney and
liver.  In kidney, the maximum combined residues were 0.473 ppm, 0.143
ppm, <0.054 ppm and <0.02 ppm in samples from the 63x, 19x, 6.3x, and
0.63x dose groups, respectively.  In liver, the maximum combined
residues were 0.124 ppm, <0.049 ppm, <0.023 ppm, and <0.02 ppm in
samples from the 63x, 19x, 6.3x, and 0.63x dose groups, respectively. 
Clear evidence for a dose response for total cyprosulfamide residues in
kidney and liver was observed; the coefficient of determination of dose
response (r2) was > 0.90 for both tissues.

In meat (muscle), residues of cyprosulfamide and AE 0852999 were below
the LOQ in all samples from all dosing groups.  In fat, two of three
animals in the highest dosing group had quantifiable cyprosulfamide
residues, yielding maximum combined residues of 0.028 ppm at the 10 ppm
dosing level.  

Potential secondary residues in meat and milk

To determine the need for tolerances for the combined residues of
cyprosulfamide and its M02 metabolite in milk and tissues, the
anticipated secondary residues in cattle matrices were estimated using
transfer coefficient factors calculated from the maximum residues of
cyprosulfamide observed at the 10 ppm dose level in the feeding study. 
The tissue transfer coefficients (calculated as maximum residue level
divided by feed level) are presented in Table 8.  The tissue transfer
coefficient for each matrix was then used to calculate the maximum
potential secondary residues by multiplying the tissue transfer
coefficient by the calculated dietary burden.  The maximum potential
residues of cyprosulfamide plus it M02 metabolite and the recommended
tolerances based on these calculations are presented in Table 9.

Table 8.    Tissue Transfer Coefficients in Dairy Cattle Milk and
Tissues.

Matrix	Maximum Combined Residues of 

Cyprosulfamide and M02(ppm)	Feeding Level

(ppm)	Transfer

Coefficient 1

Milk 	<0.005	10	<0.0005

Meat	<0.010	10	<0.0010

Fat	0.028	10	0.0028

Liver	0.124	10	0.0124

Kidney	0.473	10	0.0473

1  Calculated from the maximum residues observed at the dose level that
yielded the most quantifiable residue values divided by the dose level.

Table 9.    Maximum Potential Secondary Residues of Cyprosulfamide in
Cattle Milk and Tissues.

Matrix	Dietary Burden

(ppm)	Secondary Residues 1

(ppm)	Recommended Tolerance

(ppm)

Milk	0.16	<0.00008	Not required

Meat	0.16	<0.00016	Not required

Fat	0.16	0.000448	Not required

Liver	0.16	0.00198	0.02

Kidney	0.16	0.00757	0.02

1  Calculated from dietary burden x transfer coefficient from Table 8.

  

Conclusions.  The submitted cattle feeding study data are adequate to
satisfy data requirements.  The data indicate that no quantifiable
residues of cyprosulfamide or its metabolite AE 0852999 are expected in
milk, meat, or fat.  Therefore, no tolerances for cyprosulfamide
residues in milk, meat, or fat are required to support the proposed uses
on corn.  

Quantifiable residues were observed in kidney and liver.  When the
maximum observed combined residues in kidney at the 63x dosing level,
0.473 ppm, are corrected to a 1x dosing level, expected residues are
0.0075 ppm.  These data indicate that tolerances are needed for the
combined residues of cyprosulfamide and its benzamide metabolite in the
meat byproducts of cattle, goat, horse, and sheep; the available data
would support a tolerance at the combined LOQ, 0.02 ppm.

The lowest dosing level in the cattle feeding study is ~13x the dietary
burden to swine.  Because no quantifiable residues were observed in any
samples from the lowest dosing level, HED concludes that the proposed
uses of cyprosulfamide fall under category 3 of 40 CFR 180.6(a) for
swine; there is no reasonable expectation of finite residues in swine
commodities.

The petitioner stated that because no quantifiable residues of
cyprosulfamide or metabolites were detected in any poultry feed items,
no poultry feeding study was conducted.  In the poultry metabolism
studies, laying hens were dose at levels corresponding to ~3,800x or
4,200x the dietary burden to poultry.  The maximum residues of
cyprosulfamide and AE 0852999 observed in any matrix were 0.007 ppm and
0.712 ppm, respectively, from the study conducted at ~4,200x.  When
these combined values are corrected to a 10x dosing level, expected
residues are ~0.0017 ppm.  Therefore, HED concludes that the proposed
uses of cyprosulfamide fall under category 3 of 40 CFR 180.6(a) for
poultry; there is no reasonable expectation of finite residues in
poultry commodities.

860.1500 Crop Field Trials

The information below was obtained from Section IIA 6.3.1 of “Tier 2
Summary of the Metabolism and Residues Data for Cyprosulfamide (AE
0001789),” which was prepared by Bayer CropScience.  The information
was reviewed by HED and any necessary corrections to the data are
reflected in the information below.  The referenced study was submitted
to EPA under MRID 47069746.  

Bayer conducted crop field trials with field corn, sweet corn, and pop
corn.  The results of the field trials are discussed below and
summarized in Table 10.

Table 10.		Summary of Residue Data from Crop Field Trials with
Cyprosulfamide.

Crop matrix	Residue components1	Treatment Type2	Total Applic. Rate

(lb safener/A)

[kg safener/ha]	PHI (days)	Residue Levels (ppm)

	n	Min.	Max.	HAFT3	Median	Mean	Std. Dev.4

FIELD CORN (proposed use = 0.20 lb safener/A total application rate,
45-day PHI)

Field corn forage; 45-day PHI 5	Cyprosulfamide per se	TRTSF	0.133- 0.172

[0.149- 0.193]	43-72	44	<0.01	<0.01	0.01	0.01	0.01	NA

Field corn forage; BBCH 87-896	Cyprosulfamide per se	TRTSF	0.133- 0.172

[0.149- 0.193]	73-118	44	<0.01	<0.01	0.01	0.01	0.01	NA

Field corn forage; BBCH 87-896	Cyprosulfamide per se	TRTFF	0.194- 0.207

[0.217- 0.232]	30-67	44	<0.01	0.154	0.110	0.01	0.020	0.028

Field corn grain	Cyprosulfamide per se	TRTSF	0.133- 0.172

[0.149- 0.193]	98-156	44	<0.01	<0.01	0.01	0.01	0.01	NA

Field corn grain	Cyprosulfamide per se	TRTFF	0.194- 0.207

[0.217- 0.232]	63-111	44	<0.01	<0.01	0.01	0.01	0.01	NA

Field corn stover	Cyprosulfamide per se	TRTSF	0.133- 0.172

[0.149- 0.193]	98-156	44	<0.01	0.019	0.015	0.01	0.01	NA

Field corn stover	Cyprosulfamide per se	TRTFF	0.194- 0.207

[0.217- 0.232]	65-111	44	<0.01	0.157	0.106	0.01	0.019	0.025

SWEET CORN (proposed use = 0.20 lb safener/A total application rate,
45-day PHI)

Sweet corn forage; 45-day PHI5	Cyprosulfamide per se	TRTSF	0.133- 0.172

[0.149- 0.193]	43-81	28	<0.01	<0.01	0.01	0.01	0.01	NA

Sweet corn forage; BBCH 73-797	Cyprosulfamide per se	TRTSF	0.133- 0.172

[0.149- 0.193]	55-95	28	<0.01	<0.01	0.01	0.01	0.01	NA

Sweet corn forage; BBCH 73-797	Cyprosulfamide per se	TRTFF	0.198- 0.207

[0.222- 0.232]	13-46	28	<0.01	0.408	0.396	0.012	0.055	0.10

Sweet corn ears;8 45-day PHI5	Cyprosulfamide per se	TRTSF	0.133- 0.172

[0.149- 0.193]	43-81	28	<0.01	<0.01	0.01	0.01	0.01	NA

Sweet corn ears;8 BBCH 73-797	Cyprosulfamide per se	TRTSF	0.133- 0.172

[0.149- 0.193]	55-95	28	<0.01	<0.01	0.01	0.01	0.01	NA

Sweet corn ears;8 BBCH 73-797	Cyprosulfamide per se	TRTFF	0.198- 0.207

[0.222- 0.232]	13-46	28	<0.01	0.048	0.043	0.01	0.01	NA

Sweet corn stover	Cyprosulfamide per se	TRTSF	0.133- 0.172

[0.149- 0.193]	88-163	28	<0.01	<0.01	0.01	0.01	0.01	NA

Sweet corn stover	Cyprosulfamide per se	TRTFF	0.198- 0.207

[0.222- 0.232]	49-113	28	<0.01	1.022	0.906	0.01	0.080	0.24

POP CORN (proposed use = 0.20 lb safener/A total application rate,
45-day PHI)

Pop corn grain	Cyprosulfamide per se	TRTSF	0.164-0.168

[0.184-0.188]	112-129	6	<0.01	<0.01	0.01	0.01	0.01	NA

Pop corn grain	Cyprosulfamide per se	TRTFF	0.199-0.204

[0.223-0.229]	79-88	6	<0.01	<0.01	0.01	0.01	0.01	NA

Pop corn stover	Cyprosulfamide per se	TRTSF	0.164-0.168

[0.184-0.188]	112-129	6	<0.01	<0.01	0.01	0.01	0.01	NA

Pop corn stover	Cyprosulfamide per se	TRTFF	0.199-0.204

[0.223-0.229]	79-88	6	<0.01	<0.01	0.01	0.01	0.01	NA

1  See D351125, G.F. Kremer, 18-APR-2008.   

2  The TRTSF plot received a postemergence broadcast application of the
4.17 lb/gal FlC formulation to corn, at target growth stage V2, grown
from seeds treated with cyprosulfamide.  The TRTFF plot received two
postemergence applications of the 4.17 lb/gal FlC formulation at target
growth stages V6 and V12.  

3  HAFT = Highest average field trial result.  

4  NA = Not applicable.

5  Target sampling date was a 45-day PHI.

6  Target sampling date was normal maturity, at BBCH 85 to 87 for field
corn.

7  Target sampling date was normal maturity, at BBCH 73 to 79 for sweet
corn.

8  Ears consist of kernel plus cob with husk removed.

Field trials were conducted to evaluate the magnitude of total
cyprosulfamide residues in/on sweet corn, field corn, and popcorn
commodities of forage, ears (kernels plus cob with husk removed,
K+CWHR), grain, and stover following the use of cyprosulfamide 500 FS
and/or cyprosulfamide 500 SC [both products were 4.17 lb/gal (500 g/L)
FlC formulations].  Five sweet corn, thirteen field corn, nine
field/sweet corn, and three pop corn field trials were conducted; in the
field/sweet corn trials, a field corn variety was planted, and the
required matrices for both sweet and field corn were collected.  In each
trial, two application patterns were evaluated.  In the first plot, corn
seeds were treated with cyprosulfamide 500 FS at a rate of 0.32 mg
safener/seed, using procedures typical of commercial seed treatment
operation.  Following treatment, the treated seeds were planted at
seeding rates ranging from 30,900 to 38,800 seeds/A (76,400 to 95,900
seeds/ha), yielding soil application rates of 0.022-0.027 lb safener/A
(0.024 to 0.031 kg safener/ha).  Plants were then treated with a
broadcast foliar application of cyprosulfamide 500 SC made 10 to 42 days
after planting (BBCH 12 to BBCH 35, 2 leaves unfolded to 2 nodes
detectable) at a target V2 (second leaf collar) at rates ranging
0.137-0.149 lb safener/A (0.153 to 0.167 kg safener/ha), except for one
trial which received 0.110 lb safener/A (0.124 kg safener/ha).  The
total application rates ranged 0.162-0.172 lb safener/A (0.182-0.193 kg
safener/ha), except for one trial for which the total rate was 0.133 lb
safener/A (0.149 kg safener/ha).  The total application rates represent
~0.8-0.9x the proposed maximum seasonal rate to corn.  This plot was
designated TRTSF (treated, seed, foliar).  

In the second plot, corn plants received two applications of
cyprosulfamide 500 SC.  The first application occurred at the V6 (sixth
leaf collar) growth stage (BBCH 16 to BBCH 36, 6 leaves unfolded to 6
nodes detectable) and was a broadcast foliar spray at rates ranging
0.109-0.116 lb safener/A (0.122-0.131 kg safener/ha).  The second
application occurred at the V12 (twelfth leaf collar) growth stage (BBCH
19 to BBCH 69, 9 leaves unfolded to end of flowering) and was a directed
application to the base of the plants and surrounding soil 13 to 46 days
after the first application, at rates ranging 0.085-0.093 lb safener/A
(0.095 to 0.105 kg safener/ha).  The total application rates were
0.194-0.207 lb safener/A (0.217 to 0.232 kg ai/ha); ~1x the proposed
maximum seasonal rate.  This plot was designated TRTFF (treated, foliar,
foliar).

Field spray volumes ranged from 7 to 21 gal/A (68 to 195 L/ha).  All
trials included either urea ammonium nitrate or ammonium sulfate as a
fertilizer (with the exception of one trial) and a crop oil concentrate,
a non-ionic surfactant, or methylated seed oil as an adjuvant in the
spray mixtures.  All applications were made using ground-based
equipment.  

Single samples were collected from the control plots and duplicate
samples were collected from the treated plots for all matrices.  In the
harvest trials, field corn forage (BBCH 85 to 87), sweet corn forage
(BBCH 73 to 79), and sweet corn ears (K+CWHR) were collected at normal
maturity.  Grain and stover (fodder) were collected at earliest
commercial harvest (ECH, BBCH 89).  Additional field corn forage, sweet
corn forage, and sweet corn ear samples were collected from the TRTSF
plots at a target 45-day PHI (actual PHIs ranged from 43 to 81 days). 
In the decline trials, field corn forage was collected from TRTSF plots
at intervals of 40, 45, 55, 65, and 75 days (±1 day) and collected from
TRTFF plots at intervals of 35, 40, 45, 50, and 55 days (±1 day). 
Sweet corn forage and sweet corn ears were collected at intervals of 50,
54, 65, 74, and 79 days (no forage sample at 79 days) from the TRTSF
plots and at intervals of 28, 31, 37, 42, and 46 days from the TRTFF
plots.  Grain and stover were harvested at intervals corresponding to
harvest (ECH) - 5 days, harvest, harvest + 5 days, harvest + 10 days,
and harvest + 15 days.

The residues of cyprosulfamide and its metabolites AE 0852999, AE
2300003, and AE 2300002 were quantitated using HPLC-MS/MS Method
UB-008-P06-01.  The individual analyte residues were reported in
cyprosulfamide molar equivalents and summed to give a total
cyprosulfamide residue.  The LOQ was 0.01 ppm for all analytes in all
matrices.  

The analytical method was validated for each commodity, by measuring the
recovery of the cyprosulfamide analytes from the respective fortified
control matrices fortified at the individual LOQ with each analyte. 
Additional recoveries at higher fortification levels validated the
method for the highest residues observed in individual matrices.  Mean
recoveries (and standard deviations) for all analytes ranged from 87%
(8.8%) to 110% (2.8%) from forage samples fortified at 0.01-0.50 ppm;
90% (8.5%) to 108% (8.0%) from sweet corn ears samples fortified at
0.010 and 0.10 ppm; 87% (10.4%) to 103% (3.3%) from field corn grain
samples fortified at 0.01 and 0.10 ppm; and 81% (14.6%) to 102% (1.8%)
from stover samples fortified at 0.01-1.20 ppm.

Samples were stored frozen (<-15 ºC) for a maximum of 389 days (12.8
months) for forage, 369 days (12.1 months) for sweet corn ears, 365 days
for grain (12.0 months), and 457 days (15.0 months) for stover prior to
analysis.  Adequate storage stability data are available for
cyprosulfamide and its metabolites AE 0852999, AE 2300002, and AE
2300003 in/on corn forage, kernels, and stover to support storage
intervals up to 12 months; these studies are intended to continue
through storage intervals of 18 months.  

The results of the corn crop field trials are summarized in Table 10. 
The highest average field trial (HAFT) and maximum total cyprosulfamide
residues in/on corn forage occurred in a sweet corn forage sample with
21% dry matter (DM) harvested from the TRTFF plot at normal maturity
(14-day PHI).  The HAFT residues were 0.43 ppm with maximum residues of
0.44 ppm.  The HAFT and maximum total cyprosulfamide residues in/on
field corn forage occurred in samples harvested from the TRTFF plot at
normal maturity (42-day PHI) and were 0.14 ppm and 0.18 ppm,
respectively.

Residues of cyprosulfamide were less than the LOQ in/on all samples of
sweet corn ears (K+CWHR), with the exception of samples from one trial. 
One trial established the HAFT (0.04 ppm) and maximum (0.05 ppm)
cyprosulfamide per se residues in sweet corn ears from samples harvested
from the TRTFF plot at a 15-day PHI.  Because all other sweet corn
samples had residues less than the LOQ, with most analyte residues being
less than their limits of detection, the petitioner considered the
samples with quantifiable residues to be outliers.  The petitioner
additionally noted that residues were less than 0.01 ppm in sweet corn
kernels and cobs in the corn metabolism studies which were treated at
approximately 3x the nominal U.S. maximum seasonal rate.

No quantifiable residues of cyprosulfamide were observed in/on any
sample of field or pop corn grain.  No quantifiable residues of the
metabolites were observed in/on any sample.  

The HAFT and maximum total cyprosulfamide residues observed in/on corn
stover samples were 0.91 ppm and 1.02 ppm, respectively, and occurred
in/on sweet corn stover samples with 38% DM harvested from the TRTFF
plot.  

In the decline studies, total cyprosulfamide residue in/on corn
commodities either did not increase with increasing sampling intervals
or were below the LOQ at each interval.  The petitioner stated that
decline of total cyprosulfamide residues in/on forage was also assessed
by comparing residues in/on forage samples collected from the TRTSF plot
at a target 45-day PHI with residues in/on forage samples collected at
normal maturity.  However, residues of all analytes were below the LOQ
in/on all forage samples collected from the TRTSF plots (at the 45-day
PHI target and at maturity), with the exception of samples from one site
in CA (in which similar residues were observed at both intervals). 
Therefore, these data are not useful to assess residue decline.

With respect to the individual parent cyprosulfamide and metabolite
residue levels, the data show that the majority of the residues in all
samples were <0.01 ppm (<LOQ); those with residues above the LOQ were
found mostly in the TRTFF plots.  

Overall, the individual residues observed in the TRTSF plots were
consistent with the metabolism studies depicting seed treatment or
preemergence application.  In the TRTSF plots, parent cyprosulfamide was
observed in only one sample (field corn stover from one of the decline
trials), while the metabolites AE 0852999, AE 2300003, and AE 2300002
were occasionally observed in forage and stover samples at levels
generally less than 0.025 ppm.  No residues of parent cyprosulfamide or
metabolites were observed in field corn grain, pop corn grain, or sweet
corn kernels.  

The individual residues observed in the TRTFF plots were consistent with
the metabolism study depicting postemergence application, with the
exception of sweet corn kernels from one site.  No residues of
cyprosulfamide or metabolites were observed in/on any field corn or pop
corn grain samples.  Two samples of sweet corn kernels did contain
residues of parent, but were not considered further due to the 15-day
PHI of these samples.  Thirty-six forage samples out of 96 (field +
sweet, including decline trials) from the TRTFF plots had residues of
parent cyprosulfamide.  Thirty-one stover samples out of 84 (field +
sweet + pop, including decline trials) had residues of parent
cyprosulfamide.  

The petitioner concluded that residues from a seed treatment, a
preemergence, and/or an early postemergence application (represented by
the TRTSF plot), in which the product is entirely or mostly applied to
soil, will consist of metabolites at low levels, with no parent
cyprosulfamide, if any residues are found.  Conversely, residues, if
found, from a mid to late postemergence application (represented by the
TRTFF plot) will consist mainly of parent cyprosulfamide, with
metabolites present at lower levels.  

Conclusions.  The submitted corn field trial data are adequate provided
that acceptable storage stability data are submitted.  An adequate
number of trials were conducted in the appropriate geographical regions,
and samples were analyzed for the residues of concern using an adequate
method.  

Once acceptable storage stability data are submitted, the available corn
field trial data would support the proposed use of cyprosulfamide as an
early-season broadcast application, at the V6 growth stage, using an FlC
formulation, at ~0.1 lb ai/A, followed by a basal- directed application,
at the V12 growth stage, of the FlC formulation at up to ~0.1 lb ai/A,
for a total rate of ~0.20 lb ai/A/season.  The harvest intervals for
field corn forage and sweet corn ears in the field trials were variable,
but generally support a minimum PHI of 45 days for forage and sweet corn
ears.  The harvest intervals for corn grain and stover in the crop field
trials ranged 44-113 days and averaged 83 days.  The proposed PHI of 45
days for grain and stover is not supported by the field trial data;
however, HED has determined that a PHI for grain and stover is not
needed (see Directions for Use).  

The petitioner has not proposed any seed treatment uses of
cyprosulfamide on corn.  Therefore, the crop field trial data reflecting
the later postemergence applications (TRTFF plots) will be used for
tolerance assessment.

HED notes that quantifiable residues of cyprosulfamide were observed
in/on two samples of sweet corn ears from one field trial (Sabin, MN
TRTFF plot); residues of cyprosulfamide (and metabolites) were below the
LOQ in/on all other samples.  The petitioner considered these samples to
be outliers based on their high residue values, but did not provide any
explanation for the high residue values.  The sweet corn ears samples
with quantifiable residues were harvested 15 days following last
application, which is much less than the proposed PHI of 45 days for
sweet corn ears.  If these samples are excluded from the set of ears
samples, there are still sufficient field trials to satisfy geographic
representation requirements.  Therefore, HED concludes that the sweet
corn ears samples from the Sabin, MN TRTFF plot should not be included
in the set of residue values used for determination of the appropriate
tolerance level.

The sweet corn forage data for the TRTFF plot represent PHIs of 13-46
days, with all values except one less than the proposed PHI of 45 days
for corn forage and an average PHI of 31 days.  Due to these low PHIs,
HED will use the field corn forage data from the TRTFF plots, which
represent PHIs of 30-67 (average of 45 days), to determine an
appropriate level for a tolerance for both sweet corn and field corn
forage.

The available data support tolerances at the LOQ for residues of
cyprosulfamide per se in/on field corn grain, pop corn grain, and sweet
corn ears.  The data also support tolerances for residues of
cyprosulfamide per se in/on field corn forage and sweet corn forage at
0.20 ppm, in/on field corn stover and pop corn stover at 0.20 ppm, and
in/on sweet corn stover at 0.70 ppm.  

860.1520 Processed Food and Feed

The information below was obtained from Section IIA 6.5.4 of “Tier 2
Summary of the Metabolism and Residues Data for Cyprosulfamide (AE
0001789),” which was prepared by Bayer CropScience.  The referenced
study was submitted to EPA under MRID 47069747.  

A field trial was conducted to measure the magnitude of cyprosulfamide
residues in/on corn grain and to evaluate the need for residue analysis
of the processed commodities of corn grain.  

Three applications of a 500 g/L FlC formulation (cyprosulfamide 500 SC;
4.17 lb/gal) were made to corn at a total treatment rate of 1.100 lb
cyprosulfamide/acre (1.233 kg/ha) which represents a five-fold
exaggeration of the maximum total seasonal rate for cyprosulfamide in
the U.S.  The first application, targeted to occur at the V2 (second
leaf collar, BBCH 12-35) growth stage, was a broadcast foliar
application at a target rate of 0.49 lb cyprosulfamide/acre (549 g
cyprosulfamide/ha); the second application, targeted to occur at the V6
(sixth leaf collar BBCH 16-36) growth stage, was a broadcast foliar
application at a target rate of 0.335 lb cyprosulfamide/acre (375 g
cyprosulfamide/ha); and the third application, targeted to occur at the
V12 (twelfth leaf collar BBCH 32) growth stage, was a directed
application to the base of the plants and surrounding soil at a target
rate of 0.268 lb cyprosulfamide/acre (300 g cyprosulfamide/ha).  Each
application was made at a target concentrated spray volume of 5 to 20
gal/A. 

A single control and treated bulk sample of corn grain were collected at
maturity (BBCH 89, kernels fully ripe).  The residues of cyprosulfamide
and its metabolites AE 0852999, AE 2300003, and AE 2300002 were
quantitated using an HPLC-MS/MS method, Method UB-008-P06-02.  The LOQ
in corn grain for each analyte was 0.01 ppm.

The corn grain samples analyzed in this study were held in frozen
storage for a maximum of 14.5 months (433 days) prior to analysis. 
Freezer storage stability studies indicate that cyprosulfamide and its
metabolites are stable in/on corn grain during up to 12 months of frozen
storage.

Residues of cyprosulfamide, AE 0852999, AE 2300003, and AE 2300002 in/on
corn grain were each less than the LOQ of 0.01 ppm following treatment
at 5x.  Therefore, generation of the corn processed commodities was not
conducted.

Conclusions.  The submitted data are adequate to satisfy data
requirements for the purposes of this petition.  Because no quantifiable
residues of cyprosulfamide or metabolites were found in/on field corn
grain following treatment at 5x, no field corn processing data are
required.  No tolerances for field corn processed commodities are
needed.  

  SEQ CHAPTER \h \r 1 860.1650 Submittal of Analytical Reference
Standards

An analytical standard for cyprosulfamide is currently available in the
EPA National Pesticide Standards Repository, with an expiration date of
1/5/09 (personal communication with Dallas Wright, ACB, 10/9/07);
however, no standards are available for the metabolites to be regulated.
 Analytical reference standards of cyprosulfamide metabolite AE 0852999
(M02) and isotopically labeled standards of both parent and M02 to be
used as internal standards must be supplied and supplies replenished as
requested by the Repository.  The reference standards should be sent to
the Analytical Chemistry Lab, which is located at Fort Meade, to the
attention of either Theresa Cole or Thuy Nguyen at the following
address:

	USEPA

	National Pesticide Standards Repository/Analytical Chemistry Branch/OPP

	701 Mapes Road

	Fort George G. Meade, MD  20755-5350

(Note that the mail will be returned if the extended zip code is not
used.)

860.1850 Confined Accumulation in Rotational Crops

The information below was obtained from Section IIA 6.6.2 of “Tier 2
Summary of the Metabolism and Residues Data for Cyprosulfamide (AE
0001789),” which was prepared by Bayer CropScience.  The referenced
study was submitted to EPA under MRID 47069748.  

The residues of cyprosulfamide in rotational crops planted following the
broadcast treatment of cyprosulfamide to soil was studied.  Bare silt
loam soil was treated with either
[sulfonylbenzamide-UL-14C]cyprosulfamide at a rate of 212 g safener/ha
or [methoxybenzoyl-UL-14C]cyprosulfamide at a rate of 218 g safener/ha;
these rates are ~1x the proposed maximum seasonal rate (0.20 lb
safener/A or 225 g safener/ha).  The soil was tilled and planted with
Swiss chard (leafy vegetable), turnips (root crop), and spring wheat
(grain crop) at 30, 120, and 276 days (wheat only) following the
application of [sulfonylbenzamide-UL-14C]cyprosulfamide and at 30 days
following application of [methoxybenzoyl-UL-14C]cyprosulfamide; spring
wheat only was planted 120 and 276 days following application of
[methoxybenzoyl-UL-14C]cyprosulfamide.  Raw agricultural commodities
were harvested from each crop at the appropriate growth stages in each
rotation.

TRR levels in the 30-day crops from the [methoxybenzoyl-UL-14C] study
were:  0.012, 0.032, 0.009, and 0.027 ppm for wheat forage, hay, grain,
and straw, respectively; 0.005 ppm for Swiss chard; and 0.003 and 0.006
ppm for turnip roots and tops, respectively.  The TRR in the 120-day
crops were 0.002, 0.011, 0.009, and 0.008 ppm for wheat forage, hay,
grain, and straw, respectively.  The TRR levels in the 276-day crops
were 0.002, 0.007, 0.003, and 0.004 ppm for wheat forage, hay, grain,
and straw, respectively.  

The TRR in the 30-day crops from the [sulfonylbenzamide-UL-14C] study
were:  0.028, 0.088, 0.025, and 0.071 ppm for wheat forage, hay, grain,
and straw, respectively; 0.012 ppm for Swiss chard; and 0.005 and 0.014
ppm for turnip roots and tops, respectively.  The TRR in 120-day crops
were:  0.005, 0.020, 0.012, and 0.017 ppm for wheat forage, hay, grain,
and straw, respectively; 0.003 ppm for Swiss chard; and 0.003 and 0.004
ppm for turnip roots and tops, respectively.  The TRR levels in 276-day
crops were 0.003, 0.013, 0.006, and 0.010 ppm for wheat forage, hay,
grain, and straw, respectively.  

In the [methoxybenzoyl-UL-14C] study, samples of wheat forage, hay, and
straw from the 30-day interval and wheat hay from the 120-day interval
were subjected to extraction procedures.  Extraction of the samples with
acetonitrile/water released 16-32% TRR; additional radioactivity was
released from 30-day wheat hay and straw samples using methanol and
sequential hydrolyses.  HPLC analyses of the extracts revealed several
components, each ≤0.01 ppm.  No compounds were identified in these
samples.  

In the [sulfonylbenzamide-UL-14C] study, the following samples were
subjected to extraction procedures:  30-day Swiss chard; 30-day turnip
tops; 30-day wheat forage; 30-, 120-, and 276-day wheat hay; 30-, 120-,
and 276-day wheat straw; and 30- and 120-day wheat grain.  The remaining
samples were not extracted due to low TRR levels.  

mponents, each of which was ≤0.01 ppm.  The only identified compound
was AE 0852999, which was found in wheat forage at 23% TRR (0.006 ppm).

For 30-day wheat hay, grain, and straw, extraction with
acetonitrile/water released 25-52% TRR (0.006-0.037 ppm).  Further
extraction with methanol as well as hydrolyses released additional
radioactivity from wheat hay and straw.  HPLC analyses of the hay and
straw extracts yielded several components, of which the major component
was AE 0852999, at 25-27% TRR (0.02-0.024 ppm).  No other compounds were
identified.  For 120-day wheat hay, grain, and straw, and 276-day wheat
hay and straw, extraction with water, acetonitrile/water, and/or
methanol released a total of 40-67% TRR (0.003-0.013 ppm).  HPLC
analyses of the extracts of 276-day wheat hay, 120-day wheat grain, and
120- and 276-day wheat straw yielded several peaks, each <0.01 ppm. The
metabolite AE 0852999 was found in 276-day wheat hay and 120-day wheat
straw at 0.003-0.004 ppm (21-25% TRR).  No other compounds were
identified.

The proposed metabolic pathway for cyprosulfamide in rotated crops is
presented in the figure below, which was copied without alteration from
the Tier II Summary.

 

Conclusions.  The submitted confined rotational crop data are adequate
to satisfy data requirements.  The residues of concern in rotational
crops are cyprosulfamide and its metabolite AE 0852999 (M02) (D351495,
G. Kramer, 18-APR-2008).  The data indicate that quantifiable residues
of AE 0852999 may occur in rotated grain commodities at a 30-day
plantback interval.  Hence, limited field accumulation in rotational
crops studies are appropriate to assess the need for rotational crop
tolerances.

860.1900 Field Accumulation in Rotational Crops

The information below was obtained from Section IIA 6.6.3 of “Tier 2
Summary of the Metabolism and Residues Data for Cyprosulfamide (AE
0001789),” which was prepared by Bayer CropScience.  The referenced
studies were submitted to EPA under MRIDs 47069749 (2-month plantback
interval) and 47069750 (1-month plantback interval). 

Two limited rotational crop field trials were conducted in the U.S.  

The first study consisted of three trials with three treated plots each.
 For each plot, corn seed treated with cyprosulfamide formulated as 500
FS (4.17 lb/gal FlC formulation) at a nominal rate of 100 g safener/100
kg seed (0.1 lb safener/100 lb seed; ~2x the proposed seed treatment
rate for sorghum).  The treated corn seeds were planted at a target
seeding rate of 79,000 seeds/ha (32,000 corn seeds/A) resulting in a
target soil application rate of 25 g safener/ha (0.022 lb safener/A);
actual rates ranged 20.7-27.9 g safener/ha or 0.018-0.025 lb safener/A. 
After one month, the corn crop was destroyed in each plot and the
seedbed prepared and planted with wheat, turnips, or soybeans.  Samples
of wheat forage, hay, straw, and grain, turnip roots and tops, and
soybean forage, hay, and seed were harvested at normal maturity.

The second study consisted of three trials with three treated plots
each.  Soil in each plot was treated with a broadcast spray of the 4.17
lb/gal FlC formulation at 225 g safener/ha (0.20 lb safener/A; 1x the
proposed maximum seasonal rate to corn).  After two months, each plot
was planted with wheat, turnips, or soybeans.  Samples of wheat forage,
hay, straw, and grain, turnip roots and tops, and soybean forage, hay,
and seed were harvested at normal maturity.

Samples of rotational crop commodities were analyzed for residues of
cyprosulfamide and AE 0852999 using a modified version of HPLC-MS/MS
Method UB-008-P06-01.  The LOQ was 0.01 ppm for both analytes in all
matrices.  The analytical method was adequately validated at the LOQ for
each analyte in each commodity.  In the first study, recoveries of AE
0852999 were low for two of three wheat straw samples (50% and 67%); in
the second study, low recovery of AE 0852999 was observed from one of
seven wheat straw samples (61%).   

The storage durations and conditions of samples of rotational crop
commodities from the field rotational crop studies submitted with this
petition were not reported in the Tier II Summary.  Based on information
reported in the MRIDs for these studies, samples of rotational crop
commodities were stored frozen (<-15 C) for a maximum of 422 days (13.9
months) for turnip roots and tops, 453 days (14.9 months) for soybean
seed, 528 days (17.3 months) for soybean forage and hay, 162 days (5.3
months) for wheat grain, and 342 days (11.2 months) for wheat forage,
hay, and straw.  

No quantifiable residues of either analyte were found in/on any
rotational crop commodity in either study.  This supports rotation to
all crops 30 days after an application at 25 g safener/ha (0.022 lb
safener/A), and a rotation to all crops 60 days after an application at
225 g/ha (0.20 lb safener/A).  

Conclusions.  The submitted data are adequate to satisfy data
requirements provided that adequate supporting storage stability data
are submitted.  

Once acceptable storage stability data are submitted, the field
rotational crop data support a plantback interval of 30 days for all
crops after an application at 0.022 lb safener/A and a plantback
interval of 60 days for all crops after an application at 0.20 lb
safener/A.   The petitioner has proposed a number of plantback intervals
for various crops on the proposed labels for products containing
cyprosulfamide.  Because the petitioner has not proposed any plantback
intervals shorter than two months for any rotated crop other than corn
(0-months plantback interval for corn on all labels) and sorghum
(0-month plantback interval for sorghum on sorghum seed treatment label
only), HED concludes that the proposed rotational crop restrictions are
adequate for the purposes of this petition.  HED assumes that all
proposed plantback intervals greater than two months are needed due to
phytotoxicity concerns and/or the other active ingredients in the
products.

860.1550 Proposed Tolerances

HED has determined that the residue of concern for tolerance expression
for plant commodities is cyprosulfamide per se; for livestock feed
items, the residues of concern for tolerance expression are combined
residues of cyprosulfamide and its metabolite AE 0852999 (M02),
expressed as cyprosulfamide equivalents.  The residues of concern for
tolerance expression for livestock commodities are combined residues of
cyprosulfamide and its metabolite AE 0852999, expressed as
cyprosulfamide equivalents.  The proposed tolerance expression for
plants is adequate.  The proposed tolerance expressions for livestock
feed items and livestock commodities must be modified to specify that
combined residues are calculated as parent equivalents.  

A tolerance summary for cyprosulfamide is presented in Table 11.  

Pending submission of additional storage stability data, the available
crop field trial data support tolerances for cyprosulfamide residues
in/on the commodities listed in Table 11.  For field corn grain, sweet
corn ears (K+CWHR), and pop corn grain, all residues were below the LOQ;
therefore, the tolerance spreadsheet in the Agency’s Guidance for
Setting Pesticide Tolerances Based on Field Trial Data was not used to
calculate a tolerance for these commodities.  The tolerances for field
corn grain, sweet corn ears (K+CWHR), and pop corn grain should be set
at the LOQ for cyprosulfamide, 0.01 ppm.  

For field corn forage, field corn stover, and pop corn stover, greater
than 60% of the residues values were below the LOQ, therefore the
tolerance spreadsheet was not used to calculate a tolerance for these
commodities.  Due to the limited residue data for pop corn stover, the
residue data for field corn and pop corn stover were pooled to determine
the appropriate tolerances for these commodities.  The maximum
cyprosulfamide residues observed in/on field corn forage and stover were
0.154 ppm and 0.157 ppm, respectively.  Therefore, the tolerances for
field corn forage, field corn stover, and pop corn stover should be set
at 0.20 ppm.  

The tolerance calculations for sweet corn stover, based on results from
the FF trials, are presented in Appendix II.   The calculated results
indicate that the proposed stover tolerance is too high; a tolerance of
0.35 ppm is appropriate for sweet corn stover.  For sweet corn forage,
HED notes that the PHIs of the crop field trial samples representing the
FF application pattern were below the proposed PHI; nevertheless, HED
concurs that the proposed sweet corn forage tolerance of 0.40 ppm is
adequate. 

As noted in Table 11, revisions in the commodity definitions are needed
for corn commodities.  Separate tolerances are needed for field and pop
corn grain, and for the stovers of field corn, sweet corn, and pop corn.

The available livestock feeding study data indicate that no tolerances
are needed for poultry or swine commodities, and no tolerances are
needed for milk, fat, or meat of cattle, goat, horse, or sheep. 
Tolerances are needed for the meat byproducts of cattle, goat, horse,
and sheep, at 0.02 ppm (combined LOQ); separate tolerances are not
needed for liver and kidney.

No quantifiable residues of cyprosulfamide or metabolites were observed
in/on field corn grain following treatment at 5x; therefore, no
tolerances for processed commodities are required.

No Codex or Mexican MRLs have been established for cyprosulfamide. 

Table 11. 	Tolerance Summary for Cyprosulfamide.

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;
Correct Commodity Definition

Tolerances for residues of cyprosulfamide per se:

Corn (maize) kernel	0.01	

0.01	Separate tolerances are needed for:

Corn, field, grain

0.01	Corn, pop, grain

Corn, immature kernel	0.01	0.01	Corn, sweet, kernel plus cob with husks
removed

Field Corn Forage	0.15*	0.20	Corn, field, forage

Sweet Corn Forage	0.40*	0.40	Corn, sweet, forage

Stover	0.60*	0.35	Separate tolerances are needed for:

Corn, sweet, stover

0.20	Corn, field, stover

0.20	Corn, pop, stover

Tolerances for combined residues of cyprosulfamide and its metabolite
4-(aminosulfonyl)-N-cyclopropylbenzamide, calculated as cyprosulfamide:

Milk	0.01	Remove	Feeding study data indicate that a tolerance is not
needed for milk.

Meat	0.01	Remove	Feeding study data indicate that a tolerance is not
needed for meat.

Fat 	0.01	Remove	Feeding study data indicate that a tolerance is not
needed for fat.

Liver 	0.02	Remove	Included in meat byproduct tolerance.

Kidney	0.05	Remove	Included in meat byproduct tolerance.

Cattle, meat byproducts	None proposed	0.02

	Goat, meat byproducts	None proposed	0.02

	Horse, meat byproducts	None proposed	0.02

	Sheep, meat byproducts	None proposed	0.02

	*Proposed as parent + M02 + M10 + M11

References

DP Barcode:	D351125

Subject:	Cyprosulfamide.  Report of the Residues of Concern
Knowledgebase Subcommittee (ROCKS).

From:		G. F. Kramer

To:		Cyprosulfamide Risk Assessment Team

Date:		04/18/2008

DP Barcode:	D339779

Subject:	Thiencarbazone-methyl.  Petition to Establish Permanent
Tolerances for Use on Field Corn, Pop Corn, Sweet Corn, and Wheat. 
Summary of Analytical Chemistry and Residue Data.  

From:		P. Savoia

To:		H. Johnson

Date:		05/28/2008

MRID:		47069746.

DP Barcode:	D340598 and D340678

Subject:	Isoxaflutole.  Application for Registration of Two New Products
for Use on Corn: SC 465 Herbicide and SC 480 Herbicide.  Summary of
Analytical Chemistry and Residue Data.  Decision Nos. 379124 and 379125;
40 CFR 180.537.

From:		G. F. Kramer

To:		J. Stone and J. Miller

Date:		04/11/2008

MRIDs:	44169006, 44436001, 445063301, 45655902, 45655909, 47114034, and
47114035. 

DP Barcode:	D345603

Subject:	Cyprosulfamide.  Section 3 Registration for Use on Corn (Field,
Sweet, and Pop).  Request for Tolerance Method Validation (TMV).

From:		W. H. Donovan

To:		W. Chism

Date:		10/23/2007

DP Barcode:	D345604

Subject:	Review of Proposed Tolerance Enforcement Methods for
Cyprosulfamide 

ACB Project # B08-06.

From:		C. J. Stafford

To:		C. Eiden

Date:		05/27/2008

  SEQ CHAPTER \h \r 1 Attachments:  

International Residue Limit Status sheet

Appendix I - Chemical Name and Structure Table

Appendix II - Tolerance Assessment Calculations

Template Version September 2005



INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name: 
N-[[4-[(cyclopropylamino)carbonyl]phenyl]sulfonyl]-2-methoxybenzamide
Common Name:  Cyprosulfamide	X Proposed tolerance

( Reevaluated tolerance

( Other	Date:  10/24/07

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#7F7206

DP#: 341999

Other Identifier:  

Residue definition (step 8/CXL): N/A	Reviewer/Branch:  W. Donovan/RRB3

	Residue definition:  Cyprosulfamide per se

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

Corn (maize) kernel	0.01

Corn, immature kernel	0.01

Residue definition:  Cyprosulfamide and metabolites AE 2300002, AE
2300003, and AE 0852999

Field Corn Forage	0.15

Sweet Corn Forage	0.40

Stover	0.60

Residue definition:  Cyprosulfamide and metabolite AE 0852999

Milk	0.01

Meat	0.01

Fat	0.01

Liver	0.02

Kidney	0.05

Limits for Canada	Limits for Mexico

X No Limits

( 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:

APPENDIX I.	Chemical Names and Structures of Cyprosulfamide and
Metabolites.

The table below was obtained from “Tier 2 Summary of the Metabolism
and Residues Data for Cyprosulfamide (AE 0001789)” prepared by Bayer
CropScience (Document Number M-286420-01-1).  

APPENDIX I.	Chemical Names and Structures of Cyprosulfamide and
Metabolites.  

	Report name

Structure

IUPAC name

CAS name

[CAS number]	Molecular formula

molar mass

	C18 H18 N2 O5 S

374.4 g/mol

	Rat,

Goat,

Hen

Corn,

Soil,

Water-Sediment

	N-cyclopropyl-4-[(2-methoxybenzoyl)sulfamoyl] benzamide (IUPAC)

Benzamide, N-[[4-[(cyclopropylamino)-carbonyl]phenyl]
sulfonyl]-2-methoxy- (CAS, 9CI) 

[CAS-no: 221667-31-8]

	Cyprosulfamide 

	C15 H13 N O6 S

335.3 g/mol

	Rat (minor),

Soil, aerobic and anaerobic (major), 

Water-Sediment (major)

	4-[(2-methoxybenzoyl)sulfamoyl]benzoic acid (IUPAC)

	C10 H12 N2 O3 S

240.3 g/mol	Rat (minor),

Goat (major in milk, liver, kidney, also present as conjugates),

Hen (major)

Corn (major in forage and stover, not present in grain)

Soil, aerobic and anaerobic (major),

Succeeding crops (major),

Water-Sediment (major)

	N-cyclopropyl-4-sulfamoylbenzamide (IUPAC)

	C7 H7 N O4 S 

201.2 g/mol	Goat (minor in milk),

Soil, aerobic and anaerobic (major),

Water-Sediment (minor)

	4-sulfamoylbenzoic acid (IUPAC)

Benzoic acid, 4-(aminosulfonyl)- (CAS, 9CI)

[CAS no.: 138-41-0]

	C17 H16 N2 O5 S

360.39 g/mol	Rat (minor),

Goat (minor in milk and liver),

Soil aerobic (major),

Water-Sediment (aerobic: minor; anaerobic: major)

	N-cyclopropyl-4-[(2-hydroxybenzoyl) sulfamoyl]benzamide (IUPAC)

	C15 H14 N2 O5 S

334.35 g/mol	Soil photolysis (major),

Corn (minor in forage, stover and grain)

	N-{[4-(aminocarbonyl)phenyl]sulfonyl}-2-methoxybenzamide (IUPAC)

	C3 H7 N 

57.1 g/mol	Soil and water (postulated major metabolite),

Rat (postulated minor metabolite) 

	Cyclopropylamine (9Cl) (IUPAC)

Cyclopropaneamine (9Cl, CAS)

[CAS no.: 765-30-0]

	AE 2300015

	C8 H8 O3 

152.2 g/mol

	Rat (minor), 

Goat (major in liver),

Hen (major in eggs and liver)

Aquatic photolysis (major)

	2-methoxybenzoic acid (IUPAC)

Benzoic acid, 2-methoxy- (CAS, 9CI) 

[CAS no.: 579-75-9]

	AE 0854787

O-methylsalicylic acid,

anisic acid,

	C10 H11 N O4 S

241.3 g/mol	Aquatic photolysis (major)

Corn (minor in forage, 

not present in grain)

	4-[(cyclopropylamino)carbonyl]benzenesulfonic acid (IUPAC)

	C7 H6 O3 

138.12 g/mol

	Soil (major in anaerobic soil metabolism)

	2-methoxybenzoic acid (IUPAC)

2-hydroxy benzoic acid (CAS, 9CI)

[CAS n.: 69-72-7]

	AE 0171385

o-hydroxybenzoic acid,

	C13 H16 N2 O6 S

328.3 g/mol

lactic acid conjugate of AE 0852999

	Corn (major in forage and stover; 

not present in grain)

	3-[({4-[(cyclopropylamino)carbonyl]phenyl}
sulfonyl)amino]-2-hydroxypropanoic acid (IUPAC)

	C13 H17 N3 O5 S

327.36 g/mol

alanine conjugate of AE 0852999

	Corn (major in forage and stover; 

not present in grain)

	3-[({4-[(cyclopropylamino)carbonyl]phenyl} sulfonyl)amino]alanine
(IUPAC)

	C12 H14 N2 O4 S

282.32 g/mol

acetic acid conjugate of AE 0852999

	Corn (minor in forage and stover; 

not present in grain),

Goat (major in milk)

	4-[(acetylamino)sulfonyl]-N-cyclopropylbenzamide (IUPAC)

M13

	C14 H17 N3 O6 S

355.37 g/mol

aspartic acid conjugate of AE 0852999

	Corn (major in stover, minor in forage,

not present in grain)

	N-({4-[(cyclopropylamino)carbonyl]phenyl} sulfonyl)-alpha-asparagine
(IUPAC)

M14

	C12 H12 N2 O6 S

312.30 g/mol

oxalic acid conjugate of AE 0852999

	Corn (minor in forage and stover,

not present in grain)

	[({4-[(cyclopropylamino)carbonyl]phenyl} sulfonyl)amino] (oxo)acetic
acid (IUPAC)

M15

	

indeterminate alanine conjugate of AE 0852999	Corn (major in forage and
stover; 

not present in grain)

	3-[({4-[(cyclopropylamino)carbonyl]phenyl} sulfonyl)amino]alanine,
conjugate

	C24 H18 N2 O10 S

536.6 g/mol

glucose conjugate of AE 0001789, 

linkage of glucose in 4-position of the methoxy benzoyl ring

	Corn (major in stover; 

minor in grain)

	glucose conjugate of parent substance 

	C13 H14 N2 O5 S

310.33 g/mol

pyruvic acid conjugate of AE 0852999

	Goat (minor in milk)

	N-cyclopropyl-4-[(pyruvoylamino)sulfonyl] benzamide (IUPAC)

	C10 H11 N O4

209.2 g/mol 

glycine conjugate of AE 0854787 

(AE 0001789-anisic acid)	Goat (minor in milk, liver, kidney) 

Corn (minor in stover,

not present in grain)

	N-(2-methoxybenzoyl)glycine (IUPAC)

Glycine, N-(2-methoxybenzoyl)- (CAS, 9CI) 

(2-methoxy-benzoylamino)-acetic acid

[CAS no.: 13443-58-8]

M19	AE 0001789-sulfonamide-glycine

[((4-[(cyclopropylamino)-carbonyl]phenyl) sulfonyl)amino] acetic acid	

C12H14N2O5S

298.3 g/mol 

glycine conjugate of AE 0852999

Corn (minor in stover,

not present in  grain)

	

Appendix II.  Tolerance Assessment Calculations.

For field corn grain, sweet corn ears (K+CWHR), and pop corn grain, all
residues were below the LOQ (LOQ = 0.01 ppm for each analyte);
therefore, the tolerance spreadsheet was not used to calculate a
tolerance for these commodities.  For field corn forage, field corn
stover, and pop corn stover, greater than 60% of the residues values
were below the LOQ, therefore the tolerance spreadsheet was not used to
calculate a tolerance for these commodities.  

The dataset used to establish a tolerance for cyprosulfamide on sweet
corn stover and forage consisted of field trial data representing total
application rates of 0.20 lb ai/A (2 applications at ~0.10 lb
ai/A/application), with PHIs ranging from 44-113 and 13-46 days,
respectively.  As specified by the Guidance for Setting Pesticide
Tolerances Based on Field Trial Data SOP, the field trial application
rates are within 25% of the maximum label application rate, but the
field trial PHIs are not within 25% of the proposed PHI for either sweet
corn stover or forage.  In the case of sweet corn stover, the residue
values did not appear to depend on PHI and thus these values were
analyzed further with the tolerance spreadsheet calculator.  However, in
the case of sweet corn forage, the residue levels were highest at the
PHIs near 13 days and lowest at PHIs near 46 days.  As a result, it was
determined that the spreadsheet calculator was not appropriate for sweet
corn forage and the recommended tolerance was based on examination of
the highest residue level, 0.40 ppm.  The residue values used to
calculate the tolerance are provided in Tables II-1.

 

 

 

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6imputed censored values from the sweet corn stover dataset, the MRL
tolerance spreadsheet analysis was conducted.  The results from the
approximate Shapiro-Francia test statistic (Figure II-2) indicated that
the assumption of lognormality should not be rejected.  Visual
inspection of the lognormal probability plot (Figure II-1) provided in
the spreadsheet confirmed that the dataset was lognormal.  

Since the resulting MLE-processed dataset for cyprosulfamide on sweet
corn stover is lognormal and the dataset is comprised of more than 15
samples, the minimum of either the 95% upper confidence limit (UCL) of
the 95th percentile or the point estimate of the 99th percentile is
selected for the tolerance level.  In this case, the 95% UCL of the 95th
percentile is appropriate as indicated by the highlighted value in the
MRL printout (see Figure II-2).  Therefore, 0.35 ppm is the recommended
tolerance level for cyprosulfamide on sweet corn stover.  

Table II-1.	Residue data used to calculate tolerance for cyprosulfamide
on sweet corn stover.  

Regulator:	EPA

Chemical:	Cyprosulfamide

Crop:	Corn, sweet, stover (MLE)

PHI:	44-113 days

App. Rate:	0.20 lb ai/A

Submitter:	Bayer CropScience

MRID Citation:	MRID 47069746

PHI	Residues of cyprosulfamide per se (ppm)

53	0.0003*

63	0.0005*

91	0.0007*

91	0.0010*

111	0.0013*

111	0.0016*

113	0.0019*

113	0.0022*

92	0.0026*

98	0.0030*

98	0.0035*

91	0.0041*

70	0.0046*

65	0.0053*

65	0.0060*

62	0.0068*

62	0.0078*

77	0.0088*

77	0.0140

70	0.0120

91	0.0830

83	0.0280

83	0.0270

65	0.0120

65	0.0160

70	1.0220

70	0.7890

92	0.0170

44	0.0110

44	0.0110

49	0.0390

49	0.0170

53	0.0140

56	0.0300

56	0.0160

63	0.0210

*  Residues in/on this sample were <0.01 ppm before application of MLE
procedures.



Figure II-   SEQ Figure_II- \* ARABIC  1 .  Lognormal probability plot
of cyprosulfamide field trial data for sweet corn stover.

 

Figure II- 2.   Tolerance spreadsheet summary of cyprosulfamide field
trial data for sweet corn stover.

 

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Cyprosulfamide	Summary of Analytical Chemistry and Residue Data	DP#: 
341999