UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: June 10, 2008

MEMORANDUM

SUBJECT:	Cyprosulfamide:  Human Health Risk Assessment for Proposed Uses
on Corn (Field, Sweet, and Pop), Sorghum (Seed Treatment), Residential
Turf and Ornamentals.

PC Code:  877400	DP Barcode:  D351492

Decision No.:  378533	Registration No.: NA

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

Risk Assessment Type:  Single chemical aggregate	Case No.: NA

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

MRID No.: NA	40 CFR:  180.xxx

		              									Ver.Apr.08

FROM:	William Donovan, Ph.D., Chemist

		John Doherty, Ph.D., Toxicologist

		Seyed Tadayon, Chemist

		Reregistration Branch 3

		Health Effects Division (7509P)

THROUGH:	Catherine Eiden, Branch Chief

		Reregistration Branch 3

			and

		Dana Vogel, Designated Reviewer

P.V. Shah, Designated Reviewer

Risk Assessment Review Committee

		Health Effects Division (7509P)

TO:		Karen Angulo, RM Team 08

		Inerts Branch

		Registration Division (7505P)

Introduction

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

Pending submission of revised product labels (see Directions for Use
under Section 10.2), submission of a copy of the complete livestock
analytical enforcement method (see Residue Analytical Methods under
Section 10.2), submission of analytical reference standards (see
Submittal of Analytical Reference Standards under Section 10.2), and
submission of a revised Section F (see Proposed Tolerances under Section
10.2), 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 Storage
Stability under Section 10.2) must be fulfilled as a condition of
registration.

This HED document provides a summary of the findings from the data
evaluation and subsequent assessment of human health risk resulting from
this submission.  The hazard assessment and characterization was
conducted by John Doherty; the occupational/residential exposure data
review and dietary exposure assessment was conducted by Seyed Tadayon;
the residue chemistry data and the human health risk assessment was
conducted by William Donovan (RRB3); additionally, the drinking water
assessment was conducted by Amy McKinnon of OPP’s Environmental Fate
and Effects Division (EFED).

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc200865269"  1.0	Executive
Summary	  PAGEREF _Toc200865269 \h  6

  HYPERLINK \l "_Toc200865270"  2.0	Ingredient Profile	  PAGEREF
_Toc200865270 \h  8

  HYPERLINK \l "_Toc200865271"  2.1	Summary of Proposed Uses	  PAGEREF
_Toc200865271 \h  8

  HYPERLINK \l "_Toc200865272"  2.2	Structure and Nomenclature	  PAGEREF
_Toc200865272 \h  11

  HYPERLINK \l "_Toc200865273"  2.3	Physical and Chemical Properties
PAGEREF _Toc200865273 \h  11

  HYPERLINK \l "_Toc200865274"  3.0	Hazard Characterization/Assessment
PAGEREF _Toc200865274 \h  12

  HYPERLINK \l "_Toc200865275"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc200865275 \h  12

  HYPERLINK \l "_Toc200865276"  3.1.1	Database Summary	  PAGEREF
_Toc200865276 \h  12

  HYPERLINK \l "_Toc200865277"  3.1.2	Toxicological Effects	  PAGEREF
_Toc200865277 \h  13

  HYPERLINK \l "_Toc200865278"  3.1.3	Dose-response	  PAGEREF
_Toc200865278 \h  15

  HYPERLINK \l "_Toc200865279"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc200865279 \h  15

  HYPERLINK \l "_Toc200865280"  3.3	FQPA Considerations	  PAGEREF
_Toc200865280 \h  16

  HYPERLINK \l "_Toc200865281"  3.3.1	Adequacy of the Toxicity Database
 PAGEREF _Toc200865281 \h  16

  HYPERLINK \l "_Toc200865282"  3.3.2	Evidence of Neurotoxicity
PAGEREF _Toc200865282 \h  16

  HYPERLINK \l "_Toc200865283"  3.3.3	Developmental Toxicity Studies
PAGEREF _Toc200865283 \h  16

  HYPERLINK \l "_Toc200865284"  3.3.4	Reproductive Toxicity Study
PAGEREF _Toc200865284 \h  16

  HYPERLINK \l "_Toc200865285"  3.3.5	Additional Information from
Literature Sources	  PAGEREF _Toc200865285 \h  17

  HYPERLINK \l "_Toc200865286"  3.3.6	Pre-and/or Postnatal Toxicity
PAGEREF _Toc200865286 \h  17

  HYPERLINK \l "_Toc200865287"  3.3.7	Recommendation for a Developmental
Neurotoxicity Study	  PAGEREF _Toc200865287 \h  17

  HYPERLINK \l "_Toc200865288"  3.4	Safety Factor for Infants and
Children	  PAGEREF _Toc200865288 \h  17

  HYPERLINK \l "_Toc200865289"  3.5	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc200865289 \h  18

  HYPERLINK \l "_Toc200865290"  3.5.1	Acute Reference Dose (aRfD) -
Females age 13-49 and the General Population	  PAGEREF _Toc200865290 \h
18

  HYPERLINK \l "_Toc200865291"  3.5.2	Chronic Reference Dose (cRfD)
PAGEREF _Toc200865291 \h  18

  HYPERLINK \l "_Toc200865292"  3.5.3	Incidental Oral Exposure (Short-
and Intermediate-term)	  PAGEREF _Toc200865292 \h  19

  HYPERLINK \l "_Toc200865293"  3.5.4	Dermal Absorption	  PAGEREF
_Toc200865293 \h  19

  HYPERLINK \l "_Toc200865294"  3.5.5	Dermal Exposure (Short-, and
Intermediate-term)	  PAGEREF _Toc200865294 \h  19

  HYPERLINK \l "_Toc200865295"  3.5.6	Inhalation Exposure (Short-, and
Intermediate-term)	  PAGEREF _Toc200865295 \h  20

  HYPERLINK \l "_Toc200865296"  3.5.7	Level of Concern for Margin of
Exposure	  PAGEREF _Toc200865296 \h  21

  HYPERLINK \l "_Toc200865297"  3.5.8	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc200865297 \h  22

  HYPERLINK \l "_Toc200865298"  3.5.9	Classification of Carcinogenic
Potential	  PAGEREF _Toc200865298 \h  22

  HYPERLINK \l "_Toc200865299"  3.5.10	Summary of Toxicological Doses
and Endpoints for Cyprosulfamide for Use in Human Risk Assessments
PAGEREF _Toc200865299 \h  23

  HYPERLINK \l "_Toc200865300"  3.6	Endocrine disruption	  PAGEREF
_Toc200865300 \h  25

  HYPERLINK \l "_Toc200865301"  4.0	Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc200865301 \h  25

  HYPERLINK \l "_Toc200865302"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc200865302 \h  26

  HYPERLINK \l "_Toc200865303"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc200865303 \h  26

  HYPERLINK \l "_Toc200865304"  5.1.1	Metabolism in Primary Crops
PAGEREF _Toc200865304 \h  26

  HYPERLINK \l "_Toc200865305"  5.1.2	Metabolism in Rotational Crops
PAGEREF _Toc200865305 \h  27

  HYPERLINK \l "_Toc200865306"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc200865306 \h  28

  HYPERLINK \l "_Toc200865307"  5.1.4	Analytical Methodology	  PAGEREF
_Toc200865307 \h  28

  HYPERLINK \l "_Toc200865308"  5.1.5	Environmental Degradation
PAGEREF _Toc200865308 \h  29

  HYPERLINK \l "_Toc200865309"  5.1.6	Comparative Metabolic Profile
PAGEREF _Toc200865309 \h  29

  HYPERLINK \l "_Toc200865310"  5.1.7	Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc200865310 \h  30

  HYPERLINK \l "_Toc200865311"  5.1.8	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc200865311 \h  31

  HYPERLINK \l "_Toc200865312"  5.1.9	Drinking Water Residue Profile
PAGEREF _Toc200865312 \h  33

  HYPERLINK \l "_Toc200865313"  5.1.10	Food Residue Profile	  PAGEREF
_Toc200865313 \h  34

  HYPERLINK \l "_Toc200865314"  5.1.11	International Residue Limits
PAGEREF _Toc200865314 \h  36

  HYPERLINK \l "_Toc200865315"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc200865315 \h  36

  HYPERLINK \l "_Toc200865316"  5.2.1	Acute Dietary Exposure/Risk
PAGEREF _Toc200865316 \h  36

  HYPERLINK \l "_Toc200865317"  5.2.2	Chronic Dietary Exposure/Risk
PAGEREF _Toc200865317 \h  36

  HYPERLINK \l "_Toc200865318"  6.0	Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc200865318 \h  37

  HYPERLINK \l "_Toc200865319"  7.0	Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc200865319 \h  42

  HYPERLINK \l "_Toc200865320"  7.1	Acute Aggregate Risk	  PAGEREF
_Toc200865320 \h  42

  HYPERLINK \l "_Toc200865321"  7.2	Short-term Aggregate Risk	  PAGEREF
_Toc200865321 \h  42

  HYPERLINK \l "_Toc200865322"  7.3	Long-term Aggregate Risk	  PAGEREF
_Toc200865322 \h  43

  HYPERLINK \l "_Toc200865323"  8.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc200865323 \h  43

  HYPERLINK \l "_Toc200865324"  9.0	Occupational Exposure/Risk Pathway
PAGEREF _Toc200865324 \h  43

  HYPERLINK \l "_Toc200865325"  9.1	Short- and Intermediate-term Handler
Risk	  PAGEREF _Toc200865325 \h  43

  HYPERLINK \l "_Toc200865326"  9.2	Short- and Intermediate-term
Postapplication Risk	  PAGEREF _Toc200865326 \h  49

  HYPERLINK \l "_Toc200865327"  10.0	Data Needs and Label Requirements
PAGEREF _Toc200865327 \h  51

  HYPERLINK \l "_Toc200865328"  10.1	Toxicology	  PAGEREF _Toc200865328
\h  51

  HYPERLINK \l "_Toc200865329"  10.2	Residue Chemistry	  PAGEREF
_Toc200865329 \h  52

  HYPERLINK \l "_Toc200865330"  10.3	Occupational and Residential
Exposure	  PAGEREF _Toc200865330 \h  53

  HYPERLINK \l "_Toc200865331"  References:	  PAGEREF _Toc200865331 \h
53

  HYPERLINK \l "_Toc200865332"  Appendix A:  Toxicology Assessment
PAGEREF _Toc200865332 \h  54

  HYPERLINK \l "_Toc200865333"  A.1	Toxicology Data Requirements
PAGEREF _Toc200865333 \h  54

  HYPERLINK \l "_Toc200865334"  A.2  Toxicity Profiles	  PAGEREF
_Toc200865334 \h  55

  HYPERLINK \l "_Toc200865335"  A.3  Executive Summaries	  PAGEREF
_Toc200865335 \h  60

  HYPERLINK \l "_Toc200865336"  Appendix B:  Metabolism Assessment
PAGEREF _Toc200865336 \h  106

  HYPERLINK \l "_Toc200865337"  Appendix C:  EPA Review of Human
Research	  PAGEREF _Toc200865337 \h  113

 1.0	Executive Summary  TC \l1 "1.0	Executive Summary

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.

Use Profile

Cyprosulfamide is intended primarily to be used as a safener in
conjunction with an herbicide active ingredient in agricultural settings
on corn (field, sweet, and pop).  However, this safener is also intended
for uses on turf and ornamentals in residential settings.  The maximum
use rate allowed from all sources is 0.201 lb safener/A/year.  A variety
of applications to corn are proposed including preplant, preemergent,
and postemergent.  However, the postemergent use rates are considerably
lower than the preplant/preemergent use rates.  In addition, a sorghum
seed treatment is proposed, although the low application rate permits
this use to qualify as a non-food use.

Toxicity/Hazard

Cyprosulfamide has low toxicity (Toxicity Category III or IV) in acute
toxicity and irritation assessments and is not a skin sensitizer.  In
subchronic and chronic oral toxicity studies, the critical target organ
for cyprosulfamide is the urinary tract including the kidney, bladder
and ureters. Toxic effects in these organs include inflammation and
irritation resulting from the formation of calculi caused by deposition
of the parent compound at high doses.  In the rat, the most sensitive
species, these effects are seen at 156 mg/kg/day in males and 224
mg/kg/day in females in the chronic/carcinogenicity study.  In the rat,
at doses associated with mortality due to nephropathy (321 mg/kg/day in
males and 398 mg/kg/day in females), there were treatment related
transitional cell carcinomas in the kidney of one male and a
transitional cell carcinoma in the urinary bladder of one female.  In
mice, at a dose where there was formation of calculi in the urothelial
system (616 mg/kg/day in females), cyprosulfamide was associated with
two incidents of transitional cell papilloma in the urinary bladder.
Since the neoplasms occurred only at high doses that also demonstrated
calculi formation, cyprosulfamide was classified as “Not likely to be
a Carcinogen to Humans at doses that do not cause urothelial
cytotoxicity”.

Dietary Exposure (food and drinking water)

The environmental fate properties of cyprosulfamide were used to model
protective estimated drinking water concentrations (EDWCs) in surface
water and groundwater (the models FIRST and SCI-GROW, respectively).

No acute dietary risk assessment was warranted because no toxic effect
attributable to a single dose of cyprosulfamide was noted in the
toxicological database.  Cyprosulfamide demonstrated toxicity via the
oral route over the chronic duration.  Subsequently, chronic dietary
(food and drinking water) exposure assessments were conducted (using the
dietary model DEEM-FCID).  The modeled exposure estimates for the
chronic assessment are based on tolerance level residues, default
processing factors, assuming 100% of crops associated with the Section 3
request are treated, and include the highest modeled EDWC relevant to
the chronic exposure scenario.  The resulting chronic risk estimate for
all population subgroups were <0.1% of the cPAD (chronic PAD).  As
dietary risk estimates for all population subgroups were less than 100%
of the cPAD, no risks of concern were identified.

Residential Exposure

All cyprosulfamide residential handler Margins of Exposure (MOEs) were
estimated to be >100 for the proposed uses on turf and ornamentals, and
therefore, do not cause concern for HED.  Likewise, postapplication
risks to toddlers following the application of cyprosulfamide to home
lawns were calculated for short- term exposures.  All MOEs for the
toddler lawn exposure scenarios were >100, and therefore, are not of
concern to HED.  In addition the total MOE for combined toddler
exposures (i.e., hand-to-mouth, object-to-mouth, and incidental
ingestion of soil) is >100, and therefore, does not concern HED.

Aggregate Risk

No acute aggregate risk assessment was needed because of a lack of a
single dose effect.  The chronic aggregate risk assessment consisted of
the dietary exposure assessment where food and water exposures were far
below HED’s level of concern (<0.1% cPAD for all population
subgroups).  As identical endpoints (toxic effects) and NOAELs were
selected for short-term exposure durations across all exposure routes,
short-term aggregate MOEs were calculated for adults and children.  HED
combined the averaged food & water exposures with the oral, dermal and
inhalation residential exposures for the short-term aggregate risk
assessment. The results of this assessment indicate that aggregate risks
do not exceed HED’s level of concern for adults or children.

Occupational Exposure and Risk

HED believes short- (1-30 days) and intermediate-term (1–6 months)
exposures are possible for occupational cyprosulfamide handlers.  A MOE
of 100 is adequate to protect occupational pesticide handlers.  All
occupational handler MOEs are estimated to be >100 for the proposed
uses, and therefore, do not cause concern for HED.

There is the possibility for agricultural workers to have
postapplication exposure to cyprosulfamide following its proposed crop
usage.  A MOE of 100 is adequate to protect re-entry workers on day
zero. All MOEs are estimated to be ≥100 for the proposed uses, and
therefore, do not cause concern for HED.

Environmental Justice Considerations

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, “Federal Actions to
Address Environmental Justice in Minority Populations and Low-Income
Populations,”   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf"
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf .

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures.
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intake by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Additionally, OPP is
able to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant.  Whenever appropriate, nondietary exposures based on home use
of pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
postapplication are evaluated.  Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

Review of Human Research

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

2.0	Ingredient Profile  TC \l1 "2.0	Ingredient Profile

Cyprosulfamide is classified as a herbicide safener.  Its use affords
corn plants some degree of protection against the phytotoxic effects of
the herbicide active ingredient included in the herbicide formulation.

Applications are allowed by ground and aerial equipment.  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.

Summary of Proposed Uses  TC \l2 "2.1	Summary of Proposed Uses

Table 2.1a.		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 2.1b.		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

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

ornamental and turf  (residential use)

0.027	1	0.027	NS

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.

2.2	Structure and Nomenclature  TC \l2 "2.2	Structure and Nomenclature

Table 2.2		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

2.3	Physical and Chemical Properties  TC \l2 "2.3	Physical and Chemical
Properties

The physicochemical properties of cyprosulfamide are reported in Table
2.3.  The vapor pressure is low, so inhalation exposure is only expected
during application, and not via volatilization of deposited residues.

Table 2.	3	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	~6 x 10-9 Pa at 20 C  [H. Smeykal, 2004]

	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

3.0	Hazard Characterization/Assessment  TC \l1 "3.0	Hazard
Characterization/Assessment

The cyprosulfamide hazard characterization/assessment was developed in
consultation with the UK and PMRA, and the resulting hazard assessment
was considered by HED’s Toxicology Science Assessment Committee
(Thiencarbazone Methyl (TCM) and Cyprosulfamide (CS): ToxSAC Meeting on
March 6, 2008; J. Kidwell, 24-APR-2008).

3.1	Hazard and Dose-Response Characterization  TC \l2 "3.1	Hazard and
Dose-Response Characterization

3.1.1	Database Summary  TC \l3 "3.1.1	Database Summary

<IP_ADDRESS>	Studies available and considered  TC \l4 "<IP_ADDRESS>	Studies
available and considered

A complete battery of acute, subchronic and chronic studies in rats or
mice and dogs, carcinogenicity in rats and mice, developmental in rats
and rabbits, a reproduction study in rats, acute and subchronic
neurotoxicity screen studies in rats, as well as a battery of
mutagenicity/genetic toxicity studies, are available for the parent
cyprosulfamide.  Additional mutagenicity/genetic toxicity studies and
either 28- or 90-day subchronic studies in rats are available for two
metabolites of cyprosulfamide.

<IP_ADDRESS>	Mode of action   TC \l4 "<IP_ADDRESS>	Mode of action

The primary toxicological mode of action of cyprosulfamide is related to
the formation of calculi/stones in the urothelial tract from the
precipitation of the parent molecule.  The accumulation of
calculi/stones in the urothelial system results in irritation with
subsequent hyperplasia and eventual degenerative changes and in some
cases neoplasia.

<IP_ADDRESS>	Sufficiency of studies/data  TC \l4 "<IP_ADDRESS>	Sufficiency of
studies/data

The acute, subchronic, and chronic studies were sufficient to determine
potential human hazards associated with the proposed uses.  The data
quality is acceptable, and the number of species tested and toxic
endpoints measured are consistent with OPPTS guidelines and 40 CFR part
158.

3.1.2	Toxicological Effects  TC \l3 "3.1.2	Toxicological Effects

Study summaries of the subchronic, chronic, developmental, reproduction,
and neurotoxicity studies for cyprosulfamide are provided in Appendix A
at the end of this document.

Acute toxicity and irritation.  Cyprosulfamide has low acute toxicity
via the oral, dermal and inhalation routes of exposure.  Cyprosulfamide
has a low acute oral (LD50 > 2000 mg/kg bw), dermal (LD50 > 2000 mg/kg
bw) and inhalation toxicity (LC50 >3500 mg/m3 air) in male and female
rats.  Though it is a slight irritant to the eye, cyprosulfamide is
neither a skin irritant nor a skin sensitizer to rabbits and guinea
pigs, respectively.

Subchronic and chronic oral toxicity.  The most toxicologically
significant effect of cyprosulfamide occurs at higher doses and is in
the urothelial system including the kidney, bladder and urinary tract of
rats, dogs and mice.  The rat is the most sensitive species (LOAEL = 156
mg/kg/day in males and 224 mg/kg/day in females), followed by the dog
(LOAEL = 226 mg/kg/day in males and 242 mg/kg/day in females) and then
the mouse (LOAEL = 287 mg/kg/day in males and 616 mg/kg/day in females).
The common signs of urinary tract pathology include stones (crystals or
calculi), inflammation, hyperplasia, scarring, necrosis, erosion,
dilations, haemorrhage and infiltrates. The toxicity to the urothelial
system results from the formation of calculi and stones and resulting
irritation leading to potentially fatal nephropathy and in some cases
neoplasia.  Certain other effects of cyprosulfamide were considered
secondary to the stress caused by the nephropathy.

Developmental and reproductive toxicity.  Maternal toxicity in rats was
evident by reduced body weight and occasional kidney effects but there
were no developmental effects in the offspring.

Because excessive toxicity including mortality was noted at 500
mg/kg/day in the first study with rabbits, a second study was conducted
at 250 mg/kg/day and although maternal toxicity was evident by abortions
(2) and body weight effects in the animals aborting there were no
developmental effects in the fetuses at 250 mg/kg/day.

In the reproduction study, systemic maternal toxicity was evident at the
LOAEL 2400 ppm (approximately 202 mg/kg/day in males and from about 173
to about 260 mg/kg/day in females) as indicated by organ changes in the
spleen and urinary tract and at the greater than 1000 mg/kg/day there
was mortality among the dams associated with poor physical condition and
severe renal lesions. The LOAEL for reproductive toxicity was also 2400
ppm based on reduced rearing index.  The LOAEL for offspring toxicity
was also 2400 ppm  and at 12000 ppm developmental effects in the rat
pups included decreased pup weight, delayed vaginal opening (apparently
related to the decreased pup weight), reduced viability, reduced
lactation index, and clinical findings (paleness, cold to touch, missing
milk spot and thin appearance) at the highest dose tested.  Thus, the
effects in the pups are at the same doses showing severe toxicity in the
dams and no increase in sensitivity of the pups is indicated.

Neurotoxicity.  Specific neurotoxicity was not identified in the rat,
mouse or dog subchronic or chronic studies or in the rat acute and
subchronic neurotoxicity screen studies.

Immunotoxicity.  Cyprosulfamide was assessed in a complete battery of
subchronic, chronic, carcinogenicity, developmental and reproductive
studies as well as acute and subchronic neurotoxicity screen studies.
In general high doses typically in the range of greater than 150
mg/kg/day were required to initiate the characteristic urothelial
toxicity of cyprosulfamide, which is the most sensitive endpoint in the
database.

There were some indications of possible immunotoxicity in the form of
increased severity of lymphocytolysis in the subchronic mouse study in
females only at a high dose of about 1300 mg/kg/day.  Lymphocytolysis in
the control animals was only minimal but slight in some of the high dose
animals.  However, this difference in severity is not of concern
because: 1) the marginal change in severity between control and dosed
animals was only noted at a very high dose and may not constitute an
adverse effect, and 2) no similar effect was seen in the carcinogenicity
study in the mouse at about 600 mg/kg/day or in other species.  In
addition, HED considered the entire toxicity database for cyprosulfamide
for potential adverse effects on the thymus and spleen as indications of
potential immunotoxicity and noted changes in thymus weight and shape
and brown pigment in the spleen.  However, these were determined to be
non-specific changes not indicative of immunotoxicity.  Finally,
cyprosulfamide does not belong to a class of chemicals that would be
expected to be immunotoxic.  Therefore, based on the above
considerations, HED does not believe that conducting a special series
870.7800 immunotoxicity study will result in a NOAEL less than the NOAEL
of 39 mg//kg/day already set for cyprosulfamide and an additional
uncertainty factor (UFDB) for database uncertainties does not need to be
applied.

Mutagenicity and genetic toxicity.  None of the battery of mutagenicity
or genetic toxicity studies indicated a positive result for
cyprosulfamide.

Carcinogenicity.  In the rat, at 321 mg/kg/day in males and 398
mg/kg/day in females, these doses were also associated with mortality
due to nephropathy.  Treatment related transitional cell carcinomas in
the kidney of one male and a transitional cell carcinoma in the urinary
bladder of one female were observed.  In mice, at 616 mg/kg/day in
females, a dose where there was formation of calculi in the urothelial
system, cyprosulfamide was associated with two incidents of transitional
cell papilloma in the urinary bladder.  Since the neoplasms occurred
only at the high doses that also demonstrated calculi, cyprosulfamide
was classified as “Not likely to be a Carcinogen to Humans at doses
that do not cause urothelial cytotoxicity”.

3.1.3	Dose-response  TC \l3 "3.1.3	Dose-response

In rats, in the subchronic feeding study, the NOAELs (in mg/kg/day)
were 58 and 70 for males and females and the LOAELs (in mg/kg/day) were
240 for males and 281 for females but more toxicity in the urinary tract
was evident at the higher doses of 730 for males and 859 for females.
In the chronic study, the NOAELs (in mg/kg/day) were 39 for males and 56
for females and the LOAELs were 159 for males and 220 for females with
more severe urinary tract toxicity at 321 for males and 447 for females.
 In the rat reproduction study, the NOAEL for parental systemic toxicity
was 39 mg/kg/day and the LOAEL was 173 to 202 to 260 mg/kg/day
(different LOAELs for growth, gestation and lactation periods were
determined) based on organ weight changes in the spleen (14%, p < 0.05,
with congestion,  increased iron pigment deposits and hemopoiesis) and
kidney.  The next higher dose of greater than 1000 mg/kg/day had spleen
weight increase to 34%, and additional indications of histopathological
alterations in the spleen and indications of urinary tract changes were
noted.  The similarity in dose selection in the rat studies influenced
toxic endpoint selection.  These rat studies are all considered
co-critical as the effects were not considered cumulative given the
similarity of NOAELs/LOAELs regardless of the study/dosing duration.

In dogs, in the subchronic feeding study, the NOAELs were 221 mg/kg/day
in both sexes and the LOAEL was 416 mg/kg/day for males and 341
mg/kg/day for females based on urinary tract effects at the highest dose
tested.   In the chronic study, the NOAEL was 66 mg/kg/day for both
sexes and the LOAEL was 226 to 242 mg/kg/day for both sexes with urinary
tract toxicity at the highest dose tested.

In mice, in the subchronic feeding study, the NOAELs (in mg/kg/day) were
1110 in males (the highest dose tested) and in females the NOAEL was 398
and the LOAEL was 1207 mg/kg/day based on increased severity of
lymphocytolysis.  In the chronic carcinogenicity study, the NOAEL was 50
mg/kg/day in males and 287 mg/kg/day in females with the LOAEL being 354
mg/kg/day in males and 616 mg/kg/day in females based on urinary tract
effects.

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)  TC \l2 "3.2
Absorption, Distribution, Metabolism, Excretion (ADME)

Cyprosulfamide was demonstrated to be rapidly absorbed from the
gastrointestinal tract (70-90%, with peak plasma levels after 10-60
minutes) and a total of 79-98% excreted within 24 hours with most in the
urine and with very little (up to 0.07%) tissue retention at 96 hours.
Following a single 2 mg/kg dose labeled in either the sulfonylbenzamine
or the methoxybenzoyl moieties, 70-90% was recovered in the urine and
7-18% was recovered in the feces.  At 200 mg/kg more radioactivity
(25-30.5%) was recovered in the feces.  The kidney was not shown to
retain the test material in the time frame and doses tested (2 and 200
mg/kg following a single dose).  Metabolism of cyprosulfamide was
limited with approximately 80-90% of the administered dose excreted as
unchanged parent.  Only a maximum of 0.01% was expired as CO2 or other
volatiles.  Biliary excretion was not assessed.  In rats, the metabolic
pathway was postulated to proceed by: i. elimination of the
cyclopropylamine moiety by hydrolysis of the carboxamide bond in the
sulfonyl-benzamide part forming cyprosulfamide-descyclopropylamino; ii.
desmethylation of the methoxybenzoyl moiety leading to
cyprosulfamide-desmethyl; and hydrolytic cleavage of the carboxamide
bond in the methyoxybenzoyl group of the parent molecule resulting in
formation of cyprosulfamide cyclopropyl-sulfamoylbenzamide and
cyprosulfamide-anisic acid.

3.3	FQPA Considerations  TC \l2 "3.3	FQPA Considerations

3.3.1	Adequacy of the Toxicity Database  TC \l3 "3.3.1	Adequacy of the
Toxicity Database

The toxicology database used to assess pre- and post-natal exposure to
cyprosulfamide is considered adequate.  The following acceptable studies
are available to support this determination:

developmental toxicity study in rats

developmental toxicity study in rabbits

two-generation reproduction study in rats

acute neurotoxicity study in rats

subchronic neurotoxicity study in rats

3.3.2	Evidence of Neurotoxicity  TC \l3 "3.3.2	Evidence of Neurotoxicity

There are both acute and subchronic neurotoxicity studies with
cyprosulfamide.  In the acute study, no evidence of neurotoxicity was
apparent at the highest dose tested of 2060 mg/kg.  At this dose there
was transient urine staining  TC \l3 "3.3.2	Evidence of Neurotoxicity .
In the subchronic study, there were no effects of treatment at the
highest dose tested (592 mg/kg/day in males and 748 mg/kg/day in
females).

3.3.3	Developmental Toxicity Studies  TC \l3 "3.3.3	Developmental
Toxicity Studies

In the rat developmental toxicity study, the NOAEL for developmental
toxicity was 1000 mg/kg/day since there were no effects on development
at the highest dose tested. This study demonstrated a NOAEL for maternal
toxicity at 250 mg/kg/day based mainly on weight gain effects and
indications of kidney effects in one animal at 1000 mg/kg/day.

There are two developmental toxicity studies in rabbits and together
these studies demonstrated a NOAEL of 125 mg/kg/day for maternal
toxicity and 250 mg/kg/day for developmental toxicity.   Thus, neither
study indicated an increased sensitivity of the fetuses relative to the
does.  The first study had excessive maternal toxicity at the high dose
of 500 mg/kg/day including deaths and a second study was conducted with
only one treatment group and a control.  The second study demonstrated
significant maternal toxicity at a dose of 250 mg/kg/day including two
does that aborted and these individuals showed body weight reduction and
signs of yellow staining.  The remaining does did not have weight
effects but showed yellow sediment in the urine.

3.3.4	Reproductive Toxicity Study  TC \l3 "3.3.4	Reproductive Toxicity
Study

Since there was some evidence of systemic, reproductive and offspring
toxicity at the mid dose level dose tested, the NOAEL and LOAEL for
systemic, reproductive and offspring toxicity was 400 ppm (39 mg/kg/day
in males and 55 mg/kg/day in females) and the LOAEL was 2400 ppm (202
mg/kg/day in males and 260 mg/kg/day in females).  Parental systemic
toxicity was evident at 2400 ppm as indicated by organ changes in the
spleen and urinary tract.  At 12000 ppm, there was mortality among the
dams associated with poor physical condition and severe renal lesions.
Reproductive effects were also noted at 2400 ppm as indicated by reduced
rearing index.  Offspring toxicity at 2400 ppm was indicated by lower
pup weight.  Other developmental effects in the pups were evident at
12000 ppm and included decreased pup weight, delayed vaginal opening
(apparently related to the decreased pup weight), reduced viability (3
total litter loss in the F1 generation), reduced lactation index,
clinical findings (paleness, cold to touch, missing milk spot and thin
appearance).  Thus, the effects in the pups are at the same doses
showing severe toxicity in the dams and no increase in sensitivity of
the pups is indicated.

The reproduction study does not demonstrate increased susceptibility of
the offspring to cyprosulfamide.

3.3.5	Additional Information from Literature Sources  TC \l3 "3.3.5
Additional Information from Literature Sources

PubMed was used to assess the literature (April 14, 2008) but no
specific articles addressing the systemic toxicity of cyprosulfamide
were found.

3.3.6	Pre-and/or Postnatal Toxicity  TC \l3 "3.3.6	Pre-and/or Postnatal
Toxicity

There is no evidence of pre- and/or post-natal toxicity.

<IP_ADDRESS>	Determination of Susceptibility  TC \l4 "<IP_ADDRESS>	Determination
of Susceptibility

There is no indication of increased susceptibility of rat or rabbit
offspring to cyprosulfamide as indicated by the rat and rabbit
developmental toxicity studies and the rat reproduction study.    TC \l4
"<IP_ADDRESS>	Determination of Susceptibility

  TC \l4 "<IP_ADDRESS>	Determination of Susceptibility

<IP_ADDRESS>	Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility   TC \l4 "<IP_ADDRESS>	Degree of Concern
Analysis and Residual Uncertainties for Pre- and/or Postnatal
Susceptibility

There is no concern for increased susceptibility of offspring.

3.3.7	Recommendation for a Developmental Neurotoxicity Study

No developmental neurotoxicity study is being recommended because
cyprosulfamide does not demonstrate specific neurotoxicity in either the
acute or subchronic screen studies or in other studies in the toxicity
database.

3.4	Safety Factor for Infants and Children  TC \l2 "3.4	Safety Factor
for Infants and Children

The cyprosulfamide risk assessment team evaluated the quality of the
toxicity and exposure data and, based on these data, recommended that
the FQPA Safety Factor be reduced to 1x.  The recommendation is based on
the following:

The toxicology database for cyprosulfamide is complete except for
immunotoxicity studies.  There were some indications of possible
immunotoxicity in the form of increased severity of lymphocytolysis in
the subchronic mouse study in females only at a high dose of about 1300
mg/kg/day.  Lymphocytolysis in the control animals was only minimal but
slight in some of the high dose animals.  However, this difference in
severity is not of concern because: 1) the marginal change in severity
between control and dosed animals was only noted at a very high dose and
may not constitute an adverse effect, and 2) no similar effect was seen
in the carcinogenicity study in the mouse at about 600 mg/kg/day or in
other species.  In addition, HED considered the entire toxicity database
for cyprosulfamide for potential adverse effects on the thymus and
spleen as indications of potential immunotoxicity and noted changes in
thymus weight and shape and brown pigment in the spleen.  However, these
were determined to be non-specific changes not indicative of
immunotoxicity.  Finally, cyprosulfamide does not belong to a class of
chemicals that would be expected to be immunotoxic.  Therefore, based on
the above considerations, HED does not believe that conducting a special
series 870.7800 immunotoxicity study will result in a NOAEL less than
the NOAEL of 39 mg//kg/day already set for cyprosulfamide and an
additional uncertainty factor (UFDB) for database uncertainties does not
need to be applied.

There is no pre- or post-natal susceptibility.

There are no residual uncertainities.

The exposure assessment is protective: the chronic dietary food exposure
assessment utilizes tolerance level residues, assume 100% of crops with
requested uses of cyprosulfamide are treated, and employ default
processing factors.

The drinking water assessment generated estimated drinking water
concentrations (EDWCs) using models and associated modeling parameters
which are designed to provide conservative, health protective, high-end
estimates of water concentrations.  The highest relevant EDWCs were used
in the dietary (food and drinking water) exposure assessment.

By using these screening-level exposure assessments in the chronic
dietary (food and drinking water) assessments, risk is not
underestimated.

Residential exposure estimates do not underestimate risks as they are
primarily based on high-end screening level data sources.

3.5	Hazard Identification and Toxicity Endpoint Selection  TC \l2 "3.5
Hazard Identification and Toxicity Endpoint Selection

A summary of the toxicological endpoints and doses chosen for the
relevant exposure scenarios for human risk assessment are found in
Tables 3.5.10a and 3.5.10b.  See text below for rationales.

3.5.1	Acute Reference Dose (aRfD) - Females age 13-49 and the General
Population  TC \l3 "3.5.1	Acute Reference Dose (aRfD) - Females age
13-49 and the General Population

No selection since there was no evidence of relevant toxicity following
a single dose.

3.5.2	Chronic Reference Dose (cRfD)   TC \l3 "3.5.2	Chronic Reference
Dose (cRfD)

Study Selected:  Chronic Toxicity/Carcinogenicity Study in Rats

Dose/Endpoint for Establishing the cRfD:  NOAEL = 39 mg/kg/day (males)
based sulfonamide like crystals in urine and treatment-related
nephropathy in the kidney and urinary bladder at 159 mg/kg/day (LOAEL).

Comments:  The selection of the NOAEL of 39 mg/kg/day from the
chronic/carcinogenicity study harmonizes with the selection made by the
United Kingdom.  The selection of the rat chronic feeding study NOAEL is
supported by other studies in the toxicity data base. The rat
reproduction study also has a NOAEL of 39 mg/kg/day with a LOAEL of
approximately (there are LOAELs for growth, gestation and lactation
dosing periods) 173 to around 200 to 260 mg/kg/day; the chronic dog
study had a NOAEL of 66 mg/kg/day; and the mouse chronic study has a
NOAEL of 50 mg/kg/day.  NOAELs for the subchronic rat, dog and mouse
were 58, 221 and 398 mg/kg/day, respectively.

Chronic RfD = 39 mg/kg/day (NOAEL) = 0.39 mg/kg/day

100 (UF)

3.5.3	Incidental Oral Exposure (Short- and Intermediate-term)   TC \l3
"3.5.3	Incidental Oral Exposure (Short- and Intermediate-Term)

Study Selected:  Subchronic Toxicity Study in the Rat

Dose/Endpoint for Risk Assessment:  NOAEL = 58 mg/kg/day based on
hyperplasia on the urothelium of the urinary bladder seen at 240
mg/kg/day (LOAEL).

Comments:  The NOAEL of 58 mg/kg/day from the rat subchronic study was
selected since no indications of toxicity in the rat were noted within
the 90-day dosing period at this dose and renders the lower NOAEL from
the rat chronic feeding study of 39 mg/kg/day inappropriate because of
the longer exposure duration.  The rat reproduction study with a NOAEL
and LOAEL of 39 and 173 mg/kg/day to about 200 to 260 mg/kg/day is
considered co-critical.  The higher level of 58 mg/kg/day from the rat
subchronic study rather than 39 mg/kg/day from the reproduction study
was selected because HED does not believe that there will be toxicity in
a reproduction study at 58 mg/kg/day since the effects at the LOAEL in
the rat reproduction study (173 mg/kg/day) were not severe.  In
addition, the dog subchronic study demonstrated a NOAEL of 221 mg/kg/day
and the rat (250 mg/kg/day) and rabbit (125 mg/kg/day) studies also had
NOAELs higher than the 58 mg/kg/day selected.

3.5.4	Dermal Absorption  TC \l3 "3.5.4	Dermal Absorption

There is no in vivo dermal absorption study with cyprosulfamide.  There
are also no dermal toxicity studies to compare a common endpoint in a
common species to estimate dermal absorption.  Therefore, the default
assumption of 100% dermal absorption was applied.

3.5.5	Dermal Exposure (Short-, and Intermediate-term)

Study Selected:  Subchronic Toxicity Study in the Rat

Dose/Endpoint for Risk Assessment:  NOAEL = 58 mg/kg/day (males) based
on hyperplasia of the urothelium in the urinary bladder seen at 240
mg/kg/day (LOAEL).

Comments:  The NOAEL of 58 mg/kg/day from the rat subchronic study was
selected since no indications of toxicity in the rat were noted within
the 90-day dosing period at this dose and renders the lower NOAEL from
the rat chronic feeding study of 39 mg/kg/day inappropriate because of
the longer exposure duration.  The rat reproduction study with a NOAEL
and LOAEL of 39 and 173 to about 200 to 260 mg/kg/day is considered
co-critical.  The higher level of 58 mg/kg/day from the rat subchronic
study rather than 39 mg/kg/day from the reproduction study was selected
because HED does not believe that there will be toxicity in a
reproduction study at 58 mg/kg/day since the effects at the LOAEL in the
rat reproduction study (173 mg/kg/day) were not severe.  In addition,
the dog subchronic study demonstrated a NOAEL of 221 mg/kg/day and the
rat (250 mg/kg/day) and rabbit (125 mg/kg/day) studies also had NOAELs
higher than the 58 mg/kg/day selected.

<IP_ADDRESS> Dermal Exposure (Long-term)

Study Selected:  Chronic Toxicity/Carcinogenicity Study in Rats (with
the 2-generation reproduction study in rats as a co-critical study)

Dose/Endpoint for Risk Assessment:  NOAEL = 39 mg/kg/day (males) (from
the chronic toxicity/carcinogenicity study in the rat) based on
sulfonamide-like crystals in urine and treatment-related nephropathy in
the kidney and urinary bladder at 159 mg/kg/day (LOAEL).

In the co-critical 2-generation reproduction rat study, the parental
NOAEL = 39 mg/kg/day (males) based on organ changes in the spleen and
urinary tract seen at 202 mg/kg/day (LOAEL).

Comments:  The chronic toxicity/carcinogenicity study in rats and the
2-generation reproduction study in rats can be used as co-critical
studies since they have basically the same NOAELs/LOAELs.  It is
appropriate to use the chronic toxicity/carcinogenicity rat study, with
the 2-generation reproduction study as a co-critical study, for the
long-term exposure scenarios.

Inhalation Exposure (Short-, and Intermediate-term)

Study Selected:  Subchronic Toxicity Study in the Rat

Dose/Endpoint for Risk Assessment:  NOAEL = 58 mg/kg/day (males) based
on hyperplasia of the urothelium in the urinary bladder seen at 240
mg/kg/day (LOAEL).

Comments:  The NOAEL of 58 mg/kg/day from the rat subchronic study was
selected since no indications of toxicity in the rat were noted within
the 90-day dosing period at this dose and renders the lower NOAEL from
the rat chronic feeding study of 39 mg/kg/day inappropriate because of
the longer exposure duration.  The rat reproduction study with a NOAEL
and LOAEL of 39 and 173 to about 200 to 260 mg/kg/day is considered
co-critical.  The higher level of 58 mg/kg/day from the rat subchronic
study rather than 39 mg/kg/day from the reproduction study was selected
because HED does not believe that there will be toxicity in a
reproduction study at 58 mg/kg/day since the effects at the LOAEL in the
rat reproduction study (173 mg/kg/day) were not severe.  In addition,
the dog subchronic study demonstrated a NOAEL of 221 mg/kg/day and the
rat (250 mg/kg/day) and rabbit (125 mg/kg/day) studies also had NOAELs
higher than the 58 mg/kg/day selected.

For the short- and intermediate-term inhalation exposure scenarios,
since there are no inhalation toxicity studies available for use in
selection of the dose and endpoint for this risk assessment, the use of
an oral study (90-day rat) is appropriate for this time frame.  100%
absorption of inhaled cyprosulfamide is assumed.

<IP_ADDRESS> Inhalation Exposure (Long-term)

Study Selected:  Chronic Toxicity/Carcinogenicity Study in Rats (with
the 2-generation reproduction study in rats as a co-critical study)

Dose/Endpoint for Risk Assessment:  NOAEL = 39 mg/kg/day (males) (from
the chronic toxicity/carcinogenicity study in the rat) based on
sulfonamide-like crystals in urine and treatment-related nephropathy in
the kidney and urinary bladder at 159 mg/kg/day (LOAEL).

In the co-critical 2-generation reproduction rat study, the parental
NOAEL = 39 mg/kg/day (males) based on organ changes in the spleen and
urinary tract seen at 202 mg/kg/day (LOAEL).

Comments:  The chronic toxicity/carcinogenicity study in rats and the
2-generation reproduction study in rats can be used as co-critical
studies since they have basically the same NOAELs/LOAELs.  It is
appropriate to use the chronic toxicity/carcinogenicity rat study, with
the 2-generation reproduction study as a co-critical study, for the
long-term exposure scenarios.

For the long-term inhalation exposure scenario, since there are no
inhalation toxicity studies available for use in selection of the dose
and endpoint for this risk assessment, the rat chronic/onco oral study
is appropriate for this time frame. 100% absorption of inhaled
cyprosulfamide is assumed.

Special Note.  The selection of 39 mg/kg/day for the chronic RfD based
on the rat chronic feeding study and the selection of 59 mg/kg/day based
on the rat subchronic feeding study are harmonized with both the PSD of
the United Kingdom and the PMRA of Canada.

3.5.7	Level of Concern for Margin of Exposure  TC \l3 "3.5.7	Level of
Concern for Margin of Exposure

Table 3.5.7   Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	MOE < 100	MOE < 100	NA

Inhalation	MOE < 100	MOE  < 100	NA

Residential Exposure

Dermal	MOE < 100	MOE < 100	NA

Inhalation	MOE < 100	MOE < 100	NA

Incidental Oral	MOE < 100	MOE < 100	NA

Dietary (Food and Water)	NA	NA	exposure > 100% cPAD

(chronic exposure)

The Levels of Concern (LOCs) for the dermal, inhalation and incidental
oral routes of exposure are based on the conventional interspecies
extrapolation (10X) and intraspecies variation (10X) uncertainty
factors.  No additional uncertainty factors are necessary, nor are they
applied.  The LOCs for the dietary route are expressed as a percentage
of a maximum acceptable dose (i.e., the dose which HED has concluded
will result in no unreasonable adverse health effects).  This dose is
referred to as the population adjusted dose (PAD).  The PAD is
equivalent to the RfD divided by the FQPA Safety Factor (which has been
reduced to 1x in the case of cyprosulfamide).  For acute and non-cancer
chronic exposures, HED is concerned when estimated dietary risk exceeds
100% of the PAD.

3.5.8	Recommendation for Aggregate Exposure Risk Assessments  TC \l3
"3.5.8	Recommendation for Aggregate Exposure Risk Assessments

Under FQPA, HED must consider and aggregate pesticide exposures and risk
from three major sources: food, drinking water, and residential
exposures.  Residential exposure to cyprosulfamide is expected,
therefore, the aggregate exposure assessment for this chemical should
include the contributions from food, drinking water, and residential
sources.  Exposures across all routes may be aggregated based on the
common effect observed in the toxicity testing:  hyperplasia on the
urothelium of the urinary bladder.

3.5.9	Classification of Carcinogenic Potential  TC \l3 "3.5.9
Classification of Carcinogenic Potential

The following was taken from the CARC report (HED document No. 0054810,
February 29, 2008):

In accordance with the EPA’s Final Guidelines for Carcinogen Risk
Assessment (March, 2005), the CARC classified cyprosulfamide as “Not
likely to be Carcinogenic to Humans at doses that do not cause
urothelium cytotoxicity.”  The formation of low incidence transitional
cell tumors of the kidney and/or urinary bladder seen at the high dose
in male (at 321 mg/kg/day) or female rats (at 491 mg/kg/day) and female
mice (at 616 mg/kg/day) are considered to be related to the secondary
effects of the urothelial toxicity (irritation) and regenerative
proliferation associated with the formation of urinary tract
crystals/calculi.  This is a common mode of action for bladder
carcinogenesis in rodents for non-genotoxic chemicals.  There is also no
concern for mutagenicity.

Because the chronic Reference Dose (cRfD) has been set at the NOAEL of
39 mg/kg/day, this cRfD will be protective of both cancer and
pre-cancerous effects seen in the carcinogenicity studies at doses of
321 mg/kg/day and higher.

3.5.10	Summary of Toxicological Doses and Endpoints for Cyprosulfamide
for Use in Human Risk Assessments  TC \l3 "3.5.10	Summary of
Toxicological Doses and Endpoints for Flubendiamide for Use in Human
Risk Assessments

Table 3.5.10a Summary of Toxicological Doses and Endpoints for
Cyprosulfamide for Use in Dietary and Non-Occupational Human Health Risk
Assessments

Exposure/

Scenario	Point of Departure	Uncertainty/FQPA Safety Factors	RfD, PAD,
Level of Concern for Risk Assessment	Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children)	No
selection because no indication of significant toxicity following a
single dose.

Acute Dietary

(Females 13-49 years of age)

	Chronic Dietary (All Populations)	NOAEL= 39 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Chronic RfD =

0.39

mg/kg/day

cPAD = 0.39 mg/kg/day	Chronic feeding/carcinogenicity - rat

LOAEL = 159 mg/kg/day based on nephropathy.

Incidental Oral Short-Term (1-30 days) and Intermediate-Term (1-6
months) 	NOAEL= 58 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Residential LOC for MOE = 100

	Subchronic feeding in rats.

LOAEL = 240 mg/kg/day based on hyperplasia on the urothelium of the
urinary bladder.

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

UFH= 10x

FQPA SF= 1x

	Residential LOC for MOE = 100

	Subchronic feeding in rats.

LOAEL = 240 mg/kg/day based on hyperplasia on the urothelium of the
urinary bladder.

Dermal long term (> 6 months) 	NOAEL = 39 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Residential LOC for MOE = 100

	Chronic feeding/carcinogenicity - rat

LOAEL = 159 mg/kg/day based on nephropathy.  The rat reproduction study
with a NOAEL of 39 mg/kg/day and a LOAEL of 202 mg/kg/day based on
changes in spleen and urinary tract.

Inhalation Short- Term (1-30 days) and Intermediate-Term (1-6 months)
NOAEL=58  mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Residential LOC for MOE = 100

	Subchronic feeding in rats.

LOAEL = 240 mg/kg/day based on hyperplasia on the urothelium of the
urinary bladder.

Inhalation long term (> 6 months	NOAEL = 39 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Residential LOC for MOE = 100

	Chronic feeding/carcinogenicity - rat

LOAEL = 159 mg/kg/day based on nephropathy.  The rat reproduction study
with a NOAEL of 39 mg/kg/day and a LOAEL of 202 mg/kg/day based on
changes in spleen and urinary tract.

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans at doses that do not cause urothelium
cytotoxicity.”

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

Table 3.5.10b  Summary of Toxicological Doses and Endpoints for
Cyprosulfamide for Use in Occupational Human Health Risk Assessments

Exposure/

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

Dermal Short-Term (1-30 days)	NOAEL = 58 mg/kg/day	UFA= 10 x

UFH= 10x

	Residential LOC for MOE = 100

	Subchronic feeding in rats.

LOAEL = 240 mg/kg/day based on hyperplasia on the urothelium of the
urinary bladder.

Dermal Intermediate-Term (1-6 months)

Dermal long term (> 6 months) 	NOAEL = 39 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Residential LOC for MOE = 100

	Chronic feeding/carcinogenicity - rat

LOAEL = 159 mg/kg/day based on nephropathy.  The rat reproduction study
with a NOAEL of 39 mg/kg/day and a LOAEL of 202 mg/kg/day based on
changes in spleen and urinary tract.

Inhalation Short-Term (1-30 days)	NOAEL=58  mg/kg/day	UFA= 10x

UFH= 10x

	Residential LOC for MOE = 100

	Subchronic feeding in rats.

LOAEL = 240 mg/kg/day based on hyperplasia on the urothelium of the
urinary bladder.

Inhalation Intermediate-term (1-6 months)

Inhalation long term (> 6 months	NOAEL = 39 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Residential LOC for MOE = 100

	Chronic feeding/carcinogenicity - rat

LOAEL = 159 mg/kg/day based on nephropathy.  The rat reproduction study
with a NOAEL of 39 mg/kg/day and a LOAEL of 202 mg/kg/day based on
changes in spleen and urinary tract.

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans at doses that do not cause urothelium
cytotoxicity.”

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level.
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  MOE = margin of exposure.  LOC = level of concern.  N/A
= not applicable.

3.6	Endocrine disruption  TC \l2 "3.6	Endocrine disruption

EPA is required under the Federal Food, Drug, and Cosmetic Act (FFDCA),
as amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) “may have an effect in humans that is similar to an
effect produced by a naturally occurring estrogen, or other such
endocrine effects as the Administrator may designate.”  Following
recommendations of the Endocrine Disruptor and Testing Advisory
Committee (EDSTAC), EPA determined that there was a scientific basis for
including, as part of the program, the androgen and thyroid hormone
systems, in addition to the estrogen hormone potential effects in
wildlife.  For pesticide chemicals, EPA will use the Federal
Insecticide, Fungicide, and Rodenticide Act (FIFRA) and, to the extent
that effects in wildlife may help determine whether a substance may have
an effect in humans, FFDCA authority to require the wildlife
evaluations.  As the science develops and resources allow, screening of
additional hormone systems may be added to the Endocrine Disruptor
Screening Program (EDSP).  When additional appropriate screening and/or
testing protocols being considered under the Agency’s EDSP have been
developed, cyprosulfamide may be subjected to further screening and/or
testing to better characterize effects related to potential endocrine
disruption.

4.0	Public Health and Pesticide Epidemiology Data  TC \l1 "4.0	Public
Health and Pesticide Epidemiology Data

Cyprosulfamide is an unregistered, new herbicide safener, and therefore,
no public health, epidemiologic data, and/or incident reports are
available.  Additionally, no public health or epidemiology data were
found for this chemical when searched in the National Library of
Medicine TOXNET databases.

5.0	Dietary Exposure/Risk Characterization  TC \l1 "5.0	Dietary
Exposure/Risk Characterization

Reference: The Chemistry Science Advisory Council reviewed the
cyprosulfamide residue chemistry data assessment, from which most of the
following information was summarized: William Donovan, DP341999,
5/28/2008.

5.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "5.1
Pesticide Metabolism and Environmental Degradation

5.1.1	Metabolism in Primary Crops  TC \l3 "5.1.1	Metabolism in Primary
Crops

The metabolism of cyprosulfamide was determined for three distinct use
patterns:  seed treatment (corn and sorghum), preemergence application
(corn), and postemergence application (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 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.

The treatment rates for the preemergence 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.

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.

For sorghum, raw agricultural commodities (RACs) of forage, grain, and
stover were harvested at maturity.  The total radioactive residue (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.  Thus, 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).

The nature of the residue in corn is understood based on the submitted
studies.  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.  Several minor structurally related metabolites (≤4% TRR)
were detected, and the chemical names and structures of these compounds
are depicted in Table B.1 in Appendix B.

5.1.2	Metabolism in Rotational Crops  TC \l3 "5.1.2	Metabolism in
Rotational Crops

The submitted confined rotational crop studies have been reviewed and
deemed adequate to satisfy data requirements.  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.

Under the use rates of this study, the only quantifiable metabolite
identified was M02.  HED concludes that the nature of the residue in
rotational crops is adequately understood and that the residues of
concern in rotational crops are parent cyprosulfamide and M02.  Several
minor metabolites (<2% TRR) were also detected; see Table B.1 in
Appendix B.

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.

5.1.3	Metabolism in Livestock  TC \l3 "5.1.3	Metabolism in Livestock

The nature of the residue in livestock is adequately understood based on
acceptable studies conducted on goats and laying hens.  Metabolism
studies with lactating goats and laying hens were conducted with
cyprosulfamide separately labeled in the sulfonylbenzamide ring and in
the methoxybenzoyl ring.

The goat metabolism studies used oral dose levels of 22.9 ppm (~140x the
reasonably balanced dietary burden of 0.16 ppm for dairy cattle) in the
diet for the sulfonylbenzamide ring label study and 25.3 ppm (~160x) in
the diet for the methoxybenzoyl ring study (1 goat per label, dosed for
5 days).  The poultry metabolism studies used oral dose levels of 33.5
ppm (~4,200x the reasonably balanced dietary burden of 0.008 ppm for
poultry) in the diet for the sulfonylbenzamide ring label study and 30.5
ppm (~3800x) in the diet for the methoxybenzoyl ring study (6 hens per
label, dosed for 14 days)

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.  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).  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.  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.  Similar metabolic pathways were
observed in goats and hens.

5.1.4	Analytical Methodology  TC \l3 "5.1.4	Analytical Methodology

An HPLC/MS/MS method, Method UB-008-P06-01, was submitted for the
determination of residues of cyprosulfamide and three metabolites in/on
samples of crop commodities.  Method UB-008-P06-01, or a modified
version of the method, was used for data collection in/on plant samples
collected from supporting studies (storage stability, crop field trials,
processing, and field rotational crop trials).  It is the original
proposed enforcement method, has undergone successful independent
laboratory validation, radiovalidation, and has been considered by
BEAD/ACL chemists for suitability.  The validated limit of quantitation
(LOQ) is 0.01 ppm for each analyte in each matrix.

An HPLC/MS/MS method, Method UB-006-A06-01, was submitted for the
determination of residues of cyprosulfamide and M02 in livestock
commodities.  Method UB-006-A06-01 was used for data collection in
samples of livestock commodities from the cattle and hen feeding studies
associated with the current petition.  It is also the proposed
enforcement method for animals.  Method UB-006-A06-01, with a validated
LOQ of 0.01 ppm for each analyte in each matrix except milk (LOQ = 0.005
ppm), was adequately validated using samples of muscle, liver, kidney,
fat, milk, and poultry egg.  HED deems the method to be adequate for
data collection based on method recovery data which are sufficiently
representative of the expected residue levels for the livestock
commodities.  Adequate radiovalidation data were also submitted
demonstrating that the procedures of Method UB-006-A06-01 adequately
extract aged residues of cyprosulfamide and metabolite M02 from goat
milk, muscle, fat, and liver and hen egg.  Adequate ILV data have been
submitted for Method UB-006-A06-01 using samples of beef muscle, fat,
and hen egg.

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).

The multiresidue methods are not suitable for the analysis of
cyprosulfamide or its metabolites.  The MRM testing data will be
forwarded to FDA for inclusion of results in PAM Vol. I.

Environmental Degradation

 TC \l3 "5.1.5	Environmental Degradation

[See A. McKinnon, The Drinking Water Degradates Identification
Memorandum for cyprosulfamide, 03-MAR-2008]

Cyprosulfamide is stable to hydrolysis at pH 4, 7 and 9.  Cyprosulfamide
degrades slowly under aerobic aquatic conditions, anaerobic aquatic
conditions and anaerobic soil conditions with half lives ranging from
78.8-158 days, 198 days and 64.2 days, respectively.  Cyprosulfamide
moderately degrades via soil photolysis with a half life of
approximately 20 days.  Cyprosulfamide degrades rapidly via aqueous
photolysis with an environmental photo transformation half-life of circa
3.3 days at pH 7.  Cyprosulfamide degrades rapidly via aerobic soil
metabolism with half life ranging from 2.3 to 9.9 days assuming single
first order degradation kinetics.  In the terrestrial field dissipation
studies, cyprosulfamide dissipated with half lives ranging from 8.8 to
18.4 days.  In one study (Canada) cyprosulfamide was detected at deepest
sampling point (105 to 120 cm below grade, at 14 days) and the deepest
extent of leaching not determined in this study.  Cyprosulfamide has a
very low vapor pressure of approximately 6 x 10-9 Pa at 20 C
(extrapolated value), and may be considered non-volatile.
Cyprosulfamide is ‘mobile’ to ‘moderately mobile’ based on
adsorption KOC values in all soils ranging from 23.1 to 168.7.
Adsorption Kd values for cyprosulfamide range from 0.23 to 1.94.

5.1.6	Comparative Metabolic Profile TC \l3 "5.1.6	Comparative Metabolic
Profile

Cyprosulfamide metabolism in plants depends on the use pattern, with
seed treatment and pre-emergent applications resulting in more extensive
metabolism than obtained from post-emergent foliar applications.
Specifically, metabolites M02, M10, M11, and M15 were detected at >10%
TRR in corn forage and stover samples following early season
applications.  In contrast, the later season use, which resulted in
higher overall residue levels, demonstrated significantly less
metabolism with mostly parent cyprosulfamide being found (M16 found at
10% TRR in corn stover).  In ruminants, parent cyprosulfamide was the
predominant residue with M02 also being a major metabolite.  For
poultry, M02 was the predominant residue.  In environmental matrices,
extensive degradation was observed with M01, M02, and M03 being major
degradates in soil studies; M01, M02, and M04 being major degradates in
aquatic studies; and M07 and M08 being major degradates in aqueous
photolysis studies.

In a series of rat metabolism studies, cyprosulfamide labeled with 14C
either in the sulfonylbenzamide or methoxybenzoyl rings, the
pharmacokinetics and pathway of rat metabolism was elucidated.  In the
studies with sulfonylbenzamide ring label, 86 to 99% of the administered
dose was recovered and 69 to 90% of the dose was excreted in the urine.
Absorption was rapid and maximum plasma levels were attained 10-60
minutes post dosing.  Insignificant levels (< 0.6% total) of label
remained in the carcass after 96 hours and no individual organ was
identified to accumulate the cyprosulfamide.  In methoxybenzoyl labeled
cyprosulfamide studies, maximum plasma levels were attained after about
40 minutes post dosing and 85 to 99.9% of the dose was recovered.  After
96 hours, 82% of the label was recovered in the urine and 18% in the
feces.  Only between < 0.001 to 0.029% was retained in the individual
organs with a total of approximately 0.07% retained in the carcass.

Metabolism proceeded by elimination of the cyclopropylamine moiety by
hydrolysis of the carboxamide bond forming the descyclopropylamino
metabolite (M01).  Apparent hydrolytic cleavage of the carboxamide bond
in M01 resulted in the formation of 2-methoxybenzoic acid (M07).  Parent
cyprosulfamide is also desmethylated at the methoxybenzoyl group to form
metabolite M04.  Lastly, hydrolytic cleavage of the carboxamide bond in
M04 results in the formation of cyclopropyl-sulfamoylbenzamide (M02).
All these rat metabolites were detected in low levels so that these
compounds should be considered minor metabolites.  In order to address
the major corn metabolites (based on percentage of TRR rather than
concentration) that were not found in the rat metabolism studies, namely
M10, M11, M15 and M16, the registrant conducted DEREK (Deductive
Estimation of Risk from Existing Knowledge) analysis of these compounds.
 None of these metabolites triggered any structural alerts for toxic
effects contained in the database except for M16 which was predicted to
have similar toxic effects as parent cyprosulfamide due to the aryl
sulfonamide structure.

5.1.7	Toxicity Profile of Major Metabolites and Degradates TC \l3 "5.1.7
Toxicity Profile of Major Metabolites and Degradates

Some limited experimental information is available on the toxicity of
the major degradates/metabolites in plants and environmental matrices.
This information was supplemented by structure activity relationship
(SAR) considerations obtained via the DEREK computational model.  A
brief synopsis of this information for the major metabolites and
degradates of cyprosulfamide follows.  There is a 90-day oral rat study
on M01 and there are no effects reported at the highest dose tested
(1094 mg/kg/day).  There is a 28-day oral rat study on M02 and there are
urinary tract and hematological changes reported in the females dosed at
246 mg/kg/day, which is consistent with the effects reported for the
parent compound at similar doses.  The DEREK toxicity predictions
reported a structural alert for the aryl sulfonamide portion of the
compound and bladder cancer, bladder urothelial hyperplasia and kidney
stone formation which again is consistent with the empirical data
submitted for the parent compound.  There is a 90-day oral rat study
with M03 that showed no adverse effects at the highest dose tested (888
to 1094 mg/kg/day).  M04 is the parent compound with a methyl group on
the methoxybenzoyl ring modified to a hydroxyl group.  This minor change
in chemical structure is not expected to contribute to a different
toxicity.  M05 is structurally similar to the parent compound without
the cyclopropyl group.  The lack of the cyclopropyl group is not
expected to alter the toxicity profile from that concluded for the
parent compound.  M10 is a sulfonamide lactate metabolite of
cyprosulfamide, which did not trigger any structural alert in DEREK
(registrant analysis).  Based on its structure, the toxicity profile
should not be different from cyprosulfamide.  M11 is a sulfonamide
alanine metabolite of cyprosulfamide, which did not trigger any
structural alert in DEREK (registrant analysis).  Based on its structure
the toxicity profile should not be different from cyprosulfamide.  Taken
together, these experimental and computational results imply that the
primary biological activity is expected to reside with the parent
compound; any metabolite(s) formed in the metabolism cascade is expected
to enhance excretion and decrease toxicity.

5.1.8	Pesticide Metabolites and Degradates of Concern TC \l3 "5.1.8
Pesticide Metabolites and Degradates of Concern

Reference: the risk assessment team brought the residue of concern issue
to the ROCKS.  The outcome of that meeting is captured in the following
memo: Cyprosulfamide.  Report of the Residues of Concern Knowledgebase
Subcommittee (ROCKS).  George Kramer, PC Code: 877400.  DP No.: D351495,
4/18/08.

Plants

Regulation of cyprosulfamide per se is appropriate for corn grain and
kernels as very low residue levels were identified in these matrices and
no metabolite was identified at more than 10%TRR.  In the seed treatment
and pre-emergence corn uses, residues exceeding 10% TRR and/or 0.01 ppm
were found in forage and stover samples for M02, M10, and M11.  However,
field trial data from the seed treatment + early emergence use show <LOQ
residues (<0.01 ppm) for parent, M02, M10 & M11 in all field, sweet and
pop corn matrices except 1) field corn stover, 2) sweet corn forage and
3) sweet corn stover.  In these three matrices, most samples had
residues <LOQ, and the maximum individual residue level was only
marginally greater than the LOQ.  The maximum residue level was ≤0.025
ppm for each individually measured compound from these trials (n=44
field corn, n=28 sweet corn, n=6 pop corn).  The maximum concentration
of parent, M02, M10, and M11 measured in any field corn stover sample
was 0.019, 0.017, 0.016, and <0.010 ppm, respectively.  The maximum
concentration of parent, M02, M10, and M11 measured in any sweet corn
forage sample was <0.010, <0.010, <0.010, and 0.015 ppm, respectively.
The maximum concentration of parent, M02, M10, and M11 measured in any
sweet corn stover sample was <0.010, 0.025, 0.024, and 0.012 ppm,
respectively.  All maxima occurred in separate samples, and most samples
had residue levels <0.01 ppm.

Field trial data from the postemergent use showed higher residue levels
than found in the seed treatment + early emergence trials.  All grain
samples had residues <LOQ of 0.01 ppm. The maximum concentration of
parent, M02, M10, and M11 measured in any field corn forage sample was
0.154, <0.010, 0.015, and 0.018 ppm, respectively.  The maximum
concentration of parent, M02, M10, and M11 measured in any field corn
stover sample was 0.157, 0.024, 0.030, and <0.010 ppm, respectively.
The maximum concentration of parent, M02, M10, and M11 measured in any
sweet corn forage sample was 0.408, 0.011, 0.010, and 0.015 ppm,
respectively.  The maximum concentration of parent, M02, M10, and M11
measured in any sweet corn stover sample was 1.02, 0.037, 0.030, and
0.012 ppm, respectively.  All maxima occurred in separate samples, and
most samples had residue levels <0.01 ppm.  In addition, it is
noteworthy that the highest residue level among all four compounds for
forage and stover was parent cyprosulfamide.

Limited toxicity data on M02 show that it can not be excluded as a
residue of concern based on hazard considerations.  Metabolites M10 and
M11 are expected to be less toxic than the parent compound based on SAR
analysis (DEREK) and can thus be excluded as a residue of concern based
on hazard considerations.

Based on the above considerations, parent cyprosulfamide is the residue
of concern not only in corn grain but also in forage and stover.  The
parent compound will serve as a better indicator of potential misuse in
the only samples likely to have residues >LOQ, those from the late
season postemergent use.  Therefore, for primary crops (corn), no
metabolites need to be included as residues of concern.

In the confined rotational crop studies, very low residues were found
with the only identified compound being M02.  Accordingly, in the
limited field rotational crop studies, at the desired plant back
interval (PBI) of 60 days, parent cyprosulfamide and M02 were analyzed
in soybean (seed, forage and hay), turnip (tops and roots), and wheat
(grain, forage, hay and straw).  All samples had residues <0.01 ppm.
Thus, there is no need to establish tolerances for rotational crops when
a 60-day PBI is observed.  However, it is reasonable to include parent
cyprosulfamide and M02 as the residues of concern for risk assessment
for rotational crops in the event that new uses are proposed in the
future which require new rotational crop studies and/or different PBIs.

Livestock

In most goat tissues, the primary residue was parent cyprosulfamide with
metabolite M02 comprising up to 38% TRR in milk samples from the S-label
study.  In laying hens, M02 comprised 81-94% TRR in the S-label
matrices.  As discussed above, M02 can not be excluded as a residue of
concern based on hazard considerations.  There is no need for
differences between the residues of concern for tolerance expression and
risk assessment as the proposed analytical enforcement methods detect
all proposed residues of concern.

Water

Degradate M05 was identified as a major terminal degradate in the soil
photolysis study, and  degradates M07 and M08 were identified as major
terminal degradates in the aqueous photolysis study.  Degradates M07 and
M08 are expected to be considerably less toxic than the parent compound
based on SAR analysis.  Also, aqueous photolysis is not expected to be a
major route of exposure for cyprosulfamide residues in drinking water.
Degradates M07 and M08 and can thus be excluded as a residue of concern
based on both exposure and hazard considerations.  Degradate M05 is
structurally similar to the parent compound without the cyclopropyl
group.  The lack of the cyclopropyl group is not expected to alter the
toxicity profile from that concluded for the parent compound.  However,
M05 can be excluded as a residue of concern based on exposure
considerations as demonstrated a short half-life in the available
studies.

Degradate M01 was identified as a major terminal degradate in an
anaerobic soil metabolism study; as a major transient degradate in the
aerobic soil metabolism study; and as a major terminal degradate in the
aerobic aquatic metabolism study (14.8%, 104 days).  Degradate M02 was
identified as a major terminal degradate in the aerobic soil metabolism,
anaerobic soil metabolism and aerobic aquatic metabolism studies.  In
addition, M02 was the only major degradate identified in the terrestrial
field dissipation studies.  Degradate M03 was identified as a major
terminal degradate in the aerobic soil metabolism and anaerobic soil
metabolism studies.  Degradate M04 was identified as a major terminal
degradate in the aerobic aquatic metabolism and anaerobic aquatic
metabolism (20.8%, 155 days) studies.  M04 may be considered a major
terminal degradate since the maximum concentrations were detected at the
termination of the studies.

Degradates M01 and M03 are expected to be considerably less toxic than
the parent compound based on DEREK analysis (see ROCKS memo).
Additionally, no adverse effects were observed 90-day oral rat toxicity
study with M03.  M01 and M03 and can thus be excluded as a residue of
concern based on hazard considerations.  As discussed above, M02 can not
be excluded as a residue of concern based on hazard considerations.  As
M04 is a single demethylation product and, therefore, structurally
similar to the parent, it can not be excluded as a residue of concern.
Therefore, the ROCKS recommended the residues of concern for drinking
water are cyprosulfamide, M02, and M04.  A summary of cyprosulfamide
residue of concern decisions made by the ROCKS is presented in Table
5.1.8.

Table 5.1.8  Summary of Metabolites and Degradates to be included in the
Risk Assessment and Tolerance Expression.

Matrix	Residues Included In Risk Assessment	Residues Included In
Tolerance Expression

Plants

	Primary Crop (Corn)	Cyprosulfamide per se

	Cyprosulfamide per se

	Rotational Crops	Cyprosulfamide + M02	Not Applicable

Livestock

	Ruminant	Cyprosulfamide + M02	Cyprosulfamide + M02

	Poultry	Cyprosulfamide + M02	40 CFR 180.6(a)(3)

Drinking Water

	Cyprosulfamide + M02 & M04	Not Applicable

5.1.9	Drinking Water Residue Profile TC \l3 "5.1.9	Drinking Water
Residue Profile

The Environmental Fate and Effects Division (EFED) has provided drinking
water values for cyprosulfamide and degradates M02 and M04 (personal
communication via email fromAmy McKinnon, 4/15/2008).  At this time, the
Agency lacks monitoring exposure data for use in risk assessments, as
this is a new herbicide safener.  Drinking water concentration estimates
are made by reliance on simulation or modeling, taking into account data
on the physical characteristics and fate characteristics of
cyprosulfamide and its degradates.

Surface Water.  A Tier 1 FIRST assessment based on the maximum single
corn use rate, 0.141 lb safener/A, was used to estimate drinking water
concentrations derived from surface water sources.  The FIRST model
provided an estimated drinking water concentration (EDWC) value of 2.4
ug/L for chronic exposure scenarios.

Groundwater.  In lieu of groundwater monitoring data for cyprosulfamide,
the Tier 1 groundwater screening model SCI-GROW was used to estimate
concentration of cyprosulfamide in groundwater sources.  The highest
proposed single use rate for cyprosulfamide (0.141 lbs safener/A) was
used for the modeling, resulting in a groundwater EDWC of 0.136 μg/L.

Table 5.1.9	Summary of Estimated Surface Water and Groundwater
Concentrations

	Cyprosulfamide + M02 + M04

	Surface Water Conc., ppb a	Groundwater Conc., ppb b

Chronic	2.4	0.14

a From the Tier 1 FIRST model.

b From the Tier 1 SCI-GROW model.

5.1.10	Food Residue Profile  TC \l3 "5.1.10	Food Residue Profile

Storage Stability

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.

Crop Field Trials

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.  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.

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, 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.

Meat, Milk, Poultry, and Eggs

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.

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.

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.

Processed Food

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.

Field Rotational Crops

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.

5.1.11	International Residue Limits TC \l3 "5.1.11	International Residue
Limits

There are no Codex, Canadian, or Mexican maximum residue limits (MRLs)
established for residues of cyprosulfamide in crop or livestock
commodities.  However, tolerance harmonization is expected to be
achieved for corn grain between the U.S., Canada, and U.K. upon
registration of the proposed uses.

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

Reference: The dietary exposure and risk assessment was summarized from
the following memo: D351493, Seyed Tadayon, 5/6/2008

5.2.1	Acute Dietary Exposure/Risk  TC \l3 "5.2.1	Acute Dietary
Exposure/Risk

Because no acute toxicity endpoint was identified for cyprosulfamide, no
acute dietary analysis was performed.

5.2.2	Chronic Dietary Exposure/Risk  TC \l3 "5.2.2	Chronic Dietary
Exposure/Risk

Chronic dietary risk assessments were conducted using DEEM-FCID™,
Version 2.03.  The analyses were performed to evaluate Section 3
requests for new uses of cyprosulfamide on corn  requested in the
current petition.

The chronic assessments assumed default processing factors, that 100% of
crops with requested uses of cyprosulfamide are treated, and that all
treated crops contain residues at tolerance level. In addition,
tolerance level residues for livestock commodities were also included in
these analyses to account for the potential transfer of plant residues
to livestock tissues.  Moreover, the assessments include the modeled
chronic surface water EDWC of 2.4 µg/L to account for potential
residues in drinking water.

These assumptions result in conservative, health-protective estimates of
exposure (Table 5.2).  These estimates are well below HED’s level of
concern (100% of the chronic population-adjusted dose [cPAD]).  The
maximum estimate is less than 0.1% of the cPAD for all population
subgroups.  These analyses indicate that there are no chronic dietary
exposure considerations that would preclude registration of
cyprosulfamide for the requested uses.

Table 5.2  Chronic Dietary Exposure to Cyprosulfamide.

Population Subgroup	cPAD, mg/kg/day	DEEM-FCID (food and water)

Exposure, mg/kg/day	%cPAD

U.S. Population

0.39	0.000072	<0.1

All infants (< 1 yr)

0.000194	<0.1

Children 1-2 yrs

0.000119	<0.1

Children 3-5 yrs

0.000121	<0.1

Children 6-12 yrs

0.000087	<0.1

Youth 13-19 yrs

0.000065	<0.1

Adults 20-49 yrs

0.000065	<0.1

Adults 50+ yrs

0.000060	<0.1

Females 13-49 yrs

0.000064	<0.1

6.0	Residential (Non-Occupational) Exposure/Risk Characterization  TC
\l1 "6.0	Residential (Non-Occupational) Exposure/Risk Characterization

Reference: The residential exposure and risk assessment was reviewed by
the Exposure Science Advisory Council.   The information provided in
this Section comes from: Cyprosulfamide Occupational and Residential
Exposure/Risk Assessment for the New Use on Field Corn, Pop Corn, Sweet
Corn, Sorghum (Seed Treatment), Residential Turf and Ornamentals.  DP
Code: 351494, Seyed Tadayon, 5/28/08

Cyprosulfamide is proposed for use on residential turfgrass and
recreational sites.  The proposed labels allow application by
home-owners; therefore, short-term non-occupational handler exposure was
evaluated.  Up to 0.027 lb safener/A of the SC 450 formulated product
may be applied to residential turf and ornamentals using a low-pressure
hand wand sprayer or a garden hose-end sprayer.  HED’s Draft Standard
Operating Procedures (SOPs) for Residential Exposure Assessments, and
Recommended Revisions (HED Policy Number 11, revised 22 Feb 2001), were
used as the basis for all residential handler exposure calculations.
Data from the Outdoor Residential Exposure Task Force (ORETF) (MRID #
44972201) were used in this assessment in place of PHED data for the
garden hose-end sprayer scenario, which provided more confidence in the
exposure estimate.  The Total MOEs for residential handlers are well
above the LOC of 100, and are not of concern.  Because the endpoint used
in this assessment is from an oral study, the estimated dermal and
inhalation exposures were adjusted by applying a 100 percent dermal and
inhalation absorption rate, respectively.  As a result, the estimated
risks (MOEs) are considered highly conservative.

Residential postapplication exposure via the inhalation route is
expected to be negligible; however, dermal exposure is likely for adults
and children entering treated lawns.  Toddlers may also experience
exposure via incidental non-dietary ingestion (i.e., hand-to-mouth,
object-to-mouth (turfgrass), and soil ingestion) during postapplication
activities on treated turf.  The postapplication risk assessment is
based on generic assumptions as specified by the Recommended Revisions
to the Residential SOPs and recommended approaches by HED’s Science
Advisory Council for Exposure (ExpoSAC).

Residential short-term postapplication MOEs were estimated for “Day
0” exposure (i.e., the day of application).  The total short-term MOEs
for adults (including handler exposure which could co-occur with
postapplication exposure) and children are 7,000 and 5,300 respectively.
 These total MOEs are greater than the LOC of 100 on the day of
application, and therefore, are not of concern.

Non-Occupational/Residential/Recreational Exposure

HED’s Draft Standard Operating Procedures (SOPs) for Residential
Exposure Assessments, and Recommended Revisions (HED Policy Number 11,
revised 22 Feb 2001), were used as the basis for the residential handler
exposure calculations.  Data from the Outdoor Residential Exposure Task
Force (ORETF) (MRID # 44972201) were used in this assessment in place of
PHED data for the garden hose-end sprayer scenario, which provided more
confidence in the exposure estimate.  As shown in Table 6.0, the Total
MOEs for residential handlers are well above the LOC of 100, and are not
of concern.

Table 6.0  Handler Exposure and Risk Estimates for Residential Lawn
Applicators

Handler Scenario	Application Rate 1

 (lb ai/A)	Area Treated 2

(acres/day)	Unit Exposure 3

(mg/lb ai)	Short-/Intermediate-Term

Daily Dose 4

(mg/kg/day)	Total MOE 5

(1) Mix/load and spot application of liquid formulation (low-pressure
hand sprayer)	0.027	0.023

(1,000 ft2)	Dermal:

100	Dermal:

0.00089	65400

	Inhalation:

0.030	Inhalation:

2.6e-7

	(2) Mix/load and broadcast application of liquid formulation (garden
hose-end sprayer)	0.027	0.50	Dermal:

11	Dermal:

0.0021	27300

	Inhalation:

0.017	Inhalation:

3.28e-6

	1 Application rate is based on maximum values found in proposed labels:

2 Area treated is based on the area that can be reasonably treated in a
single day based on the application method (standard EPA/OPP/HED
values).

3 Dermal unit exposure values represent short pants and short-sleeved
shirt; inhalation values represent no respirator.  Values for
low-pressure hand wand are reported in the PHED Surrogate Exposure Guide
dated August 1998, and those for hose-end sprayer were obtained from the
ORETF data.

4 Daily Absorbed Dose (mg/kg/day) = ([unit exposure *100 % absorption] *
Application rate * Area treated) / 70 kg; where dermal absorption is
100% and inhalation absorption is assumed to be 100%.

5 Short-/Intermediate-Term Total MOE = NOAEL (58 mg/kg/day) / Total
Daily Absorbed Dose (dermal + inhalation).  The LOC is 100.

Residential Postapplication Exposure and Risk

The following postapplication exposure scenarios resulting from lawn
treatment were assessed: (1) adult and toddler postapplication dermal
exposure, (2) toddler’s incidental ingestion of pesticide residues on
lawns from hand-to-mouth transfer, (3) toddler’s object-to-mouth
transfer from mouthing of pesticide-treated turfgrass, and (4)
toddler’s incidental ingestion of soil from pesticide-treated
residential areas.

Turf transferrable residue (TTR) data were not available.  The
assessment was based on generic assumptions for TTR and transfer
coefficients, as specified by the Recommended Revisions to the
Residential SOPs and recommended approaches by HED’s Science Advisory
Council for Exposure (ExpoSAC).

The exposure and risk estimates for the residential exposure scenarios
are assessed for the day of application (day “0”) because it is
assumed that adults and toddlers could contact the lawn immediately
after application.  The equations used for the exposure calculations and
the results are presented in Tables 6.1 through 6.4.

The exposure estimates are based on some upper-percentile (i.e., maximum
application rate, initial amount of transferable residue and duration of
exposure) and some central tendency (i.e., surface area and body weight)
assumptions and are considered to be representative of high-end
exposures.  The uncertainties associated with this assessment stem from
the use of an assumed amount of pesticide available from turf, and
assumptions regarding transfer of chemical residues and hand-to mouth
activity.

The short-term MOEs for each scenario are above the LOC of 100, and are
not of concern.  As mentioned previously, the same toxicity endpoint and
study were selected to evaluate all routes of exposure; therefore, the
MOEs were combined.  As shown in Table 6.5, the total short-term MOEs
for adults (including handler exposure which could co-occur with
postapplication exposure) and children are 7,000 and 5,300,
respectively.  Although combining residential handler and
postapplication scenarios results in a highly conservative assessment,
the total MOEs are greater than the LOC of 100 on the day of
application, and therefore, are not of concern.

Recreational Postapplication Exposure

Recreational exposures to turf are expected to be similar to, or in many
cases less than, those evaluated in Residential Postapplication Exposure
and Risk; therefore, a separate recreational exposure assessment was not
included.

Off Target Non-Occupational Exposure

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

Note that, as indicated in this assessment, cyprosulfamide is directly
applied to residential turf and does not result in exposures of concern.
 It is unlikely that the potential for risk of exposure to spray drift
from the agricultural uses would be higher than that estimated for
contact with treated turf.

Table 6.1  Postapplication Dermal Exposure and Risk from Treated Lawns

Subgroup Exposed

Application Rate

 (lb ai/A)

Post-application day (t)

Fraction of ai Transferrable from the Foliage

Turf Transferrable Residue 1

(µg/cm2)

Dermal Transfer Coefficient

(cm2/hr)

 Body Weight

(kg)

 Daily Dermal Dose 2

(mg/kg/day)

Dermal MOE 3

Short-term

Adults	0.027	0	0.05	0.015	14,500

70	0.00621	9400

Children

	5,200

15	0.01040	5600

1 Turf Transferable Residue Postapplication day (µg/cm2)= Application
rate (lb ai/A) x Fraction of ai Transferable from the Foliage x (1-
Fraction of Residue That Dissipates Daily, 0.1) Postapplication day x
4.54E+8  µg/lb x 2.47E-8 A/cm2

2 Daily Dermal Dose = (Turf Transferable Residue (µg/cm2) x Absorption
Factor (100) x Dermal Transfer Coefficient (cm2/hr) x Exposure Time (2
hrs/day) x 0.001 mg/µg] / [Body Weight (kg)]

3 Dermal MOE = Dermal NOAEL / Daily Dermal Dose; where Short-term NOAEL
= 58 mg/kg/day.

Table 6.2  Postapplication Oral Hand-to-Mouth Exposure and Risk for
Children from Treated Lawns

Application Rate

 (lb ai/A)

Post-application day (t)

Fraction of ai Transferable from the Foliage

Turf Transferable Residue 1

(µg/cm2)

Hand Surface Area

(cm2/event)

Saliva Extraction Factor

 Frequency

(events/ hr)

Body Weight

(kg)

 Daily Dose2

(mg/kg/day)

Oral MOE3

	Short-term

0.027

0

0.05

0.015

20

50%

20

15	0.00040	145,000

1 Turf Transferable Residue Postapplication day (µg/cm2)= Application
rate (lb ai/A) x Fraction of ai Transferable from the Foliage x (1-
Fraction of Residue That Dissipates Daily, 0.1) Postapplication day x
4.54E+8  µg/lb x 2.47E-8 A/cm2

2 Daily Dose = (Turf Transferable Residue (µg/cm2) x Hand Surface Area
(cm2/event) x Saliva Extraction factor x Frequency (events/hr) x 0.001
mg/ µg  x  Exposure time (2 hrs/day)] / [Body Weight (kg)]

3 Oral MOE = Oral NOAEL/Daily Dose; where Short-term NOAEL = 58
mg/kg/day.

Table 6.3 Postapplication Oral Object-to-Mouth (Turfgrass) Exposure and
Risk for Children from Treated Lawns

Application Rate

 (lb ai/A)

Post-

application day

(t)

Fraction of ai Transferable from the Foliage

Grass/Object

Residue 1

(µg/cm2)

Ingestion Rate

(cm2/day)

Body

Weight

(kg)

 Daily Dose2

(mg/kg/day)

Oral MOE3

	Short-term

0.027

0

0.29

0.2

25

15	0.00010	580,000

1Grass/Object residue Postapplication day (µg/cm2) = Application rate
(lb ai/A) x Fraction of ai Transferable from the Foliage (from MRID#:
46708641) x (1- Fraction of Residue That Dissipates Daily)
Postapplication day x 4.54E+8 µg/lb x 2.47E-8 A/cm2

2 Daily Dose  = [Grass reside (µg/cm2) x Ingestion rate (cm2/day) x
0.001 mg/µg] / [Body Weight (kg)]]

3Oral MOE = Oral NOAEL / Daily Dose; where Short-term NOAEL = 58
mg/kg/day.

Table 6.4 Postapplication Incidental Soil Ingestion Exposure and Risk
for Children from Treated Lawns

Application Rate

 (lb ai/A)

Fraction of ai Retained in the Soil

Soil Residue 1 (µg/g)

Ingestion Rate (mg/day)

Body Weight (kg)	 Daily Dose2(mg/kg/day)

Oral MOE3

Short-term

0.027	1

2.0

100	15	0.00000014	58,000,000

1 Soil residue Postapplication day zero (µg/cm2) = Application rate (lb
ai/A) x Fraction of ai Retained on the Soil x (4.54E+8 µg/lb x 2.47E-8
A/cm2 x 0.67 cm3/g soil

2 Daily Dose  = [Soil reside (µg/g) x Ingestion rate (mg/day) x
0.000001 g/µg] / [Body Weight (kg)]]

3 Oral MOE = Oral NOAEL/Daily Dose; where Short-term NOAEL = 58g/kg/day.

Table 6.5  Aggregate Exposure and Risk Estimates from Residential Lawns

Scenario and Pathway

TTR/GR/SR0 (µg/cm2 or g) 1

PDR0-norm (mg/kg/day) 2

Short-Term MOE 3

Total MOE 4

Short- Term

Adult’s Scenarios

(1) Handler (Dermal) 	N/A	0.0021	27600	7000

(1) Handler (Inhalation) 	N/A	3.28e-6	18,125,000

(2) Dermal Postapplication	0.015	0.00621	9400

	Children’s Scenarios – All Postapplication

(1) Dermal 	0.015	0.01040	5600	5300

(2) Hand-to-Mouth	0.015	0.00040	145,000

	(3) Mouthing Grass/Object	0.06	0.00010	580,000

(4) Soil Ingestion	0.2	0.00000014	58,000,000

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

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

3 MOE = NOAEL/PDR; where Short- NOAEL = 58 mg/kg/day.

4 For Adults:  Total MOE = 1/ [(1/MOEHandler Dermal) + (1/MOEDermal
Postapplication) + (1/MOEInhalation) ]

  For Children:  Total MOE = 1/ [(1/MOEDermal) + (1/MOEHand-to-Mouth) +
(1/MOEGrass) + (1/MOESoil)]

7.0	Aggregate Risk Assessments and Risk Characterization  TC \l1 "7.0
Aggregate Risk Assessments and Risk Characterization

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

For this action, there is potential exposure to cyprosulfamide from
food, drinking water, and from residential use sites (as there are
residential turf and ornamental uses proposed for cyprosulfamide).
Since identical hazards (urinary tract effects/bladder effects) were
identified via the oral, dermal, and inhalation routes and short-term
residential exposures are expected, the aggregate risk assessment
considers the residential exposures plus averaged exposures from food
and drinking water as estimated from the chronic dietary analysis.

7.1	Acute Aggregate Risk TC \l2 "7.1	Acute Aggregate Risk

Not applicable due to lack of an acute toxicity endpoint.

7.2	Short-term Aggregate Risk TC \l2 "7.2	Long-Term Aggregate Risk

As identical endpoints and NOAELs were selected for short-term exposure
durations, aggregate MOEs are the same for both durations.  HED combined
the averaged food & water exposures with the oral, dermal and inhalation
residential exposures for the aggregate risk assessment. The results of
this assessment are presented in Table 7.2 and indicate that short-term
aggregate risks do not exceed HED’s level of concern for adults and
children, and that the dermal residential exposures are the primary
contributor to risks in this analysis.

Table 7.2.  Short-Term Aggregate Risk Calculations

Population	Short-Term Scenario

	NOAEL

mg/kg/day	LOC1	Max Allowable

Exposure2

mg/kg/day	Average

Food & Water

Exposure3

mg/kg/day	Residential Exposure4

mg/kg/day	Aggregate MOE

(food and

residential)5

Adult	58	100	0.58	0.000072	0.00831	6900

Child	58	100	0.58	0.000121	0.0109	5300

1 Based on the standard inter- and intra- species uncertainty factors
totaling 100.

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

3  From Table 5.2:  Adults from U.S. Population and Child from Children
3-5 years old.

4 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation
Exposure].  See Table 6.5.

 /(Avg Food & Water Exposure + Residential Exposure)]

7.3	Long-term Aggregate Risk TC \l2 "7.2	Long-Term Aggregate Risk

Refer to Section 5.2.2, which discusses chronic dietary exposure (food
and water) in detail.  The dietary route alone is relevant for
long-term/chronic exposure and risk assessment; and the chronic dietary
exposure and risk assessment conducted for cyprosulfamide is health
protective (the assessment assigned tolerance level values to all food
commodities proposed to be treated with cyprosulfamide; and modeled
residue values to all drinking water).

8.0	Cumulative Risk Characterization/Assessment  TC \l1 "8.0	Cumulative
Risk Characterization/Assessment

Although cyprosulfamide has in common with other sulfonamide chemicals
including thiencarbazone-methyl the ability to cause urinary tract
stones and in some cases tumors in the urinary tract (only at high
doses), EPA has not made a common mechanism finding for cyprosulfamide
such that cumulative risk assessment based on chemicals with a common
mechanism is necessary for cyprosulfamide and thiencarbazone-methyl.
This decision is based on the assumption that exposures to
cyprosulfamide and thiencarbazone-methyl are not additive with regard to
the formation of urinary tract stones at anticipated exposure levels.
For information regarding EPA’s efforts to determine which chemicals
have a common mechanism of toxicity and to evaluate the cumulative
effects of such chemicals, see the policy statements released by EPA’s
Office of Pesticide Programs concerning common mechanism determinations
and procedures for cumulating effects from substances found to have a
common mechanism on EPA’s website at   HYPERLINK
http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/.

9.0	Occupational Exposure/Risk Pathway  TC \l1 "9.0	Occupational
Exposure/Risk Pathway

Reference: The occupational exposure and risk assessment was reviewed by
the Exposure Science Advisory Council.   The information provided in
this Section comes from: Cyprosulfamide Occupational and Residential
Exposure/Risk Assessment for the New Use on Field Corn, Pop Corn, Sweet
Corn, Sorghum (Seed Treatment), Residential Turf and Ornamentals.  DP
Code: 351494, Seyed Tadayon, 5/28/08

9.1	Short- and Intermediate-term Handler Risk  TC \l2 "9.1	Short- and
Intermediate-Term Handler Risk

Occupational Handler Exposure

There is potential for occupational handler exposure from the proposed
uses on agricultural crops and on residential turf and ornamentals.  Up
to 0.027 lb safener/A of the SC 450 formulated product may be applied to
residential turf and ornamentals using a low-pressure hand wand sprayer
or a garden hose-end sprayer.  Up to 0.201 lb safener/A from all
registered cyprosulfamide-containing formulated products may be applied
to corn via standard agricultural ground and/or aerial equipment.   It
is anticipated that the following scenarios could result in handler
exposure:  mixer/loaders for aerial, or groundboom applications of
liquids, applicators using aerial or groundboom equipment, and flaggers
for aerial applications.  Based upon the proposed use pattern, HED
expects the most highly exposed occupational pesticide handlers are
likely to be:

	(1) Mixing/loading liquids for aerial applications (PHED);

	(2) Applying sprays via aerial equipment (PHED);

	(3) Mixing/Loading Liquid Concentrates for Grounboom Applications;

	(4) Applying Sprays via Groundboom Equipment;

	(5) Flagging to Support Aerial Applications;

	(6) Mixing/Loading Liquid and Applying with Handgun Sprayer;

	(7) Mixing/Loading Liquid and Applying with Low-Pressure Handwand;

	(8) Mixing/Loading Liquid and Applying with High-Pressure Handwand; and

	(9) Mixing/Loading Liquid and Applying with Backpack Sprayer.

No chemical specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED
(August, 1998).   For pesticide handlers, it is HED standard practice to
present estimates of dermal exposure for “baseline” that is, for
workers wearing a single layer of work clothing consisting of a long
sleeved shirt, long pants, shoes plus socks and no protective gloves, as
well as for “baseline” and the use of protective gloves or other
Personal Protective Equipment (PPE) as might be necessary.  The proposed
product label involved in this assessment directs applicators and other
handlers to wear a long sleeved shirt and long pants; chemical resistant
gloves made of any waterproof material such as polyvinyl chloride,
nitrile rubber or butyl rubber; and shoes plus socks.

HED believes most exposure durations will be short-term (1- 30 days).
However, HED’s Science Advisory Council for Exposure (ExpoSAC)
believes it is possible for commercial applicators to be exposed to
intermediate-term exposure durations (1 - 6 months).   Because the
short- and intermediate-term toxicological endpoints are the same, the
estimates of risk for short-term duration exposures are protective of
those for intermediate-term duration exposures. Long-term exposures are
not expected, therefore, a long-term assessment was not conducted.

Daily dermal or inhalation handler exposures are estimated for each
applicable handler task with the application rate, the area treated in a
day, and the applicable dermal or inhalation unit exposure using the
following formula:

Daily Exposure (mg ai/day) = Unit Exposure (mg ai/lb ai handled) x
Application Rate (lbs ai/gallon) x Amount Handled (gal/day)

Where:

Daily Exposure		=	Amount (mg ai/day) deposited on the surface of the
skin that is available for dermal absorption or amount inhaled that is
available for inhalation absorption;

Unit Exposure 		=	Unit exposure value (mg ai/lb ai) derived from August
1998 PHED data or from ORETF data;

Application Rate		=	Normalized application rate (lb ai/gal); and

	Daily Area Treated 	=	Normalized amount handled (gal/day).

The daily dermal or inhalation dose is calculated by normalizing the
daily exposure by body weight and adjusting, if necessary, with an
appropriate dermal or inhalation absorption factor using the following
formula:

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x
(Absorption Factor (%/100) / Body Weight (kg)

Where:

Average Daily Dose 		= 	Absorbed dose received from exposure to a
pesticide in a given scenario (mg ai/kg bw/day);

Daily Exposure 			=	Amount (mg ai/day) deposited on the surface of the
skin that is available for dermal absorption or amount inhaled that is
available for inhalation absorption;

Absorption Factor 		= 	A measure of the amount of chemical that crosses
a biological boundary such as the skin or lungs (% of the total
available absorbed); and

Body Weight 			= 	Body weight determined to represent the population of
interest in a risk assessment (kg).

Non-cancer dermal and inhalation risks for each applicable handler
scenario are calculated using a MOE, which is a ratio of the NOAEL to
the daily dose.  All MOE values were calculated using the formula below:

MOE= NOAEL or LOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day)

A total MOE was calculated because the dermal and inhalation
toxicological endpoints of concern are based on the same adverse
effects.  The total MOE values were calculated using the formula below:

  SEQ CHAPTER \h \r 1  Total MOE = NOAEL or LOAEL / (Dermal dose +
Inhalation Dose)

Table 9.1.1 presents the exposure/risks for short and intermediate-term
dermal and inhalation exposures at baseline, and with additional
personal protective equipment.  The combined dermal and inhalation