**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

WASHINGTON, D.C. 20460

![](media/image1.wmf){width="0.85in" height="0.925in"}

> OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: June 10, 2008

**[MEMORANDUM]{.underline}**

**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    **Case No.:** NA
  chemical aggregate                  

  **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**

[1.0 Executive Summary 6](#__RefHeading___Toc200865269)

[2.0 Ingredient Profile 8](#__RefHeading___Toc200865270)

[2.1 Summary of Proposed Uses 8](#__RefHeading___Toc200865271)

[2.2 Structure and Nomenclature 11](#__RefHeading___Toc200865272)

[2.3 Physical and Chemical Properties 11](#__RefHeading___Toc200865273)

[3.0 Hazard Characterization/Assessment
12](#__RefHeading___Toc200865274)

[3.1 Hazard and Dose-Response Characterization
12](#__RefHeading___Toc200865275)

[3.1.1 Database Summary 12](#__RefHeading___Toc200865276)

[3.1.2 Toxicological Effects 13](#__RefHeading___Toc200865277)

[3.1.3 Dose-response 15](#__RefHeading___Toc200865278)

[3.2 Absorption, Distribution, Metabolism, Excretion (ADME)
15](#__RefHeading___Toc200865279)

[3.3 FQPA Considerations 16](#__RefHeading___Toc200865280)

[3.3.1 Adequacy of the Toxicity Database
16](#__RefHeading___Toc200865281)

[3.3.2 Evidence of Neurotoxicity 16](#__RefHeading___Toc200865282)

[3.3.3 Developmental Toxicity Studies 16](#__RefHeading___Toc200865283)

[3.3.4 Reproductive Toxicity Study 16](#__RefHeading___Toc200865284)

[3.3.5 Additional Information from Literature Sources
17](#__RefHeading___Toc200865285)

[3.3.6 Pre-and/or Postnatal Toxicity 17](#__RefHeading___Toc200865286)

[3.3.7 Recommendation for a Developmental Neurotoxicity Study
17](#__RefHeading___Toc200865287)

[3.4 Safety Factor for Infants and Children
17](#__RefHeading___Toc200865288)

[3.5 Hazard Identification and Toxicity Endpoint Selection
18](#__RefHeading___Toc200865289)

[3.5.1 Acute Reference Dose (aRfD) - Females age 13-49 and the General
Population 18](#__RefHeading___Toc200865290)

[3.5.2 Chronic Reference Dose (cRfD) 18](#__RefHeading___Toc200865291)

[3.5.3 Incidental Oral Exposure (Short- and Intermediate-term)
19](#__RefHeading___Toc200865292)

[3.5.4 Dermal Absorption 19](#__RefHeading___Toc200865293)

[3.5.5 Dermal Exposure (Short-, and Intermediate-term)
19](#__RefHeading___Toc200865294)

[3.5.6 Inhalation Exposure (Short-, and Intermediate-term)
20](#__RefHeading___Toc200865295)

[3.5.7 Level of Concern for Margin of Exposure
21](#__RefHeading___Toc200865296)

[3.5.8 Recommendation for Aggregate Exposure Risk Assessments
22](#__RefHeading___Toc200865297)

[3.5.9 Classification of Carcinogenic Potential
22](#__RefHeading___Toc200865298)

[3.5.10 Summary of Toxicological Doses and Endpoints for Cyprosulfamide
for Use in Human Risk Assessments 23](#__RefHeading___Toc200865299)

[3.6 Endocrine disruption 25](#__RefHeading___Toc200865300)

[4.0 Public Health and Pesticide Epidemiology Data
25](#__RefHeading___Toc200865301)

[5.0 Dietary Exposure/Risk Characterization
26](#__RefHeading___Toc200865302)

[5.1 Pesticide Metabolism and Environmental Degradation
26](#__RefHeading___Toc200865303)

[5.1.1 Metabolism in Primary Crops 26](#__RefHeading___Toc200865304)

[5.1.2 Metabolism in Rotational Crops 27](#__RefHeading___Toc200865305)

[5.1.3 Metabolism in Livestock 28](#__RefHeading___Toc200865306)

[5.1.4 Analytical Methodology 28](#__RefHeading___Toc200865307)

[5.1.5 Environmental Degradation 29](#__RefHeading___Toc200865308)

[5.1.6 Comparative Metabolic Profile 29](#__RefHeading___Toc200865309)

[5.1.7 Toxicity Profile of Major Metabolites and Degradates
30](#__RefHeading___Toc200865310)

[5.1.8 Pesticide Metabolites and Degradates of Concern
31](#__RefHeading___Toc200865311)

[5.1.9 Drinking Water Residue Profile 33](#__RefHeading___Toc200865312)

[5.1.10 Food Residue Profile 34](#__RefHeading___Toc200865313)

[5.1.11 International Residue Limits 36](#__RefHeading___Toc200865314)

[5.2 Dietary Exposure and Risk 36](#__RefHeading___Toc200865315)

[5.2.1 Acute Dietary Exposure/Risk 36](#__RefHeading___Toc200865316)

[5.2.2 Chronic Dietary Exposure/Risk 36](#__RefHeading___Toc200865317)

[6.0 Residential (Non-Occupational) Exposure/Risk Characterization
37](#__RefHeading___Toc200865318)

[7.0 Aggregate Risk Assessments and Risk Characterization
42](#__RefHeading___Toc200865319)

[7.1 Acute Aggregate Risk 42](#__RefHeading___Toc200865320)

[7.2 Short-term Aggregate Risk 42](#__RefHeading___Toc200865321)

[7.3 Long-term Aggregate Risk 43](#__RefHeading___Toc200865322)

[8.0 Cumulative Risk Characterization/Assessment
43](#__RefHeading___Toc200865323)

[9.0 Occupational Exposure/Risk Pathway
43](#__RefHeading___Toc200865324)

[9.1 Short- and Intermediate-term Handler Risk
43](#__RefHeading___Toc200865325)

[9.2 Short- and Intermediate-term Postapplication Risk
49](#__RefHeading___Toc200865326)

[10.0 Data Needs and Label Requirements
51](#__RefHeading___Toc200865327)

[10.1 Toxicology 51](#__RefHeading___Toc200865328)

[10.2 Residue Chemistry 52](#__RefHeading___Toc200865329)

[10.3 Occupational and Residential Exposure
53](#__RefHeading___Toc200865330)

[References: 53](#__RefHeading___Toc200865331)

[Appendix A: Toxicology Assessment 54](#__RefHeading___Toc200865332)

[A.1 Toxicology Data Requirements 54](#__RefHeading___Toc200865333)

[A.2 Toxicity Profiles 55](#__RefHeading___Toc200865334)

[A.3 Executive Summaries 60](#__RefHeading___Toc200865335)

[Appendix B: Metabolism Assessment 106](#__RefHeading___Toc200865336)

[Appendix C: EPA Review of Human Research
113](#__RefHeading___Toc200865337)

[]{#__RefHeading___Toc200865269 .anchor}**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," <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.

[]{#__RefHeading___Toc200865270 .anchor}**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.

1.  []{#__RefHeading___Toc200865271 .anchor}**Summary of Proposed Uses**

  ------------------------------------------------------------------------------------------------
  **Table 2.1a.                                                                          
  Summary of                                                                             
  Proposed                                                                               
  End-Use                                                                                
  Products.**                                                                            
  ------------- ----------- ---------------- ------------- ------------- --------------- ---------
  Trade Name    EPA File    Cyprosulfamide   Formulation   Target Crops  Target Pests    Label
                Symbol No.  Concentration    Type                                        Date

  SC 450        264-RNAR    1.88 lb/gal^1^   FlC           Field corn,   Safener         4/16/07
  Herbicide                                                sweet corn,                   
                                                           popcorn, and                  
                                                           corn grown                    
                                                           for silage,                   
                                                           grain or seed                 

  SC 465        264-RNAA    1.25 lb/gal^2^   FlC           Field corn    Safener         4/16/07
  Herbicide                                                and corn                      
                                                           grown for                     
                                                           silage                        

  SC 480        264-RNAT    2.0 lb/gal^3^    FlC           Field corn    Safener         4/16/07
  Herbicide                                                and corn                      
                                                           grown for                     
                                                           silage                        

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

^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    |           |              |          |          |    |
| Cyprosu       |           |              |          |          |    |
| lfamide.^1^** |           |              |          |          |    |
+===============+===========+==============+==========+==========+====+
| Applic.       | Trade     | Applic. Rate | Max. No. | Max.     | P  |
| Timing,       | Name;     |              | Applic.  | Seasonal | HI |
|               | Fo        | (lb          | per      | Applic.  |    |
| Type, and     | rmulation | safener/A)   | Season   | Rate     | (d |
|               |           |              |          |          | ay |
| Equipment     | \[EPA     |              |          | (lb      | s) |
|               | Reg.      |              |          | sa       |    |
|               | No.\]     |              |          | fener/A) |    |
+---------------+-----------+--------------+----------+----------+----+
| Corn          |           |              |          |          |    |
| (including    |           |              |          |          |    |
| field corn,   |           |              |          |          |    |
| sweet corn,   |           |              |          |          |    |
| popcorn, and  |           |              |          |          |    |
| corn grown    |           |              |          |          |    |
| for silage,   |           |              |          |          |    |
| grain, or     |           |              |          |          |    |
| seed)         |           |              |          |          |    |
+---------------+-----------+--------------+----------+----------+----+
| Preplant      | SC 450    | 0.020        | 2        | 0.040    | NS |
|               | H         | (coarse      |          | (from    |    |
| Su            | erbicide; | soils with   |          | 1.88     |    |
| rface-applied |           | ≤2.0% OM)    |          | lb/gal   |    |
| or            | 1.88      |              |          | FlC      |    |
| incorporated  | lb/gal    | 0.026-0.033  |          | form     |    |
|               | FlC       | (coarse      |          | ulation) |    |
| Ground and    |           | soils with   |          |          |    |
| aerial        | \[2       | \>2.0% OM,   |          | 0.201    |    |
|               | 64-RNAR\] | medium, and  |          | (from    |    |
|               |           | fine soils)  |          | all      |    |
|               | ai =      |              |          | sources) |    |
|               | thi       |              |          |          |    |
|               | encarbazo |              |          |          |    |
|               | ne-methyl |              |          |          |    |
|               | 1.88      |              |          |          |    |
|               | lb/gal    |              |          |          |    |
|               |           |              |          |          |    |
|               | safener = |              |          |          |    |
|               | cypro     |              |          |          |    |
|               | sulfamide |              |          |          |    |
|               | 1.88      |              |          |          |    |
|               | lb/gal    |              |          |          |    |
+---------------+-----------+--------------+----------+----------+----+
| Preplant      |           |              |          |          | NS |
| /preemergence |           |              |          |          |    |
| burndown      |           |              |          |          |    |
|               |           |              |          |          |    |
| Ground and    |           |              |          |          |    |
| aerial        |           |              |          |          |    |
+---------------+-----------+--------------+----------+----------+----+
| Preemergence  |           |              |          |          | NS |
|               |           |              |          |          |    |
| During or     |           |              |          |          |    |
| after         |           |              |          |          |    |
| planting      |           |              |          |          |    |
|               |           |              |          |          |    |
| Ground and    |           |              |          |          |    |
| aerial        |           |              |          |          |    |
+---------------+-----------+--------------+----------+----------+----+
| Early         |           |              |          |          | 45 |
| postemergence |           |              |          |          |    |
|               |           |              |          |          |    |
| Ground and    |           |              |          |          |    |
| aerial        |           |              |          |          |    |
+---------------+-----------+--------------+----------+----------+----+
| Postemergence |           | 0.013        |          |          | 45 |
|               |           |              |          |          |    |
| Broadcast or  |           |              |          |          |    |
| directed      |           |              |          |          |    |
| spray         |           |              |          |          |    |
|               |           |              |          |          |    |
| Ground and    |           |              |          |          |    |
| aerial        |           |              |          |          |    |
+---------------+-----------+--------------+----------+----------+----+
| ornamental    |           | 0.027        | 1        | 0.027    | NS |
| and turf      |           |              |          |          |    |
| (residential  |           |              |          |          |    |
| use)          |           |              |          |          |    |
+---------------+-----------+--------------+----------+----------+----+
| **Use         |           |              |          |          |    |
| Directions    |           |              |          |          |    |
| and           |           |              |          |          |    |
| L             |           |              |          |          |    |
| imitations:** |           |              |          |          |    |
| 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            |           |              |          |          |    |
| c             |           |              |          |          |    |
| yprosulfamide |           |              |          |          |    |
| 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      | SC 465    | 0.033        | 1        | 0.055    | NS |
|               | Herbicide | (coarse      |          | from     |    |
| Su            |           | soils with   |          | 1.25     |    |
| rface-applied | 1.25      | ≤2.0% OM)    |          | lb/gal   |    |
| or            | lb/gal    |              |          | FlC      |    |
| incorporated  | FlC       | 0.044-0.055  |          | for      |    |
|               |           | (coarse      |          | mulation |    |
| Ground)       | \[2       | soils with   |          |          |    |
|               | 64-RNAA\] | \>2.0% OM,   |          | 0.201    |    |
|               |           | medium, and  |          | (from    |    |
|               | ai =      | fine soils)  |          | all      |    |
|               | thi       |              |          | sources) |    |
|               | encarbazo |              |          |          |    |
|               | ne-methyl |              |          |          |    |
|               | 0.75      |              |          |          |    |
|               | lb/gal    |              |          |          |    |
|               |           |              |          |          |    |
|               | ai =      |              |          |          |    |
|               | iso       |              |          |          |    |
|               | xaflutole |              |          |          |    |
|               | 1.88      |              |          |          |    |
|               | lb/gal    |              |          |          |    |
|               |           |              |          |          |    |
|               | safener = |              |          |          |    |
|               | cypro     |              |          |          |    |
|               | sulfamide |              |          |          |    |
|               | 1.25      |              |          |          |    |
|               | lb/gal    |              |          |          |    |
+---------------+-----------+--------------+----------+----------+----+
| Preplant      |           |              |          |          | NS |
| /preemergence |           |              |          |          |    |
| burndown      |           |              |          |          |    |
|               |           |              |          |          |    |
| Ground        |           |              |          |          |    |
+---------------+-----------+--------------+----------+----------+----+
| Preemergence  |           |              |          |          | NS |
| during or     |           |              |          |          |    |
| after         |           |              |          |          |    |
| planting      |           |              |          |          |    |
|               |           |              |          |          |    |
| Ground        |           |              |          |          |    |
+---------------+-----------+--------------+----------+----------+----+
| Early         |           |              |          |          | 45 |
| postemergence |           |              |          |          |    |
|               |           |              |          |          |    |
| Ground        |           |              |          |          |    |
+---------------+-----------+--------------+----------+----------+----+
| **Use         |           |              |          |          |    |
| Directions    |           |              |          |          |    |
| and           |           |              |          |          |    |
| L             |           |              |          |          |    |
| imitations:** |           |              |          |          |    |
| 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      | SC 480    | 0.047-0.141  | 1        | 0.141    | NS |
|               | Herbicide | (application |          | (from    |    |
| Su            |           | rate is      |          | 2.0      |    |
| rface-applied | 2.0       | dependent on |          | lb/gal   |    |
| or            | lb/gal    | soil         |          | FlC      |    |
| incorporated  | FlC       | texture,     |          | form     |    |
|               |           | %OM, and     |          | ulation) |    |
| Ground)       | \[2       | timing of    |          |          |    |
|               | 64-RNAT\] | application) |          | 0.201    |    |
|               |           |              |          | (from    |    |
|               | ai =      |              |          | all      |    |
|               | iso       |              |          | sources) |    |
|               | xaflutole |              |          |          |    |
|               | 2.0       |              |          |          |    |
|               | lb/gal    |              |          |          |    |
|               |           |              |          |          |    |
|               | safener = |              |          |          |    |
|               | cypro     |              |          |          |    |
|               | sulfamide |              |          |          |    |
|               | 2.0       |              |          |          |    |
|               | lb/gal    |              |          |          |    |
+---------------+-----------+--------------+----------+----------+----+
| Preplant/     |           |              |          |          | NS |
|               |           |              |          |          |    |
| Preemergence  |           |              |          |          |    |
| burndown      |           |              |          |          |    |
|               |           |              |          |          |    |
| Ground        |           |              |          |          |    |
+---------------+-----------+--------------+----------+----------+----+
| Preemergence  |           |              |          |          | NS |
| during or     |           |              |          |          |    |
| after         |           |              |          |          |    |
| planting      |           |              |          |          |    |
|               |           |              |          |          |    |
| Ground        |           |              |          |          |    |
+---------------+-----------+--------------+----------+----------+----+
| Early         |           |              |          |          | 45 |
| postemergence |           |              |          |          |    |
|               |           |              |          |          |    |
| Ground        |           |              |          |          |    |
+---------------+-----------+--------------+----------+----------+----+
| **Use         |           |              |          |          |    |
| Directions    |           |              |          |          |    |
| and           |           |              |          |          |    |
| L             |           |              |          |          |    |
| imitations:** |           |              |          |          |    |
| 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          | FS 500    | 0.052 lb     | 1        | 0.052 lb | NA |
| treatment     | Sorghum   | safener/     |          | safener/ |    |
|               | Seed      |              |          |          |    |
| Mist type or  | P         | 100 lb of    |          | 100 lb   |    |
| slurry seed   | rotectant | seed         |          | of seed  |    |
| treatment     |           |              |          |          |    |
| equipment     | 4.17      |              |          |          |    |
|               | lb/gal    |              |          |          |    |
|               | FlC       |              |          |          |    |
+---------------+-----------+--------------+----------+----------+----+
| **Use         |           |              |          |          |    |
| Directions    |           |              |          |          |    |
| and           |           |              |          |          |    |
| L             |           |              |          |          |    |
| imitations:** |           |              |          |          |    |
| Use of        |           |              |          |          |    |
| treated seed  |           |              |          |          |    |
| for food,     |           |              |          |          |    |
| feed, or oil  |           |              |          |          |    |
| purposes is   |           |              |          |          |    |
| prohibited.   |           |              |          |          |    |
+---------------+-----------+--------------+----------+----------+----+

^1^ NS = Not specified. NA = Not applicable.

[]{#__RefHeading___Toc200865272 .anchor}**2.2 Structure and
Nomenclature**

+----------------+-----------------------------------------------------+
| **Table 2.2    |                                                     |
| Cyprosulfamide |                                                     |
| N              |                                                     |
| omenclature**. |                                                     |
+================+=====================================================+
| Chemical       | ![](media/image2.wmf){width="2.8854166666666665in"  |
| structure      | height="1.3791666666666667in"}                      |
+----------------+-----------------------------------------------------+
| Common name    | Cyprosulfamide                                      |
+----------------+-----------------------------------------------------+
| Company        | AE 0001789                                          |
| experimental   |                                                     |
| name           |                                                     |
+----------------+-----------------------------------------------------+
| IUPAC name     | *N*-cycl                                            |
|                | opropyl-4-\[(2-methoxybenzoyl)sulfamoyl\]-benzamide |
+----------------+-----------------------------------------------------+
| CAS name       | N-\[\[4-\[(cyclopropylam                            |
|                | ino)carbonyl\]phenyl\]sulfonyl\]-2-methoxybenzamide |
|                | (9CI)                                               |
+----------------+-----------------------------------------------------+
| CAS registry   | 221667-31-8                                         |
| number         |                                                     |
+----------------+-----------------------------------------------------+
| End-use        | SC 450 Herbicide (EPA File Symbol No. 264-RNAR),    |
| product (EP)   | 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                                         |
+----------------+-----------------------------------------------------+

[]{#__RefHeading___Toc200865273 .anchor}**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]{.underline}     |               |
|                     |                               |               |
|                     | 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        | pKa = 4.2                     |               |
| constant, pK~a~     |                               |               |
+---------------------+-------------------------------+---------------+
| Octanol/water       | 1.77, at pH 4, 23 C           |               |
| partition           |                               |               |
| coefficient,        | -0.80, at pH 7, 23 C          |               |
| Log(K~OW~)          |                               |               |
|                     | -1.81, at pH 9, 23 C          |               |
+---------------------+-------------------------------+---------------+
| UV/visible          | λ~1~ = 202 nm                 |               |
| absorption spectrum |                               |               |
|                     | λ~2~ = 241 nm                 |               |
+---------------------+-------------------------------+---------------+

[]{#__RefHeading___Toc200865274 .anchor}**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).

[]{#__RefHeading___Toc200865275 .anchor}**3.1 Hazard and Dose-Response
Characterization**

[]{#__RefHeading___Toc200865276 .anchor}**3.1.1 Database Summary**

**3.1.1.1 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.

**3.1.1.2 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.

**3.1.1.3 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.

[]{#__RefHeading___Toc200865277 .anchor}**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 (LD~50~ \> 2000 mg/kg bw), dermal (LD~50~ \> 2000
mg/kg bw) and inhalation toxicity (LC~50~ \>3500 mg/m^3^ 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 (UF~DB~) 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".

[]{#__RefHeading___Toc200865278 .anchor}**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.

[]{#__RefHeading___Toc200865279 .anchor}**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 CO~2~ 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.

[]{#__RefHeading___Toc200865280 .anchor}**3.3 FQPA Considerations**

[]{#__RefHeading___Toc200865281 .anchor}**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

    []{#__RefHeading___Toc200865282 .anchor}**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. 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).

[]{#__RefHeading___Toc200865283 .anchor}**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.

[]{#__RefHeading___Toc200865284 .anchor}**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.

[]{#__RefHeading___Toc200865285 .anchor}**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.

[]{#__RefHeading___Toc200865286 .anchor}**3.3.6 Pre-and/or Postnatal
Toxicity**

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

**3.3.6.1 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.

**3.3.6.2 Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility**

There is no concern for increased susceptibility of offspring.

[]{#__RefHeading___Toc200865287 .anchor}**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.

[]{#__RefHeading___Toc200865288 .anchor}**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 (UF~DB~) for
    database uncertainties does not need to be applied.

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-   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.

    []{#__RefHeading___Toc200865289 .anchor}**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.

[]{#__RefHeading___Toc200865290 .anchor}**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.

[]{#__RefHeading___Toc200865291 .anchor}**3.5.2 Chronic Reference Dose
(cRfD)**

[Study Selected]{.underline}: Chronic Toxicity/Carcinogenicity Study in
Rats

[Dose/Endpoint for Establishing the cRfD]{.underline}: 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:]{.underline} 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)]{.underline} = **0.39         |
| mg/kg/day**                                                           |
|                                                                       |
| *100 (UF)*                                                            |
+-----------------------------------------------------------------------+

[]{#__RefHeading___Toc200865292 .anchor}**3.5.3 Incidental Oral Exposure
(Short- and Intermediate-term)**

[Study Selected]{.underline}: Subchronic Toxicity Study in the Rat

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

[Comments]{.underline}: 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.

[]{#__RefHeading___Toc200865293 .anchor}**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.

[]{#__RefHeading___Toc200865294 .anchor}**3.5.5 Dermal Exposure (Short-,
and Intermediate-term)**

[Study Selected]{.underline}: Subchronic Toxicity Study in the Rat

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

[Comments]{.underline}: 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.

**3.5.5.1 Dermal Exposure (Long-term)**

[Study Selected]{.underline}: Chronic Toxicity/Carcinogenicity Study in
Rats (with the 2-generation reproduction study in rats as a co-critical
study)

[Dose/Endpoint for Risk Assessment]{.underline}: 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]{.underline}: 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.

6.  []{#__RefHeading___Toc200865295 .anchor}**Inhalation Exposure
    (Short-, and Intermediate-term)**

[Study Selected]{.underline}: Subchronic Toxicity Study in the Rat

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

[Comments]{.underline}: 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]{.underline} 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.

**3.5.6.1 Inhalation Exposure (Long-term)**

[Study Selected]{.underline}: Chronic Toxicity/Carcinogenicity Study in
Rats (with the 2-generation reproduction study in rats as a co-critical
study)

[Dose/Endpoint for Risk Assessment]{.underline}: 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]{.underline}: 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]{.underline} 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.

[]{#__RefHeading___Toc200865296 .anchor}**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** | **Interme    | **Long-Term**  |
|                    |                | diate-Term** |                |
|                    | **(1 - 30      |              | **(\> 6        |
|                    | Days)**        | **(1 - 6     | Months)**      |
|                    |                | 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       | MOE \< 100     | MOE \< 100   | NA             |
| Oral**             |                |              |                |
+--------------------+----------------+--------------+----------------+
| **Dietary (Food    | NA             | NA           | exposure \>    |
| and Water)**       |                |              | 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.

[]{#__RefHeading___Toc200865297 .anchor}**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.

[]{#__RefHeading___Toc200865298 .anchor}**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.

[]{#__RefHeading___Toc200865299 .anchor}**3.5.10 Summary of
Toxicological Doses and Endpoints for Cyprosulfamide for Use in Human
Risk Assessments**

+----------+--------+-----------+---------+--------------------------+
| **Table  |        |           |         |                          |
| 3.5.10a  |        |           |         |                          |
| Summary  |        |           |         |                          |
| of       |        |           |         |                          |
| Toxic    |        |           |         |                          |
| ological |        |           |         |                          |
| Doses    |        |           |         |                          |
| and      |        |           |         |                          |
| E        |        |           |         |                          |
| ndpoints |        |           |         |                          |
| for      |        |           |         |                          |
| Cypros   |        |           |         |                          |
| ulfamide |        |           |         |                          |
| for Use  |        |           |         |                          |
| in       |        |           |         |                          |
| Dietary  |        |           |         |                          |
| and      |        |           |         |                          |
| Non-Occu |        |           |         |                          |
| pational |        |           |         |                          |
| Human    |        |           |         |                          |
| Health   |        |           |         |                          |
| Risk     |        |           |         |                          |
| Asses    |        |           |         |                          |
| sments** |        |           |         |                          |
+==========+========+===========+=========+==========================+
| E        | Point  | Uncerta   | RfD,    | Study and Toxicological  |
| xposure/ | of     | inty/FQPA | PAD,    | Effects                  |
|          | Dep    | Safety    | Level   |                          |
| Scenario | arture | Factors   | of      |                          |
|          |        |           | Concern |                          |
|          |        |           | for     |                          |
|          |        |           | Risk    |                          |
|          |        |           | Ass     |                          |
|          |        |           | essment |                          |
+----------+--------+-----------+---------+--------------------------+
| Acute    | No     |           |         |                          |
| Dietary  | sel    |           |         |                          |
| (General | ection |           |         |                          |
| Pop      | b      |           |         |                          |
| ulation, | ecause |           |         |                          |
| i        | no     |           |         |                          |
| ncluding | indi   |           |         |                          |
| Infants  | cation |           |         |                          |
| and      | of     |           |         |                          |
| C        | signi  |           |         |                          |
| hildren) | ficant |           |         |                          |
|          | to     |           |         |                          |
|          | xicity |           |         |                          |
|          | fol    |           |         |                          |
|          | lowing |           |         |                          |
|          | a      |           |         |                          |
|          | single |           |         |                          |
|          | dose.  |           |         |                          |
+----------+--------+-----------+---------+--------------------------+
| Acute    |        |           |         |                          |
| Dietary  |        |           |         |                          |
|          |        |           |         |                          |
| (Females |        |           |         |                          |
| 13-49    |        |           |         |                          |
| years of |        |           |         |                          |
| age)     |        |           |         |                          |
+----------+--------+-----------+---------+--------------------------+
| Chronic  | NOAEL= | UF~A~=    | Chronic | Chronic                  |
| Dietary  | 39     | 10x       | RfD =   | f                        |
| (All     | mg/    |           |         | eeding/carcinogenicity - |
| Popu     | kg/day | UF~H~=    | 0.39    | rat                      |
| lations) |        | 10x       |         |                          |
|          |        |           | mg      | LOAEL = 159 mg/kg/day    |
|          |        | FQPA SF=  | /kg/day | based on nephropathy.    |
|          |        | 1x        |         |                          |
|          |        |           | cPAD =  |                          |
|          |        |           | 0.39    |                          |
|          |        |           | mg      |                          |
|          |        |           | /kg/day |                          |
+----------+--------+-----------+---------+--------------------------+
| In       | NOAEL= | UF~A~=    | Resi    | Subchronic feeding in    |
| cidental | 58     | 10x       | dential | rats.                    |
| Oral     | mg/    |           | LOC for |                          |
| Sh       | kg/day | UF~H~=    | MOE =   | LOAEL = 240 mg/kg/day    |
| ort-Term |        | 10x       | 100     | based on hyperplasia on  |
| (1-30    |        |           |         | the urothelium of the    |
| days)    |        | FQPA SF=  |         | urinary bladder.         |
| and      |        | 1x        |         |                          |
| I        |        |           |         |                          |
| ntermedi |        |           |         |                          |
| ate-Term |        |           |         |                          |
| (1-6     |        |           |         |                          |
| months)  |        |           |         |                          |
+----------+--------+-----------+---------+--------------------------+
| Dermal   | NOAEL  | UF~A~= 10 | Resi    | Subchronic feeding in    |
| Sh       | = 58   | x         | dential | rats.                    |
| ort-Term | mg/    |           | LOC for |                          |
| (1-30    | kg/day | UF~H~=    | MOE =   | LOAEL = 240 mg/kg/day    |
| days)    |        | 10x       | 100     | based on hyperplasia on  |
| and      |        |           |         | the urothelium of the    |
| I        |        | FQPA SF=  |         | urinary bladder.         |
| ntermedi |        | 1x        |         |                          |
| ate-Term |        |           |         |                          |
| (1-6     |        |           |         |                          |
| months)  |        |           |         |                          |
+----------+--------+-----------+---------+--------------------------+
| Dermal   | NOAEL  | UF~A~=    | Resi    | Chronic                  |
| long     | = 39   | 10x       | dential | f                        |
| term (\> | mg/    |           | LOC for | eeding/carcinogenicity - |
| 6        | kg/day | UF~H~=    | MOE =   | rat                      |
| months)  |        | 10x       | 100     |                          |
|          |        |           |         | LOAEL = 159 mg/kg/day    |
|          |        | FQPA SF=  |         | based on nephropathy.    |
|          |        | 1x        |         | 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.           |
+----------+--------+-----------+---------+--------------------------+
| In       | NO     | UF~A~=    | Resi    | Subchronic feeding in    |
| halation | AEL=58 | 10x       | dential | rats.                    |
| Short-   | mg/    |           | LOC for |                          |
| Term     | kg/day | UF~H~=    | MOE =   | LOAEL = 240 mg/kg/day    |
| (1-30    |        | 10x       | 100     | based on hyperplasia on  |
| days)    |        |           |         | the urothelium of the    |
| and      |        | FQPA SF=  |         | urinary bladder.         |
| I        |        | 1x        |         |                          |
| ntermedi |        |           |         |                          |
| ate-Term |        |           |         |                          |
| (1-6     |        |           |         |                          |
| months)  |        |           |         |                          |
+----------+--------+-----------+---------+--------------------------+
| In       | NOAEL  | UF~A~=    | Resi    | Chronic                  |
| halation | = 39   | 10x       | dential | f                        |
| long     | mg/    |           | LOC for | eeding/carcinogenicity - |
| term (\> | kg/day | UF~H~=    | MOE =   | rat                      |
| 6 months |        | 10x       | 100     |                          |
|          |        |           |         | LOAEL = 159 mg/kg/day    |
|          |        | FQPA SF=  |         | based on nephropathy.    |
|          |        | 1x        |         | 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   | Cla    |           |         |                          |
| (oral,   | ssific |           |         |                          |
| dermal,  | ation: |           |         |                          |
| inh      | "Not   |           |         |                          |
| alation) | likely |           |         |                          |
|          | to be  |           |         |                          |
|          | Carcin |           |         |                          |
|          | ogenic |           |         |                          |
|          | to     |           |         |                          |
|          | Humans |           |         |                          |
|          | at     |           |         |                          |
|          | doses  |           |         |                          |
|          | that   |           |         |                          |
|          | do not |           |         |                          |
|          | cause  |           |         |                          |
|          | urot   |           |         |                          |
|          | helium |           |         |                          |
|          | cy     |           |         |                          |
|          | totoxi |           |         |                          |
|          | city." |           |         |                          |
+----------+--------+-----------+---------+--------------------------+

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.
UF~A~ = extrapolation from animal to human (interspecies). UF~H~ =
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       |        |         |            |                          |
| Toxic    |        |         |            |                          |
| ological |        |         |            |                          |
| Doses    |        |         |            |                          |
| and      |        |         |            |                          |
| E        |        |         |            |                          |
| ndpoints |        |         |            |                          |
| for      |        |         |            |                          |
| Cypros   |        |         |            |                          |
| ulfamide |        |         |            |                          |
| for Use  |        |         |            |                          |
| in       |        |         |            |                          |
| Occu     |        |         |            |                          |
| pational |        |         |            |                          |
| Human    |        |         |            |                          |
| Health   |        |         |            |                          |
| Risk     |        |         |            |                          |
| Asses    |        |         |            |                          |
| sments** |        |         |            |                          |
+==========+========+=========+============+==========================+
| E        | Point  | Unce    | Level of   | Study and Toxicological  |
| xposure/ | of     | rtainty | Concern    | Effects                  |
|          | Dep    | Factors | for Risk   |                          |
| Scenario | arture |         | Assessment |                          |
+----------+--------+---------+------------+--------------------------+
| Dermal   | NOAEL  | UF~A~=  | R          | Subchronic feeding in    |
| Sh       | = 58   | 10 x    | esidential | rats.                    |
| ort-Term | mg/    |         | LOC for    |                          |
| (1-30    | kg/day | UF~H~=  | MOE = 100  | LOAEL = 240 mg/kg/day    |
| days)    |        | 10x     |            | based on hyperplasia on  |
|          |        |         |            | the urothelium of the    |
|          |        |         |            | urinary bladder.         |
+----------+--------+---------+------------+--------------------------+
| Dermal   |        |         |            |                          |
| I        |        |         |            |                          |
| ntermedi |        |         |            |                          |
| ate-Term |        |         |            |                          |
| (1-6     |        |         |            |                          |
| months)  |        |         |            |                          |
+----------+--------+---------+------------+--------------------------+
| Dermal   | NOAEL  | UF~A~=  | R          | Chronic                  |
| long     | = 39   | 10x     | esidential | f                        |
| term (\> | mg/    |         | LOC for    | eeding/carcinogenicity - |
| 6        | kg/day | UF~H~=  | MOE = 100  | rat                      |
| months)  |        | 10x     |            |                          |
|          |        |         |            | LOAEL = 159 mg/kg/day    |
|          |        | FQPA    |            | based on nephropathy.    |
|          |        | SF= 1x  |            | 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.           |
+----------+--------+---------+------------+--------------------------+
| In       | NO     | UF~A~=  | R          | Subchronic feeding in    |
| halation | AEL=58 | 10x     | esidential | rats.                    |
| Sh       | mg/    |         | LOC for    |                          |
| ort-Term | kg/day | UF~H~=  | MOE = 100  | LOAEL = 240 mg/kg/day    |
| (1-30    |        | 10x     |            | based on hyperplasia on  |
| days)    |        |         |            | the urothelium of the    |
|          |        |         |            | urinary bladder.         |
+----------+--------+---------+------------+--------------------------+
| In       |        |         |            |                          |
| halation |        |         |            |                          |
| I        |        |         |            |                          |
| ntermedi |        |         |            |                          |
| ate-term |        |         |            |                          |
| (1-6     |        |         |            |                          |
| months)  |        |         |            |                          |
+----------+--------+---------+------------+--------------------------+
| In       | NOAEL  | UF~A~=  | R          | Chronic                  |
| halation | = 39   | 10x     | esidential | f                        |
| long     | mg/    |         | LOC for    | eeding/carcinogenicity - |
| term (\> | kg/day | UF~H~=  | MOE = 100  | rat                      |
| 6 months |        | 10x     |            |                          |
|          |        |         |            | LOAEL = 159 mg/kg/day    |
|          |        | FQPA    |            | based on nephropathy.    |
|          |        | SF= 1x  |            | 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   | Cla    |         |            |                          |
| (oral,   | ssific |         |            |                          |
| dermal,  | ation: |         |            |                          |
| inh      | "Not   |         |            |                          |
| alation) | likely |         |            |                          |
|          | to be  |         |            |                          |
|          | Carcin |         |            |                          |
|          | ogenic |         |            |                          |
|          | to     |         |            |                          |
|          | Humans |         |            |                          |
|          | at     |         |            |                          |
|          | doses  |         |            |                          |
|          | that   |         |            |                          |
|          | do not |         |            |                          |
|          | cause  |         |            |                          |
|          | urot   |         |            |                          |
|          | helium |         |            |                          |
|          | cy     |         |            |                          |
|          | totoxi |         |            |                          |
|          | city." |         |            |                          |
+----------+--------+---------+------------+--------------------------+

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.
UF~A~ = extrapolation from animal to human (interspecies). UF~H~ =
potential variation in sensitivity among members of the human population
(intraspecies). MOE = margin of exposure. LOC = level of concern. N/A =
not applicable.

[]{#__RefHeading___Toc200865300 .anchor}**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.

[]{#__RefHeading___Toc200865301 .anchor}**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.

[]{#__RefHeading___Toc200865302 .anchor}**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.

[]{#__RefHeading___Toc200865303 .anchor}**5.1 Pesticide Metabolism and
Environmental Degradation**

[]{#__RefHeading___Toc200865304 .anchor}**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 (\[sulfonylbenzamide-UL-^14^C\],
S-label) or the methoxybenzoyl ring (\[methoxybenzoyl-UL ^14^C\],
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.

[]{#__RefHeading___Toc200865305 .anchor}**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 \[sulfonylbenzamide-UL-^14^C\]cyprosulfamide at a
rate of 212 g safener/ha or \[methoxybenzoyl-UL-^14^C\]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
\[sulfonylbenzamide-UL-^14^C\]cyprosulfamide and at 30 days following
application of \[methoxybenzoyl-UL-^14^C\]cyprosulfamide; spring wheat
only was planted 120 and 276 days following application of
\[methoxybenzoyl-UL-^14^C\]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.

[]{#__RefHeading___Toc200865306 .anchor}**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
\[sulfonylbenzamide-UL-^14^C\]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
\[methoxybenzoyl-UL-^14^C\]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
\[sulfonylbenzamide-UL-^14^C\]cyprosulfamide in laying hens involved
hydrolysis of the amide bond of the sulfonylbenzamide moiety to produce
AE 0852999. The metabolism of
\[methoxybenzoyl-ring-UL-^14^C\]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.

[]{#__RefHeading___Toc200865307 .anchor}**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.

5.  []{#__RefHeading___Toc200865308 .anchor}**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 K~OC~ values in
all soils ranging from 23.1 to 168.7. Adsorption K~d~ values for
cyprosulfamide range from 0.23 to 1.94.

[]{#__RefHeading___Toc200865309 .anchor}**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 ^14^C
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.

[]{#__RefHeading___Toc200865310 .anchor}**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.

[]{#__RefHeading___Toc200865311 .anchor}**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 Residues Included In
                                  Risk Assessment      Tolerance Expression

  Plants          Primary Crop    Cyprosulfamide *per  Cyprosulfamide *per
                  (Corn)          se*                  se*

                  Rotational      Cyprosulfamide + M02 Not Applicable
                  Crops                                

  Livestock       Ruminant        Cyprosulfamide + M02 Cyprosulfamide + M02

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

  Drinking Water                  Cyprosulfamide + M02 Not Applicable
                                  & M04                
  -------------------------------------------------------------------------

[]{#__RefHeading___Toc200865312 .anchor}**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     | **Groundwater       |
|                          | Conc., ppb ^a^**    | Conc., ppb ^b^**    |
+--------------------------+---------------------+---------------------+
| Chronic                  | 2.4                 | 0.14                |
+--------------------------+---------------------+---------------------+
| ^a^ From the Tier 1      |                     |                     |
| FIRST model.             |                     |                     |
|                          |                     |                     |
| ^b^ From the Tier 1      |                     |                     |
| SCI-GROW model.          |                     |                     |
+--------------------------+---------------------+---------------------+

[]{#__RefHeading___Toc200865313 .anchor}**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.

[]{#__RefHeading___Toc200865314 .anchor}**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.

[]{#__RefHeading___Toc200865315 .anchor}**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

[]{#__RefHeading___Toc200865316 .anchor}**5.2.1 Acute Dietary
Exposure/Risk**

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

[]{#__RefHeading___Toc200865317 .anchor}**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,         DEEM-FCID (food  
                               mg/kg/day     and water)       
  ---------------------------- ------------- ---------------- ------------
                                             Exposure,        %cPAD
                                             mg/kg/day        

  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
  ------------------------------------------------------------------------

[]{#__RefHeading___Toc200865318 .anchor}**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]{.underline}

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** | **A        | *     | *     | **Short |      |
|                      | pplication | *Area | *Unit | -/Inter |      |
|                      | Rate ^1^** | Tr    | Exp   | mediate |      |
|                      |            | eated | osure | -Term** |      |
|                      | **(lb      | ^2^** | ^3^** |         |      |
|                      | ai/A)**    |       |       |         |      |
|                      |            | **(ac | **(   |         |      |
|                      |            | res/d | mg/lb |         |      |
|                      |            | ay)** | ai)** |         |      |
+----------------------+------------+-------+-------+---------+------+
|                      |            |       |       | **Daily | **T  |
|                      |            |       |       | Dose    | otal |
|                      |            |       |       | ^4^**   | MOE  |
|                      |            |       |       |         | ^    |
|                      |            |       |       | *       | 5^** |
|                      |            |       |       | *(mg/kg |      |
|                      |            |       |       | /day)** |      |
+----------------------+------------+-------+-------+---------+------+
| \(1\) Mix/load and   | 0.027      | 0.023 | De    | Dermal: | 6    |
| spot application of  |            |       | rmal: |         | 5400 |
| liquid formulation   |            | (     |       | 0.00089 |      |
| (low-pressure hand   |            | 1,000 | 100   |         |      |
| sprayer)             |            | f     |       |         |      |
|                      |            | t^2^) |       |         |      |
+----------------------+------------+-------+-------+---------+------+
|                      |            |       | I     | Inha    |      |
|                      |            |       | nhala | lation: |      |
|                      |            |       | tion: |         |      |
|                      |            |       |       | 2.6e-7  |      |
|                      |            |       | 0.030 |         |      |
+----------------------+------------+-------+-------+---------+------+
| \(2\) Mix/load and   | 0.027      | 0.50  | De    | Dermal: | 2    |
| broadcast            |            |       | rmal: |         | 7300 |
| application of       |            |       |       | 0.0021  |      |
| liquid formulation   |            |       | 11    |         |      |
| (garden hose-end     |            |       |       |         |      |
| sprayer)             |            |       |       |         |      |
+----------------------+------------+-------+-------+---------+------+
|                      |            |       | I     | Inha    |      |
|                      |            |       | nhala | lation: |      |
|                      |            |       | tion: |         |      |
|                      |            |       |       | 3.28e-6 |      |
|                      |            |       | 0.017 |         |      |
+----------------------+------------+-------+-------+---------+------+

^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]{.underline}

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]{.underline}

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]{.underline}

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.

+------+------+------+-------+-------+------+-----+-------+----------+
| **T  |      |      |       |       |      |     |       |          |
| able |      |      |       |       |      |     |       |          |
| 6.1  |      |      |       |       |      |     |       |          |
| Pos  |      |      |       |       |      |     |       |          |
| tapp |      |      |       |       |      |     |       |          |
| lica |      |      |       |       |      |     |       |          |
| tion |      |      |       |       |      |     |       |          |
| De   |      |      |       |       |      |     |       |          |
| rmal |      |      |       |       |      |     |       |          |
| Expo |      |      |       |       |      |     |       |          |
| sure |      |      |       |       |      |     |       |          |
| and  |      |      |       |       |      |     |       |          |
| Risk |      |      |       |       |      |     |       |          |
| from |      |      |       |       |      |     |       |          |
| Tre  |      |      |       |       |      |     |       |          |
| ated |      |      |       |       |      |     |       |          |
| Law  |      |      |       |       |      |     |       |          |
| ns** |      |      |       |       |      |     |       |          |
+------+------+------+-------+-------+------+-----+-------+----------+
| **   | *    | **   | **Fra | *     | **De | **B | **    | **Dermal |
| Subg | *App | Post | ction | *Turf | rmal | ody | Daily | MOE      |
| roup | lica | -app | of ai | Tra   | Tran | We  | D     | ^3^**    |
| E    | tion | lica | Tra   | nsfer | sfer | igh | ermal |          |
| xpos | Ra   | tion | nsfer | rable | C    | t** | Dose  |          |
| ed** | te** | day  | rable | Re    | oeff |     | ^2^** |          |
|      |      | (    | from  | sidue | icie | **  |       |          |
|      | *    | t)** | the   | ^1^** | nt** | (kg | **(mg |          |
|      | *(lb |      | Foli  |       |      | )** | /kg/d |          |
|      | ai/  |      | age** | **(µ  | **   |     | ay)** |          |
|      | A)** |      |       | g/cm^ | (cm^ |     |       |          |
|      |      |      |       | 2^)** | 2^/h |     |       |          |
|      |      |      |       |       | r)** |     |       |          |
+------+------+------+-------+-------+------+-----+-------+----------+
|      |      |      |       |       |      |     |       | **Shor   |
|      |      |      |       |       |      |     |       | t-term** |
+------+------+------+-------+-------+------+-----+-------+----------+
| Ad   | 0    | 0    | 0.05  | 0.015 | 14   | 70  | 0.    | 9400     |
| ults | .027 |      |       |       | ,500 |     | 00621 |          |
+------+------+------+-------+-------+------+-----+-------+----------+
| Chil |      |      |       |       | 5    | 15  | 0.    | 5600     |
| dren |      |      |       |       | ,200 |     | 01040 |          |
+------+------+------+-------+-------+------+-----+-------+----------+

^1^ Turf Transferable Residue ~Postapplication\ day~ (µg/cm^2^)=
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/cm^2^

^2^ Daily Dermal Dose = (Turf Transferable Residue (µg/cm^2^) x
Absorption Factor (100) x Dermal Transfer Coefficient (cm^2^/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>
<colgroup>
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 11%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 7%" />
<col style="width: 10%" />
<col style="width: 10%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="10"><strong>Table 6.2 Postapplication Oral Hand-to-Mouth
Exposure and Risk for Children from Treated Lawns</strong></td>
</tr>
<tr class="even">
<td rowspan="2"><p><strong>Application Rate</strong></p>
<p><strong>(lb ai/A)</strong></p></td>
<td rowspan="2"><strong>Post-application day (t)</strong></td>
<td rowspan="2"><strong>Fraction of ai Transferable from the
Foliage</strong></td>
<td rowspan="2"><p><strong>Turf Transferable Residue
<sup>1</sup></strong></p>
<p><strong>(µg/cm<sup>2</sup>)</strong></p></td>
<td rowspan="2"><p><strong>Hand Surface Area</strong></p>
<p><strong>(cm<sup>2</sup>/event)</strong></p></td>
<td rowspan="2"><strong>Saliva Extraction Factor</strong></td>
<td rowspan="2"><p><strong>Frequency</strong></p>
<p><strong>(events/ hr)</strong></p></td>
<td rowspan="2"><p><strong>Body Weight</strong></p>
<p><strong>(kg)</strong></p></td>
<td rowspan="2"><p><strong>Daily Dose<sup>2</sup></strong></p>
<p><strong>(mg/kg/day)</strong></p></td>
<td><strong>Oral MOE<sup>3</sup></strong></td>
</tr>
<tr class="odd">
<td><strong>Short-term</strong></td>
</tr>
<tr class="even">
<td>0.027</td>
<td>0</td>
<td>0.05</td>
<td>0.015</td>
<td>20</td>
<td>50%</td>
<td>20</td>
<td>15</td>
<td>0.00040</td>
<td>145,000</td>
</tr>
</tbody>
</table>

^1^ Turf Transferable Residue ~Postapplication\ day~ (µg/cm^2^)=
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/cm^2^

^2^ Daily Dose = (Turf Transferable Residue (µg/cm^2^) x Hand Surface
Area (cm^2^/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     |        |        |        |        |        |      |      |
| P       |        |        |        |        |        |      |      |
| ostappl |        |        |        |        |        |      |      |
| ication |        |        |        |        |        |      |      |
| Oral    |        |        |        |        |        |      |      |
| O       |        |        |        |        |        |      |      |
| bject-t |        |        |        |        |        |      |      |
| o-Mouth |        |        |        |        |        |      |      |
| (Tur    |        |        |        |        |        |      |      |
| fgrass) |        |        |        |        |        |      |      |
| E       |        |        |        |        |        |      |      |
| xposure |        |        |        |        |        |      |      |
| and     |        |        |        |        |        |      |      |
| Risk    |        |        |        |        |        |      |      |
| for     |        |        |        |        |        |      |      |
| C       |        |        |        |        |        |      |      |
| hildren |        |        |        |        |        |      |      |
| from    |        |        |        |        |        |      |      |
| Treated |        |        |        |        |        |      |      |
| Lawns** |        |        |        |        |        |      |      |
+---------+--------+--------+--------+--------+--------+------+------+
| **Appl  | **P    | **Fr   | **Gr   | **Ing  | **     | **D  | **   |
| ication | ost-** | action | ass/Ob | estion | Body** | aily | Oral |
| Rate**  |        | of ai  | ject** | Rate** |        | D    | MOE^ |
|         | *      | Transf |        |        | **We   | ose^ | 3^** |
| **(lb   | *appli | erable | **R    | **(    | ight** | 2^** |      |
| ai/A)** | cation | from   | esidue | cm^2^/ |        |      |      |
|         | day**  | the    | ^1^**  | day)** | **     | **(  |      |
|         |        | Fol    |        |        | (kg)** | mg/k |      |
|         | *      | iage** | **     |        |        | g/da |      |
|         | *(t)** |        | (µg/cm |        |        | y)** |      |
|         |        |        | ^2^)** |        |        |      |      |
+---------+--------+--------+--------+--------+--------+------+------+
|         |        |        |        |        |        |      | **   |
|         |        |        |        |        |        |      | Shor |
|         |        |        |        |        |        |      | t-te |
|         |        |        |        |        |        |      | rm** |
+---------+--------+--------+--------+--------+--------+------+------+
| 0.027   | 0      | 0.29   | 0.2    | 25     | 15     | 0.0  | 580  |
|         |        |        |        |        |        | 0010 | ,000 |
+---------+--------+--------+--------+--------+--------+------+------+

^1^Grass/Object residue ~Postapplication\ day~ (µg/cm^2^) = 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/cm^2^

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

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

+------+-------+---------+------------+---------+-----------+-------+
| **T  |       |         |            |         |           |       |
| able |       |         |            |         |           |       |
| 6.4  |       |         |            |         |           |       |
| Pos  |       |         |            |         |           |       |
| tapp |       |         |            |         |           |       |
| lica |       |         |            |         |           |       |
| tion |       |         |            |         |           |       |
| In   |       |         |            |         |           |       |
| cide |       |         |            |         |           |       |
| ntal |       |         |            |         |           |       |
| Soil |       |         |            |         |           |       |
| I    |       |         |            |         |           |       |
| nges |       |         |            |         |           |       |
| tion |       |         |            |         |           |       |
| Expo |       |         |            |         |           |       |
| sure |       |         |            |         |           |       |
| and  |       |         |            |         |           |       |
| Risk |       |         |            |         |           |       |
| for  |       |         |            |         |           |       |
| Chil |       |         |            |         |           |       |
| dren |       |         |            |         |           |       |
| from |       |         |            |         |           |       |
| Tre  |       |         |            |         |           |       |
| ated |       |         |            |         |           |       |
| Law  |       |         |            |         |           |       |
| ns** |       |         |            |         |           |       |
+------+-------+---------+------------+---------+-----------+-------+
| *    | **Fra | **Soil  | *          | **Body  | **Daily   | *     |
| *App | ction | Residue | *Ingestion | Weight  | Do        | *Oral |
| lica | of ai | ^1^     | Rate       | (kg)**  | se^2^(mg/ | MOE   |
| tion | Ret   | (       | (mg/day)** |         | kg/day)** | ^3^** |
| Ra   | ained | µg/g)** |            |         |           |       |
| te** | in    |         |            |         |           |       |
|      | the   |         |            |         |           |       |
| *    | S     |         |            |         |           |       |
| *(lb | oil** |         |            |         |           |       |
| ai/  |       |         |            |         |           |       |
| A)** |       |         |            |         |           |       |
+------+-------+---------+------------+---------+-----------+-------+
|      |       |         |            |         |           | **Sh  |
|      |       |         |            |         |           | ort-t |
|      |       |         |            |         |           | erm** |
+------+-------+---------+------------+---------+-----------+-------+
| 0    | 1     | 2.0     | 100        | 15      | 0         | 58,00 |
| .027 |       |         |            |         | .00000014 | 0,000 |
+------+-------+---------+------------+---------+-----------+-------+

^1^ Soil residue ~Postapplication\ day\ zero~ (µg/cm^2^) = Application
rate (lb ai/A) x Fraction of ai Retained on the Soil x (4.54E+8 µg/lb x
2.47E-8 A/cm^2^ x 0.67 cm^3^/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                                                     
  Lawn**s                                                              

  **Scenario and      **TTR/GR/SR~0~   **PDR~0-norm~   **Short-Term    **Total MOE
  Pathway**           (µg/cm^2^ or g)  (mg/kg/day)     MOE ^3^**       ^4^**
                      ^1^**            ^2^**                           

                                                                       **Short-
                                                                       Term**

  **Adult's                                                            
  Scenarios**                                                          

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

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

  \(2\) Dermal        0.015            0.00621         9400            
  Postapplication                                                      

  **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      0.06             0.00010         580,000         
  Grass/Object                                                         

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

^1^ TTR=turf transferable residue on day "0\"; GR=grass/object residue
on day "0\"; SR~0~=soil residue on day "0\".

^2^ PDR~0norm~=potential dose rate on day "0".

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

^4^ For Adults: Total MOE = 1/ \[(1/MOE~Handler~ ~Dermal~) +
(1/MOE~Dermal\ Postapplication~) + (1/MOE~Inhalation~) \]

For Children: Total MOE = 1/ \[(1/MOE~Dermal~) +
(1/MOE~Hand-to-Mouth~) + (1/MOE~Grass~) + (1/MOE~Soil~)\]

[]{#__RefHeading___Toc200865319 .anchor}**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.

[]{#__RefHeading___Toc200865320 .anchor}**7.1 Acute Aggregate Risk**

Not applicable due to lack of an acute toxicity endpoint.

[]{#__RefHeading___Toc200865321 .anchor}**7.2 Short-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.     |        |      |         |        |          |            |
| Sh       |        |      |         |        |          |            |
| ort-Term |        |      |         |        |          |            |
| A        |        |      |         |        |          |            |
| ggregate |        |      |         |        |          |            |
| Risk     |        |      |         |        |          |            |
| Calcul   |        |      |         |        |          |            |
| ations** |        |      |         |        |          |            |
+==========+========+======+=========+========+==========+============+
| Po       | Short* |      |         |        |          |            |
| pulation | -*Term |      |         |        |          |            |
|          | Sc     |      |         |        |          |            |
|          | enario |      |         |        |          |            |
+----------+--------+------+---------+--------+----------+------------+
|          | NOAEL  | LO   | Max     | A      | Res      | Aggregate  |
|          |        | C^1^ | Al      | verage | idential | MOE        |
|          | mg/    |      | lowable |        | Exp      |            |
|          | kg/day |      |         | Food & | osure^4^ | (food and  |
|          |        |      | Expo    | Water  |          |            |
|          |        |      | sure^2^ |        | m        | resid      |
|          |        |      |         | Expos  | g/kg/day | ential)^5^ |
|          |        |      | mg      | ure^3^ |          |            |
|          |        |      | /kg/day |        |          |            |
|          |        |      |         | mg/    |          |            |
|          |        |      |         | kg/day |          |            |
+----------+--------+------+---------+--------+----------+------------+
| Adult    | 58     | 100  | 0.58    | 0.     | 0.00831  | 6900       |
|          |        |      |         | 000072 |          |            |
+----------+--------+------+---------+--------+----------+------------+
| Child    | 58     | 100  | 0.58    | 0.     | 0.0109   | 5300       |
|          |        |      |         | 000121 |          |            |
+----------+--------+------+---------+--------+----------+------------+

^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.

^5^ Aggregate MOE = \[(NOAEL /(Avg Food & Water Exposure + Residential
Exposure)\]

[]{#__RefHeading___Toc200865322 .anchor}**7.3 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).

[]{#__RefHeading___Toc200865323 .anchor}**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
[[http://www.epa.gov/pesticides/cumulative/.]{.underline}](http://www.epa.gov/pesticides/cumulative/.)

[]{#__RefHeading___Toc200865324 .anchor}**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

[]{#__RefHeading___Toc200865325 .anchor}**9.1 Short- and
Intermediate-term Handler Risk**

[Occupational Handler Exposure]{.underline}

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:

Number range CHAPTER 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
exposure risks for mixer/loaders are not of concern (i.e., MOEs\>100),
provided the mixer/loaders wear protective gloves as directed on the
label. 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.

HED has no data to assess exposures to pilots using open cockpits.  The
only data available are for exposure to pilots in enclosed cockpits. 
Therefore, risks to pilots are assessed using the engineering control
(enclosed cockpits) and baseline attire (long-sleeve shirt, long pants,
shoes, and socks); pilots are not required to wear protective gloves.
With this level of protection, there are no risks of concern for
applicators.

<table>
<colgroup>
<col style="width: 10%" />
<col style="width: 0%" />
<col style="width: 7%" />
<col style="width: 0%" />
<col style="width: 7%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 17%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 16%" />
<col style="width: 0%" />
<col style="width: 1%" />
<col style="width: 15%" />
<col style="width: 20%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="15"><strong>Table 9.1.1 Cyprosulfamide Occupational Short
and Intermediate-Term Dermal and Inhalation Exposures and
Risks</strong></th>
</tr>
<tr class="odd">
<th colspan="2">Crop or Target</th>
<th>App Rate (lb ai/acre)<sup>a</sup></th>
<th colspan="2">Area Treated Daily (acres)<sup>b</sup></th>
<th colspan="4"><p>Dermal and Inhalation Unit Exposures</p>
<p>(mg/lb ai)</p></th>
<th colspan="3">Doses (mg/kg/day)<sup>g</sup></th>
<th colspan="2">MOEs<sup>h</sup></th>
<th>Combined MOEs<sup>i</sup></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td colspan="15"><em>Mixing/Loading Liquid Concentrates for Aerial
Applications</em></td>
</tr>
<tr class="even">
<td colspan="2" rowspan="2">corn</td>
<td rowspan="2">0.141</td>
<td colspan="2" rowspan="2">1200</td>
<td colspan="4"><p><u>Dermal</u></p>
<p>Baseline<sup>c</sup>: 2.9</p>
<p>SL w/gloves<sup>d</sup>: 0.023</p></td>
<td colspan="3"><p><u>Dermal</u></p>
<p>Baseline: 7.00</p>
<p>SL w/gloves: 0.056</p></td>
<td colspan="2"><p><u>Dermal</u></p>
<p>Baseline: 8</p>
<p>SL w/gloves: 1,000</p></td>
<td rowspan="2"><p>Baseline Dermal and Inhalation:</p>
<p>PPE – SL w/gloves + Baseline Inhalation:
<strong>1,000</strong></p></td>
</tr>
<tr class="odd">
<td colspan="4"><p><u>Inhalation</u></p>
<p>Baseline<sup>e</sup>: 0.0012</p></td>
<td colspan="3"><p><u>Inhalation</u></p>
<p>Baseline: 0.003</p></td>
<td colspan="2"><p><u>Inhalation</u></p>
<p>Baseline: 19,000</p></td>
</tr>
<tr class="even">
<td colspan="15"><em>Mixing/Loading Liquid Concentrates for Grounboom
Applications</em></td>
</tr>
<tr class="odd">
<td colspan="2" rowspan="2">corn</td>
<td rowspan="2">0.141</td>
<td colspan="3" rowspan="2">200</td>
<td colspan="2"><p><u>Dermal</u></p>
<p>Baseline<sup>c</sup>: 2.9</p>
<p>SL w/gloves<sup>d</sup>: 0.023</p></td>
<td colspan="3"><p><u>Dermal</u></p>
<p>Baseline: 1.17</p>
<p>SL w/gloves: 0.0093</p></td>
<td colspan="3"><p><u>Dermal</u></p>
<p>Baseline: 48</p>
<p>SL w/gloves: 6,045</p></td>
<td rowspan="2"><p>Baseline Dermal and Inhalation:</p>
<p>PPE – SL w/gloves + Baseline Inhalation:
<strong>5,750</strong></p></td>
</tr>
<tr class="even">
<td colspan="2"><p><u>Inhalation</u></p>
<p>Baseline<sup>e</sup>: 0.0012</p></td>
<td colspan="3"><p><u>Inhalation</u></p>
<p>Baseline: 0.00048</p></td>
<td colspan="3"><p><u>Inhalation</u></p>
<p>Baseline: 116,000</p></td>
</tr>
<tr class="odd">
<td colspan="15"><em>Applying Sprays via Aerial Equipment</em></td>
</tr>
<tr class="even">
<td colspan="2" rowspan="2">corn</td>
<td rowspan="2">0.141</td>
<td colspan="2" rowspan="2">1200</td>
<td colspan="4"><p><u>Dermal</u></p>
<p>Engineering control<sup>f</sup>: 0.005</p></td>
<td colspan="3"><p><u>Dermal</u></p>
<p>Engineering control: 0.0121</p></td>
<td colspan="2"><p><u>Dermal</u></p>
<p>Engineering control:4,633</p></td>
<td rowspan="2">Engineering control Dermal + Inhalation:
<strong>4,570</strong></td>
</tr>
<tr class="odd">
<td colspan="4"><p><u>Inhalation</u></p>
<p>Engineering control: 0.000068</p></td>
<td colspan="3"><p><u>Inhalation</u></p>
<p>Engineering control: 0.000164</p></td>
<td colspan="2"><p><u>Inhalation</u></p>
<p>Engineering control: 340,700</p></td>
</tr>
<tr class="even">
<td colspan="15"><em>Flagging to Support Aerial Applications</em></td>
</tr>
<tr class="odd">
<td rowspan="2">corn</td>
<td colspan="3" rowspan="2">0.141</td>
<td colspan="3" rowspan="2">350</td>
<td colspan="3"><p><u>Dermal</u></p>
<p>Baseline<sup>f</sup>: 0.01</p></td>
<td colspan="3"><p><u>Dermal</u></p>
<p>Baseline: 0.0078</p></td>
<td><p><u>Dermal</u></p>
<p>Baseline: 7500</p></td>
<td rowspan="2">Baseline Dermal and Inhalation:
<strong>7,250</strong></td>
</tr>
<tr class="even">
<td colspan="3"><p><u>Inhalation</u></p>
<p>Baseline: 0.00035</p></td>
<td colspan="3"><p><u>Inhalation</u></p>
<p>Baseline: 0.00025</p></td>
<td><p><u>Inhalation</u></p>
<p>Baseline: 235,000</p></td>
</tr>
<tr class="odd">
<td colspan="15"><em>Applying Sprays via Groundboom Equipment</em></td>
</tr>
<tr class="even">
<td colspan="2" rowspan="2">corn</td>
<td rowspan="2">0.141</td>
<td colspan="2" rowspan="2">200</td>
<td colspan="4"><p><u>Dermal</u></p>
<p>0.014</p></td>
<td colspan="3"><p><u>Dermal</u></p>
<p><u>0.00564</u></p></td>
<td colspan="2"><p><u>Dermal</u></p>
<p><u>9,929</u></p></td>
<td rowspan="2">Dermal + Inhalation: <strong>9,430</strong></td>
</tr>
<tr class="odd">
<td colspan="4"><p><u>Inhalation</u></p>
<p><u>0.00074</u></p></td>
<td colspan="3"><p><u>Inhalation</u>:</p>
<p>0.000298</p></td>
<td colspan="2"><p><u>Inhalation</u></p>
<p><u>187,847</u></p></td>
</tr>
<tr class="even">
<td colspan="15"><em>Mixing/Loading Liquid and Applying with Handgun
Sprayer</em></td>
</tr>
<tr class="odd">
<td colspan="2" rowspan="2">Turf</td>
<td rowspan="2"><p>0.027</p>
<p>Ib ai/A</p></td>
<td colspan="2" rowspan="2">5A</td>
<td colspan="4">0.50 (gloves)</td>
<td colspan="3"><p><u>Dermal:</u></p>
<p>0.00096</p></td>
<td colspan="2"><p><u>Dermal</u></p>
<p>60,500</p></td>
<td rowspan="2"><strong>48,000</strong></td>
</tr>
<tr class="even">
<td colspan="4">0.0019</td>
<td colspan="3"><p><u>Inhalation:</u></p>
<p>0.0002565</p></td>
<td colspan="2"><p><u>Inhalation</u></p>
<p>226,000</p></td>
</tr>
<tr class="odd">
<td colspan="15"><em>Mixing/Loading Liquid and Applying with
Low-Pressure Handwand</em></td>
</tr>
<tr class="even">
<td colspan="2" rowspan="2">Turf</td>
<td rowspan="2"><p>0.01</p>
<p>lb ai/gal</p></td>
<td colspan="2" rowspan="2"><p>40</p>
<p>gals</p></td>
<td colspan="4">100</td>
<td colspan="3"><p><u>Dermal:</u></p>
<p>0.571</p></td>
<td colspan="2"><p><u>Dermal</u></p>
<p>102</p></td>
<td rowspan="2"><strong>100</strong></td>
</tr>
<tr class="odd">
<td colspan="4">0.03</td>
<td colspan="3"><p><u>Inhalation:</u></p>
<p>0.00017</p></td>
<td colspan="2"><p><u>Inhalation</u></p>
<p>341,000</p></td>
</tr>
<tr class="even">
<td colspan="15"><em>Mixing/Loading Liquid and Applying with
High-Pressure Handwand</em></td>
</tr>
<tr class="odd">
<td colspan="2" rowspan="2">Ornamentals</td>
<td rowspan="2"><p>0.01</p>
<p>lb ai/gal</p></td>
<td colspan="2" rowspan="2"><p>1000</p>
<p>gals</p></td>
<td colspan="4">2.5 (gloves)</td>
<td colspan="3"><p><u>Dermal:</u></p>
<p>0.357</p></td>
<td colspan="2"><p><u>Dermal</u></p>
<p>163</p></td>
<td rowspan="2"><strong>155</strong></td>
</tr>
<tr class="even">
<td colspan="4">0.12</td>
<td colspan="3"><p><u>Inhalation:</u></p>
<p>0.0171</p></td>
<td colspan="2"><p><u>Inhalation</u></p>
<p>3,400</p></td>
</tr>
<tr class="odd">
<td colspan="15"><em>Mixing/Loading Liquid and Applying with Backpack
Sprayer</em></td>
</tr>
<tr class="even">
<td colspan="2" rowspan="2">Turf and Ornamentals</td>
<td rowspan="2"><p>0.01</p>
<p>lb ai/gal</p></td>
<td colspan="2" rowspan="2"><p>40</p>
<p>gals</p></td>
<td colspan="4">2.5 (gloves)</td>
<td colspan="3"><p><u>Dermal:</u></p>
<p>0.0142</p></td>
<td colspan="2"><p><u>Dermal</u></p>
<p>4100</p></td>
<td rowspan="2"><strong>4,036</strong></td>
</tr>
<tr class="odd">
<td colspan="4">0.03</td>
<td colspan="3"><p><u>Inhalation:</u></p>
<p>0.000171</p></td>
<td colspan="2"><p><u>Inhalation</u></p>
<p>338,000</p></td>
</tr>
<tr class="even">
<td colspan="15"><em>Mixing/Loading water soluble granular and Applying
with Backpack Sprayer, handgun sprayer, low pressure handwand or high
pressure handwand</em></td>
</tr>
<tr class="odd">
<td colspan="2" rowspan="2">Turf</td>
<td rowspan="2">0.027</td>
<td colspan="2" rowspan="2">5A or 40 gals</td>
<td colspan="4">No Data</td>
<td colspan="3"><p><u>Dermal:</u></p>
<p>Not Assessed</p></td>
<td colspan="2"><p><u>Dermal</u></p>
<p>Not Assessed</p></td>
<td rowspan="2"><strong>Not Assessed</strong></td>
</tr>
<tr class="even">
<td colspan="4">No Data</td>
<td colspan="3"><p><u>Inhalation:</u></p>
<p>Not Assessed</p></td>
<td colspan="2"><p><u>Inhalation</u></p>
<p>Not Assessed</p></td>
</tr>
</tbody>
</table>

a Application rates are the maximum application rates determined from
proposed labels for cyprosulfamide

b Amount handled per day values are HED estimates of acres treated per
day based on Exposure SAC SOP #9 "Standard Values for Daily Acres
Treated in Agriculture," industry sources, and HED estimates.

c Baseline Dermal: Long-sleeve shirt, long pants, and no gloves.

d Dermal SL w/gloves: Single layer plus chemical-resistant gloves.

e Baseline Inhalation: no respirator.

f Engineering control: enclosed cockpit

g Dose (mg/kg/day) = Unit exposure(mg/lb ai) x App Rate (lb ai/acre) x
Area Treated (acres/day) x %Absorption (100% dermal and 100% inhalation)
/ Body weight (70 kg).

h MOE = LOAEL/Dose; where the short- and intermediate-term dermal and
inhalation NOAEL = 58 mg/kg/day

i Combined MOEs =LOAEL / (Dermal dose + Inhalation Dose)

**[Seed Treatment]{.underline}**

There is potential for occupational exposure from the proposed use
(i.e., Sorghum) as a seed treatment. It is anticipated that the
following scenarios could result in handler exposure. The exposure
assessment scenarios are as follows:

-   Loading (open)/applying a liquid formulation for seed treatment;

-   Sewing bags of treated seed;

-   Bagging treated seeds;

-   Multiple activities involved in seed treatment; and

-   Planting of treated seed**.**

    The unit exposures are based on SOPs #14 and #15. SOP #14 contains
    all the known scenarios associated with seed treatment facilities
    and planting treated seed. The data contained in this document are
    for worker exposure estimation and are mostly generated by the
    industry. Exposure estimates are from actual seed treatment studies
    and are based on physical factors or a handler scenario (e.g.,
    commercial seed treatment, on farm seed treatment, planters, etc).
    The unit exposures are based on a central tendency from multiple
    studies summarized in SOP #14.

For pesticide handlers, it is HED standard practice to present estimates
of dermal exposure for "baseline" (i.e., 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 product label directs workers involved with
treated the seed to wear long-sleeve shirt and long pants, chemical
resistant footwear plus socks, chemical resistant gloves, a chemical
resistant apron, and a dust/mist filtering respirator or a NIOSH
approved respirator with an R, P or HE filter. Baggers and bag sewers
must wear a long-sleeved shirt and long pants, shoes plus socks,
chemical resistant gloves, and a dust/mist filtering respirator or a
NIOSH approved respirator with an R, P or HE filter.

HED believes most exposure durations will be short-term (1 - 30 days).
However, HED's Science Advisory Council for Exposure (ExpoSAC) maintains
it is possible for commercial applicators to be exposed to
intermediate-term exposure durations (1 - 6 months). In addition, the
short- and intermediate-term toxicological endpoints are the same,
therefore, 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.

The following equations were used to calculate seed treatment handler
exposure and risk:

\(1\) Inhalation Dose (mg/kg/day) = Rate (lb ai/lbs seed) **x** UE
(mg/lb ai) **x** AT (lbs/day) / BW (kg)

Where:

Rate (Application Rate) = Maximum application rate on product label (lb
ai/lbs seed);

> UE (Unit Exposure) = Exposure value derived from SOP 15 (mg/lb ai);

AT (Amount treated) = Max. lbs. of seed treated/day (lbs/day); and

BW = Body weight (kg).

\(2\) Inhalation MOE = NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day)

Table 9.1.2 presents the estimated risks for workers based on the short
and intermediate-term inhalation exposures at baseline. HED has
determined that risks are not of concern (i.e., MOEs\>100).

+-----------------+--------+--------+------------+------------+------+
| **Table 9.1.2   |        |        |            |            |      |
| Occupational    |        |        |            |            |      |
| Handler         |        |        |            |            |      |
| Exposures and   |        |        |            |            |      |
| Risks**         |        |        |            |            |      |
+=================+========+========+============+============+======+
| Inhalation Unit | Appli  | lbs    | Short- and | Short- and | T    |
| Exposures       | cation | seed   | Interme    | Interme    | otal |
|                 | rate   | t      | diate-term | diate-term | MOE  |
| (mg/lb ai)^a^   | (lb    | reated | Doses      | Dermal and |      |
|                 | ai/100 | or     | (mg/       | Inhalation |      |
|                 | lb     | pl     | kg/day)^c^ | MOEs^d^    |      |
|                 | seed)  | anted/ |            |            |      |
|                 |        | day^b^ |            |            |      |
+-----------------+--------+--------+------------+------------+------+
| Dermal Unit     |        |        |            |            |      |
| Exposures       |        |        |            |            |      |
| (mg/lb ai)^a^   |        |        |            |            |      |
+-----------------+--------+--------+------------+------------+------+
| *Loading        |        |        |            |            |      |
| (open)/applying |        |        |            |            |      |
| liquid for seed |        |        |            |            |      |
| treatment*      |        |        |            |            |      |
+-----------------+--------+--------+------------+------------+------+
| 0.00034         | 0.052  | 7      | I          | I          | 450  |
|                 |        | 18,000 | nhalation: | nhalation: |      |
|                 |        |        | 0.0018     | 31000      |      |
+-----------------+--------+--------+------------+------------+------+
| 0.0230          |        |        | De         | Dermal:460 |      |
|                 |        |        | rmal:0.123 |            |      |
+-----------------+--------+--------+------------+------------+------+
| *Sewing bags of |        |        |            |            |      |
| treated seed*   |        |        |            |            |      |
+-----------------+--------+--------+------------+------------+------+
| 0.00023         | 0.052  | 7      | Inhalati   | I          | 1633 |
|                 |        | 18,000 | on:0.00122 | nhalation: |      |
|                 |        |        |            | 46000      |      |
+-----------------+--------+--------+------------+------------+------+
| 0.0062          |        |        | De         | D          |      |
|                 |        |        | rmal:0.033 | ermal:1700 |      |
+-----------------+--------+--------+------------+------------+------+
| *Bagging seeds  |        |        |            |            |      |
| after seed      |        |        |            |            |      |
| treatment*      |        |        |            |            |      |
+-----------------+--------+--------+------------+------------+------+
| 0.00016         | 0.052  | 7      | Inhalati   | I          | 1134 |
|                 |        | 18,000 | on:0.00085 | nhalation: |      |
|                 |        |        |            | 66000      |      |
+-----------------+--------+--------+------------+------------+------+
| 0.0091          |        |        | De         | D          |      |
|                 |        |        | rmal:0.049 | ermal:1200 |      |
+-----------------+--------+--------+------------+------------+------+
| *Multiple       |        |        |            |            |      |
| activities      |        |        |            |            |      |
| involved in     |        |        |            |            |      |
| seed treatment* |        |        |            |            |      |
+-----------------+--------+--------+------------+------------+------+
| 0.0016          | 0.052  | 7      | Inhalat    | I          | 240  |
|                 |        | 18,000 | ion:0.0085 | nhalation: |      |
|                 |        |        |            | 6600       |      |
+-----------------+--------+--------+------------+------------+------+
| 0.042           |        |        |            |            |      |
+-----------------+--------+--------+------------+------------+------+
|                 |        |        | De         | Dermal:250 |      |
|                 |        |        | rmal:0.224 |            |      |
+-----------------+--------+--------+------------+------------+------+
| *Planting of    |        |        |            |            |      |
| treated seed*   |        |        |            |            |      |
+-----------------+--------+--------+------------+------------+------+
| 0.0034          | 0.052  | 12,000 | Inhalat    | Inhalat    | 2500 |
|                 |        |        | ion:0.0003 | ion:185000 |      |
+-----------------+--------+--------+------------+------------+------+
| 0.2500          |        |        | Der        | D          |      |
|                 |        |        | mal:0.0223 | ermal:2500 |      |
+-----------------+--------+--------+------------+------------+------+

a Baseline Inhalation and dermal unit exposures are taken from the
ExpoSAC Policy 14.

b Lbs of seed treated or planted/day values are based on ExpoSAC Policy
15.

c Inhalation and dermal dose (mg/kg/day) = \[unit exposure (mg/lb ai) \*
Appl. rate (lb ai/lbs seed) \* Amount treated / body weight (70 kg)\].

d MOE = NOAEL (58 mg/kg/day) / inhalation or Dermal dose (mg/kg/day). UF
= 100.

[]{#__RefHeading___Toc200865326 .anchor}**9.2 Short- and
Intermediate-term Postapplication Risk**

There is the possibility for agricultural workers to have
postapplication exposure to cyprosulfamide following its proposed
agricultural crop uses. Therefore, occupational postapplication risks
were assessed.

HED uses a concept known as the *transfer coefficient* to numerically
represent the postapplication exposures one would receive (generally
presented as cm^2^/hour). A transfer coefficient is a measure of the
residue transferred from a treated surface to a person who is doing a
task or activity in a treated area. These values are the ratio of an
exposure for a given task or activity to the amount of pesticide residue
on treated surfaces available for transfer. HED has developed a series
of standard transfer coefficients that are unique for variety of job
tasks or activities that are used in lieu of chemical- and
scenario-specific data. HED used *Policy 003.1 Science Advisory Council
for Exposure Policy Regarding Agricultural Transfer Coefficients* to
estimate transfer coefficients for the various tasks that
postapplication workers might perform on each crop grouping. HED assumes
an 8 hour workday for postapplication workers and assumes 70 kilograms
for an adult (average adult weight).

For cyprosulfamide, the exposure durations for non-cancer
postapplication risk assessment were short-term (30 days) and
intermediate-term (greater than 30 days up to several months). However,
since the dermal toxicological endpoint of concern is the same for
short- and intermediate-term exposures, the short- and intermediate-term
postapplication risks are numerically identical. HED has established
levels of concern (LOCs) for occupational postapplication risks --
margins of exposure of less than 100 for occupational non-cancer dermal
risks are a concern.

Inhalation exposures are thought to be negligible in outdoor
postapplication scenarios, since cyprosulfamide has low vapor pressure
and the dilution factor outdoors is considered infinite.

[Occupational Postapplication Exposure]{.underline}

Since no postapplication data were submitted in support of this
registration action, exposures during postapplication activities were
estimated using dermal transfer coefficients from the Science Advisory
Council for Exposure Policy Number 3.1: Agricultural Transfer
Coefficients, August 2000, summarized in Table 9.2.1 below and the
following assumptions:

Assumptions:

-   Application Rate = 0.141lb ai/A

-   Exposure Duration = 8 hours per day

-   Body Weight = 70 kg

-   Dermal Absorption = 100%

-   Fraction of a.i. retained on foliage is assumed to be 20% (0.20) on
    day zero (= % dislodgeable foliar residue, DFR, after initial
    treatment). This fraction is assumed to further dissipate at the
    rate of 10% (0.10) per day on following days. These are default
    values established by HED's Science Advisory Council (SAC) for
    Exposure.

  -----------------------------------------------------------------------------
  **Table 9.2.1                                         
  Anticipated                                           
  Postapplication                                       
  Activities and                                        
  Dermal Transfer                                       
  Coefficients**                                        
  ----------------- ---------------- ------------------ -----------------------
  Proposed Crops    Policy Crop      Transfer           Activities
                    Group Category   Coefficients       
                                     (cm^2^/hr)         

  Corn              Field / row      100                Hand weeding, scouting
                    crop, low /                         
                    medium                              

                                     1500               Scouting, irrigation

  Corn              Field / row      400                Scouting
                    crop, tall                          

                                     1000               Irrigation

                                     17,000             Hand harvesting
  -----------------------------------------------------------------------------

Daily dermal exposures were calculated on each postapplication day after
application using the following equation:

*DE~(t)~ (mg/day) = (TR~(t)~ (µg/cm^2^) x TC (cm^2^/hr) x Hr/Day)/1000
(µg/mg)*

Where:

> DE(t) = Daily exposure or amount deposited on the surface of the skin
> at time (t) attributable for activity in a previously treated area,
> also referred to as potential dose (mg ai/day);

TR(t) = Transferable residues that can be dislodgeable foliar residue at
time "t" (µg/cm^2^);

TC = Transfer Coefficient (cm^2^/hour); and

Hr/day = Exposure duration meant to represent a typical workday (hours).

Note that the (TR~(t)~) input may represent levels on the day of
application in the case of short-term risk calculations. Once daily
exposures are calculated, the calculation of daily absorbed dose and the
resulting Margin of Exposures use the same algorithms that are described
above for the handler exposures. These calculations are completed for
each day or appropriate block of time after application. For
pre-emergence spray, the application rate of 0.141 lb ai/A is higher
than the recommended application rate of 0.013 lb ai/A for post
emergence application. Therefore the risk presented is highly
conservative.

For corn, wheat and soybean applications, risks are not of concern
(i.e., MOE\>100) on day 0 (REI = 12 hours) for all of the exposure
activities. Table 9.2.2 presents a summary of occupational
postapplication risks associated with use of cyprosulfamide.

+-----------+--------+--------------------------+--------+-----------+
| **Table   |        |                          |        |           |
| 9.2.2     |        |                          |        |           |
| Summary   |        |                          |        |           |
| of        |        |                          |        |           |
| Occ       |        |                          |        |           |
| upational |        |                          |        |           |
| Postap    |        |                          |        |           |
| plication |        |                          |        |           |
| Risks for |        |                          |        |           |
| Cyprosu   |        |                          |        |           |
| lfamide** |        |                          |        |           |
+===========+========+==========================+========+===========+
| Crop      | Appli  | Transfer Coefficient     | Day    | MOE at    |
| Grouping  | cation | (µg/cm^2^)               | after  | Day 0     |
|           | rate   |                          | Appli  |           |
|           |        |                          | cation | (Level of |
|           | (lb    |                          |        | Concern = |
|           | ai     |                          |        | 100)      |
|           | /acre) |                          |        |           |
+-----------+--------+--------------------------+--------+-----------+
| Corn      | 0.141  | 100 (Hand weeding,       | 0 (12  | 16,000    |
|           |        | scouting)                | hours) |           |
+-----------+--------+--------------------------+--------+-----------+
|           |        | 1500 (Scouting,          |        | 1070      |
|           |        | irrigation)              |        |           |
+-----------+--------+--------------------------+--------+-----------+
|           |        | 400 (Scouting)           |        | 4,000     |
+-----------+--------+--------------------------+--------+-----------+
|           |        | 1000 (Irrigation)        |        | 1,605     |
+-----------+--------+--------------------------+--------+-----------+
|           |        | 17,000 (Hand harvesting, |        | 100       |
|           |        | Detasseling)             |        |           |
+-----------+--------+--------------------------+--------+-----------+

Cyprosulfamide is classified in acute toxicity category III for acute
dermal toxicity and category IV for primary eye irritation and primary
skin irritation. It is not a dermal sensitizer. A restricted entry
interval (REI) of 12 hours is appropriate and meets the requirements of
the Worker Protection Standard for Agricultural Pesticides (WPS).

[]{#__RefHeading___Toc200865327 .anchor}**10.0 Data Needs and Label
Requirements**

[]{#__RefHeading___Toc200865328 .anchor}**10.1 Toxicology**

+-----------------------------------------------------------------------+
| **Guideline Number: 870.7800**                                        |
|                                                                       |
| **Study Title**: **Immunotoxicity**                                   |
+-----------------------------------------------------------------------+
| **Rationale for Requiring the Data**                                  |
+-----------------------------------------------------------------------+
| This is a new data requirement under 40 CFR Part 158 as a part of the |
| data requirements for registration of a pesticide (food and non-food  |
| uses).                                                                |
|                                                                       |
| The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes         |
| functional immunotoxicity testing and is designed to evaluate the     |
| potential of a repeated chemical exposure to produce adverse effects  |
| (i.e., suppression) on the immune system. Immunosuppression is a      |
| deficit in the ability of the immune system to respond to a challenge |
| of bacterial or viral infections such as tuberculosis (TB), Severe    |
| Acquired Respiratory Syndrome (SARS), or neoplasia. Because the       |
| immune system is highly complex, studies not specifically conducted   |
| to assess immunotoxic endpoints are inadequate to characterize a      |
| pesticide's potential immunotoxicity. While data from hematology,     |
| lymphoid organ weights, and histopathology in routine chronic or      |
| subchronic toxicity studies may offer useful information on potential |
| immunotoxic effects, these endpoints alone are insufficient to        |
| predict immunotoxicity.                                               |
+-----------------------------------------------------------------------+
| **Practical Utility of the Data**                                     |
+-----------------------------------------------------------------------+
| **How will the data be used?**                                        |
|                                                                       |
| Immunotoxicity studies provide critical scientific information needed |
| to characterize potential hazard to the human population on the       |
| immune system from pesticide exposure. Since epidemiologic data on    |
| the effects of chemical exposures on immune parameters are limited    |
| and are inadequate to characterize a pesticide's potential            |
| immunotoxicity in humans, animal studies are used as the most         |
| sensitive endpoint for risk assessment. These animal studies can be   |
| used to select endpoints and doses for use in risk assessment of all  |
| exposure scenarios and are considered a primary data source for       |
| reliable reference dose calculation. For example, animal studies have |
| demonstrated that immunotoxicity in rodents is one of the more        |
| sensitive manifestations of TCDD                                      |
| (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental,            |
| reproductive, and endocrinologic toxicities. Additionally, the EPA    |
| has established an oral reference dose (RfD) for tributyltin oxide    |
| (TBTO) based on observed immunotoxicity in animal studies (IRIS,      |
| 1997).                                                                |
|                                                                       |
| **How could the data impact the Agency\'s future decision-making?**   |
|                                                                       |
| If the immunotoxicity study shows that the test material poses either |
| a greater or a diminished risk than that given in the interim         |
| decision's conclusion, the risk assessments for the test material may |
| need to be revised to reflect the magnitude of potential risk derived |
| from the new data.                                                    |
|                                                                       |
| If the Agency does not have this data, a 10X database uncertainty     |
| factor may be applied for conducting a risk assessment from the       |
| available studies.                                                    |
+-----------------------------------------------------------------------+

[]{#__RefHeading___Toc200865329 .anchor}**10.2 Residue Chemistry**

[860.1200 Directions for Use]{.underline}

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

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

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

[860.1340 Residue Analytical Method]{.underline}

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

[860.1380 Storage Stability]{.underline}

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

[860.1550 Proposed Tolerances]{.underline}

-   The petitioner is required to submit a revised Section F to reflect
    the revised tolerances and commodity definitions recommended in the
    Introduction of this document.

[860.1650 Submittal of Analytical Reference Standards]{.underline}

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

    []{#__RefHeading___Toc200865330 .anchor}**10.3 Occupational and
    Residential Exposure**

None

[]{#__RefHeading___Toc200865331 .anchor}**References:**

CARC Memo: TXR 0054810, Jessica Kidwell, 2/29/2008

Residue Chemistry Summary Memo: D341999, William Donovan, 5/28/08

Dietary Exposure Memo: D351493, Seyed Tadayon, 5/6/08

ROCKS Memo: D351495, George Kramer, 4/18/08

ToxSAC Memo: Jessica Kidwell, 4/24/2008

Occupational & Residential Exposure Memo: D351494, Seyed Tadayon,
5/28/08

[]{#__RefHeading___Toc200865332 .anchor}**Appendix A: Toxicology
Assessment**

[]{#__RefHeading___Toc200865333 .anchor}**A.1 Toxicology Data
Requirements**

The requirements (40 CFR 158.340) for food uses for cyprosulfamide are
in Table 1. Use of the new guideline numbers does not imply that the new
(1998) guideline protocols were used.

+-----------------------------------------+-------------+-------------+
| **Test**                                | **          |             |
|                                         | Technical** |             |
+=========================================+=============+=============+
|                                         | *           | **          |
|                                         | *Required** | Satisfied** |
+-----------------------------------------+-------------+-------------+
| 870.1100 Acute Oral Toxicity            | yes         | yes         |
|                                         |             |             |
| 870.1200 Acute Dermal Toxicity          | yes         | yes         |
|                                         |             |             |
| 870.1300 Acute Inhalation Toxicity      | yes         | yes         |
|                                         |             |             |
| 870.2400 Primary Eye Irritation         | yes         | yes         |
|                                         |             |             |
| 870.2500 Primary Dermal Irritation      | yes         | yes         |
|                                         |             |             |
| 870.2600 Dermal Sensitization           | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.3100 Oral Subchronic (rodent)       | Yes         | Yes         |
|                                         |             |             |
| 870.3150 Oral Subchronic (nonrodent)    | Yes         | Yes         |
|                                         |             |             |
| 870.3200 21-Day Dermal                  | No          | N/A         |
|                                         |             |             |
| 870.3250 90-Day Dermal                  | No          | N/A         |
|                                         |             |             |
| 870.3465 90-Day Inhalation              | No          | N/A         |
+-----------------------------------------+-------------+-------------+
| 870.3700a Developmental Toxicity        | Yes         | Yes         |
| (rodent)                                |             |             |
|                                         | Yes         | Yes         |
| 870.3700b Developmental Toxicity        |             |             |
| (nonrodent)                             | Yes         | Yes         |
|                                         |             |             |
| 870.3800 Reproduction                   |             |             |
+-----------------------------------------+-------------+-------------+
| 870.4100a Chronic Toxicity (rodent)     | Yes         | Yes         |
|                                         |             |             |
| 870.4100b Chronic Toxicity (nonrodent)  | Yes         | Yes         |
|                                         |             |             |
| 870.4200a Oncogenicity (rat)            | Yes         | Yes         |
|                                         |             |             |
| 870.4200b Oncogenicity (mouse)          | Yes         | Yes         |
|                                         |             |             |
| 870.4300 Chronic/Oncogenicity - rat     | Yes         | Yes         |
+-----------------------------------------+-------------+-------------+
| 870.5100 Mutagenicity---Gene Mutation - | Yes         | Yes         |
| bacterial                               |             |             |
|                                         | Yes         | Yes         |
| 870.5300 Mutagenicity---Gene Mutation - |             |             |
| mammalian                               | Yes         | Yes         |
|                                         |             |             |
| 870.5xxx Mutagenicity---Structural      | Yes         | Yes         |
| Chromosomal Aberrations                 |             |             |
|                                         |             |             |
| 870.5xxx Mutagenicity---Other Genotoxic |             |             |
| Effects                                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.6100a Acute Delayed Neurotox. (hen) | no          | \-          |
|                                         |             |             |
| 870.6100b 90-Day Neurotoxicity (hen)    | no          | \-          |
|                                         |             |             |
| 870.6200a Acute Neurotox. Screening     | Yes         | Yes         |
| Battery (rat)                           |             |             |
|                                         | Yes         | Yes         |
| 870.6200b 90-Day Neuro. Screening       |             |             |
| Battery (rat)                           | No          | N/A         |
|                                         |             |             |
| 870.6300 Develop. Neuro                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.7485 General Metabolism             | Yes         | Yes         |
|                                         |             |             |
| 870.7600 Dermal Penetration             | No          | N/A         |
+-----------------------------------------+-------------+-------------+
| Special Studies for Ocular Effects      | No          | No          |
|                                         |             |             |
| > Acute Oral (rat)                      |             |             |
| >                                       |             |             |
| > Subchronic Oral (rat)                 |             |             |
| >                                       |             |             |
| > Six-month Oral (dog)                  |             |             |
+-----------------------------------------+-------------+-------------+

[]{#__RefHeading___Toc200865334 .anchor}**A.2 Toxicity Profiles**

+----------+----------------------+-------+------------+--------------+
| **Table  |                      |       |            |              |
| A.2.1    |                      |       |            |              |
| Acute    |                      |       |            |              |
| Toxicity |                      |       |            |              |
| P        |                      |       |            |              |
| rofile - |                      |       |            |              |
| Test     |                      |       |            |              |
| Sub      |                      |       |            |              |
| stance** |                      |       |            |              |
+----------+----------------------+-------+------------+--------------+
| G        | Study Type           | MR    | Results    | Toxicity     |
| uideline |                      | ID(s) |            | Category     |
| No.      |                      |       |            |              |
+----------+----------------------+-------+------------+--------------+
| 870.1100 | Acute oral - rat     | 470   | LD~50~ \>  | III          |
|          |                      | 69801 | 2000 mg/kg |              |
|          |                      |       |            |              |
|          |                      | \(2   |            |              |
|          |                      | 005\) |            |              |
+----------+----------------------+-------+------------+--------------+
| 870.1200 | Acute dermal - rat   | 470   | LD~50~ =   | III          |
|          |                      | 69802 | 2000 mg/kg |              |
|          |                      |       |            |              |
|          |                      | \(2   |            |              |
|          |                      | 005\) |            |              |
+----------+----------------------+-------+------------+--------------+
| 870.1300 | Acute inhalation -   | 470   | LC~50~ \>  | III          |
|          | rat                  | 69803 | 3513       |              |
|          |                      |       | mg/m^3^    |              |
|          |                      | \(2   |            |              |
|          |                      | 004\) |            |              |
+----------+----------------------+-------+------------+--------------+
| 870.2400 | Acute eye            | 470   | Not        | IV           |
|          | irritation - rabbit  | 69805 | irritating |              |
|          |                      |       |            |              |
|          |                      | \(2   |            |              |
|          |                      | 004\) |            |              |
+----------+----------------------+-------+------------+--------------+
| 870.2500 | Acute dermal         | 470   | Not        | IV           |
|          | irritation - rabbit  | 69804 | irritating |              |
|          |                      |       |            |              |
|          |                      | \(2   |            |              |
|          |                      | 005\) |            |              |
+----------+----------------------+-------+------------+--------------+
| 870.2600 | Skin sensitization - | 470   | Not a      | N/A          |
|          | guinea pig           | 69806 | sensitizer |              |
|          |                      |       |            |              |
|          |                      | \(2   |            |              |
|          |                      | 005\) |            |              |
+----------+----------------------+-------+------------+--------------+

+--------+------------+-----------------+------------------------------+
| *      |            |                 |                              |
| *Table |            |                 |                              |
| A.2.2  |            |                 |                              |
| Subch  |            |                 |                              |
| ronic, |            |                 |                              |
| C      |            |                 |                              |
| hronic |            |                 |                              |
| and    |            |                 |                              |
| Other  |            |                 |                              |
| To     |            |                 |                              |
| xicity |            |                 |                              |
| Pro    |            |                 |                              |
| file** |            |                 |                              |
+========+============+=================+==============================+
| **Gui  | **Study    | **MRID No.      | **Results**                  |
| deline | Type**     | (year)/         |                              |
| No.**  |            | Classification  |                              |
|        |            | /Doses**        |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 90-Day     | 47069808 (2003) | NOAEL = 57.9 for males and   |
| 0.3100 | oral       |                 | 70.1 for females mg/kg/day   |
|        | toxicity - | Accep           |                              |
|        | rat        | table/Guideline | LOAEL = 240 in males and 281 |
|        |            |                 | in females mg/kg/day based   |
|        |            | 0, 1000, 4000   | on and urinary crystals/     |
|        |            | or 12000 ppm    | hyperplasia in urinary       |
|        |            |                 | system.                      |
|        |            | M: 0, 58, 240   |                              |
|        |            | or 720          |                              |
|        |            | mg/kg/day.      |                              |
|        |            |                 |                              |
|        |            | F: 0, 70, 281   |                              |
|        |            | or 859          |                              |
|        |            | mg/kg/day.      |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 90-day     | 47069809 (2003) | NOAEL = 398 mg/kg/day in     |
| 0.3100 | oral       |                 | females and 1110 mg/kg/day   |
|        | toxicity - | Accep           | in males.                    |
|        | mouse      | table/Guideline |                              |
|        |            |                 | LOAEL = severity of          |
|        |            | 0, 500, 2000 or | lymphocytolysis in the       |
|        |            | 7000 ppm        | thymus in females.           |
|        |            |                 |                              |
|        |            | M: 0, 79, 321   |                              |
|        |            | or 1110         |                              |
|        |            | mg/kg/day.      |                              |
|        |            |                 |                              |
|        |            | F: 0, 95, 398   |                              |
|        |            | or 1297         |                              |
|        |            | mg/kg/day       |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 90-Day     | 47069811 (2005) | NOAEL = 221 mg/kg/day for    |
| 0.3150 | oral       |                 | both sexes                   |
|        | toxicity - | Accep           |                              |
|        | dog        | table/Guideline | LOAEL = 416 mg/kg/day for    |
|        |            |                 | males and 341 mg/kg/day for  |
|        |            | 0, 2500, 7500   | females. Based on urinary    |
|        |            | or 15000 ppm    | tract effects.               |
|        |            |                 |                              |
|        |            | M: 0, 75, 221   |                              |
|        |            | or 416          |                              |
|        |            | mg/kg/day.      |                              |
|        |            |                 |                              |
|        |            | F: 0, 79, 221   |                              |
|        |            | or 341          |                              |
|        |            | mg/kg/day.      |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 21/28-Day  | No study and    | N/A                          |
| 0.3200 | dermal     | not required.   |                              |
|        | toxicity   |                 |                              |
|        | (species)  |                 |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 90-Day     | No study and    | N/A                          |
| 0.3250 | dermal     | not required.   |                              |
|        | toxicity   |                 |                              |
|        | (species)  |                 |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 90-Day     | No Study and    | N/A                          |
| 0.3465 | inhalation | not required.   |                              |
|        | toxicity   |                 |                              |
|        | (species)  |                 |                              |
+--------+------------+-----------------+------------------------------+
| 870    | Prenatal   | 47069814 (2005) | **Maternal** NOAEL = 250     |
| .3700a | dev        |                 | mg/kg/day                    |
|        | elopmental | Accep           |                              |
|        | in rats    | table/Guideline | LOAEL = 1000 mg/kg/day based |
|        |            |                 | mainly on body weight        |
|        |            | 0, 60, 250 or   | effect.                      |
|        |            | 1000 mg/kg/day  |                              |
|        |            |                 | **Developmental** NOAEL =    |
|        |            |                 | 1000 mg/kg/day. No effects   |
|        |            |                 | at the highest dose tested.  |
+--------+------------+-----------------+------------------------------+
| 870    | Prenatal   | 47069812 (2005) | **Maternal** NOAEL = 125     |
| .3700b | dev        |                 | mg/kg/day.                   |
|        | elopmental | Accep           |                              |
|        | in rabbits | table/Guideline | LOAEL = 500 mg/kg/day        |
|        |            |                 | exceeds MTD based on deaths, |
|        |            | 0, 50, 125 or   | body weight decrease,        |
|        |            | 500 mg/kg/day.  | reduced food consumption and |
|        |            |                 | kidney effects.              |
+--------+------------+-----------------+------------------------------+
| 870    | Prenatal   | 47069813 (2005) | **Materna**l NOAEL = Not     |
| .3700b | dev        |                 | established.                 |
|        | elopmental | Acceptabl       |                              |
|        | in rabbits | e/Non-Guideline | LOAEL = 250 mg/kg/day based  |
|        |            |                 | on reduced body weight and   |
|        |            | 0 or 250        | food consumption and kidney  |
|        |            | mg/kg/day.      | effects.                     |
|        |            |                 |                              |
|        |            |                 | **Developmenta**l LOAEL \>   |
|        |            |                 | 250 mg/kg/day. mg/kg/day. No |
|        |            |                 | effects at highest dose      |
|        |            |                 | tested.                      |
+--------+------------+-----------------+------------------------------+
| 87     | Re         | 47069815 (2007) | **Parental/Systemic** NOAEL  |
| 0.3800 | production |                 | = 39 for males and 55 for    |
|        | and        | Accep           | females mg/kg/day            |
|        | fertility  | table/Guideline |                              |
|        | effects    |                 | LOAEL = 202 for males and    |
|        |            | 0, 480, 2400 or | 260 for females mg/kg/day    |
|        | In rats    | 12000 ppm.      | based on organ weight        |
|        |            |                 | changes in spleen and        |
|        |            | M: 0, 39.2,     | urinary tract. .             |
|        |            | 202.3 or 1006.9 |                              |
|        |            | for FO and 0,   | **Reproductive** NOAEL = 202 |
|        |            | 50.3, 251.5 or  | for males and 260 for        |
|        |            | 1292.4 for F1   | females mg/kg/day            |
|        |            | mg/kg/day.      |                              |
|        |            |                 | LOAEL = 1006.9 for males and |
|        |            | F: 0, 55.3,     | 1350.2 for females mg/kg/day |
|        |            | 260.3 or 1350.2 | based on reduced rearing     |
|        |            | for FO and 0,   | index.                       |
|        |            | 68.5, 323.7 or  |                              |
|        |            | 1696.5 for F1   | **Offspring** NOAEL = 202    |
|        |            | mg/kg/day.      | for males and 260 for        |
|        |            |                 | females mg/kg/day            |
|        |            |                 |                              |
|        |            |                 | LOAEL = 1006.9 for males and |
|        |            |                 | 1350.2 for females mg/kg/day |
|        |            |                 | based on pup body weight     |
|        |            |                 | decrease.                    |
+--------+------------+-----------------+------------------------------+
| 870    | Chronic    | See 870.4300.   |                              |
| .4100a | toxicity   |                 |                              |
|        | in the     |                 |                              |
|        | rat.       |                 |                              |
+--------+------------+-----------------+------------------------------+
| 870    | Chronic    | 47069816 (2006) | NOAEL = 66 in males and 67   |
| .4100b | toxicity   |                 | in females mg/kg/day         |
|        | (dog)      | Accep           |                              |
|        |            | table/Guideline | LOAEL = 226 in males and 242 |
|        |            |                 | in females mg/kg/day based   |
|        |            | 0, 1000, 2500   | on urothelial effects.       |
|        |            | or 8000 ppm.    |                              |
|        |            |                 |                              |
|        |            | M: 0, 29, 66 or |                              |
|        |            | 226 mg/kg/day   |                              |
|        |            |                 |                              |
|        |            | F: 0, 28, 67 or |                              |
|        |            | 242 mg/kg/day.  |                              |
+--------+------------+-----------------+------------------------------+
| 87     | Carci      | 47069818 (2006) | NOAEL = 50 in males and 354  |
| 0.4200 | nogenicity |                 | in females mg/kg/day         |
|        |            | Accep           |                              |
|        | (mouse)    | table/Guideline | LOAEL = 287 in males and 616 |
|        |            |                 | in females mg/kg/day based   |
|        |            | 0, 350, 2000 or | on urothelial effects.       |
|        |            | 3500 ppm.       |                              |
|        |            |                 | Transitional cell papilloma  |
|        |            | M: 0, 50, 287   | in female urinary bladder.   |
|        |            | or 506          | Histiocytic sarcoma in       |
|        |            | mg/kg/day.      | females.                     |
|        |            |                 |                              |
|        |            | F: 0, 63, 354   |                              |
|        |            | or 616          |                              |
|        |            | mg/kg/day.      |                              |
+--------+------------+-----------------+------------------------------+
| 870    | Combined   | 47069817 (2006) | NOAEL = 39 for males and 56  |
| .4300. | chronic    |                 | for females mg/kg/day        |
|        | and        | Accep           |                              |
|        | carcin     | table/Guideline | LOAEL = 159 for males and    |
|        | ogen-icity |                 | 220 for females mg/kg/day    |
|        | in the     | 0, 1000, 4000   | based mainly on kidney and   |
|        | rat.       | or 8000 ppm     | urothelial toxicity.         |
|        |            |                 |                              |
|        |            | M: 0, 39, 159   | Transitional cell carcinoma  |
|        |            | or 321          | in one male and one female.  |
|        |            | mg/kg/day.      |                              |
|        |            |                 |                              |
|        |            | F: 0, 56, 220   |                              |
|        |            | or 447          |                              |
|        |            | mg/kg/day.      |                              |
+--------+------------+-----------------+------------------------------+
| Gene   | Ames test  | 47069819 (2006) | Not mutagenic at up to 5000  |
| Mu     |            |                 | µg/plate.                    |
| tation |            | Accep           |                              |
|        |            | table/Guideline |                              |
| 870\.  |            |                 |                              |
| 5100   |            |                 |                              |
+--------+------------+-----------------+------------------------------+
| Gene   | Ames test  | 47069820        | Not mutagenic.               |
| mu     |            | (2004/2005)     |                              |
| tation |            |                 |                              |
|        |            | Accep           |                              |
| 87     |            | table/Guideline |                              |
| 0.5100 |            |                 |                              |
+--------+------------+-----------------+------------------------------+
| F      | V79/HPRT   | 47069823 (2006) | Negative                     |
| orward | test       |                 |                              |
| mu     |            | Accep           |                              |
| tation |            | table/Guideline |                              |
|        |            |                 |                              |
| 87     |            |                 |                              |
| 0.5300 |            |                 |                              |
+--------+------------+-----------------+------------------------------+
| Chrom  |            | 479069826       | No clastogenic effect at up  |
| o-some |            |                 | to 1600 µg/ml.               |
| abbe   |            | Accep           |                              |
| ration |            | table/Guideline |                              |
|        |            |                 |                              |
| 87     |            |                 |                              |
| 0.5375 |            |                 |                              |
+--------+------------+-----------------+------------------------------+
| 87     | Mi         | 47069829        | No evidence of clastogenic   |
| 0.5395 | cronucleus | (2004/2006)     | effect after two doses up to |
|        | test *in   |                 | 2000 mg/kg/(ip)              |
|        | vivo*.     | Accept          |                              |
|        |            | able/Guideline. |                              |
+--------+------------+-----------------+------------------------------+
| 870    | Acute      | 47069830 (2006) | NOAEL = 508 mg/kg/day        |
| .6200a | neu        | Accep           |                              |
|        | rotoxicity | table/Guideline | LOAEL = 2060 mg/kg/day based |
|        | screening  |                 | on transient urinary         |
|        | battery -  | 0, 125, 508 or  | staining.                    |
|        | rats       | 2060 mg/kg/day. |                              |
+--------+------------+-----------------+------------------------------+
| 870    | Subchronic | 47069831 (2006) | NOAEL \> 592 in males and    |
| .6200b | neu        |                 | 748 in females mg/kg/day.    |
|        | rotoxicity | 0, 1000, 3000   |                              |
|        | screening  | or 9000 ppm     | LOAEL = Not established      |
|        | battery -  |                 | since no effects at the      |
|        | rats       | Accep           | highest dose tested.         |
|        |            | table/Guideline |                              |
|        |            |                 |                              |
|        |            | M: 0, 65.2, 193 |                              |
|        |            | or 592          |                              |
|        |            | mg/kg/day.      |                              |
|        |            |                 |                              |
|        |            | F: 0, 84.5, 251 |                              |
|        |            | or 748          |                              |
|        |            | mg/kg/day.      |                              |
+--------+------------+-----------------+------------------------------+
| 87     | Dev        | No study and    | N/A                          |
| 0.6300 | elopmental | not required.   |                              |
|        | neu        |                 |                              |
|        | rotoxicity |                 |                              |
+--------+------------+-----------------+------------------------------+
| 87     | Metabolism | 47069832 (2006) | Absorption, excretion,       |
| 0.7485 | and        | and 47069833    | distribution (very little),  |
|        | pharma     | (2006)          | metabolism and               |
|        | cokinetics |                 | identification of            |
|        |            | Accep           | metabolites established.     |
|        | (species)  | table/Guideline |                              |
+--------+------------+-----------------+------------------------------+
| 87     | Dermal     | No study in     | N/A                          |
| 0.7600 | p          | laboratory      |                              |
|        | enetration | animals         |                              |
|        |            |                 |                              |
|        | (species)  |                 |                              |
+--------+------------+-----------------+------------------------------+
|        | Special    | No special      | N/A                          |
|        | studies    | studies.        |                              |
+--------+------------+-----------------+------------------------------+

[]{#__RefHeading___Toc200865335 .anchor}**A.3 Executive Summaries**

**Note; The Executive Summaries were prepared by the testing laboratory
and/or the Bayer Crop Science staff. They were reviewed by both the PSD
of the United Kingdom and HED toxicologists. The Executive Summary is
presented together with the comments made by the PSD reviewer and the
HED reviewer in boxes following the Executive Summary. The HED
Reviewer\'s comment box includes the classification in HED
terminology.**

**A.3.1 Subchronic Toxicity**

**870.3100 90-Day Oral Toxicity - Rat**

AE 0001789 (batch number R174, 95.9% w/w purity) was administered
continuously via the diet to separate groups of Wistar rats
(10/sex/group) at dose levels of 0, 1 000, 4 000 and 12 000 ppm
equivalent to 58, 240 and 720 mg/kg/day in males and 70, 281 and 859
mg/kg/day in females, respectively, for at least 90 days.

[At 12 000 ppm]{.underline}, there were two female mortalities during
week 5 of the study. One female was found dead on Day 33, clinicals
signs observed prior to death were soiled fur on the muzzle, neck and
forelimbs. A second female was sacrificed for humane reasons on Day 36,
clinical signs observed prior to death were soiled fur on the nose,
forelimbs and anogenital region, wasted appearance and clonic
convulsions. This animal lost 60g in body weight between weeks 4 and 5.
In animals surviving to terminal sacrifice, treatment-related signs
consisted of soiled fur in the anogenital region (observed on one
occasion in two males) and hair loss noted in two males and one female.
Absolute body weight in males was reduced by 5-7% between weeks 5 and
13. Body weight gain was also reduced at a number of time intervals, the
effect being most pronounced between weeks 4 and 5 where there was a 64%
reduction in body weight gain compared with the controls. In females
absolute body weight was reduced by 6% between weeks 4 and 5. There was
an actual loss of body weight of 0.7 g/day during this interval, however
this effect on body weight was accentuated by a marked loss in body
weight of one of the decedent females. Food consumption in males was
reduced by 9 and 13% on weeks 1 and 5 respectively and by 17% in females
during week 5. Urinalysis revealed sulfonamide-like crystals in the
urine of 8/10 males and 7/8 females. Microscopic examination of the two
decedent females, showed no clear treatment-related cause of death.
However, both animals presented a range of lesions with a number of
similarities to those observed on target organs at terminal sacrifice.
At terminal sacrifice, in male animals, kidney to body weight ratio was
increased by 12%, absolute kidney weight and relative kidney/brain
weight were also slightly increased by 4-5%. In female animals, absolute
and relative kidney weights were increased by 11-13%. At microscopic
examination, effects were seen in the liver and thymus of males and the
kidneys, spleen and urinary bladder of both sexes. In the liver slight
centrilobular hepatocellular hypertrophy was noted in 8/10 males. In the
urinary bladder simple hyperplasia of the urothelium was noted in 2/10
males and 5/8 females. Examination of the kidney revealed a slight
increase in the incidence and/or severity of basophilic tubules and
hyperplasia of collecting ducts and pelvic epithelium, in both sexes. In
addition, metaplasia of the collecting duct epithelium was seen in 1/8
females and brown pigment in the proximal tubules was noted in 2/10
males and 1/8 females examined. In the spleen brown pigment in the red
pulp was seen in animals from all dosage groups but the severity was
marginally greater in a few animals dosed at 12 000 ppm compared to
controls. Examination of the thymus showed a marginal increase in
severity of decreased size of the cortex (involution) in a few males
dosed at 12 000 ppm.

[At 4 000 ppm]{.underline}, treatment-related effects were confined to
microscopic findings in the urinary bladder which consisted of simple
hyperplasia of the urothelium in 1/10 males and 1/10 females.

[At 1 000 ppm]{.underline}, one male was sacrificed for humane reasons
on Day 71 following an accidental trauma. No treatment-related findings
were observed at 1 000 ppm in either sex.

The No Observed Effect Level (NOEL) in the Wistar rat when administered
AE 0001789 in the diet over a 90-day period was 1000 ppm (equivalent to
58 mg/kg/day for males and 70 mg/kg/day for females).

+------------------+------------+---+-------+-------+-------+-------+
| **EVALUATION,    |            |   |       |       |       |       |
| SUMMARY AND      |            |   |       |       |       |       |
| CONCLUSION BY    |            |   |       |       |       |       |
| REGULATORY       |            |   |       |       |       |       |
| AUTHORITY**      |            |   |       |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+
| **Name of        | Pesticides |   |       |       |       |       |
| authority**      | Safety     |   |       |       |       |       |
|                  | Di         |   |       |       |       |       |
|                  | rectorate, |   |       |       |       |       |
|                  | UK         |   |       |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+
| **Reviewer's     | R          |   |       |       |       |       |
| Comments**       | eliability |   |       |       |       |       |
|                  | rating:    |   |       |       |       |       |
|                  | Totally    |   |       |       |       |       |
|                  | reliable   |   |       |       |       |       |
|                  |            |   |       |       |       |       |
|                  | The study  |   |       |       |       |       |
|                  | (Mc        |   |       |       |       |       |
|                  | Elligott   |   |       |       |       |       |
|                  | A. ; 2003, |   |       |       |       |       |
|                  | SA 02352)  |   |       |       |       |       |
|                  | is         |   |       |       |       |       |
|                  | compliant  |   |       |       |       |       |
|                  | with OECD  |   |       |       |       |       |
|                  | 408 (1998) |   |       |       |       |       |
|                  | with the   |   |       |       |       |       |
|                  | following  |   |       |       |       |       |
|                  | deviation: |   |       |       |       |       |
|                  |            |   |       |       |       |       |
|                  | The        |   |       |       |       |       |
|                  | guideline  |   |       |       |       |       |
|                  | specifies  |   |       |       |       |       |
|                  | that       |   |       |       |       |       |
|                  | hist       |   |       |       |       |       |
|                  | opathology |   |       |       |       |       |
|                  | of the     |   |       |       |       |       |
|                  | brain      |   |       |       |       |       |
|                  | should     |   |       |       |       |       |
|                  | include    |   |       |       |       |       |
|                  | inv        |   |       |       |       |       |
|                  | estigation |   |       |       |       |       |
|                  | of         |   |       |       |       |       |
|                  | 'repr      |   |       |       |       |       |
|                  | esentative |   |       |       |       |       |
|                  | regions    |   |       |       |       |       |
|                  | including  |   |       |       |       |       |
|                  | cerebrum,  |   |       |       |       |       |
|                  | cerebellum |   |       |       |       |       |
|                  | and        |   |       |       |       |       |
|                  | medulla    |   |       |       |       |       |
|                  | pons'. The |   |       |       |       |       |
|                  | study      |   |       |       |       |       |
|                  | report     |   |       |       |       |       |
|                  | states     |   |       |       |       |       |
|                  | only that  |   |       |       |       |       |
|                  | the brain  |   |       |       |       |       |
|                  | was        |   |       |       |       |       |
|                  | in         |   |       |       |       |       |
|                  | vestigated |   |       |       |       |       |
|                  | histopatho |   |       |       |       |       |
|                  | logically. |   |       |       |       |       |
|                  | The        |   |       |       |       |       |
|                  | Notifier   |   |       |       |       |       |
|                  | states     |   |       |       |       |       |
|                  | that       |   |       |       |       |       |
|                  | '          |   |       |       |       |       |
|                  | Routinely, |   |       |       |       |       |
|                  | three      |   |       |       |       |       |
|                  | transverse |   |       |       |       |       |
|                  | sections   |   |       |       |       |       |
|                  | are made   |   |       |       |       |       |
|                  | for        |   |       |       |       |       |
|                  | histopa    |   |       |       |       |       |
|                  | thological |   |       |       |       |       |
|                  | ex         |   |       |       |       |       |
|                  | amination: |   |       |       |       |       |
|                  |            |   |       |       |       |       |
|                  | 1\. the    |   |       |       |       |       |
|                  | first      |   |       |       |       |       |
|                  | section at |   |       |       |       |       |
|                  | the level  |   |       |       |       |       |
|                  | of optic   |   |       |       |       |       |
|                  | chiasm     |   |       |       |       |       |
|                  | including  |   |       |       |       |       |
|                  | the basal  |   |       |       |       |       |
|                  | ganglia,   |   |       |       |       |       |
|                  | septum,    |   |       |       |       |       |
|                  | cortex,    |   |       |       |       |       |
|                  | anterior   |   |       |       |       |       |
|                  | hy         |   |       |       |       |       |
|                  | pothalamus |   |       |       |       |       |
|                  |            |   |       |       |       |       |
|                  | 2\. the    |   |       |       |       |       |
|                  | second     |   |       |       |       |       |
|                  | section at |   |       |       |       |       |
|                  | the level  |   |       |       |       |       |
|                  | of         |   |       |       |       |       |
|                  | h          |   |       |       |       |       |
|                  | ippocampus |   |       |       |       |       |
|                  | containing |   |       |       |       |       |
|                  | the cortex |   |       |       |       |       |
|                  | and brain  |   |       |       |       |       |
|                  | stem at    |   |       |       |       |       |
|                  | the        |   |       |       |       |       |
|                  | transition |   |       |       |       |       |
|                  | of         |   |       |       |       |       |
|                  | di         |   |       |       |       |       |
|                  | encephalon |   |       |       |       |       |
|                  | to         |   |       |       |       |       |
|                  | mes        |   |       |       |       |       |
|                  | encephalon |   |       |       |       |       |
|                  |            |   |       |       |       |       |
|                  | 3\. the    |   |       |       |       |       |
|                  | third      |   |       |       |       |       |
|                  | section    |   |       |       |       |       |
|                  | containing |   |       |       |       |       |
|                  | the        |   |       |       |       |       |
|                  | cerebellum |   |       |       |       |       |
|                  | and brain  |   |       |       |       |       |
|                  | stem       |   |       |       |       |       |
|                  | (medulla   |   |       |       |       |       |
|                  | o          |   |       |       |       |       |
|                  | blongata)' |   |       |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+
|                  | It is not  |   |       |       |       |       |
|                  | clear how  |   |       |       |       |       |
|                  | the        |   |       |       |       |       |
|                  | conclusion |   |       |       |       |       |
|                  | was drawn  |   |       |       |       |       |
|                  | that the   |   |       |       |       |       |
|                  | crystals   |   |       |       |       |       |
|                  | in the     |   |       |       |       |       |
|                  | urine were |   |       |       |       |       |
|                  | 'su        |   |       |       |       |       |
|                  | lphonamide |   |       |       |       |       |
|                  | like'      |   |       |       |       |       |
|                  | using      |   |       |       |       |       |
|                  | these      |   |       |       |       |       |
|                  | methods    |   |       |       |       |       |
|                  | given. The |   |       |       |       |       |
|                  | Notifier   |   |       |       |       |       |
|                  | states     |   |       |       |       |       |
|                  | that       |   |       |       |       |       |
|                  | 'These     |   |       |       |       |       |
|                  | crystals   |   |       |       |       |       |
|                  | have been  |   |       |       |       |       |
|                  | identified |   |       |       |       |       |
|                  | visually   |   |       |       |       |       |
|                  | under the  |   |       |       |       |       |
|                  | microscope |   |       |       |       |       |
|                  | based on   |   |       |       |       |       |
|                  | the        |   |       |       |       |       |
|                  | specific   |   |       |       |       |       |
|                  | shape of   |   |       |       |       |       |
|                  | such       |   |       |       |       |       |
|                  | crystals.  |   |       |       |       |       |
|                  | These      |   |       |       |       |       |
|                  | crystals   |   |       |       |       |       |
|                  | look like  |   |       |       |       |       |
|                  | shocks of  |   |       |       |       |       |
|                  | wheat or   |   |       |       |       |       |
|                  | radiall    |   |       |       |       |       |
|                  | y-striated |   |       |       |       |       |
|                  | spherules' |   |       |       |       |       |
|                  |            |   |       |       |       |       |
|                  | At l2000   |   |       |       |       |       |
|                  | ppm in     |   |       |       |       |       |
|                  | males,     |   |       |       |       |       |
|                  | kidney to  |   |       |       |       |       |
|                  | bodyweight |   |       |       |       |       |
|                  | ratio was  |   |       |       |       |       |
|                  | increased  |   |       |       |       |       |
|                  | by 12%     |   |       |       |       |       |
|                  | (p\<0.01)  |   |       |       |       |       |
|                  | compared   |   |       |       |       |       |
|                  | to         |   |       |       |       |       |
|                  | controls.  |   |       |       |       |       |
|                  | Absolute   |   |       |       |       |       |
|                  | kidney     |   |       |       |       |       |
|                  | weight and |   |       |       |       |       |
|                  | relative   |   |       |       |       |       |
|                  | ki         |   |       |       |       |       |
|                  | dney/brain |   |       |       |       |       |
|                  | weights    |   |       |       |       |       |
|                  | were also  |   |       |       |       |       |
|                  | slightly   |   |       |       |       |       |
|                  | increased  |   |       |       |       |       |
|                  | by 4-5%.   |   |       |       |       |       |
|                  | In females |   |       |       |       |       |
|                  | absolute   |   |       |       |       |       |
|                  | and        |   |       |       |       |       |
|                  | relative   |   |       |       |       |       |
|                  | kidney     |   |       |       |       |       |
|                  | weights    |   |       |       |       |       |
|                  | were       |   |       |       |       |       |
|                  | increased  |   |       |       |       |       |
|                  | by 11-12%, |   |       |       |       |       |
|                  | although   |   |       |       |       |       |
|                  | none of    |   |       |       |       |       |
|                  | these      |   |       |       |       |       |
|                  | increases  |   |       |       |       |       |
|                  | were       |   |       |       |       |       |
|                  | sta        |   |       |       |       |       |
|                  | tistically |   |       |       |       |       |
|                  | si         |   |       |       |       |       |
|                  | gnificant. |   |       |       |       |       |
|                  |            |   |       |       |       |       |
|                  | Although   |   |       |       |       |       |
|                  | some       |   |       |       |       |       |
|                  | m          |   |       |       |       |       |
|                  | icroscopic |   |       |       |       |       |
|                  | changes    |   |       |       |       |       |
|                  | were       |   |       |       |       |       |
|                  | observed   |   |       |       |       |       |
|                  | in the     |   |       |       |       |       |
|                  | liver and  |   |       |       |       |       |
|                  | spleen     |   |       |       |       |       |
|                  | there were |   |       |       |       |       |
|                  | no         |   |       |       |       |       |
|                  | correlated |   |       |       |       |       |
|                  | clinical   |   |       |       |       |       |
|                  | chemical   |   |       |       |       |       |
|                  | or         |   |       |       |       |       |
|                  | haem       |   |       |       |       |       |
|                  | atological |   |       |       |       |       |
|                  | findings.  |   |       |       |       |       |
|                  |            |   |       |       |       |       |
|                  | Urine      |   |       |       |       |       |
|                  | analysis   |   |       |       |       |       |
|                  | revealed   |   |       |       |       |       |
|                  | an         |   |       |       |       |       |
|                  | apparent   |   |       |       |       |       |
|                  | increase   |   |       |       |       |       |
|                  | in urine   |   |       |       |       |       |
|                  | volume in  |   |       |       |       |       |
|                  | females.   |   |       |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+
|                  | **Males**  |   |       |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+
|                  | **P        |   | *     |       |       |       |
|                  | arameter** |   | *Dose |       |       |       |
|                  |            |   | le    |       |       |       |
|                  |            |   | vel** |       |       |       |
|                  |            |   | (ppm) |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+
|                  |            |   | **0** | **1   | **4   | **12  |
|                  |            |   |       | 000** | 000** | 000** |
+------------------+------------+---+-------+-------+-------+-------+
|                  | **Kidney   | * | 3.01  | 3.07  | 3.00  | 3.16  |
|                  | weight**   | * |       |       |       |       |
|                  |            | M |       |       |       |       |
|                  | \(g\)      | * |       |       |       |       |
|                  |            | * |       |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+
|                  | **Kidney   |   | 0.585 | 0.584 | 0.592 | 0.    |
|                  | weight**   |   |       |       |       | 657\* |
|                  |            |   |       |       |       |       |
|                  | (% body    |   |       |       |       |       |
|                  | weight)    |   |       |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+
|                  | **Kidney   |   | 14    | 14    | 14    | 14    |
|                  | weight**   |   | 2.512 | 5.006 | 1.698 | 8.282 |
|                  |            |   |       |       |       |       |
|                  | (% brain   |   |       |       |       |       |
|                  | weight)    |   |       |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+
|                  | **urine    |   | 3.9   | 4.7   | 3.6   | 4.6   |
|                  | volume**   |   |       |       |       |       |
|                  |            |   |       |       |       |       |
|                  | \(ml\)     |   |       |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+
|                  | *          |   |       |       |       |       |
|                  | *Females** |   |       |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+
|                  | **P        |   | *     |       |       |       |
|                  | arameter** |   | *Dose |       |       |       |
|                  |            |   | le    |       |       |       |
|                  |            |   | vel** |       |       |       |
|                  |            |   | (ppm) |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+
|                  |            |   | **0** | **1   | **4   | **12  |
|                  |            |   |       | 000** | 000** | 000** |
+------------------+------------+---+-------+-------+-------+-------+
|                  | **Kidney   | * | 1.74  | 1.81  | 1.76  | 1.93  |
|                  | weight**   | * |       |       |       |       |
|                  |            | F |       |       |       |       |
|                  | \(g\)      | * |       |       |       |       |
|                  |            | * |       |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+
|                  | **Kidney   |   | 0.630 | 0.630 | 0.629 | 0.697 |
|                  | weight**   |   |       |       |       |       |
|                  |            |   |       |       |       |       |
|                  | (% body    |   |       |       |       |       |
|                  | weight)    |   |       |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+
|                  | **Kidney   |   | 8     | 9     | 9     | 9     |
|                  | weight**   |   | 8.034 | 2.363 | 0.922 | 9.777 |
|                  |            |   |       |       |       |       |
|                  | (% brain   |   |       |       |       |       |
|                  | weight)    |   |       |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+
|                  | **urine    |   | 2.4   | 2.4   | 2.2   | 5.0   |
|                  | volume**   |   |       |       |       |       |
|                  |            |   |       |       |       |       |
|                  | \(ml\)     |   |       |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+
| **Conclusions**  | The        |   |       |       |       |       |
|                  | results of |   |       |       |       |       |
|                  | this study |   |       |       |       |       |
|                  | indicate   |   |       |       |       |       |
|                  | that       |   |       |       |       |       |
|                  | cypr       |   |       |       |       |       |
|                  | osulfamide |   |       |       |       |       |
|                  | is of      |   |       |       |       |       |
|                  | relatively |   |       |       |       |       |
|                  | low        |   |       |       |       |       |
|                  | toxicity   |   |       |       |       |       |
|                  | in the     |   |       |       |       |       |
|                  | rat. The   |   |       |       |       |       |
|                  | main       |   |       |       |       |       |
|                  | target     |   |       |       |       |       |
|                  | organs     |   |       |       |       |       |
|                  | were with  |   |       |       |       |       |
|                  | the kidney |   |       |       |       |       |
|                  | and        |   |       |       |       |       |
|                  | urinary    |   |       |       |       |       |
|                  | bladder,   |   |       |       |       |       |
|                  | with       |   |       |       |       |       |
|                  | effects    |   |       |       |       |       |
|                  | also seen  |   |       |       |       |       |
|                  | on the     |   |       |       |       |       |
|                  | liver      |   |       |       |       |       |
|                  | (males     |   |       |       |       |       |
|                  | only),     |   |       |       |       |       |
|                  | thymus     |   |       |       |       |       |
|                  | (males     |   |       |       |       |       |
|                  | only) and  |   |       |       |       |       |
|                  | spleen.    |   |       |       |       |       |
|                  |            |   |       |       |       |       |
|                  | The        |   |       |       |       |       |
|                  | changes    |   |       |       |       |       |
|                  | seen in    |   |       |       |       |       |
|                  | the kidney |   |       |       |       |       |
|                  | (          |   |       |       |       |       |
|                  | basophilic |   |       |       |       |       |
|                  | tubules    |   |       |       |       |       |
|                  | and        |   |       |       |       |       |
|                  | h          |   |       |       |       |       |
|                  | yperplasia |   |       |       |       |       |
|                  | of         |   |       |       |       |       |
|                  | collecting |   |       |       |       |       |
|                  | ducts and  |   |       |       |       |       |
|                  | pelvic     |   |       |       |       |       |
|                  | e          |   |       |       |       |       |
|                  | pithelium) |   |       |       |       |       |
|                  | and        |   |       |       |       |       |
|                  | bladder    |   |       |       |       |       |
|                  | (simple    |   |       |       |       |       |
|                  | h          |   |       |       |       |       |
|                  | yperplasia |   |       |       |       |       |
|                  | of the     |   |       |       |       |       |
|                  | u          |   |       |       |       |       |
|                  | rothelium) |   |       |       |       |       |
|                  | are        |   |       |       |       |       |
|                  | consistent |   |       |       |       |       |
|                  | with a     |   |       |       |       |       |
|                  | local      |   |       |       |       |       |
|                  | in         |   |       |       |       |       |
|                  | flammatory |   |       |       |       |       |
|                  | response   |   |       |       |       |       |
|                  | (hy        |   |       |       |       |       |
|                  | perplasia) |   |       |       |       |       |
|                  | due to the |   |       |       |       |       |
|                  | presence   |   |       |       |       |       |
|                  | 'sulphona  |   |       |       |       |       |
|                  | mide-like" |   |       |       |       |       |
|                  | crystals   |   |       |       |       |       |
|                  | which were |   |       |       |       |       |
|                  | observed   |   |       |       |       |       |
|                  | in the     |   |       |       |       |       |
|                  | urine from |   |       |       |       |       |
|                  | rats       |   |       |       |       |       |
|                  | treated at |   |       |       |       |       |
|                  | doses      |   |       |       |       |       |
|                  | [\>]{.unde |   |       |       |       |       |
|                  | rline}4000 |   |       |       |       |       |
|                  | ppm.       |   |       |       |       |       |
|                  |            |   |       |       |       |       |
|                  | In the     |   |       |       |       |       |
|                  | spleen, an |   |       |       |       |       |
|                  | increase   |   |       |       |       |       |
|                  | in the     |   |       |       |       |       |
|                  | severity   |   |       |       |       |       |
|                  | of brown   |   |       |       |       |       |
|                  | pigment in |   |       |       |       |       |
|                  | the red    |   |       |       |       |       |
|                  | pulp was   |   |       |       |       |       |
|                  | seen at    |   |       |       |       |       |
|                  | the top    |   |       |       |       |       |
|                  | dose 12000 |   |       |       |       |       |
|                  | ppm        |   |       |       |       |       |
|                  | compared   |   |       |       |       |       |
|                  | to         |   |       |       |       |       |
|                  | controls.  |   |       |       |       |       |
|                  | The        |   |       |       |       |       |
|                  | effects    |   |       |       |       |       |
|                  | was        |   |       |       |       |       |
|                  | considered |   |       |       |       |       |
|                  | by the     |   |       |       |       |       |
|                  | authors to |   |       |       |       |       |
|                  | be a       |   |       |       |       |       |
|                  | c          |   |       |       |       |       |
|                  | onsequence |   |       |       |       |       |
|                  | of an      |   |       |       |       |       |
|                  | increase   |   |       |       |       |       |
|                  | in the     |   |       |       |       |       |
|                  | turnover   |   |       |       |       |       |
|                  | of red     |   |       |       |       |       |
|                  | cells in   |   |       |       |       |       |
|                  | affected   |   |       |       |       |       |
|                  | animals,   |   |       |       |       |       |
|                  | although   |   |       |       |       |       |
|                  | haem       |   |       |       |       |       |
|                  | atological |   |       |       |       |       |
|                  | analysis   |   |       |       |       |       |
|                  | didn't     |   |       |       |       |       |
|                  | support    |   |       |       |       |       |
|                  | this       |   |       |       |       |       |
|                  | theory.    |   |       |       |       |       |
|                  |            |   |       |       |       |       |
|                  | In the     |   |       |       |       |       |
|                  | absence of |   |       |       |       |       |
|                  | any other  |   |       |       |       |       |
|                  | effects    |   |       |       |       |       |
|                  | the        |   |       |       |       |       |
|                  | changes    |   |       |       |       |       |
|                  | seen in    |   |       |       |       |       |
|                  | the thymus |   |       |       |       |       |
|                  | in a few   |   |       |       |       |       |
|                  | top dose   |   |       |       |       |       |
|                  | males      |   |       |       |       |       |
|                  | (decreased |   |       |       |       |       |
|                  | size of    |   |       |       |       |       |
|                  | the cortex |   |       |       |       |       |
|                  | (i         |   |       |       |       |       |
|                  | nvolution) |   |       |       |       |       |
|                  | was likely |   |       |       |       |       |
|                  | a result   |   |       |       |       |       |
|                  | of stress  |   |       |       |       |       |
|                  | rather     |   |       |       |       |       |
|                  | than an    |   |       |       |       |       |
|                  | effect on  |   |       |       |       |       |
|                  | the immune |   |       |       |       |       |
|                  | system     |   |       |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+
|                  | A NOAEL of |   |       |       |       |       |
|                  | 1000 ppm   |   |       |       |       |       |
|                  | (          |   |       |       |       |       |
|                  | equivalent |   |       |       |       |       |
|                  | to mean    |   |       |       |       |       |
|                  | achieved   |   |       |       |       |       |
|                  | dietary    |   |       |       |       |       |
|                  | intakes of |   |       |       |       |       |
|                  | 58 and     |   |       |       |       |       |
|                  | 70 mg/kg   |   |       |       |       |       |
|                  | bw/d in    |   |       |       |       |       |
|                  | males and  |   |       |       |       |       |
|                  | females    |   |       |       |       |       |
|                  | res        |   |       |       |       |       |
|                  | pectively) |   |       |       |       |       |
|                  | based on   |   |       |       |       |       |
|                  | h          |   |       |       |       |       |
|                  | yperplasia |   |       |       |       |       |
|                  | of the     |   |       |       |       |       |
|                  | urothelium |   |       |       |       |       |
|                  | in the     |   |       |       |       |       |
|                  | urinary    |   |       |       |       |       |
|                  | bladder at |   |       |       |       |       |
|                  | 4000 ppm   |   |       |       |       |       |
|                  | with       |   |       |       |       |       |
|                  | 'Sulphona  |   |       |       |       |       |
|                  | mide-like' |   |       |       |       |       |
|                  | crystals   |   |       |       |       |       |
|                  | also seen  |   |       |       |       |       |
|                  | in the     |   |       |       |       |       |
|                  | urine at   |   |       |       |       |       |
|                  | this dose. |   |       |       |       |       |
+------------------+------------+---+-------+-------+-------+-------+

+-----------------------------------------------------------------------+
| HED Reviewer comments:                                                |
|                                                                       |
| The study is classified as ACCEPTABLE/GUIDELINE and satisfies the     |
| requirement for a series 870.3100 subchronic toxicity study in the    |
| rat. HED concurs with the assignment of the NOAEL and LOAEL.          |
+-----------------------------------------------------------------------+

**870.3100 90-Day Oral Toxicity - Mouse (MRID No.: 47069809)**

AE 0001789 (Batch number R174, 95.9 % w/w purity), was administered
continuously via the diet to groups of C57BL/6 mice (10/sex/group) at
concentrations of 0, 500, 2000 and 7000 ppm for at least 90 days
(equating approximately to 0, 79, 321 and 1110 mg/kg/day in males and 0,
95, 398 and 1297 mg/kg/day in females).

At 7 000 ppm, the only treatment-related finding was an increased
incidence and severity of lymphocytolysis in the thymus of female mice
only.

At 2 000 and 500 ppm, no treatment-related findings were observed in
either sex.

The NOEL of AE 0001789 in this study was 2 000 ppm in females (equating
398 mg/kg/day) and 7 000 ppm in males (equating to 1 110 mg/kg/day).

+------------------+---------------------------------------------------+
| **EVALUATION,    |                                                   |
| SUMMARY AND      |                                                   |
| CONCLUSION BY    |                                                   |
| REGULATORY       |                                                   |
| AUTHORITY**      |                                                   |
+------------------+---------------------------------------------------+
| **Name of        | Pesticides Safety Directorate, UK                 |
| authority**      |                                                   |
+------------------+---------------------------------------------------+
| **Reviewer's     | Reliability rating: Totally reliable              |
| Comments**       |                                                   |
|                  | The study (Kennel P., 2003, SA 03005) is          |
|                  | compliant with OECD 408 (1998) with the following |
|                  | deviation:                                        |
|                  |                                                   |
|                  | The guideline specifies that histopathology of    |
|                  | the brain should include investigation of         |
|                  | 'representative regions including cerebrum,       |
|                  | cerebellum and medulla pons'. The study report    |
|                  | states only that the brain was investigated       |
|                  | histopathologically. The Notifier states that     |
|                  | 'Routinely, three transverse sections are made    |
|                  | for histopathological examination:                |
|                  |                                                   |
|                  | 1\. the first section at the level of optic       |
|                  | chiasm including the basal ganglia, septum,       |
|                  | cortex, anterior hypothalamus                     |
|                  |                                                   |
|                  | 2\. the second section at the level of            |
|                  | hippocampus containing the cortex and brain stem  |
|                  | at the transition of diencephalon to              |
|                  | mesencephalon                                     |
|                  |                                                   |
|                  | 3\. the third section containing the cerebellum   |
|                  | and brain stem (medulla oblongata)'               |
|                  |                                                   |
|                  | The epididymides and ovaries were not weighed, as |
|                  | specified in OECD 408, however this is not        |
|                  | considered to affect the integrity of the study   |
|                  | in the absence of effects on these organs in      |
|                  | other studies in the mouse or in other species    |
+------------------+---------------------------------------------------+
|                  | The only notable finding in this 90 day mouse     |
|                  | study was at the top dose with a treatment        |
|                  | related increase in the incidence and severity of |
|                  | lymphocytolysis in the thymus. There were no      |
|                  | other treatment-related findings.                 |
+------------------+---------------------------------------------------+
| **Conclusions**  | The results of this study indicate that           |
|                  | cyprosulfamide is of low toxicity in the mouse.   |
|                  | The only finding was increase in the incidence    |
|                  | and severity of lymphocytolysis in the thymus in  |
|                  | high dose females, which was considered by the    |
|                  | Notifier to be stress related change, although    |
|                  | there was little evidence of any effects which    |
|                  | could cause stress in these animals. There was no |
|                  | evidence of any signs of toxicity including an    |
|                  | absence of any clinical signs, nor any effects on |
|                  | the immune system.                                |
+------------------+---------------------------------------------------+
|                  | Based on an absence of effects in males the NOAEL |
|                  | was 7000 ppm (equivalent to a mean achieved       |
|                  | dietary intake 1110 mg/kg bw/day) and in females  |
|                  | 2000 ppm (equivalent to a mean achieved dietary   |
|                  | intake 398 mg/kg bw/day) based on the effects     |
|                  | seen in the thymus.                               |
+------------------+---------------------------------------------------+

+-----------------------------------------------------------------------+
| HED Reviewer Comments:                                                |
|                                                                       |
| **Classification/Acceptable Guideline.** The study serves as a dose   |
| range finding study for the definitive carcinogenicity study in mice. |
+-----------------------------------------------------------------------+

**870.3150 90-Day Oral Toxicity - Dog (MRID No.: 47069811)**

Technical grade AE 0001789 (Batch number 08466/0013, 97.4% purity) was
administered in the diet to Beagle dogs (4/sex/dose) at dose levels of 0
(concurrent vehicle control), 2 500, 7 500 and 15 000 ppm for a period
of at least 90 days (equivalent to 75, 221 and 416 mg/kg/day for the
males and 79, 221 and 341 for the females, respectively). Clinical
observations were conducted twice daily, food consumption was measured
daily and body weights were taken weekly. Clinical chemistry,
haematology and urinalysis were performed on all animals once prior to
administration of the test substance and during study weeks five, nine
and twelve. Ophthalmic examinations were performed pre-exposure and
pre-sacrifice. A gross necropsy was performed, organ weights were taken
and tissues were examined microscopically.

[At 15 000 ppm]{.underline}: One female was sacrificed for humane
reasons. This death was considered treatment‑related due to the kidney
calculi and abscessation. There was a body weight loss in the females
and no effect on body weight for the males. There was a reduction of
about 15% compared to controls in food consumption for both sexes.
Elevated urea nitrogen compared to pre-test values was observed in males
(from 92 to 169 %) and in females (from 177 to 554%); elevated serum
creatinine was also observed in males and females (from 44 to 60% and 44
to 210%, respectively). Elevated serum phosphorus was only noticed in
females (from 49% compared to pre-test values at termination).
Treatment-related urinalysis findings were: elevated urine volume in
males, a decrease in urine specific gravity in males and females,
decreased pH in females.

Calculi in the renal pelvis were seen in 3/4 males and all females,
renal pelvis dilatation was observed in one male and one female. Calculi
were observed in the ureter and urinary bladder of one male and dilated
ureters were seen in one female. Correlated microscopic changes of the
urinary tract were inflammatory changes, renal pelvis epithelium
hyperplasia and necrosis and associated changes in the ureters and
urinary bladder of males and females.

[At 7 500 ppm]{.underline}: The only treatment-related finding was a
decrease in urine specific gravity in females.

[At 2 500 ppm]{.underline}: No treatment-related effects were observed.

The No Observed Adverse Effect Level for this study was 7 500 ppm
(equilavent to 221 mg/kg/day for males and females) as there were no
microscopic pathology observations to correlate with the decrease in
urine specific gravity in the 7 500 ppm females.

<table>
<colgroup>
<col style="width: 23%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 1%" />
<col style="width: 3%" />
<col style="width: 6%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 7%" />
<col style="width: 0%" />
<col style="width: 1%" />
<col style="width: 1%" />
<col style="width: 7%" />
<col style="width: 0%" />
<col style="width: 7%" />
<col style="width: 1%" />
<col style="width: 2%" />
<col style="width: 0%" />
<col style="width: 11%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="19"><strong>EVALUATION, SUMMARY AND CONCLUSION BY
REGULATORY AUTHORITY</strong></td>
</tr>
<tr class="even">
<td><strong>Name of</strong> <strong>authority</strong></td>
<td colspan="18">Pesticides Safety Directorate, UK</td>
</tr>
<tr class="odd">
<td rowspan="15"><strong>Reviewer’s Comments</strong></td>
<td colspan="18">Reliability rating: Totally reliable</td>
</tr>
<tr class="even">
<td colspan="18">The study (M-263605-01-1) is fully compliant with OECD
409 (1998). Although reticulocyte counts are listed under haematological
investigations in the study no results are reported, however red cell
morphology has been assessed</td>
</tr>
<tr class="odd">
<td colspan="18"><p>There was a treatment-related decrease in
bodyweights for the top dose females (a loss in weight of -874 g for the
high-dose group during the study), top dose males gained weight but only
30% of the gain seen in males. Food consumption was decreased in both
sexes at the top dose.</p>
<p>Bodyweight changes in 90 day dog study;</p></td>
</tr>
<tr class="even">
<td><strong>Dose</strong></td>
<td colspan="14"><strong>Bodyweight (g)</strong></td>
<td colspan="3"><strong>weight</strong></td>
</tr>
<tr class="odd">
<td><strong>ppm</strong></td>
<td colspan="2">Day 0</td>
<td colspan="2">week 1</td>
<td colspan="2">week2</td>
<td colspan="3">week 3</td>
<td colspan="2">week 7</td>
<td colspan="3">week 12</td>
<td colspan="3"><strong>change (kg)</strong></td>
</tr>
<tr class="even">
<td colspan="18"><strong>male</strong></td>
</tr>
<tr class="odd">
<td>0</td>
<td colspan="2">7943</td>
<td colspan="2">8342</td>
<td colspan="2">8529</td>
<td colspan="3">8376</td>
<td colspan="2">8590</td>
<td colspan="3">8876</td>
<td colspan="3">932.7</td>
</tr>
<tr class="even">
<td>2500</td>
<td colspan="2">7851</td>
<td colspan="2">8196</td>
<td colspan="2">8482</td>
<td colspan="3">8426</td>
<td colspan="2">8827</td>
<td colspan="3">8921</td>
<td colspan="3">1070</td>
</tr>
<tr class="odd">
<td>7500</td>
<td colspan="2">8471</td>
<td colspan="2">8848</td>
<td colspan="2">9239</td>
<td colspan="3">9092</td>
<td colspan="2">9383</td>
<td colspan="3">9721</td>
<td colspan="3">1250.5</td>
</tr>
<tr class="even">
<td>15000</td>
<td colspan="2">8052</td>
<td colspan="2">8201</td>
<td colspan="2">8260</td>
<td colspan="3">8175</td>
<td colspan="2">8392</td>
<td colspan="3">8329</td>
<td colspan="3">277.2</td>
</tr>
<tr class="odd">
<td colspan="18"><strong>Female</strong></td>
</tr>
<tr class="even">
<td>0</td>
<td colspan="2">7046</td>
<td colspan="2">7218</td>
<td colspan="2">7268</td>
<td colspan="3">7219</td>
<td colspan="2">7437</td>
<td colspan="3">7504</td>
<td colspan="3">458</td>
</tr>
<tr class="odd">
<td>2500</td>
<td colspan="2">7110</td>
<td colspan="2">7294</td>
<td colspan="2">7495</td>
<td colspan="3">7314</td>
<td colspan="2">7460</td>
<td colspan="3">7515</td>
<td colspan="3">404.5</td>
</tr>
<tr class="even">
<td>7500</td>
<td colspan="2">7003</td>
<td colspan="2">7206</td>
<td colspan="2">7285</td>
<td colspan="3">7155</td>
<td colspan="2">7464</td>
<td colspan="3">7596</td>
<td colspan="3">592.8</td>
</tr>
<tr class="odd">
<td>15000</td>
<td colspan="2">6661</td>
<td colspan="2">6881</td>
<td colspan="2">6817</td>
<td colspan="3">6516</td>
<td colspan="2">6566</td>
<td colspan="3">5786</td>
<td colspan="3">-874.2</td>
</tr>
<tr class="even">
<td></td>
<td colspan="18">Food consumption in 90 day dog study;</td>
</tr>
<tr class="odd">
<td rowspan="6"></td>
<td colspan="2"></td>
<td colspan="4"><strong>Dose group</strong></td>
<td colspan="8"><strong>Food consumption (kg)</strong></td>
<td colspan="4"></td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="4"><strong>ppm</strong></td>
<td colspan="5"><strong>Males</strong></td>
<td colspan="3"><strong>Females</strong></td>
<td colspan="4"></td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="4">0</td>
<td colspan="5">24.7</td>
<td colspan="3">19.3</td>
<td colspan="4"></td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="4">2500</td>
<td colspan="5">23.9</td>
<td colspan="3">17.9</td>
<td colspan="4"></td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="4">7500</td>
<td colspan="5">24.9</td>
<td colspan="3">19.6</td>
<td colspan="4"></td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="4">15000</td>
<td colspan="5">21.2</td>
<td colspan="3">16.5</td>
<td colspan="4"></td>
</tr>
<tr class="odd">
<td></td>
<td colspan="18"></td>
</tr>
<tr class="even">
<td></td>
<td colspan="18">A very high WBC (57.8 x10<sup>3</sup>/mm<sup>3</sup>)
in one early death high-dose group female (VG3102) on Study Day 35 day
was thought to be due to kidney changes described microscopically
(abscess). Mild treatment related anaemia was evident with statistically
significant decrease in erythrocyte counts, haemoglobin, and hematocrit
in the high-dose group females at termination. Some haematological
changes (MCV, MCHC, RDW, and HDW) were also noted at 7500 ppm although
these were fairly minor in magnitude. Some statistically significant but
small changes in haematological parameters were noted in males mostly at
the top dose changes (MCV, MCHC, RDW, and HDW). In males at doses
<u>&gt;</u> 7500 ppm there was a clear increase in % reticulocytes which
correlated to the pattern of mild anaemia.</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="6"><strong>Haematological</strong></td>
<td colspan="12"><strong>Dose Group (ppm)</strong></td>
</tr>
<tr class="even">
<td></td>
<td colspan="6"><strong>Findings</strong></td>
<td colspan="12"><strong>males</strong></td>
</tr>
<tr class="odd">
<td rowspan="21"></td>
<td colspan="6"></td>
<td colspan="2"><strong>0</strong></td>
<td colspan="4"><strong>2500</strong></td>
<td colspan="4"><strong>7500</strong></td>
<td colspan="2"><strong>15000</strong></td>
</tr>
<tr class="even">
<td colspan="4" rowspan="4"><strong>WBCs
(10<sup>3</sup>/mm<sup>3</sup>)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="2">9.3</td>
<td colspan="4">7.9</td>
<td colspan="4">8.5</td>
<td colspan="2">9.9</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 35</strong></td>
<td colspan="2">9.7</td>
<td colspan="4">8.5</td>
<td colspan="4">10.0</td>
<td colspan="2">10.9</td>
</tr>
<tr class="even">
<td colspan="2"><strong>day 63</strong></td>
<td colspan="2">9.8</td>
<td colspan="4">8.2</td>
<td colspan="4">9.9</td>
<td colspan="2">11.4</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 84</strong></td>
<td colspan="2">9.6</td>
<td colspan="4">7.7</td>
<td colspan="4">10.9</td>
<td colspan="2">8.2</td>
</tr>
<tr class="even">
<td colspan="4" rowspan="4"><strong>RBCs
(10<sup>6</sup>/mm3)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="2">6.92</td>
<td colspan="4">7.01</td>
<td colspan="4">7.16</td>
<td colspan="2">7.02</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 35</strong></td>
<td colspan="2">6.89</td>
<td colspan="4">6.69</td>
<td colspan="4">6.99</td>
<td colspan="2">6.63</td>
</tr>
<tr class="even">
<td colspan="2"><strong>day 63</strong></td>
<td colspan="2">7.00</td>
<td colspan="4">7.34</td>
<td colspan="4">6.91</td>
<td colspan="2">6.30</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 84</strong></td>
<td colspan="2">7.17</td>
<td colspan="4">7.20</td>
<td colspan="4">6.90</td>
<td colspan="2">6.46</td>
</tr>
<tr class="even">
<td colspan="4" rowspan="4"><strong>Hgb (g/dl)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="2">16.1</td>
<td colspan="4">16.3</td>
<td colspan="4">17.0</td>
<td colspan="2">16.5</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 35</strong></td>
<td colspan="2">16.5</td>
<td colspan="4">15.8</td>
<td colspan="4">17.0</td>
<td colspan="2">16.0</td>
</tr>
<tr class="even">
<td colspan="2"><strong>day 63</strong></td>
<td colspan="2">16.8</td>
<td colspan="4">17.4</td>
<td colspan="4">16.8</td>
<td colspan="2">15.6</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 84</strong></td>
<td colspan="2">17.2</td>
<td colspan="4">17.1</td>
<td colspan="4">17.0</td>
<td colspan="2">16.2</td>
</tr>
<tr class="even">
<td colspan="4" rowspan="4"><strong>Hct (%)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="2">45.8</td>
<td colspan="4">46.1</td>
<td colspan="4">48.0</td>
<td colspan="2">47.3</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 35</strong></td>
<td colspan="2">46.8</td>
<td colspan="4">45.0</td>
<td colspan="4">48.0</td>
<td colspan="2">46.6</td>
</tr>
<tr class="even">
<td colspan="2"><strong>day 63</strong></td>
<td colspan="2">47.5</td>
<td colspan="4">49.2</td>
<td colspan="4">47.0</td>
<td colspan="2">46.2</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 84</strong></td>
<td colspan="2">48.9</td>
<td colspan="4">48.8</td>
<td colspan="4">48.4</td>
<td colspan="2">48.7</td>
</tr>
<tr class="even">
<td colspan="4" rowspan="4"><strong>MCHC (g/dl)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="2">35.1</td>
<td colspan="4">35.4</td>
<td colspan="4">35.6</td>
<td colspan="2">34.7</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 35</strong></td>
<td colspan="2">35.3</td>
<td colspan="4">35.2</td>
<td colspan="4">35.4</td>
<td colspan="2">34.4*</td>
</tr>
<tr class="even">
<td colspan="2"><strong>day 63</strong></td>
<td colspan="2">35.3</td>
<td colspan="4">35.3</td>
<td colspan="4">35.8</td>
<td colspan="2">33.8*</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 84</strong></td>
<td colspan="2">35.2</td>
<td colspan="4">35.2</td>
<td colspan="4">35.2</td>
<td colspan="2">33.4*</td>
</tr>
<tr class="even">
<td></td>
<td colspan="4" rowspan="4"><strong>MCV (µm<sup>3</sup>)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="2">66.2</td>
<td colspan="4">65.8</td>
<td colspan="4">67.0</td>
<td colspan="2">67.5</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><strong>day 35</strong></td>
<td colspan="2">67.9</td>
<td colspan="4">67.5</td>
<td colspan="4">68.7</td>
<td colspan="2">70.4</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2"><strong>day 63</strong></td>
<td colspan="2">67.9</td>
<td colspan="4">67.4</td>
<td colspan="4">68.0</td>
<td colspan="2">73.2*</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><strong>day 84</strong></td>
<td colspan="2">68.2</td>
<td colspan="4">68.0</td>
<td colspan="4">70.1</td>
<td colspan="2">75.3*</td>
</tr>
<tr class="even">
<td></td>
<td colspan="4" rowspan="4"><strong>RDW (%)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="2">14.1</td>
<td colspan="4">13.9</td>
<td colspan="4">13.8</td>
<td colspan="2">14.2</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><strong>day 35</strong></td>
<td colspan="2">12.6</td>
<td colspan="4">12.8</td>
<td colspan="4">12.7</td>
<td colspan="2">12.5</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2"><strong>day 63</strong></td>
<td colspan="2">12.8</td>
<td colspan="4">12.8</td>
<td colspan="4">12.4</td>
<td colspan="2">13.7</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><strong>day 84</strong></td>
<td colspan="2">12.9</td>
<td colspan="4">12.8</td>
<td colspan="4">13.3</td>
<td colspan="2">11.9*</td>
</tr>
<tr class="even">
<td></td>
<td colspan="4" rowspan="4"><strong>HDW (%)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="2">1.59</td>
<td colspan="4">1.67</td>
<td colspan="4">1.67</td>
<td colspan="2">1.61</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><strong>day 35</strong></td>
<td colspan="2">1.60</td>
<td colspan="4">1.61</td>
<td colspan="4">1.61</td>
<td colspan="2">1.58</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2"><strong>day 63</strong></td>
<td colspan="2">1.66</td>
<td colspan="4">1.66</td>
<td colspan="4">1.62</td>
<td colspan="2">1.93*</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><strong>day 84</strong></td>
<td colspan="2">1.73</td>
<td colspan="4">1.71</td>
<td colspan="4">1.84*</td>
<td colspan="2">1.57*</td>
</tr>
<tr class="even">
<td></td>
<td colspan="4" rowspan="4"><strong>Reticulocytes (%)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="2">0.5</td>
<td colspan="4">0.6</td>
<td colspan="4">0.9</td>
<td colspan="2">0.7</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><strong>day 35</strong></td>
<td colspan="2">0.7</td>
<td colspan="4">0.9</td>
<td colspan="4">1.3</td>
<td colspan="2">1.0</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2"><strong>day 63</strong></td>
<td colspan="2">0.9</td>
<td colspan="4">0.9</td>
<td colspan="4">1.0</td>
<td colspan="2">2.9*</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><strong>day 84</strong></td>
<td colspan="2">1.0</td>
<td colspan="4">1.0</td>
<td colspan="4">2.0*</td>
<td colspan="2">1.6</td>
</tr>
<tr class="even">
<td></td>
<td colspan="6"><strong>Haematological</strong></td>
<td colspan="12"><strong>FEmales</strong></td>
</tr>
<tr class="odd">
<td rowspan="25"></td>
<td colspan="6"><strong>Findings</strong></td>
<td colspan="2"><strong>0</strong></td>
<td colspan="4"><strong>2500</strong></td>
<td colspan="4"><strong>7500</strong></td>
<td colspan="2"><strong>15000</strong></td>
</tr>
<tr class="even">
<td colspan="4" rowspan="4"><strong>WBCs
(10<sup>3</sup>/mm<sup>3</sup>)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="2">7.7</td>
<td colspan="4">12.3</td>
<td colspan="4">8.3</td>
<td colspan="2">8.2</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 35</strong></td>
<td colspan="2">8.7</td>
<td colspan="4">10.2</td>
<td colspan="4">10.0</td>
<td colspan="2">20.9</td>
</tr>
<tr class="even">
<td colspan="2"><strong>day 63</strong></td>
<td colspan="2">8.7</td>
<td colspan="4">9.8</td>
<td colspan="4">10.2</td>
<td colspan="2">10.3</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 84</strong></td>
<td colspan="2">7.9</td>
<td colspan="4">10.2</td>
<td colspan="4">9.3</td>
<td colspan="2">5.7</td>
</tr>
<tr class="even">
<td colspan="4" rowspan="4"><strong>RBCs
(10<sup>6</sup>/mm3)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="2">7.42</td>
<td colspan="4">6.98</td>
<td colspan="4">7.26</td>
<td colspan="2">7.33</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 35</strong></td>
<td colspan="2">6.84</td>
<td colspan="4">6.37</td>
<td colspan="4">7.12</td>
<td colspan="2">6.12</td>
</tr>
<tr class="even">
<td colspan="2"><strong>day 63</strong></td>
<td colspan="2">6.75</td>
<td colspan="4">6.61</td>
<td colspan="4">6.76</td>
<td colspan="2">6.04</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 84</strong></td>
<td colspan="2">7.05</td>
<td colspan="4">6.51</td>
<td colspan="4">6.59</td>
<td colspan="2">5.18*</td>
</tr>
<tr class="even">
<td colspan="4" rowspan="4"><strong>Hgb (g/dl)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="2">17.4</td>
<td colspan="4">16.3</td>
<td colspan="4">16.9</td>
<td colspan="2">17.2</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 35</strong></td>
<td colspan="2">16.5</td>
<td colspan="4">15.2</td>
<td colspan="4">16.7</td>
<td colspan="2">14.5</td>
</tr>
<tr class="even">
<td colspan="2"><strong>day 63</strong></td>
<td colspan="2">16.1</td>
<td colspan="4">15.7</td>
<td colspan="4">16.0</td>
<td colspan="2">14.6</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 84</strong></td>
<td colspan="2">16.9</td>
<td colspan="4">15.7</td>
<td colspan="4">15.9</td>
<td colspan="2">12.5*</td>
</tr>
<tr class="even">
<td colspan="4" rowspan="4"><strong>Hct (%)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="2">49.3</td>
<td colspan="4">47.2</td>
<td colspan="4">48.7</td>
<td colspan="2">49.2</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 35</strong></td>
<td colspan="2">46.3</td>
<td colspan="4">42.8</td>
<td colspan="4">48.8</td>
<td colspan="2">41.9</td>
</tr>
<tr class="even">
<td colspan="2"><strong>day 63</strong></td>
<td colspan="2">45.3</td>
<td colspan="4">44.8</td>
<td colspan="4">46.7</td>
<td colspan="2">43.1</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 84</strong></td>
<td colspan="2">48.1</td>
<td colspan="4">44.9</td>
<td colspan="4">46.2</td>
<td colspan="2">38.0*</td>
</tr>
<tr class="even">
<td colspan="4" rowspan="4"><strong>MCHC (g/dl)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="2">35.4</td>
<td colspan="4">34.6</td>
<td colspan="4">34.7</td>
<td colspan="2">35.0</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 35</strong></td>
<td colspan="2">35.6</td>
<td colspan="4">35.5</td>
<td colspan="4">34.3*</td>
<td colspan="2">34.7</td>
</tr>
<tr class="even">
<td colspan="2"><strong>day 63</strong></td>
<td colspan="2">35.6</td>
<td colspan="4">35.0</td>
<td colspan="4">34.3*</td>
<td colspan="2">33.8*</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 84</strong></td>
<td colspan="2">35.1</td>
<td colspan="4">35.0</td>
<td colspan="4">34.4*</td>
<td colspan="2">32.9*</td>
</tr>
<tr class="even">
<td colspan="4" rowspan="4"><strong>MCV (µm<sup>3</sup>)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="3">66.4</td>
<td colspan="4">67.4</td>
<td colspan="4">67.1</td>
<td>67.1</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 35</strong></td>
<td colspan="3">67.7</td>
<td colspan="4">67.2</td>
<td colspan="4">68.5</td>
<td>68.5</td>
</tr>
<tr class="even">
<td colspan="2"><strong>day 63</strong></td>
<td colspan="3">67.2</td>
<td colspan="4">67.8</td>
<td colspan="4">69.1</td>
<td>71.5</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>day 84</strong></td>
<td colspan="3">68.2</td>
<td colspan="4">68.9</td>
<td colspan="4">70.2*</td>
<td>73.4*</td>
</tr>
<tr class="even">
<td></td>
<td colspan="4" rowspan="4"><strong>RDW (%)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="2">13.5</td>
<td colspan="4">13.3</td>
<td colspan="4">13.1</td>
<td colspan="2">13.1</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><strong>day 35</strong></td>
<td colspan="2">12.9</td>
<td colspan="4">12.4</td>
<td colspan="4">12.3</td>
<td colspan="2">12.4</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2"><strong>day 63</strong></td>
<td colspan="2">12.1</td>
<td colspan="4">12.7</td>
<td colspan="4">12.2</td>
<td colspan="2">12.5</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><strong>day 84</strong></td>
<td colspan="2">12.3</td>
<td colspan="4">12.4</td>
<td colspan="4">12.2</td>
<td colspan="2">11.7</td>
</tr>
<tr class="even">
<td></td>
<td colspan="4" rowspan="4"><strong>HDW (%)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="2">1.57</td>
<td colspan="4">1.50</td>
<td colspan="4">1.52</td>
<td colspan="2">1.43</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><strong>day 35</strong></td>
<td colspan="2">1.72</td>
<td colspan="4">1.55</td>
<td colspan="4">1.55</td>
<td colspan="2">1.58</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2"><strong>day 63</strong></td>
<td colspan="2">1.66</td>
<td colspan="4">1.68</td>
<td colspan="4">1.59</td>
<td colspan="2">1.73</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><strong>day 84</strong></td>
<td colspan="2">1.57</td>
<td colspan="4">1.58</td>
<td colspan="4">1.59</td>
<td colspan="2">1.64</td>
</tr>
<tr class="even">
<td></td>
<td colspan="4" rowspan="4"><strong>Reticulocytes (%)</strong></td>
<td colspan="2"><strong>day -7</strong></td>
<td colspan="2">0.5</td>
<td colspan="4">0.7</td>
<td colspan="4">0.7</td>
<td colspan="2">0.3</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><strong>day 35</strong></td>
<td colspan="2">1.0</td>
<td colspan="4">0.7</td>
<td colspan="4">0.9</td>
<td colspan="2">0.9</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2"><strong>day 63</strong></td>
<td colspan="2">0.7</td>
<td colspan="4">0.9</td>
<td colspan="4">0.7</td>
<td colspan="2">1.4</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><strong>day 84</strong></td>
<td colspan="2">0.7</td>
<td colspan="4">0.7</td>
<td colspan="4">1.0</td>
<td colspan="2">0.9</td>
</tr>
<tr class="even">
<td></td>
<td colspan="18">Urinalysis revealed a number of treatment related
effects at 15000 ppm; elevated urine volume in males, decreased specific
gravity in males and females and a decrease in pH in females. The only
effect evident at 7500 ppm was a decreased specific gravity in
females.</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="6"><strong>Urinalysis</strong></td>
<td colspan="12"><strong>Dose Group (ppm)</strong></td>
</tr>
<tr class="even">
<td></td>
<td colspan="6"><strong>Findings</strong></td>
<td colspan="12"><strong>males</strong></td>
</tr>
<tr class="odd">
<td rowspan="13"></td>
<td colspan="6"></td>
<td colspan="2"><strong>0</strong></td>
<td colspan="4"><strong>2500</strong></td>
<td colspan="4"><strong>7500</strong></td>
<td colspan="2"><strong>15000</strong></td>
</tr>
<tr class="even">
<td colspan="4" rowspan="4"><strong>pH</strong></td>
<td colspan="2"><strong>day 0</strong></td>
<td colspan="2">8.0</td>
<td colspan="4">7.5</td>
<td colspan="4">7.6</td>
<td colspan="2">8.3</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>1 month</strong></td>
<td colspan="2">8.8</td>
<td colspan="4">8.8</td>
<td colspan="4">8.4</td>
<td colspan="2">7.6</td>
</tr>
<tr class="even">
<td colspan="2"><strong>2 month</strong></td>
<td colspan="2">7.6</td>
<td colspan="4">9.0</td>
<td colspan="4">8.1</td>
<td colspan="2">7.5</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>term.</strong></td>
<td colspan="2">7.4</td>
<td colspan="4">7.5</td>
<td colspan="4">7.9</td>
<td colspan="2">7.6</td>
</tr>
<tr class="even">
<td colspan="4" rowspan="4"><strong>Specific Gravity</strong></td>
<td colspan="2"><strong>day 0</strong></td>
<td colspan="2">1.028</td>
<td colspan="4">1.020</td>
<td colspan="4">1.012</td>
<td colspan="2">1.020</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>1 month</strong></td>
<td colspan="2">1.022</td>
<td colspan="4">1.021</td>
<td colspan="4">1.014</td>
<td colspan="2">1.015</td>
</tr>
<tr class="even">
<td colspan="2"><strong>2 month</strong></td>
<td colspan="2">1.018</td>
<td colspan="4">1.033</td>
<td colspan="4">1.019</td>
<td colspan="2">1.012</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>term.</strong></td>
<td colspan="2">1.028</td>
<td colspan="4">1.034</td>
<td colspan="4">1.010</td>
<td colspan="2">1.004*</td>
</tr>
<tr class="even">
<td colspan="4" rowspan="4"><strong>Urine volume (ml)</strong></td>
<td colspan="2"><strong>day 0</strong></td>
<td colspan="2">171.5</td>
<td colspan="4">181.0</td>
<td colspan="4">135.0</td>
<td colspan="2">111.3</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>1 month</strong></td>
<td colspan="2">223.3</td>
<td colspan="4">383.8</td>
<td colspan="4">203.3</td>
<td colspan="2">840.5</td>
</tr>
<tr class="even">
<td colspan="2"><strong>2 month</strong></td>
<td colspan="2">373.3</td>
<td colspan="4">295.3</td>
<td colspan="4">266.5</td>
<td colspan="2">582.0</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>term.</strong></td>
<td colspan="2">137.0</td>
<td colspan="4">298.3</td>
<td colspan="4">185.8</td>
<td colspan="2">815.3</td>
</tr>
<tr class="even">
<td></td>
<td colspan="6"><strong>Urinalysis</strong></td>
<td colspan="12"><strong>FEmales</strong></td>
</tr>
<tr class="odd">
<td rowspan="13"></td>
<td colspan="6"><strong>Findings</strong></td>
<td colspan="2"><strong>0</strong></td>
<td colspan="4"><strong>2500</strong></td>
<td colspan="4"><strong>7500</strong></td>
<td colspan="2"><strong>15000</strong></td>
</tr>
<tr class="even">
<td colspan="4" rowspan="4"><strong>pH</strong></td>
<td colspan="2"><strong>day 0</strong></td>
<td colspan="2">7.9</td>
<td colspan="4">7.0</td>
<td colspan="4">7.9</td>
<td colspan="2">8.8</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>1 month</strong></td>
<td colspan="2">8.4</td>
<td colspan="4">7.8</td>
<td colspan="4">7.6</td>
<td colspan="2">6.2*</td>
</tr>
<tr class="even">
<td colspan="2"><strong>2 month</strong></td>
<td colspan="2">9.0</td>
<td colspan="4">7.6</td>
<td colspan="4">8.5*</td>
<td colspan="2">6.3*</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>term.</strong></td>
<td colspan="2">8.0</td>
<td colspan="4">7.3</td>
<td colspan="4">6.9</td>
<td colspan="2">7.2</td>
</tr>
<tr class="even">
<td colspan="4" rowspan="4"><strong>Specific Gravity</strong></td>
<td colspan="2"><strong>day 0</strong></td>
<td colspan="2">1.030</td>
<td colspan="4">1.022</td>
<td colspan="4">1.014</td>
<td colspan="2">1.034</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>1 month</strong></td>
<td colspan="2">1.021</td>
<td colspan="4">1.027</td>
<td colspan="4">1.021</td>
<td colspan="2">1.011</td>
</tr>
<tr class="even">
<td colspan="2"><strong>2 month</strong></td>
<td colspan="2">1.027</td>
<td colspan="4">1.031</td>
<td colspan="4">1.032</td>
<td colspan="2">1.011</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>term.</strong></td>
<td colspan="2">1.031</td>
<td colspan="4">1.018</td>
<td colspan="4">1.008*</td>
<td colspan="2">1.009*</td>
</tr>
<tr class="even">
<td colspan="4" rowspan="4"><strong>Urine volume (ml)</strong></td>
<td colspan="2"><strong>day 0</strong></td>
<td colspan="2">102.5</td>
<td colspan="4">151.0</td>
<td colspan="4">173.0*</td>
<td colspan="2">61.8</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>1 month</strong></td>
<td colspan="2">303.0</td>
<td colspan="4">158.5</td>
<td colspan="4">271.8</td>
<td colspan="2">303.7</td>
</tr>
<tr class="even">
<td colspan="2"><strong>2 month</strong></td>
<td colspan="2">263.8</td>
<td colspan="4">204.5</td>
<td colspan="4">183.5</td>
<td colspan="2">428.7</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>term.</strong></td>
<td colspan="2">128.8</td>
<td colspan="4">194.0</td>
<td colspan="4">217.5</td>
<td colspan="2">339.7</td>
</tr>
<tr class="even">
<td></td>
<td colspan="18">Gross pathological examination revealed a small thymus
in three of the four females at the top dose (mean absolute weight
control 8.529g cf. 15000ppm 3.936g; mean relative (to bw) weight control
0.112% cf. 15000ppm 0.102g) these differences were considered to be due
to the reduced overall bodyweight in the top dose group.</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="18">There was a statistically significant decrease in
absolute testes weight at the top dose, and a non-statistically
significant decrease in relative (to bodyweight) testes weight. There
were no other related findings.</td>
</tr>
<tr class="even">
<td></td>
<td colspan="18">Absolute and relative (to bw) testes weight in 90 day
dog study</td>
</tr>
<tr class="odd">
<td rowspan="6"></td>
<td colspan="2"></td>
<td colspan="4"><strong>Dose group</strong></td>
<td colspan="8"><strong>Testes weight</strong></td>
<td colspan="4"></td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="4"><strong>ppm</strong></td>
<td colspan="5"><strong>absolute (g)</strong></td>
<td colspan="3"><strong>relative (%)</strong></td>
<td colspan="4"></td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="4">0</td>
<td colspan="5">12.983</td>
<td colspan="3">0.146</td>
<td colspan="4"></td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="4">2500</td>
<td colspan="5">13.668</td>
<td colspan="3">0.152</td>
<td colspan="4"></td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="4">7500</td>
<td colspan="5">14.036</td>
<td colspan="3">0.147</td>
<td colspan="4"></td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="4">15000</td>
<td colspan="5">9.964*</td>
<td colspan="3">0.123</td>
<td colspan="4"></td>
</tr>
<tr class="odd">
<td></td>
<td colspan="18">*= p&lt;0.05</td>
</tr>
<tr class="even">
<td><strong>Conclusions</strong></td>
<td colspan="18"><p>The top dose in this 90 day study causing a weight
loss in females and the death (<em>in-extremis</em>) of a female
probably due to kidney calculi and resultant abscessation. There was
also a reduction in food consumption. Overall bodyweight gain was
reduced in males at the top dose (<u>ca</u> 70% lower than controls)
there was also a slight reduction in food consumption.</p>
<p>The urinary system was found to be the main target of toxicity as is
also the case in short-term toxicity studies in the rat and mouse.
Inflammatory changes were evident in the renal pelvis, epithelial
hyperplasia and necrosis, and associated changes in the ureters
(dilatation) and urinary bladder. Gross necropsy revealed the probable
cause of these changes with calculi observed in the kidneys, ureters and
urinary bladder. Clinical chemistry revealed some related findings at
15000 ppm; elevated urea nitrogen in both sexes, elevated serum
creatinine in both sexes and elevated serum phosphorus in females.
Urinalysis at 15000 ppm also revealed elevated urine volume in males,
decrease in urine specific gravity in both sexes and decreased pH in
females. A decrease in urine specific gravity was also seen in females
at 7500 ppm, although without histopathological correlate.</p>
<p>In addition cyprosulfamide appeared to cause mild anaemia in top dose
females characterised by statistically significant decrease in
erythrocyte counts, haemoglobin, and hematocrit. There were also some
slight changes in haematological parameters at 7500 ppm, although minor
in nature. There was some evidence for a similar effect in males
although this was marginal. There were no correlated microscopic
findings.</p>
<p>A NOAEL of 7500 ppm (equivalent to mean achieved dietary intakes of
221 mg/kg bw/day in males and females) can be determined for this study,
based on the clear effects on the urinary system, bodyweight changes and
mild anaemia at the top dose. The effects observed at 7500 ppm were not
biologically significant and not considered adverse.</p></td>
</tr>
</tbody>
</table>

# 

I

+-----------------------------------------------------------------------+
| HED Reviewer Comments:                                                |
|                                                                       |
| **Classification: Acceptable/Guideline.** The study satisfies the     |
| guideline requirement for a series 870.3150 subchronic toxicity study |
| in dogs. HED concurs with the assignment of the NOAEL and LOAEL.      |
+-----------------------------------------------------------------------+

**870.3200 21/28-Day Dermal Toxicity -- Rat -**

**No study available and not required.**

**870.3465 90-Day Inhalation -- Rat**

**No study available and not required.**

**A.3.2 Prenatal Developmental Toxicity**

**870.3700a Prenatal Developmental Toxicity Study - Rat (MRID No.:
47069814)**

In a developmental toxicity study AE 0001789 (batch number 08466/0013,
97.4% w/w purity) was administered daily by gavage from gestation day
(GD) 6 to 20 to groups of 25 pregnant Sprague-Dawley female rats per
dose-group. The doses given were 0, 60, 250 and 1000 mg/kg/day in
suspension in aqueous solution of 0.5% methylcellulose 400. Clinical
observations were recorded daily and body weights were recorded for all
females on GD 0, 6, 8, 10, 12, 14, 16, 18 and 21. Food consumption was
also measured for all the females during the intervals GD l-6, 6-8,
8-10, 10-12, 12-14, 14-16, 16-18 and 18-21. At scheduled sacrifice, on
GD 21, the gravid uterine weight was recorded and the dams were
evaluated for number of corpora lutea, number and status of
implantations (resorptions, dead and live fœtuses). In addition, the
kidney and the urinary bladder of all dams were examined for signs of
gritty material. These organs were retained from all females, the kidney
was examined histopathologically at all dose levels, whilst the urinary
bladder was examined at 1000 mg/kg/day and from the control group only.
Live fœtuses were removed from the uteri, counted, weighed, sexed and
examined externally. Approximately half of the live fœtuses from each
litter were fixed in Bouin\'s solution and subsequently dissected for
internal examination. The remaining half were eviscerated, fixed in
absolute ethanol and stained according to a modification of the Tyl and
Marr technique for skeletal examination of bone and cartilage.

There were no mortalities or treatment-related signs in any dose group.

At 1000 mg/kg/day, body weight change was reduced in dams by 32% between
GD 6 to 8, thereafter, body weight change was comparable to the
controls. Maternal corrected body weight change was reduced by 11%
compared to controls. At autopsy, one female was noted with yellow
sediment in both kidneys and prominent lobulation of the liver, one
female had an enlarged liver with white foci on the left lobe and one
female had a white area on the left lobe. At microscopic examination,
one female was found to have a moderate bilateral papillary necrosis in
the kidney, associated with mixed cell infiltrate. The change correlated
with the macroscopic finding of yellow bilateral sediment in the kidney
of this female. No litter parameters were affected, including the number
of live fœtuses, early and late resorptions, fœtal death status,
percentage of male fœtuses and mean body weights. At external, visceral
and skeletal fœtal examination, no treatment-related findings were
observed.

At 250 and 60 mg/kg/day, there were no treatment-related maternal,
litter based or fœtal findings at either dosage.

In conclusion, a dose level of 1000 mg/kg/day AE 0001789 caused toxic
effects to the dams and was a No Observed Effect Level (NOEL) in terms
of fœtal development. A dose level of 250 mg/kg/day was the NOEL for
maternal toxicity.

<table>
<colgroup>
<col style="width: 23%" />
<col style="width: 22%" />
<col style="width: 1%" />
<col style="width: 10%" />
<col style="width: 1%" />
<col style="width: 8%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 7%" />
<col style="width: 2%" />
<col style="width: 10%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="11"><strong>EVALUATION, SUMMARY AND CONCLUSION BY
REGULATORY AUTHORITY</strong></td>
</tr>
<tr class="even">
<td><strong>Name of authority</strong></td>
<td colspan="10">Pesticides Safety Directorate, UK</td>
</tr>
<tr class="odd">
<td rowspan="12"><strong>Reviewer’s Comments</strong></td>
<td colspan="10"><p>Reliability rating: totally reliable</p>
<p>The study (M-261462-01-2) is fully compliant with OECD 414 (2001).
Dosing from Day 6-20 of gestation is acceptable.</p>
<p>Maternal bodyweight effects were clearly seen at the top
dose.</p></td>
</tr>
<tr class="even">
<td rowspan="2"><strong>Maternal weight (g) Pregnant
females</strong></td>
<td colspan="9"><strong>Dose level</strong> (mg/kg bw/d)</td>
</tr>
<tr class="odd">
<td colspan="3"><strong>0</strong></td>
<td colspan="2"><strong>60</strong></td>
<td colspan="2"><strong>250</strong></td>
<td colspan="2"><strong>1000</strong></td>
</tr>
<tr class="even">
<td>Gestation day 0</td>
<td colspan="3">269.2</td>
<td colspan="2">269.4</td>
<td colspan="2">269.2</td>
<td colspan="2">269.7</td>
</tr>
<tr class="odd">
<td>Gestation day 6</td>
<td colspan="3">305.8</td>
<td colspan="2">305.0</td>
<td colspan="2">302.9</td>
<td colspan="2">303.2</td>
</tr>
<tr class="even">
<td>Gestation day 8</td>
<td colspan="3">314.2</td>
<td colspan="2">312.6</td>
<td colspan="2">309.9</td>
<td colspan="2">309.0</td>
</tr>
<tr class="odd">
<td>Gestation day 10</td>
<td colspan="3">324.5</td>
<td colspan="2">322.5</td>
<td colspan="2">319.4</td>
<td colspan="2">321.1</td>
</tr>
<tr class="even">
<td>Gestation day 12</td>
<td colspan="3">335.0</td>
<td colspan="2">333.0</td>
<td colspan="2">330.0</td>
<td colspan="2">330.6</td>
</tr>
<tr class="odd">
<td>Gestation day 14</td>
<td colspan="3">342.0</td>
<td colspan="2">342.1</td>
<td colspan="2">339.2</td>
<td colspan="2">340.4</td>
</tr>
<tr class="even">
<td>Gestation day 16</td>
<td colspan="3">359.4</td>
<td colspan="2">358.3</td>
<td colspan="2">355.9</td>
<td colspan="2">358.4</td>
</tr>
<tr class="odd">
<td>Gestation day 18</td>
<td colspan="3">387.9</td>
<td colspan="2">385.6</td>
<td colspan="2">383.4</td>
<td colspan="2">386.4</td>
</tr>
<tr class="even">
<td>Gestation day 21</td>
<td colspan="3">436.5</td>
<td colspan="2">432.1</td>
<td colspan="2">432.2</td>
<td colspan="2">434.8</td>
</tr>
<tr class="odd">
<td rowspan="5"></td>
<td colspan="10"><p><u>External Observations</u>: There were three
fetuses observed with malformations, two at 250 mg/kg bw/day and one at
60 mg/kg bw/day. At 250 mg/kg/day, one fetus had an umbilical hernia and
one fetus had anasarca, whilst at 60 mg/kg/day one fetus had a cleft
palate. In isolation and in the absence of a dose response, these
malformations were considered to be incidental.</p>
<p><u>Visceral Observations</u>: At 1000 mg/kg bw/day, one fetus had the
malformation retinal fold associated with a small lens, whilst a second
fetus had the malformation right-sided aortic arch and pulmonary trunk.
As these two malformations occurred in isolation, they were considered
to be incidental. In addition, the incidence of the malformation absent
renal papilla {unilateral} was marginally higher in terms of both mean
percentage of fetuses affected and percentage of litters affected
compared with the control group. The incidence was not statistically
significant for either parameter, when compared to the control group.
The incidence in terms of litters, and was just within the historical
control range, although over in terms of fetuses. Overall it is
considered that it is unlikely that this finding was treatment
related.</p></td>
</tr>
<tr class="even">
<td colspan="2" rowspan="2"><strong>Observation</strong>: Absent renal
papilla (unilateral)</td>
<td colspan="7"><strong>Dose level</strong> <strong>(mg/kg
bw/day)</strong></td>
<td rowspan="2"><strong>Historical Control Range</strong></td>
</tr>
<tr class="odd">
<td><strong>0</strong></td>
<td colspan="2"><strong>60</strong></td>
<td colspan="2"><strong>250</strong></td>
<td colspan="2"><strong>1000</strong></td>
</tr>
<tr class="even">
<td colspan="2">Mean % fetuses affected</td>
<td>0.6</td>
<td colspan="2">0.0</td>
<td colspan="2">0.6</td>
<td colspan="2">1.9</td>
<td>0.0-1.0</td>
</tr>
<tr class="odd">
<td colspan="2">Mean % litters affected</td>
<td>4.0</td>
<td colspan="2">0.0</td>
<td colspan="2">4.0</td>
<td colspan="2">8.0</td>
<td>0.0-8.3</td>
</tr>
<tr class="even">
<td></td>
<td colspan="10"><u>Skeletal Observations</u>: Two fetuses with
malformations were noted, one occurred at 1000 mg/kg bw/day and
comprised of hemivertebra in the atlas vertebra and malpositioned axis
vertebra. The second malformation occurred at 60 mg/kg bw/day, where one
fetus had a small and split palatine (the same fetus which had a cleft
palate at the external observation). In isolation, these malformations
are considered to be incidental. The following two variants were found
at a higher incidence at 1000 mg/kg bw/day; incomplete parietal
ossification and incomplete interparietal ossification. In addition, the
incidence of 13th costal cartilage absent (unilateral/bilateral),
classified as a variant, was marginally higher at 1000 mg/kg bw/day,
compared with the controls. However, as in all three cases the incidence
was found not to be statistically significantly different from the
control group at both the fetal and litter level, these findings were
considered to be incidental.</td>
</tr>
<tr class="odd">
<td><strong>Conclusions</strong></td>
<td colspan="10"><p>No evidence of teratogenicity was seen in this
study.</p>
<p>A NOAEL for maternal toxicity of 250 mg/kg bw/day can be determined,
based on the reduced weight gain and effects on the kidneys seen at the
top dose level of 1000 mg/kg bw/day. A NOEL for developmental toxicity
of 1000 mg/kg bw/day can be based on the absence of any affect on fetal
parameters.</p></td>
</tr>
</tbody>
</table>

+-----------------------------------------------------------------------+
| HED Reviewer Comments:                                                |
|                                                                       |
| **Classification: Acceptable/Guideline.** The study satisfied the     |
| guideline requirement for a serried 870.3700 developmental toxicity   |
| study in rats. HED concurs with the assignment of the NOAEL and       |
| LOAEL.                                                                |
+-----------------------------------------------------------------------+

**870.3700b Prenatal Developmental Toxicity Study - Rabbit**

**First study (MRID No.: 47069812)**

Twenty‑five time-mated female New Zealand White Rabbits per group were
exposed to AE 0001789, a herbicide safener belonging to the reverse
sulfamide family, (batch number 08466/0013, a white powder, 97.4% w/w
purity) by gavage from Gestation Day (GD) 6 to 28. The doses given were
0, 50, 125 and 500 mg/kg/day in suspension in aqueous solution of 0.5%
methylcellulose 400. The high dose level of 500 mg/kg/day was terminated
prior to commencement of scheduled autopsy, due to the high mortality
rate observed at this dosage.

Maternal body weights were recorded for all surviving females on GD 3,
6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 and 29. Food consumption was
measured for all surviving females during the intervals GD 3‑6, 6‑8,
8‑10, 10‑14, 14‑18, 18‑22, 22‑26 and 26‑29. Clinical observations were
recorded daily. At scheduled sacrifice, on GD 29, the gravid uterine
weight and the number of ribs (in pregnant females) were recorded and
the dams were evaluated for number of corpora lutea, number and status
of implantations (resorptions, dead and live fœtuses). The urinary
bladder and kidney were retained from all females at 50 and
125 mg/kg/day and the control group, but were examined microscopically
at 125 mg/kg/day and from the control group only. Live fœtuses were
removed from the uteri, counted, weighed and examined externally. The
heads of fœtuses from approximately half of each litter were immersed in
Bouin's fluid and the internal structures examined after fixation. The
bodies of all fœtuses were dissected for soft tissue anomalies and
sexed. Fœtuses were eviscerated, skinned and fixed in absolute ethanol
before staining. A modification of the Staples and Schnell technique was
applied and a subsequent skeletal examination was performed.

At 500 mg/kg/day

Between GD 9 and 20, seven of 25 dams died; four were killed for humane
reasons and three were found dead. The principal clinical signs observed
were yellow sediment in the urine in all animals, associated with red
traces on the cage tray in five cases. All animals showed a marked body
weight loss, associated with very poor food consumption prior to death.
At autopsy, the principal target organs were the kidney and urinary
bladder, where yellow sediments were noted in the kidney of 4/7 females
and in the urinary bladder of 2/7 females. In addition, a marbled
pattern was observed on the kidney in 2/7 cases and red contents in the
urinary bladder in 1/7 females. As this dose level had clearly exceeded
a Maximum Tolerated Dose (MTD), treatment at 500 mg/kg/day was
terminated. Surviving females were killed prior to scheduled autopsy
with no macroscopic examination performed and no tissues taken. Of the
females surviving until termination of this dose level,
treatment-related clinical signs consisted of yellow sediment in the
urine in 3/18 dams and few faeces in 4/18 dams. Two females showed a
significant body weight loss of between 0.21 and 0.29 kg, and poor food
consumption prior to necropsy.

At 125 mg/kg/day

At this dosage, treatment-related clinical signs consisted of yellow
sediment in the urine in 2/25 dams. No effect on mean body weight
change, mean corrected body weight change or mean food consumption was
noted. At autopsy, yellow sediment in the kidney was noted in 1/25
females. No treatment-related changes were detected at the microscopic
examination of the kidney or urinary bladder. As a consequence, the
macroscopic finding of marbled pattern on the kidney in the decedent
female and yellow sediment in the kidney in one female at scheduled
sacrifice were regarded as not adverse findings. No litter parameters
were affected at this dosage. There were no external, visceral or
skeletal findings at the fœtal evaluation which were considered to be
treatment-related at this dosage.

At 50 mg/kg/day

There were no treatment-related clinical signs, and mean body weight
change, mean corrected body weight change and mean food consumption were
unaffected by treatment. At autopsy, 1/25 females had a kidney with a
marbled pattern appearance, but in the absence of microscopic findings
in the kidney at 125 mg/kg/day, this finding was considered to be not an
adverse finding. No treatment-related effects on litter parameters were
observed at this dosage. There were no external, visceral or skeletal
findings at the fœtal evaluation which were considered to be
treatment-related at this dosage.

In conclusion, a dose level of 500 mg/kg/day clearly exceeded a Maximum
Tolerated Dose (MTD) in the pregnant rabbit. A dose level of
125 mg/kg/day was a No Observed Adverse Effect Level (NOAEL) in the dam
due to the findings observed in the kidney, whilst being a No Observed
Effect Level (NOEL) in the foetus, in the New Zealand White Rabbit.

<table style="width:100%;">
<colgroup>
<col style="width: 24%" />
<col style="width: 0%" />
<col style="width: 23%" />
<col style="width: 0%" />
<col style="width: 1%" />
<col style="width: 10%" />
<col style="width: 1%" />
<col style="width: 9%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 4%" />
<col style="width: 3%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="13"><strong>EVALUATION, SUMMARY AND CONCLUSION BY
REGULATORY AUTHORITY</strong></td>
</tr>
<tr class="even">
<td colspan="2"><strong>Name of authority</strong></td>
<td colspan="11">Pesticides Safety Directorate, UK</td>
</tr>
<tr class="odd">
<td colspan="2" rowspan="2"><strong>Reviewer’s Comments</strong></td>
<td colspan="11"><p>Reliability rating: totally reliable</p>
<p>The study (M-261462-01-2) is fully compliant with OECD 414 (2001).
Dosing from Day 6-28 of gestation is acceptable.</p>
<p>Between GD 9 and 20, 7/25 dams died; four were killed for humane
reasons and three were found dead. The principal clinical signs observed
were yellow sediment in the urine in all animals, associated with red
traces on the cage tray in five cases. All animals had few/no faeces on
one or more occasion and one female had reduced motor activity, tremors
and was warm to touch on the day of death. All animals showed a marked
body weight loss, associated with very poor food consumption prior to
death. At autopsy, the principal target organs were the kidney and
urinary bladder, where yellow sediments were noted in the kidney of 4/7
females and in the urinary bladder of 2/7 females. In addition, a
marbled pattern was observed on the kidney in 2/7 cases and red contents
in the urinary bladder in 1/7 females. As this dose level had clearly
exceeded a Maximum Tolerated Dose (MTD), treatment at 500 mg/kg bw/day
was terminated. Surviving females were killed prior to scheduled autopsy
with no macroscopic examination performed and no tissues taken.</p>
<p>At 125 mg/kg/day, one female was found dead on GD 19, shortly after
dosing, prior adverse findings. At autopsy, red contents were found in
the trachea, all lobes of the lung were discoloured and a marbled
pattern was noted on the kidney. This animal was considered to have died
due to gavage error.</p>
<p>At 50 mg/kg/day, one female was found dead on GD 15; this animal had
reduced activity and slow respiration on GD 15. At autopsy, macroscopic
findings consisted of red contents in the trachea, and haemorrhaging and
discoloration in the lungs. The cause of death was judged to have been
gavage error.</p>
<p>At 125 mg/kg/day, yellow sediment was observed in the urine of 2/25
dams.</p>
<p>At autopsy, yellow sediment in the kidney was noted in 1/25 females
at 125 mg/kg bw/day, whilst the decedent female at 125 mg/kg bw/day and
1/25 females at 50 mg/kg bw/day had a kidney with a marbled pattern
appearance. There were no microscopic findings in this organ at 125
mg/kg/day. These changes were clearly treatment related although not
adverse.</p>
<p>Microscopic examination of the urinary bladder and kidney at 125
mg/kg bw/day revealed no treatment-related findings were noted.</p>
<p>Maternal bodyweight effects were clearly seen at the 500 mg/kg bw/day
but not at 50 or 125 mg/kg bw/day.</p></td>
</tr>
<tr class="even">
<td colspan="2" rowspan="2"><strong>Maternal weight (kg) Pregnant
females</strong></td>
<td colspan="9"><strong>Dose level</strong> (mg/kg bw/d)</td>
</tr>
<tr class="odd">
<td></td>
<td><strong>0</strong></td>
<td colspan="2"><strong>50</strong></td>
<td colspan="3"><strong>125</strong></td>
<td><strong>500</strong></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">Gestation day 3</td>
<td colspan="4">3.48</td>
<td colspan="2">3.52</td>
<td colspan="3">3.46</td>
<td>not applicable</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">Gestation day 6</td>
<td colspan="4">3.48</td>
<td colspan="2">3.50</td>
<td colspan="3">3.46</td>
<td>not applicable</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">Gestation day 8</td>
<td colspan="4">3.49</td>
<td colspan="2">3.50</td>
<td colspan="3">3.46</td>
<td>not applicable</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">Gestation day 10</td>
<td colspan="4">3.51</td>
<td colspan="2">3.51</td>
<td colspan="3">3.48</td>
<td>not applicable</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">Gestation day 12</td>
<td colspan="4">3.52</td>
<td colspan="2">3.53</td>
<td colspan="3">3.51</td>
<td>not applicable</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">Gestation day 14</td>
<td colspan="4">3.55</td>
<td colspan="2">3.55</td>
<td colspan="3">3.54</td>
<td>not applicable</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">Gestation day 16</td>
<td colspan="4">3.59</td>
<td colspan="2">3.57</td>
<td colspan="3">3.58</td>
<td>not applicable</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">Gestation day 18</td>
<td colspan="4">3.61</td>
<td colspan="2">3.60</td>
<td colspan="3">3.60</td>
<td>not applicable</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">Gestation day 20</td>
<td colspan="4">3.62</td>
<td colspan="2">3.62</td>
<td colspan="3">3.64</td>
<td>not applicable</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">Gestation day 22</td>
<td colspan="4">3.64</td>
<td colspan="2">3.65</td>
<td colspan="3">3.67</td>
<td>not applicable</td>
</tr>
<tr class="even">
<td></td>
<td colspan="12"><p><u>External Observations</u>: There were no
treatment related findings.</p>
<p><u>Visceral Observations</u>. There were no treatment related
findings</p>
<p><u>Skeletal Observations:</u> The incidence variants were higher in
both treated groups or at 125 mg/kg bw/day alone, compared to the
controls, in terms of both fetal and litter parameters: 13th thoracic
rib(s) (unilateral/bilateral) short, 13th thoracic rib(s)
(unilateral/bilateral) (including short) detached, hyoid centrum
incomplete ossification or unossified, hindpaws 5th middle or 5th distal
phalanges unossified, less than 15 caudal vertebrae. These findings were
all within the historical control range for both fetal and litter
parameters at the higher dose level of 125 mg/kg/day, and there was no
clear dose response the relationship to treatment was considered
equivocal. The apparent effects seen on the 5th middle or 5th distal
phalanges are difficult to dismiss as not being a possible treatment
related effect based on the results of this study alone. However taken
in the context of the second developmental study in the rabbit these
changes are likely incidental.</p></td>
</tr>
<tr class="odd">
<td rowspan="18"></td>
<td colspan="4" rowspan="2"><strong>Observation</strong>:</td>
<td colspan="6"><strong>Dose level</strong> <strong>(mg/kg
bw/day)</strong></td>
<td colspan="2" rowspan="2"><strong>Historical Control
Range</strong></td>
</tr>
<tr class="even">
<td><strong>0</strong></td>
<td colspan="2"><strong>50</strong></td>
<td colspan="2"><strong>125</strong></td>
<td><strong>500</strong></td>
</tr>
<tr class="odd">
<td colspan="12"><strong>13th thoracic rib(s)
(unilateral/bilateral)</strong></td>
</tr>
<tr class="even">
<td colspan="4">Mean % fetuses affected</td>
<td>12.4</td>
<td colspan="2">18.1</td>
<td colspan="2">16.6</td>
<td>na</td>
<td colspan="2">11.5-19.7</td>
</tr>
<tr class="odd">
<td colspan="4">Mean % litters affected</td>
<td>47.6</td>
<td colspan="2">82.6</td>
<td colspan="2">70.8</td>
<td>na</td>
<td colspan="2">58.3-78.3</td>
</tr>
<tr class="even">
<td colspan="12"><strong>13th thoracic rib(s) (unilateral/bilateral)
(inc. short detached)</strong></td>
</tr>
<tr class="odd">
<td colspan="4">Mean % fetuses affected</td>
<td>7.7</td>
<td colspan="2">11.9</td>
<td colspan="2">9.5</td>
<td>na</td>
<td colspan="2">5.1-12.7</td>
</tr>
<tr class="even">
<td colspan="4">Mean % litters affected</td>
<td>23.8</td>
<td colspan="2">69.6</td>
<td colspan="2">45.8</td>
<td>na</td>
<td colspan="2">33.3-58.3</td>
</tr>
<tr class="odd">
<td colspan="12"><strong>hyoid centrum incomplete ossification or
unossified</strong></td>
</tr>
<tr class="even">
<td colspan="4">Mean % fetuses affected</td>
<td>17.9</td>
<td colspan="2">25.2</td>
<td colspan="2">21.1</td>
<td>na</td>
<td colspan="2">15.4-26.2</td>
</tr>
<tr class="odd">
<td colspan="4">Mean % litters affected</td>
<td>28.6</td>
<td colspan="2">60.9</td>
<td colspan="2">54.2</td>
<td>na</td>
<td colspan="2">37.5-63.6</td>
</tr>
<tr class="even">
<td colspan="12"><strong>hindpaws 5th middle or 5th distal phalanges
unossified</strong></td>
</tr>
<tr class="odd">
<td colspan="4">Mean % fetuses affected</td>
<td>0.5</td>
<td colspan="2">0.5</td>
<td colspan="2">1.5</td>
<td>na</td>
<td colspan="2">0.0-1.7</td>
</tr>
<tr class="even">
<td colspan="4">Mean % litters affected</td>
<td>4.8</td>
<td colspan="2">4.3</td>
<td colspan="2">12.5</td>
<td>na</td>
<td colspan="2">0.0-13.6</td>
</tr>
<tr class="odd">
<td colspan="12"><strong>less than 15 caudal vertebrae</strong></td>
</tr>
<tr class="even">
<td colspan="4">Mean % fetuses affected</td>
<td>0.5</td>
<td colspan="2">2.9</td>
<td colspan="2">1.8</td>
<td>na</td>
<td colspan="2">0.0-2.3</td>
</tr>
<tr class="odd">
<td colspan="4">Mean % litters affected</td>
<td>4.8</td>
<td colspan="2">26.1</td>
<td colspan="2">16.7</td>
<td>na</td>
<td colspan="2">0.0-20.3</td>
</tr>
<tr class="even">
<td colspan="12">na not applicable</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="12"></td>
</tr>
<tr class="even">
<td><strong>Conclusions</strong></td>
<td colspan="12"><p>No evidence of teratogenicity was seen in this
study.</p>
<p>A NOAEL for maternal toxicity of 125 mg/kg bw/day can be determined,
based on the marked toxicity seen at 500 mg/kg bw/day. A NOEL for
developmental toxicity of 125 mg/kg bw/day can be based on the absence
of any affect on fetal parameters.</p></td>
</tr>
</tbody>
</table>

+-----------------------------------------------------------------------+
| HED Reviewer Comments:                                                |
|                                                                       |
| **Classification: Acceptable/Guideline.** This study satisfies the    |
| guideline requirement for a series 870.3700 developmental toxicity    |
| study in rabbits when taken together with the follow up study (MRID   |
| No.: 47069813).                                                       |
+-----------------------------------------------------------------------+

**Second Study (MRID No.: 87069813).**

Twenty-five time-mated female New Zealand White Rabbits per group were
exposed to AE 0001789, a herbicide safener belonging to the reverse
sulfamide family, (batch number 08466/0013, a white powder, 97.4% w/w
purity) by gavage from Gestation Day (GD) 6 to 28. The doses given were
0 and 250 mg/kg/day in suspension in aqueous solution of 0.5%
methylcellulose 400. This study was conducted as a complementary study
to SA 03349 developmental toxicity study in the rabbit with the same
compound, where the high dose level of 500 mg/kg/day was found to be too
toxic to the dams.

Maternal body weights were recorded for all surviving females on GD 3,
6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 and 29. Food consumption was
measured for all surviving females during the intervals GD 3-6, 6-8,
8-10, 10-14, 14-18, 18-22, 22-26 and 26-29. Clinical observations were
recorded daily. At scheduled sacrifice, on GD 29, the gravid uterine
weight and the number of ribs were recorded and the dams were evaluated
for number of corpora lutea, number and status of implantations
(resorptions, dead and live fœtuses). The urinary bladder and kidney
were retained from all females but not histologically examined. Live
fœtuses were removed from the uteri, counted, weighed and examined
externally. The heads of fœtuses from approximately half of each litter
were immersed in Bouin's fluid and the internal structures examined
after fixation. The bodies of all fœtuses were dissected for soft tissue
anomalies and sexed. Fœtuses were eviscerated, skinned and fixed in
absolute ethanol before staining. A modification of the Staples and
Schnell technique was applied and a subsequent skeletal examination was
performed.

In the treatment group at 250 mg/kg/day, two dams were sent to necropsy
on GD 28 after aborting. Clinical signs for the first female consisted
of few/mucoid faeces on several occasions, yellow sediment in the urine
on GD 24-26 and 28, and anogenital soiling, red traces on tray and
placental tissue on tray on GD 28. Clinical signs for the second female
included no/few faeces on several occasions, yellow sediment in the
urine on GD 23-28, red traces on tray on GD 26-28 and
placental/fœtoplacental tissue on tray on GD 28. Between GD 10 and 28
the first female lost 0.49 kg, whilst between GD 20 and 28 the second
female lost 0.57 kg in body weight. In both cases, the body weight loss
was associated with a marked reduction in food consumption. No
treatment-related findings were observed in either female at the
macroscopic examination.

In surviving females, 5/23 animals had yellow sediment in the urine on
one or more occasions. In addition, one female had red traces on tray on
GD 28. No effect on mean maternal body weight change, mean maternal
corrected body weight change or mean maternal food consumption was
observed at this dosage. No treatment-related necropsy findings were
observed in the dams at the macroscopic examination.

At Caesarean section, no effect on litter parameters was observed. No
treatment-related findings were observed at the external, visceral or
skeletal fœtal examination.

In conclusion, a dose level of 250 mg/kg/day, was considered to cause
clear maternal toxicity but no developmental toxicity.

+---------------+------------------------------------------------------+
| **EVALUATION, |                                                      |
| SUMMARY AND   |                                                      |
| CONCLUSION BY |                                                      |
| REGULATORY    |                                                      |
| AUTHORITY**   |                                                      |
+---------------+------------------------------------------------------+
| **Name of     | Pesticides Safety Directorate, UK                    |
| authority**   |                                                      |
+---------------+------------------------------------------------------+
| **Reviewer's  | Reliability rating: totally reliable                 |
| Comments**    |                                                      |
|               | The study (M-273153-01-2) is fully compliant with    |
|               | OECD 414 (2001), although only has a control and one |
|               | treatment group, This study was designed to          |
|               | supplement the first study. Dosing from Day 6-28 of  |
|               | gestation is acceptable.                             |
+---------------+------------------------------------------------------+
|               | In the only treatment group there two dams were sent |
|               | to necropsy on GD 28 after aborting clinical signs   |
|               | in one/both of these two animals included no/few     |
|               | faeces, mucoid faeces, yellow sediment in the urine, |
|               | anogenital soiling, red traces on tray and placental |
|               | tissue on tray. Both females displaying marked       |
|               | bodyweight loss during most the dosing period. In    |
|               | both cases, the bodyweight loss was associated with  |
|               | a marked reduction in food consumption. There were   |
|               | no marked effects on bodyweight gain in the other    |
|               | females.                                             |
|               |                                                      |
|               | There were no effects on litter parameters.          |
|               |                                                      |
|               | [External Observations]{.underline}: At 250          |
|               | mg/kg/day one fetus had multiple malformations       |
|               | consisting of macroglossia, small naris, head        |
|               | misshapen, malpositioned or elongated digit, and     |
|               | fleshy hindpaw, tail and neck. In the control group  |
|               | four fetuses from separate litters had different     |
|               | malformations consisting of cleft palate, absent eye |
|               | bulge, malpositioned umbilical cord and ectrodactyly |
|               | of forepaws. As these malformations occurred as      |
|               | isolated incidences, they were considered to be      |
|               | incidental. The only anomalies observed in the       |
|               | treated group were short tail in one fetus and       |
|               | swollen abdomen in two fetuses from separate         |
|               | litters. At such low incidences these findings were  |
|               | considered to have occurred by chance.               |
|               |                                                      |
|               | [Visceral Observations]{.underline}. At 250 mg/kg    |
|               | bw/day, one fetus had the following malformations:   |
|               | ventricular septum defect in the cranial region,     |
|               | left and right ventricles of the heart enlarged plus |
|               | dilated pulmonary trunk. In the control group there  |
|               | were four fetuses from separate litters with         |
|               | malformations. One fetus had dilated cerebral        |
|               | lateral ventricles, retinal fold and microphthalmia  |
|               | (unilateral) plus a small thalamus, a second fetus   |
|               | had a ventricular septum defect in the median region |
|               | of the heart and a diaphragmatic hernia,             |
|               | diaphragmatic hernia was also observed in a third    |
|               | fetus whilst retroesophageal aortic arch was noted   |
|               | in a fourth fetus. In isolation, the malformations   |
|               | observed at 250 mg/kg bw/day are considered to be    |
|               | incidental.                                          |
|               |                                                      |
|               | Two fetuses from separate litters at 250 mg/kg       |
|               | bw/day had the anomaly misshapen kidney(s), compared |
|               | with no incidences in the control group. The mean    |
|               | percentage of fetuses affected was within the        |
|               | historical control range, whilst the percentage of   |
|               | litters affected was marginally outside the          |
|               | historical control range.                            |
|               |                                                      |
|               | The incidence of the variant findings misshapen      |
|               | thymus and small gall bladder, were higher at 250    |
|               | mg/kg bw/day compared with the controls. However, as |
|               | the mean percentage of fetuses with misshapen thymus |
|               | and percentage of litters affected in the treated    |
|               | group was well within the in-house historical        |
|               | control range, this finding was considered to be     |
|               | unrelated to treatment.                              |
|               |                                                      |
|               | The mean percentage of fetuses with a small gall     |
|               | bladder and percentage of litters affected at 250    |
|               | mg/kg bw/day were very marginally outside the        |
|               | in-house historical control range. To further        |
|               | evaluate the relevance of the slightly higher        |
|               | incidence of misshapen kidney(s), and small gall     |
|               | bladder at 250 mg/kg bw/day, statistical analysis    |
|               | was conducted on these parameters at both the fetal  |
|               | and litter level. As neither parameter was           |
|               | statistically significantly increased at the fetal   |
|               | or litter level, these findings were considered to   |
|               | have occurred by chance                              |
+---------------+------------------------------------------------------+

+---------------+----------------+-------------+-------------+------+
| **EVALUATION, |                |             |             |      |
| SUMMARY AND   |                |             |             |      |
| CONCLUSION BY |                |             |             |      |
| REGULATORY    |                |             |             |      |
| AUTHORITY**   |                |             |             |      |
+---------------+----------------+-------------+-------------+------+
| **Name of     | Pesticides     |             |             |      |
| authority**   | Safety         |             |             |      |
|               | Directorate,   |             |             |      |
|               | UK             |             |             |      |
+---------------+----------------+-------------+-------------+------+
|               | **             | **Dose      |             | **Hi |
|               | Observation**: | level**     |             | stor |
|               |                | **(mg/kg    |             | ical |
|               |                | bw/day)**   |             | Con  |
|               |                |             |             | trol |
|               |                |             |             | Ran  |
|               |                |             |             | ge** |
+---------------+----------------+-------------+-------------+------+
|               |                | **0**       | **250**     |      |
+---------------+----------------+-------------+-------------+------+
|               | **misshapen    |             |             |      |
|               | kidney(s)**    |             |             |      |
+---------------+----------------+-------------+-------------+------+
|               | Mean % fetuses | 0.0         | 0.9         | 0.0  |
|               | affected       |             |             | -0.9 |
+---------------+----------------+-------------+-------------+------+
|               | Mean % litters | 0.0         | 8.7         | 0.0  |
|               | affected       |             |             | -8.3 |
+---------------+----------------+-------------+-------------+------+
|               | misshapen      |             |             |      |
|               | thymus         |             |             |      |
+---------------+----------------+-------------+-------------+------+
|               | Mean % fetuses | 7.0         | 8.5         | 3.5- |
|               | affected       |             |             | 13.4 |
+---------------+----------------+-------------+-------------+------+
|               | Mean % litters | 33.3        | 52.2        | 2    |
|               | affected       |             |             | 0.8- |
|               |                |             |             | 57.1 |
+---------------+----------------+-------------+-------------+------+
|               | **small gall   |             |             |      |
|               | bladder**      |             |             |      |
+---------------+----------------+-------------+-------------+------+
|               | Mean % fetuses | 0.0         | 1.5         | 0.0  |
|               | affected       |             |             | -1.3 |
+---------------+----------------+-------------+-------------+------+
|               | Mean % litters | 0.0         | 13.0        | 0.0- |
|               | affected       |             |             | 12.5 |
+---------------+----------------+-------------+-------------+------+
|               | [Skeletal      |             |             |      |
|               | Observations   |             |             |      |
|               | :]{.underline} |             |             |      |
|               | At 250 mg/kg   |             |             |      |
|               | bw/day, two    |             |             |      |
|               | fetuses from   |             |             |      |
|               | separate       |             |             |      |
|               | litters had    |             |             |      |
|               | malformations; |             |             |      |
|               | one fetus had  |             |             |      |
|               | fused thoracic |             |             |      |
|               | centrum whilst |             |             |      |
|               | the second     |             |             |      |
|               | fetus had      |             |             |      |
|               | fused caudal   |             |             |      |
|               | vertebrae      |             |             |      |
|               | which were     |             |             |      |
|               | malpositioned  |             |             |      |
|               | and bipartite. |             |             |      |
|               | In the control |             |             |      |
|               | group there    |             |             |      |
|               | were four      |             |             |      |
|               | malformed      |             |             |      |
|               | fetuses from   |             |             |      |
|               | four separate  |             |             |      |
|               | litters. Two   |             |             |      |
|               | fetuses had    |             |             |      |
|               | total          |             |             |      |
|               | sternoschisis  |             |             |      |
|               | with absent    |             |             |      |
|               | lst digit on   |             |             |      |
|               | forepaws in    |             |             |      |
|               | one case. The  |             |             |      |
|               | two other      |             |             |      |
|               | fetuses had    |             |             |      |
|               | fused centrum  |             |             |      |
|               | in the         |             |             |      |
|               | thoracic or    |             |             |      |
|               | lumbar region, |             |             |      |
|               | plus absent    |             |             |      |
|               | radius and lst |             |             |      |
|               | digit of       |             |             |      |
|               | forepaws in    |             |             |      |
|               | one case. As   |             |             |      |
|               | the            |             |             |      |
|               | malformations  |             |             |      |
|               | occurred as    |             |             |      |
|               | isolated       |             |             |      |
|               | incidences at  |             |             |      |
|               | 250 mg/kg      |             |             |      |
|               | bw/day, they   |             |             |      |
|               | were           |             |             |      |
|               | considered to  |             |             |      |
|               | be incidental. |             |             |      |
|               |                |             |             |      |
|               | The occurrence |             |             |      |
|               | of anomalies   |             |             |      |
|               | was very       |             |             |      |
|               | similar        |             |             |      |
|               | between the    |             |             |      |
|               | treated and    |             |             |      |
|               | control        |             |             |      |
|               | groups,        |             |             |      |
|               | occurred at a  |             |             |      |
|               | higher         |             |             |      |
|               | frequency in   |             |             |      |
|               | the control    |             |             |      |
|               | group, or as   |             |             |      |
|               | isolated       |             |             |      |
|               | findings, and  |             |             |      |
|               | were therefore |             |             |      |
|               | regarded as    |             |             |      |
|               | chance         |             |             |      |
|               | findings. The  |             |             |      |
|               | variant        |             |             |      |
|               | findings of 5  |             |             |      |
|               | distal         |             |             |      |
|               | phalanges of   |             |             |      |
|               | hindpaws       |             |             |      |
|               | unossified,    |             |             |      |
|               | and less than  |             |             |      |
|               | 15 caudal      |             |             |      |
|               | vertebrae,     |             |             |      |
|               | occurred at a  |             |             |      |
|               | higher         |             |             |      |
|               | incidence in   |             |             |      |
|               | the treated    |             |             |      |
|               | group compared |             |             |      |
|               | to the         |             |             |      |
|               | controls.      |             |             |      |
|               | However, as    |             |             |      |
|               | the incidence  |             |             |      |
|               | for both mean  |             |             |      |
|               | percentage of  |             |             |      |
|               | fetuses        |             |             |      |
|               | affected and   |             |             |      |
|               | percentage of  |             |             |      |
|               | litters        |             |             |      |
|               | affected for   |             |             |      |
|               | each parameter |             |             |      |
|               | was within the |             |             |      |
|               | in-house       |             |             |      |
|               | historical     |             |             |      |
|               | control range, |             |             |      |
|               | these findings |             |             |      |
|               | were           |             |             |      |
|               | considered to  |             |             |      |
|               | have occurred  |             |             |      |
|               | by chance. The |             |             |      |
|               | following      |             |             |      |
|               | variant        |             |             |      |
|               | findings       |             |             |      |
|               | occurred at a  |             |             |      |
|               | higher         |             |             |      |
|               | incidence in   |             |             |      |
|               | the treated    |             |             |      |
|               | group compared |             |             |      |
|               | to the         |             |             |      |
|               | controls; l3th |             |             |      |
|               | thoracic ribs  |             |             |      |
|               | detached,      |             |             |      |
|               | pubis          |             |             |      |
|               | unossified,    |             |             |      |
|               | and insertion  |             |             |      |
|               | point(s) of    |             |             |      |
|               | pelvic girdle  |             |             |      |
|               | unossified.    |             |             |      |
|               | Since the      |             |             |      |
|               | incidence of   |             |             |      |
|               | these findings |             |             |      |
|               | was slightly   |             |             |      |
|               | outside the    |             |             |      |
|               | in-house       |             |             |      |
|               | historical     |             |             |      |
|               | control range  |             |             |      |
|               | at the litter  |             |             |      |
|               | level or at    |             |             |      |
|               | both the fetal |             |             |      |
|               | and litter     |             |             |      |
|               | level,         |             |             |      |
|               | statistical    |             |             |      |
|               | analysis was   |             |             |      |
|               | conducted on   |             |             |      |
|               | these          |             |             |      |
|               | parameters at  |             |             |      |
|               | both the fetal |             |             |      |
|               | and litter     |             |             |      |
|               | level. None of |             |             |      |
|               | the parameters |             |             |      |
|               | analysed were  |             |             |      |
|               | found to be    |             |             |      |
|               | statistically  |             |             |      |
|               | significant at |             |             |      |
|               | either the     |             |             |      |
|               | fetal or       |             |             |      |
|               | litter level.  |             |             |      |
|               |                |             |             |      |
|               | Considering    |             |             |      |
|               | the skeletal   |             |             |      |
|               | observations   |             |             |      |
|               | over the two   |             |             |      |
|               | developmental  |             |             |      |
|               | studies in the |             |             |      |
|               | rabbit there   |             |             |      |
|               | was no dose    |             |             |      |
|               | relationships  |             |             |      |
|               | for any        |             |             |      |
|               | findings.      |             |             |      |
|               | Therefore it   |             |             |      |
|               | is considered  |             |             |      |
|               | based on the   |             |             |      |
|               | HC data,       |             |             |      |
|               | statistical    |             |             |      |
|               | analysis and   |             |             |      |
|               | lack of dose   |             |             |      |
|               | response these |             |             |      |
|               | changes are    |             |             |      |
|               | non-specific   |             |             |      |
|               | or chance      |             |             |      |
|               | findings.      |             |             |      |
+---------------+----------------+-------------+-------------+------+
|               | **             | **Dose      |             | **Hi |
|               | Observation**: | level**     |             | stor |
|               |                | **(mg/kg    |             | ical |
|               |                | bw/day)**   |             | Con  |
|               |                |             |             | trol |
|               |                |             |             | Ran  |
|               |                |             |             | ge** |
+---------------+----------------+-------------+-------------+------+
|               |                | **0**       | **250**     |      |
+---------------+----------------+-------------+-------------+------+
|               | **13th         |             |             |      |
|               | thoracic       |             |             |      |
|               | rib(s)         |             |             |      |
|               | (unilate       |             |             |      |
|               | ral/bilateral) |             |             |      |
|               | (inc. short    |             |             |      |
|               | detached**     |             |             |      |
+---------------+----------------+-------------+-------------+------+
|               | Mean % fetuses | 11.3        | 13.4        | 5.1- |
|               | affected       |             |             | 12.7 |
+---------------+----------------+-------------+-------------+------+
|               | Mean % litters | 54.2        | 69.6        | 2    |
|               | affected       |             |             | 3.8- |
|               |                |             |             | 58.3 |
+---------------+----------------+-------------+-------------+------+
|               | **hindpaws 5th |             |             |      |
|               | middle or 5th  |             |             |      |
|               | distal         |             |             |      |
|               | phalanges      |             |             |      |
|               | unossified**   |             |             |      |
+---------------+----------------+-------------+-------------+------+
|               | Mean % fetuses | 0.5         | 1.2         | 0.0  |
|               | affected       |             |             | -1.7 |
+---------------+----------------+-------------+-------------+------+
|               | Mean % litters | 4.2         | 8.7         | 00-  |
|               | affected       |             |             | 13.6 |
+---------------+----------------+-------------+-------------+------+
|               | **Pubis        |             |             |      |
|               | (unilate       |             |             |      |
|               | ral/bilateral) |             |             |      |
|               | unossified**   |             |             |      |
+---------------+----------------+-------------+-------------+------+
|               | Mean % fetuses | 0.5         | 1.0         | 0.0  |
|               | affected       |             |             | -1.2 |
+---------------+----------------+-------------+-------------+------+
|               | Mean % litters | 4.2         | 8.7         | 0.0  |
|               | affected       |             |             | -8.3 |
+---------------+----------------+-------------+-------------+------+
|               | **Insertion    |             |             |      |
|               | points (s)     |             |             |      |
|               | (unilate       |             |             |      |
|               | ral/bilateral) |             |             |      |
|               | unossified**   |             |             |      |
+---------------+----------------+-------------+-------------+------+
|               | Mean % fetuses | 1.0         | 1.3         | 0.0  |
|               | affected       |             |             | -2.1 |
+---------------+----------------+-------------+-------------+------+
|               | Mean % litters | 4.2         | 13.0        | 0.0- |
|               | affected       |             |             | 12.5 |
+---------------+----------------+-------------+-------------+------+
|               | **less than 15 |             |             |      |
|               | caudal         |             |             |      |
|               | vertebrae**    |             |             |      |
+---------------+----------------+-------------+-------------+------+
|               | Mean % fetuses | 0.7         | 2.3         | 0.0  |
|               | affected       |             |             | -2.3 |
+---------------+----------------+-------------+-------------+------+
|               | Mean % litters | 8.3         | 13.0        | 0.0- |
|               | affected       |             |             | 20.8 |
+---------------+----------------+-------------+-------------+------+
|               |                |             |             |      |
+---------------+----------------+-------------+-------------+------+
| **            | No evidence of |             |             |      |
| Conclusions** | teratogenicity |             |             |      |
|               | was seen in    |             |             |      |
|               | this study.    |             |             |      |
|               |                |             |             |      |
|               | No NOAEL for   |             |             |      |
|               | maternal       |             |             |      |
|               | toxicity can   |             |             |      |
|               | be determined  |             |             |      |
|               | due to the     |             |             |      |
|               | clear maternal |             |             |      |
|               | effects seen   |             |             |      |
|               | at the only    |             |             |      |
|               | treatment      |             |             |      |
|               | level of       |             |             |      |
|               | 250 mg/kg      |             |             |      |
|               | bw/day. A NOEL |             |             |      |
|               | for            |             |             |      |
|               | developmental  |             |             |      |
|               | toxicity of    |             |             |      |
|               | 250 mg/kg      |             |             |      |
|               | bw/day can be  |             |             |      |
|               | based on the   |             |             |      |
|               | absence of any |             |             |      |
|               | affect on      |             |             |      |
|               | fetal          |             |             |      |
|               | parameters.    |             |             |      |
+---------------+----------------+-------------+-------------+------+

+-----------------------------------------------------------------------+
| **HED Reviewer Comments:**                                            |
|                                                                       |
| **Classification: Acceptable/Non-Guideline.** The study together with |
| study MRID No.: 47069812 satisfies the guideline requirement for a    |
| series 870.3700 developmental toxicity study in rabbits. HED concurs  |
| with the assignment of the NOAEL and LOAEL based on the results of    |
| the two studies.                                                      |
+-----------------------------------------------------------------------+

**A.3.3 Reproductive Toxicity**

**870.3800 Reproduction and Fertility Effects - Rat (MRID No.:
47069815)**

AE 0001789 (batch number 08466/0013, a white powder, 97.4% w/w purity)
was administered to groups of 25 male and 25 female rats at
concentrations of 0 (control), 480, 2400 and 12000 ppm in their diet
continuously throughout a multi-generation study. Test substance intake
was determined as follows based on consumption during the premating
period:

F0: 39.2, 202.3 and 1006.9 mg/kg (males); 55.3, 260.3 and 1350.2 mg/kg
(females).\
F1: 50.3, 251.5 and 1292.4 mg/kg (males); 68.5, 323.7 and 1696.5 mg/kg
(females).

Test diets were fed continuously to male and female rats in the F0
parental generation throughout premating, mating, gestation, and
lactation periods. After weaning of the F1 generation at 4 weeks of age,
selected weanlings were maintained in their same dietary groups through
maturation, mating, gestation, and lactation. The final necropsy took
place when the F2 offspring were weaned at 4 weeks of age.

Body weights, food consumption and clinical signs were monitored
regularly. Reproductive parameters such as mating performance,
fertility, duration of pregnancy, oestrus cycling and sperm analyses
were examined in F0 and F1 rats. Litter parameters such as litter size,
gender ratio, pup weight, pup viability, body weight gain and clinical
signs were studied in F1 and F2 offspring. Developmental milestones were
evaluated in F1 weanlings. At necropsy, implantation sites in F0 and F1
females were recorded. Selected organs were weighed in adult rats and
weanlings and histopathology including ovarian follicle staging (only
F1) was performed in a number of organs of F0 and F1 parental rats.

At 12 000 ppm:

Mortality was increased in F0 and F1 females due to poor general
condition and severe renal alterations. Additionally an increase in
water intake and urination was found in F1 rats. Body weight gain was
decreased in F1 males (slightly) and females during the premating phase
and in F0 and F1 females during gestation and lactation, whereas food
intake data were unchanged.

At necropsy thin female rats were found more often in treatedgroups than
at 0 ppm. Additionally, kidneys of F1 females were found to be
discoloured, enlarged and/or changed at their surface. In F0 and/or F1
females, ovaries showed an increased incidence of foamy corpus luteum
cells, the uterus exhibited more unregressed implantation sites and the
vagina showed a mucified epithelium more often. The number of primary
follicles and corpora lutea was unchanged.

In the kidneys of F0 and F1 rats, precipitates of foreign material were
found more frequently in the collecting ducts and renal pelvis. As
sequels of these precipitations, transitional cell hyperplasia, tubular
basophilia, intratubular granulocytes, papillary necrosis, medullary
fibrosis, renal pelvic dilation and/or vaculation/inclusions in the
proximal tubules were observed. In females these findings correlated
with increased relative kidney weights. Hypertrophy was recorded in the
ureters and/or hyperplasia of the transitional epithelium of the urinary
bladder was present more frequently in females.

In the adrenal cortex the incidence of hypertrophy of the zona
glomerulosa was increased mostly in females secondary to marked renal
lesions. In the liver hepatocellular glycogen content was reduced in F0
and F1 females. In the F0 and F1 generations, increased ferrous pigment
deposits, congestion and increased haemopoiesis were noted in the spleen
and absolute and relative spleen weights were increased.

Sperm analyses and examination of œstrus cycling revealed no
substance-related effects. F0 females exhibited a reduced rearing index
due to maternal death during lactation.

There was a reduced viability index in F1 pups (including 3 total litter
losses) and a reduced lactation index in F1 and F2 pups. More pups
showing clinical findings (paleness, cold to touch, missing milk spot,
thin) were evident. The pup/litter weights were depressed at 12000 ppm.
Due to depressed body weight, vaginal opening in F1 females was delayed.
Ano-genital distance measurements in F2 pups did not indicate any
treatment-related effect.

At 2400 ppm:

Treatment-related changes were limited to histopathological changes in
the kidneys, urinary bladder and spleen of the F0 and F1 rats. Foreign
material (F0 females) and renal pelvic dilation (F1 males) were observed
in the kidneys. Hypertrophy was recorded in the urinary bladder in F2
females.

In F0 and F1 males, increased ferrous pigment deposits, congestion
and/or increased haemopoiesis were noted in the spleen and absolute and
relative spleen weights increased in both sexes from F0 and F1
generations.

At 480 ppm:

No treatment-related findings were reported.

Thus, under the conditions described, the parental systemic LOAEL in
rats was 2400 ppm (corresponding to 202 mg/kg bw/day in males and 260
mg/kg bw/day in females), and the parental systemic NOAEL was 480 ppm
(39 mg/kg bw/day in males and 55 mg/kg bw/day in females), based on
organ changes in the spleen and urinary tract.

The NOAEL for parental reproductive parameters was 2400 ppm (173 mg/kg
bw/day) due to a reduced rearing index.

The offspring NOAEL (=NOEL) was at 2400 ppm (173 mg/kg bw/day) due to
pup weight decrease.

+----------------+-----------------------------------------------------+
| **EVALUATION,  |                                                     |
| SUMMARY AND    |                                                     |
| CONCLUSION BY  |                                                     |
| REGULATORY     |                                                     |
| AUTHORITY**    |                                                     |
+----------------+-----------------------------------------------------+
| **Name of      | Pesticides Safety Directorate, UK                   |
| authority**    |                                                     |
+----------------+-----------------------------------------------------+
| **Reviewer's   | Reliability rating: Totally reliable                |
| Comments**     |                                                     |
|                | The study \[M-283510-01-2\] is fully compliant with |
|                | OECD 416 (2001)                                     |
|                |                                                     |
|                | PSD has concerns regarding the use of the           |
|                | Bonferroni correction: the Notifier is therefore    |
|                | requested to provide a reanalysis of the            |
|                | statistical significance of the relevant parameters |
|                | without the use of this correction.                 |
+----------------+-----------------------------------------------------+
|                | Evaluation of vaginal smears performed at the end   |
|                | of the premating periods indicated that there were  |
|                | no treatment related effects on the oestrus cycle   |
|                | in F0 or F1 rats. Sperm parameters were             |
|                | investigated in controls and top dose animals;      |
|                | there were no treatment related effects on          |
|                | epididymal sperm count, sperm motility and          |
|                | morphology and testicular spermatids counts in F1   |
|                | or in F2 rats.                                      |
|                |                                                     |
|                | The parameters of the reproductive performance such |
|                | as insemination, fertility and gestation indices as |
|                | well as gestation length and the number of litters  |
|                | born were not influenced by treatment.              |
|                |                                                     |
|                | Low fertility indices were noted in 2400 and 12000  |
|                | ppm F0 pairs followed by a low number of litters    |
|                | and pups born, if data of the scheduled co-housing  |
|                | period is considered alone. However all six 12000   |
|                | ppm F0 females failing to litter after planned      |
|                | cohabitations were co-housed additionally with      |
|                | males of the same group already shown to be         |
|                | fertile. All of these females had pups (no further  |
|                | litter data were recorded from these females)       |
|                | demonstrating that at 12000 ppm 25 of 25 F0 females |
|                | were fertile and that there was no effect of the    |
|                | compound on fertility. Therefore given no           |
|                | indication of test substance-induced infertility    |
|                | was found at other parameters such as spermatology  |
|                | and histology of reproductive organs and all 12000  |
|                | ppm F1 pairs had been shown to be fertile these low |
|                | fertility indices were likely incidental.           |
|                |                                                     |
|                | The rearing index was reduced at 12000ppm for F0    |
|                | females mostly as result of intercurrent deaths     |
|                | (resulting from renal lesions caused by             |
|                | precipitation of foreign material in the kidneys    |
|                | and lower urinary tract) of females during the      |
|                | lactation period.                                   |
|                |                                                     |
|                | The litter data such as mean number of              |
|                | implantations, prenatal loss, live birth index, sex |
|                | distribution, numbers of pups born and litter sizes |
|                | were not affected by treatment.                     |
|                |                                                     |
|                | The viability index was unchanged up to 2400 ppm    |
|                | and reduced at 12000 ppm for F1 pups as a result of |
|                | an increase in pup deaths including 2 total litter  |
|                | losses. The viability of F2 pups was unchanged up   |
|                | to 12000 ppm. The lactation indices were slightly   |
|                | reduced for F1 and F2 pups at 12000 ppm.            |
|                |                                                     |
|                | At 12000 ppm higher number of pups found to be      |
|                | pale, cold to touch, thin and/or showing no milk    |
|                | spot. The development of pup litter weights were    |
|                | unaffected up to 2400ppm and depressed at 12000ppm. |
|                | The effects on pup weights were not solely due to   |
|                | reduced food consumption. Developmental milestone   |
|                | measurements in F1 pups revealed a slight           |
|                | prolongation of vaginal opening likely due to the   |
|                | retarded bodyweights. Anogenital distances in F2    |
|                | pups were not changed up to 12000 ppm.              |
|                |                                                     |
|                | At pup or weanling necropsies no remarkable         |
|                | microscopical findings were noted in the F1 or F2   |
|                | generations up to 12000 ppm. Changed weights of     |
|                | brain, thymus and/or spleen of pups were likely to  |
|                | be a result of the depressed bodyweights.           |
+----------------+-----------------------------------------------------+
|                |                                                     |
+----------------+-----------------------------------------------------+
|                | The treatment-related general toxicity findings in  |
|                | this study are consistent to those seen in the 90   |
|                | day study in the rat in terms of dose level and     |
|                | organs/tissues affected.                            |
|                |                                                     |
|                | . .                                                 |
+----------------+-----------------------------------------------------+
|                | Mortality was increased at 12000 ppm in F0 and F1   |
|                | females due to clinical findings of poor general    |
|                | condition and severe renal effects. Additionally in |
|                | this dose an increase in water intake and urination |
|                | was noted in F1 rats.                               |
|                |                                                     |
|                | At 12000 ppm the bodyweight gain was decreased in   |
|                | F1 males and females during the premating phase and |
|                | in F0 and F1 females during gestation and           |
|                | lactation.                                          |
|                |                                                     |
|                | Gross necropsy revealed discolouration, enlargement |
|                | and/or changed surface in the kidneys of 12000 ppm  |
|                | F1 females. Microscopic examination of the kidneys  |
|                | of 12000ppm rats precipitates of foreign material   |
|                | were found more frequently in the collecting ducts  |
|                | and renal pelvis. In the kidneys of both 2400 and   |
|                | 12000 ppm parental animals transitional cell        |
|                | hyperplasia, tubular basophilia, intratubular       |
|                | granulocytes, papillary necrosis, medullary         |
|                | fibrosis, renal pelvic dilation and/or              |
|                | vacuolation/inclusions in the proximal tubules were |
|                | observed. At 12000 ppm in females these findings    |
|                | correlated with increased relative kidney weights.  |
|                | At doses [\>]{.underline}2400ppm hypertrophy was    |
|                | recorded in the ureters and/or hyperplasia of the   |
|                | transitional epithelium of the urinary bladder was  |
|                | present more frequently in females                  |
|                |                                                     |
|                | In high dose F0 and/or Fl females ovaries showed an |
|                | increased incidence of foamy corpus luteum cells,   |
|                | the uterus exhibited more unregressed implantation  |
|                | sites and the vagina showed a mucified epithelium   |
|                | more often. The number of primary follicles and     |
|                | corpora lutea were unchanged.                       |
|                |                                                     |
|                | In the adrenal cortex the incidence of hypertrophy  |
|                | of the zona glomerulosa was increased at 12000 ppm  |
|                | mostly in females likely as a secondary consequence |
|                | of the marked renal lesions.                        |
|                |                                                     |
|                | In the liver hepatocellular glycogen content was    |
|                | reduced in 12000 ppm F0 and F1 females.             |
|                |                                                     |
|                | In the spleen increased ferrous pigment deposits,   |
|                | congestion and increased haemopoiesis were noted at |
|                | doses [\>]{.underline}2400 ppm in males and/or      |
|                | females (F0 and F1). At doses [\>]{.underline}2400  |
|                | ppm absolute and relative spleen weights increased  |
|                | in FO and F 1 rats.                                 |
|                |                                                     |
|                | From 2400 ppm onwards thyroid weights were          |
|                | increased in F1 females, although, without any      |
|                | morphological correlate.                            |
+----------------+-----------------------------------------------------+
| *              | Dosing with cyprosulfamide did not directly cause   |
| *Conclusions** | any reproductive toxicity a reduced rearing index   |
|                | due to maternal toxicity. Therefore the NOAEL for   |
|                | reproduction was 2400 ppm (173 mg/kg bw/day).       |
|                |                                                     |
|                | A parental NOAEL of 480 ppm (equivalent to 39 mg/kg |
|                | bw/day in males and 55 mg/kg bw/day in females),    |
|                | was based on organ changes in the spleen and        |
|                | urinary tract.                                      |
|                |                                                     |
|                | The offspring NOAEL was at 2400 ppm (equivalent to  |
|                | 173 mg/kg bw/day) due to pup weight decrease.       |
+----------------+-----------------------------------------------------+

+-----------------------------------------------------------------------+
| HED reviewer comments:                                                |
|                                                                       |
| **Classification: Acceptable/Guideline.** This study satisfies the    |
| guideline requirement for a series 870.3700 reproduction study in     |
| rats. HED concurs with the assignment of the NOAEL and LOAEL.         |
+-----------------------------------------------------------------------+

**A.3.4 Chronic Toxicity**

**870.4100a (870.4300) Chronic Toxicity -- Rat**

**See under Carcinogenicity study - rat.**

**870.4100b Chronic Toxicity - Dog (MRID No.: 47069816)**

Technical grade AE 0001789 (batch 08466/0013, 97.4 to 97.5% of purity)
was administered in the diet to Beagle dogs (4/sex/dose) at dose levels
of 0, 1000, 2500, and 8000 ppm for 370-372 days. Clinical observations
were conducted daily, food consumption was measured daily, and body
weights were taken weekly. Ophthalmic examinations were performed once
pre-exposure and just prior to necropsy. Clinical chemistry and
haematology measurements were taken once pre-exposure and during study
weeks 12, 26, 39, and 53. Urinalysis measurements were taken once
pre-exposure and during study weeks 13, 26, 39 and 53. A gross necropsy
was performed, organ weights were taken, and tissues were examined
microscopically.

[At 8000 ppm]{.underline}

At gross pathology treatment-related findings occurred in two 8000 ppm
group males: multiple raised black zones in the mucosa of the urinary
bladder; multiple yellow pinpoint calculi in the urinary bladder; and
thickness and abnormal consistency of the urinary bladder.

Treatment-related microscopic findings were noted in the kidney and the
urinary bladder.

In the urinary bladder, stone(s) were observed at the microscopic level
in one male. In two males, slight to moderate chronic mucosal
haemorrhage and minimal to slight urothelial hyperplasia were noted.
Stone(s) were also observed at the microscopic level in one female.
Minimal suburothelial mononuclear cell infiltrates were observed in one
male and one female. In the kidney, one female had some microscopic
intrapelvic stones. Associated with these stones, there were other
minimal changes such as pelvic epithelium hyperplasia, pelvic epithelial
erosion and suburothelial mononuclear cell infiltrate.

[At 2500 and 1000 ppm]{.underline}

No treatment-related effects were observed.

In conclusion, the NOEL was 2500 ppm (66 and 67 mg/kg/day for males and
females, respectively).

# 

+---------------+-------------+------+-------+-------+-------+-------+
| **EVALUATION, |             |      |       |       |       |       |
| SUMMARY AND   |             |      |       |       |       |       |
| CONCLUSION BY |             |      |       |       |       |       |
| REGULATORY    |             |      |       |       |       |       |
| AUTHORITY**   |             |      |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
| **Name of     | Pesticides  |      |       |       |       |       |
| authority**   | Safety      |      |       |       |       |       |
|               | D           |      |       |       |       |       |
|               | irectorate, |      |       |       |       |       |
|               | UK          |      |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
| **Reviewer's  | Reliability |      |       |       |       |       |
| Comments**    | rating:     |      |       |       |       |       |
|               | Totally     |      |       |       |       |       |
|               | reliable    |      |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               | The study   |      |       |       |       |       |
|               | (M-2        |      |       |       |       |       |
|               | 83194-02-1) |      |       |       |       |       |
|               | is fully    |      |       |       |       |       |
|               | compliant   |      |       |       |       |       |
|               | with OECD   |      |       |       |       |       |
|               | 409 (1998). |      |       |       |       |       |
|               | Although    |      |       |       |       |       |
|               | r           |      |       |       |       |       |
|               | eticulocyte |      |       |       |       |       |
|               | counts are  |      |       |       |       |       |
|               | listed      |      |       |       |       |       |
|               | under       |      |       |       |       |       |
|               | hae         |      |       |       |       |       |
|               | matological |      |       |       |       |       |
|               | inv         |      |       |       |       |       |
|               | estigations |      |       |       |       |       |
|               | in the      |      |       |       |       |       |
|               | study no    |      |       |       |       |       |
|               | results are |      |       |       |       |       |
|               | reported,   |      |       |       |       |       |
|               | however red |      |       |       |       |       |
|               | cell        |      |       |       |       |       |
|               | morphology  |      |       |       |       |       |
|               | has been    |      |       |       |       |       |
|               | assessed    |      |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               | > Hae       |      |       |       |       |       |
|               | matological |      |       |       |       |       |
|               | > e         |      |       |       |       |       |
|               | xaminations |      |       |       |       |       |
|               | > revealed  |      |       |       |       |       |
|               | > st        |      |       |       |       |       |
|               | atistically |      |       |       |       |       |
|               | >           |      |       |       |       |       |
|               | significant |      |       |       |       |       |
|               | > decreases |      |       |       |       |       |
|               | > in RBC,   |      |       |       |       |       |
|               | > h         |      |       |       |       |       |
|               | aemoglobin, |      |       |       |       |       |
|               | > and       |      |       |       |       |       |
|               | >           |      |       |       |       |       |
|               |  hematocrit |      |       |       |       |       |
|               | > in males  |      |       |       |       |       |
|               | > at 2500   |      |       |       |       |       |
|               | > and 8000  |      |       |       |       |       |
|               | > ppm at 6, |      |       |       |       |       |
|               | > 9, and 12 |      |       |       |       |       |
|               | > months.   |      |       |       |       |       |
|               | >           |      |       |       |       |       |
|               | > These     |      |       |       |       |       |
|               | > treatment |      |       |       |       |       |
|               | > related   |      |       |       |       |       |
|               | > finding   |      |       |       |       |       |
|               | > were      |      |       |       |       |       |
|               | > similar   |      |       |       |       |       |
|               | > to the    |      |       |       |       |       |
|               | > mild      |      |       |       |       |       |
|               | > anaemia   |      |       |       |       |       |
|               | > observed  |      |       |       |       |       |
|               | > in the 90 |      |       |       |       |       |
|               | > day dog   |      |       |       |       |       |
|               | > study     |      |       |       |       |       |
|               | > although  |      |       |       |       |       |
|               | > in the    |      |       |       |       |       |
|               | > opposite  |      |       |       |       |       |
|               | > sex.      |      |       |       |       |       |
|               | > However   |      |       |       |       |       |
|               | > looking   |      |       |       |       |       |
|               | > at the    |      |       |       |       |       |
|               | > trend     |      |       |       |       |       |
|               | > over time |      |       |       |       |       |
|               | > the dose  |      |       |       |       |       |
|               | > r         |      |       |       |       |       |
|               | elationship |      |       |       |       |       |
|               | > is        |      |       |       |       |       |
|               | > marginal  |      |       |       |       |       |
|               | > and in    |      |       |       |       |       |
|               | > addition  |      |       |       |       |       |
|               | > all       |      |       |       |       |       |
|               | > values    |      |       |       |       |       |
|               | > were well |      |       |       |       |       |
|               | > within    |      |       |       |       |       |
|               | > the       |      |       |       |       |       |
|               | >           |      |       |       |       |       |
|               |  historical |      |       |       |       |       |
|               | > control   |      |       |       |       |       |
|               | > range.    |      |       |       |       |       |
|               | > Overall   |      |       |       |       |       |
|               | > the       |      |       |       |       |       |
|               | > changes   |      |       |       |       |       |
|               | > are not   |      |       |       |       |       |
|               | >           |      |       |       |       |       |
|               |  considered |      |       |       |       |       |
|               | > b         |      |       |       |       |       |
|               | iologically |      |       |       |       |       |
|               | > s         |      |       |       |       |       |
|               | ignificant. |      |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             |      |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               | **Haema     |      | *     |       |       |       |
|               | tological** |      | *Dose |       |       |       |
|               |             |      | Group |       |       |       |
|               |             |      | (p    |       |       |       |
|               |             |      | pm)** |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               | *           |      | **ma  |       |       |       |
|               | *Findings** |      | les** |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             |      | **0** | **1   | **2   | **8   |
|               |             |      |       | 000** | 500** | 000** |
+---------------+-------------+------+-------+-------+-------+-------+
|               | **RBCs      | *    | 6.83  | 6.75  | 6.33  | 6.63  |
|               | (1          | *day |       |       |       |       |
|               | 0^6^/mm3)** | -4** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **3  | 7.27  | 6.72  | 6.36  | 6.54  |
|               |             | mont |       |       |       |       |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **6  | 7.53  | 7.22  | 7     | 6     |
|               |             | mont |       |       | .02\* | .82\* |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **9  | 7.88  | 7.56  | 7     | 6     |
|               |             | mont |       |       | .14\* | .98\* |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **12 | 7.69  | 7.65  | 7.6\* | 7     |
|               |             | mont |       |       |       | .12\* |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               | **Hgb       | *    | 16.1  | 15.7  | 14.8  | 15.1  |
|               | (g/dl)**    | *day |       |       |       |       |
|               |             | -4** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **3  | 16.9  | 15.4  | 15.0  | 15.4  |
|               |             | mont |       |       |       |       |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **6  | 17.5  | 16.6  | 16.7  | 16.1  |
|               |             | mont |       |       |       |       |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **9  | 18.3  | 17.3  | 1     | 1     |
|               |             | mont |       |       | 6.8\* | 6.3\* |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **12 | 18.5  | 18.0  | 1     | 1     |
|               |             | mont |       |       | 7.6\* | 7.1\* |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               | **Hct (%)** | *    | 45.3  | 44.9  | 42.5  | 44.0  |
|               |             | *day |       |       |       |       |
|               |             | -4** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **3  | 47.3  | 43.3  | 42.1  | 43.7  |
|               |             | mont |       |       |       |       |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **6  | 48.7  | 46.2  | 4     | 4     |
|               |             | mont |       |       | 6.7\* | 4.6\* |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **9  | 53.5  | 50.6  | 49.5  | 48.1  |
|               |             | mont |       |       |       |       |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **12 | 50.6  | 49.7  | 48.6  | 47.4  |
|               |             | mont |       |       |       |       |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               | **Haema     |      | *     |       |       |       |
|               | tological** |      | *FEMA |       |       |       |
|               |             |      | LES** |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               | *           |      | **0** | **1   | **2   | **8   |
|               | *Findings** |      |       | 000** | 500** | 000** |
+---------------+-------------+------+-------+-------+-------+-------+
|               | **RBCs      | *    | 6.24  | 6.52  | 6.86  | 6.82  |
|               | (1          | *day |       |       |       |       |
|               | 0^6^/mm3)** | -4** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **3  | 6.29  | 6.77  | 6.96  | 6.57  |
|               |             | mont |       |       |       |       |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **6  | 6.37  | 6.73  | 6.97  | 6.74  |
|               |             | mont |       |       |       |       |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **9  | 6.87  | 7.16  | 7.21  | 7.35  |
|               |             | mont |       |       |       |       |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **12 | 6.94  | 6.79  | 7.29  | 6.56  |
|               |             | mont |       |       |       |       |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               | **Hgb       | *    | 14.4  | 15.1  | 16.4  | 16.1  |
|               | (g/dl)**    | *day |       |       |       |       |
|               |             | -4** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **3  | 15.0  | 15.9  | 16.8  | 15.8  |
|               |             | mont |       |       |       |       |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **6  | 15.0  | 15.8  | 17.1  | 16.3  |
|               |             | mont |       |       |       |       |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **9  | 15.9  | 16.8  | 17.3  | 17.4  |
|               |             | mont |       |       |       |       |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **12 | 16.7  | 16.3  | 17.8  | 16.2  |
|               |             | mont |       |       |       |       |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               | **Hct (%)** | *    | 41.3  | 43.6  | 47.3  | 46.5  |
|               |             | *day |       |       |       |       |
|               |             | -4** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **3  | 41.6  | 44.2  | 4     | 4     |
|               |             | mont |       |       | 7.4\* | 5.2\* |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **6  | 41.6  | 43.9  | 47.3  | 45.6  |
|               |             | mont |       |       |       |       |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **9  | 46.9  | 48.8  | 50.5  | 52.0  |
|               |             | mont |       |       |       |       |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             | **12 | 46.4  | 45.1  | 49.7  | 45.1  |
|               |             | mont |       |       |       |       |
|               |             | hs** |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               | Urinalysis  |      |       |       |       |       |
|               | revealed no |      |       |       |       |       |
|               | clear       |      |       |       |       |       |
|               | treatment   |      |       |       |       |       |
|               | related     |      |       |       |       |       |
|               | effects.    |      |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
|               |             |      |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+
| **            | Following   |      |       |       |       |       |
| Conclusions** | one years   |      |       |       |       |       |
|               | dietary     |      |       |       |       |       |
|               | treatment   |      |       |       |       |       |
|               | with        |      |       |       |       |       |
|               | cyp         |      |       |       |       |       |
|               | rosulfamide |      |       |       |       |       |
|               | there were  |      |       |       |       |       |
|               | clear       |      |       |       |       |       |
|               | treatment   |      |       |       |       |       |
|               | related     |      |       |       |       |       |
|               | findings at |      |       |       |       |       |
|               | the top     |      |       |       |       |       |
|               | dose only   |      |       |       |       |       |
|               | (8000 ppm)  |      |       |       |       |       |
|               | with the    |      |       |       |       |       |
|               | urinary     |      |       |       |       |       |
|               | bladder and |      |       |       |       |       |
|               | kidney as   |      |       |       |       |       |
|               | the target  |      |       |       |       |       |
|               | organs.     |      |       |       |       |       |
|               |             |      |       |       |       |       |
|               | In the      |      |       |       |       |       |
|               | urinary     |      |       |       |       |       |
|               | bladder     |      |       |       |       |       |
|               | gross       |      |       |       |       |       |
|               | pathology   |      |       |       |       |       |
|               | revealed    |      |       |       |       |       |
|               | multiple    |      |       |       |       |       |
|               | raised      |      |       |       |       |       |
|               | black zones |      |       |       |       |       |
|               | in the      |      |       |       |       |       |
|               | mucosa,     |      |       |       |       |       |
|               | multiple    |      |       |       |       |       |
|               | yellow      |      |       |       |       |       |
|               | pinpoint    |      |       |       |       |       |
|               | calculi and |      |       |       |       |       |
|               | thick,      |      |       |       |       |       |
|               | abnormal    |      |       |       |       |       |
|               | consistency |      |       |       |       |       |
|               | in two high |      |       |       |       |       |
|               | dose males. |      |       |       |       |       |
|               | Micr        |      |       |       |       |       |
|               | oscopically |      |       |       |       |       |
|               | stone(s)    |      |       |       |       |       |
|               | were        |      |       |       |       |       |
|               | observed in |      |       |       |       |       |
|               | one high    |      |       |       |       |       |
|               | dose male   |      |       |       |       |       |
|               | and female. |      |       |       |       |       |
|               | In 2 males  |      |       |       |       |       |
|               | slight to   |      |       |       |       |       |
|               | moderate    |      |       |       |       |       |
|               | chronic     |      |       |       |       |       |
|               | mucosal     |      |       |       |       |       |
|               | haemorrhage |      |       |       |       |       |
|               | and minimal |      |       |       |       |       |
|               | to slight   |      |       |       |       |       |
|               | urothelial  |      |       |       |       |       |
|               | hyperplasia |      |       |       |       |       |
|               | were noted. |      |       |       |       |       |
|               | Minimal     |      |       |       |       |       |
|               | su          |      |       |       |       |       |
|               | burothelial |      |       |       |       |       |
|               | mononuclear |      |       |       |       |       |
|               | cell        |      |       |       |       |       |
|               | infiltrate  |      |       |       |       |       |
|               | was         |      |       |       |       |       |
|               | observed in |      |       |       |       |       |
|               | one male    |      |       |       |       |       |
|               | and one     |      |       |       |       |       |
|               | female.     |      |       |       |       |       |
|               |             |      |       |       |       |       |
|               | In the      |      |       |       |       |       |
|               | kidney, one |      |       |       |       |       |
|               | female had  |      |       |       |       |       |
|               | some        |      |       |       |       |       |
|               | microscopic |      |       |       |       |       |
|               | intrapelvic |      |       |       |       |       |
|               | stones.     |      |       |       |       |       |
|               | Associated  |      |       |       |       |       |
|               | with these  |      |       |       |       |       |
|               | stones,     |      |       |       |       |       |
|               | there were  |      |       |       |       |       |
|               | other       |      |       |       |       |       |
|               | minimal     |      |       |       |       |       |
|               | changes:    |      |       |       |       |       |
|               | pelvic      |      |       |       |       |       |
|               | epithelium  |      |       |       |       |       |
|               | h           |      |       |       |       |       |
|               | yperplasia, |      |       |       |       |       |
|               | pelvic      |      |       |       |       |       |
|               | epithelial  |      |       |       |       |       |
|               | erosion and |      |       |       |       |       |
|               | su          |      |       |       |       |       |
|               | burothelial |      |       |       |       |       |
|               | mononuclear |      |       |       |       |       |
|               | cell        |      |       |       |       |       |
|               | infiltrate. |      |       |       |       |       |
|               |             |      |       |       |       |       |
|               | In addition |      |       |       |       |       |
|               | cyp         |      |       |       |       |       |
|               | rosulfamide |      |       |       |       |       |
|               | appeared to |      |       |       |       |       |
|               | cause mild  |      |       |       |       |       |
|               | anaemia     |      |       |       |       |       |
|               | with males  |      |       |       |       |       |
|               | at 2500 and |      |       |       |       |       |
|               | 8000 ppm at |      |       |       |       |       |
|               | 6, 9, and   |      |       |       |       |       |
|               | 12 months.  |      |       |       |       |       |
|               | However the |      |       |       |       |       |
|               | dose        |      |       |       |       |       |
|               | r           |      |       |       |       |       |
|               | elationship |      |       |       |       |       |
|               | is marginal |      |       |       |       |       |
|               | and in      |      |       |       |       |       |
|               | addition    |      |       |       |       |       |
|               | all values  |      |       |       |       |       |
|               | were well   |      |       |       |       |       |
|               | within the  |      |       |       |       |       |
|               | historical  |      |       |       |       |       |
|               | control     |      |       |       |       |       |
|               | range.      |      |       |       |       |       |
|               | Overall the |      |       |       |       |       |
|               | changes are |      |       |       |       |       |
|               | not         |      |       |       |       |       |
|               | considered  |      |       |       |       |       |
|               | b           |      |       |       |       |       |
|               | iologically |      |       |       |       |       |
|               | s           |      |       |       |       |       |
|               | ignificant. |      |       |       |       |       |
|               |             |      |       |       |       |       |
|               | A NOAEL of  |      |       |       |       |       |
|               | 2500 ppm    |      |       |       |       |       |
|               | (equivalent |      |       |       |       |       |
|               | to mean     |      |       |       |       |       |
|               | achieved    |      |       |       |       |       |
|               | dietary     |      |       |       |       |       |
|               | intakes of  |      |       |       |       |       |
|               | 66 and      |      |       |       |       |       |
|               | 67 mg/kg    |      |       |       |       |       |
|               | bw/day in   |      |       |       |       |       |
|               | males and   |      |       |       |       |       |
|               | females     |      |       |       |       |       |
|               | re          |      |       |       |       |       |
|               | spectively) |      |       |       |       |       |
|               | can be      |      |       |       |       |       |
|               | determined  |      |       |       |       |       |
|               | for this    |      |       |       |       |       |
|               | study,      |      |       |       |       |       |
|               | based on    |      |       |       |       |       |
|               | the clear   |      |       |       |       |       |
|               | effects on  |      |       |       |       |       |
|               | the kidney  |      |       |       |       |       |
|               | and urinary |      |       |       |       |       |
|               | bladder.    |      |       |       |       |       |
+---------------+-------------+------+-------+-------+-------+-------+

+-----------------------------------------------------------------------+
| HED Reviewer Comments.                                                |
|                                                                       |
| **Classification: Acceptable/Guideline.** This study satisfies the    |
| series 870.4100 guideline requirement for a chronic oral study in     |
| dogs. HED concurs with the assignment of the NOAEL and LOAEL.         |
+-----------------------------------------------------------------------+

**A.3.5 Carcinogenicity**

**870.4200a Carcinogenicity Study - rat (Combined chronic
feeding/carcinogenicity, MRID No.: 47069817)**

AE 0001789, (batch number 08466/0013, a white powder, 97.4 to 97.5 %
w/w purity) was administered to groups of 60 male and 60 female
Wistar rats by continuous dietary treatment at 1000, 4000 and 8000 ppm,
corresponding to 39, 159 and 321 mg/kg/day in males and 56, 220 and
447 mg/kg/day in females, respectively, over a 24-month period.
Additionally, groups of 10 male and 10 female rats were treated at 200,
1000, 4000 and 8000 ppm AE 0001789, corresponding to 9, 45, 181 and
364 mg/kg/day in males and 13, 62, 249 and 491 mg/kg/day in females,
over a 12-month period to investigate chronic toxicity only. Mortality
and clinical signs were checked daily. Detailed physical examinations
including palpation for masses were performed at least weekly throughout
the study. Body weight was recorded weekly for the first 13 weeks, then
approximately every 4 weeks thereafter. Food consumption was recorded
twice weekly for the first 6 weeks of the study, then weekly up to
Week 13, then every 4 weeks thereafter. Ophthalmology examinations were
performed on all animals during acclimatization and after approximately
12 and 24 months. Neurotoxicity assessment (motor activity, sensory
reactivity and grip strength) was performed on all surviving animals
allocated to the chronic phase of each group during Month 12.
Haematology and clinical chemistry determinations and urinalysis were
performed during Months 4, 6/7, 12, 18 and 24/25 on selected animals. At
the scheduled chronic and carcinogenicity phase sacrifice, selected
organs were weighed and designated tissues sampled and examined
microscopically.

At 8000 ppm:

The mortality rate was higher in females than in the corresponding
control group after 24 months of treatment and was largely due to
secondary treatment-related nephropathy following product
administration.

Treatment-related clinical signs consisted of soiled anogenital region
in approximately 14 to 20% of animals of both sexes during the first
year of treatment and in 53% of males and 31% of females during the
second year of treatment. In addition, a slightly increased incidence of
red genital discharge, reduced motor activity, general pallor, wasted
appearance and hunched posture was noted in females, mainly during the
second year of treatment. Mean cumulative body weight gain was reduced
during the first week of treatment by 7 and 12% in males and females,
respectively, compared to the controls. Thereafter, mean body weight and
body weight gain parameters were comparable to controls in both sexes
throughout the study.

Urinalysis revealed the presence of sulfonamide-like crystals throughout
the study in both sexes, the effect being more pronounced in females
than in males.

At the 12-month interim sacrifice, treatment-related non-neoplastic
findings were seen microscopically in the kidney and the urinary
bladder. In the kidney, a tendency towards a higher incidence and/or
increased severity of treatment-related findings observed in the
carcinogenicity phase, i.e. unilateral pelvic dilatation, bilateral
papillary necrosis/loss/scarring, bilateral cortical/medullary scarring
and pelvic epithelium hyperplasia, was noted in one or both sexes.
Urothelial hyperplasia was noted in the urinary bladder in both sexes.
In addition, a treatment-induced nephropathy, which was considered to be
the cause of death, was observed in a prematurely sacrificed female
allocated to the chronic phase. Treatment-induced nephropathy was
characterized by stones, papillary necrosis/loss/scarring, collecting
duct hyperplasia, bilateral cortico-medullary scarring, pelvic
dilatation and/or bilateral cortex/medulla tubular dilatation.

For animals allocated to the carcinogenicity phase of the study, 14/31
premature deaths in females were attributed to a treatment-induced
nephropathy. Treatment-related macroscopic findings consisted of
abnormal shape, pelvic dilatation, irregular surface, gritty content and
stones in the kidney in females and stones in the urinary bladder in
males.

At the carcinogenicity phase (24-month) sacrifice, treatment-related
macroscopic findings in the kidney consisted of abnormal shape, pelvic
dilatation and gritty content in both sexes and irregular surface and
stones in females only. Stones were also observed in the urinary bladder
in both sexes. At the microscopic examination of unscheduled and
scheduled deaths, treatment-related effects were found in the urinary
tract, i.e. kidney, urinary bladder, and ureters. In the kidney, a
treatment-induced nephropathy was observed in both sexes, with a higher
severity in females. A slightly increased severity in simple pelvic
epithelium hyperplasia was noted in both sexes. Nodular pelvic
epithelium hyperplasia was observed in 2/60 females and a higher
incidence of intrapelvic mineral deposit was noted in females.
Intraluminal stones and multifocal/diffuse urothelial hyperplasia were
observed in the urinary bladder and in a number of ureters in both
sexes. An increased incidence of the commonly occurring lesion diffuse
bilateral tubular degeneration of the testis and bilateral oligospermia
of the epididymis was observed.

Neoplastic changes comprised a treatment-related transitional cell
carcinoma in the kidney of one male and a transitional cell carcinoma in
the urinary bladder of one female. These findings were considered to be
secondary to the combination of hyperplastic and inflammatory changes
associated with the presence of stones.

At 4000 ppm:

Treatment-related clinical signs consisted of soiled anogenital region
in approximately 5 to 9% of the animals of both sexes during the first
year of treatment and in 35% of males and 22% of females during the
second year of treatment. In males, mean cumulative body weight gain was
reduced during the first week of treatment by 5%, when compared to
controls.

Urinalysis revealed the presence of sulfonamide-like crystals throughout
the study in both sexes, the effect being more pronounced in females
than in males.

At the carcinogenicity phase (24-month) sacrifice, treatment-related
macroscopic findings consisted of pelvic dilatation, gritty content and
stones in the kidney in females and stones in the urinary bladder in
1/34 females. At the microscopic examination of unscheduled and
scheduled deaths, treatment-related effects were found in the kidney and
urinary bladder. In the kidney, stones, collecting duct hyperplasia and
bilateral cortex/medulla tubular dilatation were observed in females and
pelvic dilatation in both sexes. A slightly increased severity in simple
pelvic epithelium hyperplasia was noted in both sexes. Intraluminal
stones and multifocal/diffuse urothelial hyperplasia were observed in
the urinary bladder in females.

At 1000 ppm:

The only treatment-related changes observed at this dose level were a
slightly increased incidence of soiled anogenital region at the physical
examination in males and a tendency towards lower urinary protein levels
at urinalysis performed in Month 6/7, 12 and 18 in males. These minor
changes in the absence of corresponding histopathological findings were
considered not to be adverse.

At 200 ppm:

No treatment-related changes were observed in either sex.

In conclusion, dietary administration of AE 0001789 over a 24-month
period to the Wistar rat, at dose levels up to 8000 ppm (corresponding
to 321 mg/kg/day in males and 447 mg/kg/day in females), produced a
transitional cell carcinoma in the kidney of one male and a transitional
cell carcinoma in the urinary bladder of one female. The incidence of
these tumors was very low and was considered to be secondary to the
chronic hyperplastic changes resulting from chronic irritation due to
the presence of stones. Thus, AE 0001789 was considered not to be
directly carcinogenic in the rat.

The No Observed Adverse Effect Level (NOAEL) over a 12‑month period of
dietary administration with AE 0001789 to the Wistar rat was 4000 ppm in
both sexes (equivalent to 181 mg/kg body weight/day in males and
249 mg/kg body weight/day in females).

The NOAEL over a 24‑month period of dietary administration with
AE 0001789 to the Wistar rat was 1000 ppm in both sexes (equivalent to
39 mg/kg/day in males and 56 mg/kg/day in females).

<table>
<colgroup>
<col style="width: 23%" />
<col style="width: 18%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="10"><strong>EVALUATION, SUMMARY AND CONCLUSION BY
REGULATORY AUTHORITY</strong></td>
</tr>
<tr class="even">
<td><strong>Name of authority</strong></td>
<td colspan="9">Pesticides Safety Directorate, UK</td>
</tr>
<tr class="odd">
<td><strong>Reviewer’s Comments</strong></td>
<td colspan="9"><p>Reliability rating: Totally reliable</p>
<p>The study (M-281767-01-2) is fully compliant with OECD 453.</p>
<p>During the first year of treatment the mortality rate was not
affected by treatment in either sex.</p>
<p>After at least 104 weeks of treatment the mortality rate was not
affected by treatment in males and was slightly higher at 8000 ppm in
females compared to controls, where 14 out of 31 unscheduled mortalities
were attributed to treatment-related nephropathy. However survival rates
in males across all groups was poor with survival rates at 104 weeks
falling to 41.1%, 49.2%, 27.4%, and 34.4% at 0, 1000, 4000 and 8000 ppm
respectively.</p>
<p>Survival in males at doses of 4000 ppm and 8000 ppm drop below 50% at
around week 94. This weakens the carcinogenicity assessment at these
dose levels.</p></td>
</tr>
<tr class="even">
<td rowspan="11"></td>
<td rowspan="3"><strong>Week</strong></td>
<td colspan="8"><strong>Survival in carcinogenicity group (60
animals/sex/group)</strong></td>
</tr>
<tr class="odd">
<td colspan="4"><strong>M</strong></td>
<td colspan="4"><strong>F</strong></td>
</tr>
<tr class="even">
<td><strong>0</strong></td>
<td><strong>1000</strong></td>
<td><strong>4000</strong></td>
<td><strong>8000</strong></td>
<td><strong>0</strong></td>
<td><strong>500</strong></td>
<td><strong>2500</strong></td>
<td><strong>5000</strong></td>
</tr>
<tr class="odd">
<td rowspan="2"><strong>60</strong></td>
<td>57</td>
<td>57</td>
<td>53</td>
<td>51</td>
<td>58</td>
<td>57</td>
<td>59</td>
<td>58</td>
</tr>
<tr class="even">
<td>95.0%</td>
<td>95.0%</td>
<td>88.3%</td>
<td>85.0%</td>
<td>96.7%</td>
<td>95.0%</td>
<td>98.3%</td>
<td>96.7%</td>
</tr>
<tr class="odd">
<td rowspan="2"><strong>75</strong></td>
<td>52</td>
<td>51</td>
<td>47</td>
<td>45</td>
<td>53</td>
<td>51</td>
<td>58</td>
<td>49</td>
</tr>
<tr class="even">
<td>86.7%</td>
<td>85.0%</td>
<td>78.3%</td>
<td>75.0%</td>
<td>88.3%</td>
<td>85.0%</td>
<td>96.7%</td>
<td>81.7%</td>
</tr>
<tr class="odd">
<td rowspan="2"><strong>90</strong></td>
<td>42</td>
<td>43</td>
<td>36</td>
<td>35</td>
<td>48</td>
<td>47</td>
<td>51</td>
<td>42</td>
</tr>
<tr class="even">
<td>70.0%</td>
<td>71.7%</td>
<td>60.0%</td>
<td>58.3%</td>
<td>80.0%</td>
<td>78.3%</td>
<td>85.0%</td>
<td>70.0%</td>
</tr>
<tr class="odd">
<td rowspan="2"><strong>100</strong></td>
<td>35</td>
<td>32</td>
<td>21</td>
<td>25</td>
<td>42</td>
<td>45</td>
<td>42</td>
<td>31</td>
</tr>
<tr class="even">
<td>58.3%</td>
<td>53.3%</td>
<td>35.0%</td>
<td>41.7%</td>
<td>70.0%</td>
<td>75.0%</td>
<td>70.0%</td>
<td>51.7%</td>
</tr>
<tr class="odd">
<td></td>
<td rowspan="2"><strong>105</strong></td>
<td>27</td>
<td>29</td>
<td>16</td>
<td>20</td>
<td>38</td>
<td>36</td>
<td>36</td>
<td>31</td>
</tr>
<tr class="even">
<td></td>
<td>45.0%</td>
<td>48.3%</td>
<td>26.7%</td>
<td>33.3%</td>
<td>63.3%</td>
<td>60.0%</td>
<td>60.0%</td>
<td>51.7%</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="9"></td>
</tr>
<tr class="even">
<td></td>
<td colspan="9">Unlike the previous short term studies there was no
clear evidence of effects on haematological parameters.</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="9"></td>
</tr>
<tr class="even">
<td></td>
<td colspan="9"><p>Sulfonamide-like crystals were observed at 8000 and
4000 ppm in both sexes. This finding was dose-related in terms of
incidence and/or severity on most occasions, the effect being more
pronounced in females than in males. No sulfonamide-like crystals were
observed at 1000 ppm, 200 ppm or in control animals in either sex.</p>
<p>A lower urinary protein levels was noted throughout the study in both
sexes at 8000 and 4000 ppm (except for females at Month 24) compared to
controls. The same variation was seen in males at 1000 ppm at Month 6/7,
12 and 18. This change was considered not to be adverse in view of its
low magnitude.</p>
<p>At Month 12, a higher urinary volume was noted at 8000 ppm in females
(+59%, p≤0.05). This change was not observed during the second year of
the study.</p>
<p>Gross necropsy of both premature decedents and at terminal sacrifice
revealed treatment related changes in the kidneys and urinary bladder at
doses <u>&gt;</u>4000 ppm. Findings in the kidneys included abnormal
shape, pelvic dilatation, irregular surface, gritty content and stones.
In the urinary bladder stones were observed.</p>
<p>Microscopic examinations at 12 month sacrifice revealed a number of
non-neoplastic changes at the top dose; a slightly higher incidence
and/or a slight increase in severity of unilateral pelvic dilatation,
bilateral papillary necrosis/loss/scarring, bilateral cortical/medullary
scarring and pelvic epithelium hyperplasia, was noted in the kidney in
one or both sexes. Treatment-related urothelial hyperplasia was noted in
the urinary bladder in a few animals of both sexes. There was no
evidence of a neoplastic effect at 12 months.</p>
<p>At 24 months treatment-related non-neoplastic effects were observed
in the urinary tract, i.e. kidney, urinary bladder and ureter, including
a combination of hyperplastic and inflammatory changes associated with
the presence of stones.</p>
<p>Treatment-induced nephropathy was observed at a higher incidence in
both sexes in the kidney at 8000 ppm, with an increased severity in
females, and at 4000 ppm in a higher incidence in females only.
Treatment-induced nephropathy is a general term which incorporates some
or all of the following findings: stones, papillary
necrosis/loss/scarring, collecting duct hyperplasia, bilateral
cortico-medullary scarring, pelvic dilatation and bilateral
cortex/medulla tubular dilatation. In addition, an increased incidence
of pelvic dilatation was noted at 4000 ppm in males.</p>
<p>A slight increase in severity of simple pelvic epithelium hyperplasia
was observed in both sexes at 8000 and 4000 ppm. Nodular pelvic
epithelium hyperplasia was observed in 2/60 females and a higher
incidence of intrapelvic mineral deposit was observed in 14/60 females
at 8000 ppm.</p>
<p>Intraluminal stones and multifocal/diffuse urothelial hyperplasia
were observed in the urinary bladder in both sexes at 8000 ppm and in
females at 4000 ppm. These lesions were considered to be
treatment-related. Suburothelial mononuclear cell infiltrate and mixed
cell infiltrate were considered to be associated lesions</p>
<p>There was a treatment related increase (<u>ca</u> three times the
numbers in controls) in the incidence of the diffuse bilateral tubular
degeneration of the testis (associated with diffuse interstitial oedema
and/or focal/multifocal mineralization in most cases) and bilateral
oligospermia of the epididymis (associated with epithelial degenerative
change) observed at 8000 ppm.</p></td>
</tr>
</tbody>
</table>

<table>
<colgroup>
<col style="width: 23%" />
<col style="width: 18%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="10"><strong>EVALUATION, SUMMARY AND CONCLUSION BY
REGULATORY AUTHORITY</strong></td>
</tr>
<tr class="even">
<td><strong>Name of authority</strong></td>
<td colspan="9">Pesticides Safety Directorate, UK</td>
</tr>
<tr class="odd">
<td><strong>Reviewer’s Comments</strong></td>
<td colspan="9"><p>Reliability rating: Totally reliable</p>
<p>The study (M-281767-01-2) is fully compliant with OECD 453.</p>
<p>During the first year of treatment the mortality rate was not
affected by treatment in either sex.</p>
<p>After at least 104 weeks of treatment the mortality rate was not
affected by treatment in males and was slightly higher at 8000 ppm in
females compared to controls, where 14 out of 31 unscheduled mortalities
were attributed to treatment-related nephropathy. However survival rates
in males across all groups was poor with survival rates at 104 weeks
falling to 41.1%, 49.2%, 27.4%, and 34.4% at 0, 1000, 4000 and 8000 ppm
respectively.</p>
<p>Survival in males at doses of 4000 ppm and 8000 ppm drop below 50% at
around week 94. This weakens the carcinogenicity assessment at these
dose levels.</p></td>
</tr>
<tr class="even">
<td rowspan="11"></td>
<td rowspan="3"><strong>Week</strong></td>
<td colspan="8"><strong>Survival in carcinogenicity group (60
animals/sex/group)</strong></td>
</tr>
<tr class="odd">
<td colspan="4"><strong>M</strong></td>
<td colspan="4"><strong>F</strong></td>
</tr>
<tr class="even">
<td><strong>0</strong></td>
<td><strong>1000</strong></td>
<td><strong>4000</strong></td>
<td><strong>8000</strong></td>
<td><strong>0</strong></td>
<td><strong>500</strong></td>
<td><strong>2500</strong></td>
<td><strong>5000</strong></td>
</tr>
<tr class="odd">
<td rowspan="2"><strong>60</strong></td>
<td>57</td>
<td>57</td>
<td>53</td>
<td>51</td>
<td>58</td>
<td>57</td>
<td>59</td>
<td>58</td>
</tr>
<tr class="even">
<td>95.0%</td>
<td>95.0%</td>
<td>88.3%</td>
<td>85.0%</td>
<td>96.7%</td>
<td>95.0%</td>
<td>98.3%</td>
<td>96.7%</td>
</tr>
<tr class="odd">
<td rowspan="2"><strong>75</strong></td>
<td>52</td>
<td>51</td>
<td>47</td>
<td>45</td>
<td>53</td>
<td>51</td>
<td>58</td>
<td>49</td>
</tr>
<tr class="even">
<td>86.7%</td>
<td>85.0%</td>
<td>78.3%</td>
<td>75.0%</td>
<td>88.3%</td>
<td>85.0%</td>
<td>96.7%</td>
<td>81.7%</td>
</tr>
<tr class="odd">
<td rowspan="2"><strong>90</strong></td>
<td>42</td>
<td>43</td>
<td>36</td>
<td>35</td>
<td>48</td>
<td>47</td>
<td>51</td>
<td>42</td>
</tr>
<tr class="even">
<td>70.0%</td>
<td>71.7%</td>
<td>60.0%</td>
<td>58.3%</td>
<td>80.0%</td>
<td>78.3%</td>
<td>85.0%</td>
<td>70.0%</td>
</tr>
<tr class="odd">
<td rowspan="2"><strong>100</strong></td>
<td>35</td>
<td>32</td>
<td>21</td>
<td>25</td>
<td>42</td>
<td>45</td>
<td>42</td>
<td>31</td>
</tr>
<tr class="even">
<td>58.3%</td>
<td>53.3%</td>
<td>35.0%</td>
<td>41.7%</td>
<td>70.0%</td>
<td>75.0%</td>
<td>70.0%</td>
<td>51.7%</td>
</tr>
<tr class="odd">
<td></td>
<td rowspan="2"><strong>105</strong></td>
<td>27</td>
<td>29</td>
<td>16</td>
<td>20</td>
<td>38</td>
<td>36</td>
<td>36</td>
<td>31</td>
</tr>
<tr class="even">
<td></td>
<td>45.0%</td>
<td>48.3%</td>
<td>26.7%</td>
<td>33.3%</td>
<td>63.3%</td>
<td>60.0%</td>
<td>60.0%</td>
<td>51.7%</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="9"></td>
</tr>
<tr class="even">
<td></td>
<td colspan="9">Unlike the previous short term studies there was no
clear evidence of effects on haematological parameters.</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="9"></td>
</tr>
<tr class="even">
<td></td>
<td colspan="9"><p>Sulfonamide-like crystals were observed at 8000 and
4000 ppm in both sexes. This finding was dose-related in terms of
incidence and/or severity on most occasions, the effect being more
pronounced in females than in males. No sulfonamide-like crystals were
observed at 1000 ppm, 200 ppm or in control animals in either sex.</p>
<p>A lower urinary protein levels was noted throughout the study in both
sexes at 8000 and 4000 ppm (except for females at Month 24) compared to
controls. The same variation was seen in males at 1000 ppm at Month 6/7,
12 and 18. This change was considered not to be adverse in view of its
low magnitude.</p>
<p>At Month 12, a higher urinary volume was noted at 8000 ppm in females
(+59%, p≤0.05). This change was not observed during the second year of
the study.</p>
<p>Gross necropsy of both premature decedents and at terminal sacrifice
revealed treatment related changes in the kidneys and urinary bladder at
doses <u>&gt;</u>4000 ppm. Findings in the kidneys included abnormal
shape, pelvic dilatation, irregular surface, gritty content and stones.
In the urinary bladder stones were observed.</p>
<p>Microscopic examinations at 12 month sacrifice revealed a number of
non-neoplastic changes at the top dose; a slightly higher incidence
and/or a slight increase in severity of unilateral pelvic dilatation,
bilateral papillary necrosis/loss/scarring, bilateral cortical/medullary
scarring and pelvic epithelium hyperplasia, was noted in the kidney in
one or both sexes. Treatment-related urothelial hyperplasia was noted in
the urinary bladder in a few animals of both sexes. There was no
evidence of a neoplastic effect at 12 months.</p>
<p>At 24 months treatment-related non-neoplastic effects were observed
in the urinary tract, i.e. kidney, urinary bladder and ureter, including
a combination of hyperplastic and inflammatory changes associated with
the presence of stones.</p>
<p>Treatment-induced nephropathy was observed at a higher incidence in
both sexes in the kidney at 8000 ppm, with an increased severity in
females, and at 4000 ppm in a higher incidence in females only.
Treatment-induced nephropathy is a general term which incorporates some
or all of the following findings: stones, papillary
necrosis/loss/scarring, collecting duct hyperplasia, bilateral
cortico-medullary scarring, pelvic dilatation and bilateral
cortex/medulla tubular dilatation. In addition, an increased incidence
of pelvic dilatation was noted at 4000 ppm in males.</p>
<p>A slight increase in severity of simple pelvic epithelium hyperplasia
was observed in both sexes at 8000 and 4000 ppm. Nodular pelvic
epithelium hyperplasia was observed in 2/60 females and a higher
incidence of intrapelvic mineral deposit was observed in 14/60 females
at 8000 ppm.</p>
<p>Intraluminal stones and multifocal/diffuse urothelial hyperplasia
were observed in the urinary bladder in both sexes at 8000 ppm and in
females at 4000 ppm. These lesions were considered to be
treatment-related. Suburothelial mononuclear cell infiltrate and mixed
cell infiltrate were considered to be associated lesions</p>
<p>There was a treatment related increase (<u>ca</u> three times the
numbers in controls) in the incidence of the diffuse bilateral tubular
degeneration of the testis (associated with diffuse interstitial oedema
and/or focal/multifocal mineralization in most cases) and bilateral
oligospermia of the epididymis (associated with epithelial degenerative
change) observed at 8000 ppm.</p></td>
</tr>
</tbody>
</table>

+-----------------------------------------------------------------------+
| HED Comments:                                                         |
|                                                                       |
| **Classification: Acceptable/Guideline.** This study satisfies the    |
| guideline requirement for a series 870.4300 combined chronic feeding  |
| carcinogenicity study in rats. HED concurs with the assignment of the |
| NOAEL and LOAEL. The HED CARC determined that the study was adequate  |
| for assessing carcinogenic potential in the rat.                      |
+-----------------------------------------------------------------------+

**870.4200b Carcinogenicity (feeding) - Mouse (MRID No.: 47069818)**

The objective of this study was to investigate the oncogenic potential
of AE 0001789 (batch number 08466/0013, a white powder, 97.4-97.5% w/w
purity) in the C57BL/6J mouse following continuous dietary treatment at
350, 2000 and 3500 ppm for 18 months. In addition, an interim sacrifice
was performed after 52 weeks of treatment to assess chronic toxicity.

Groups of 60 male and 60 female C57BL/6J mice were initially intended to
be fed diet containing 0, 350, 2000 or 7000 ppm of AE 0001789 for at
least 78 weeks. Since the Maximum Tolerated Dose was exceeded in females
at 7000 ppm during the first weeks of treatment, an additional treatment
group (60 animals/sex) at 3500 ppm was added to the study approximately
one month after the start of treatment. The high rate of mortality
observed in both sexes at 7000 ppm led to the early termination of this
treatment group, with all surviving females being sacrificed during Week
6 (study Day 40) and all males being sacrificed during Week 46 (study
Day 320). After 52 weeks, 10 males and 10 females from each group
allocated to the chronic phase of the study were necropsied at the
scheduled interim sacrifice. The remaining 50 animals/sex/group,
allocated to the carcinogenicity phase of the study, continued treatment
until the scheduled final sacrifice of the study after at least 78 weeks
of treatment (corresponding to a mean intake of AE 0001789 over 18
months of 0, 50, 287 and 506 mg/kg/day in males and 0, 63, 354, 616
mg/kg/day in females, at 0, 350, 2000 and 3500 ppm, respectively).
Mortality and clinical signs were checked daily. Additionally, detailed
physical examinations including palpation for masses were performed
weekly throughout treatment. Body weight and food consumption were
measured weekly for the first 13 weeks of the study, then approximately
monthly thereafter. Haematology determinations were performed at
approximately 12 and 18 months from designated animals. Where possible,
blood smears were prepared from moribund animals just before sacrifice.
All animals were subjected to necropsy, with selected organs weighed at
scheduled interim and final sacrifice. Designated tissues were fixed and
examined microscopically. In addition, urinary bladder stones sampled
from one male and one female at 3500 ppm and from one male at 2000 ppm
were analyzed for the presence of test substance. For the dose group
treated at 3500 ppm, all parameters were assessed on the same study days
as the other dose groups, resulting in staggered calendar dates.

At 7000 ppm:

The dietary level of 7000 ppm exceeded the Maximum Tolerated Dose in
both males and females (marked individual body weight loss and mortality
in both sexes), leading to early sacrifice of all males and females on
Day 320 and 40, respectively. Fifteen females were either found dead or
were killed for humane reasons between Days 11 and 35. In males, 5
animals died prematurely during the first three months of treatment and
26 animals were either found dead or were killed for humane reasons
between Days 218 and 316. In both sexes, most animals showed a severe
body weight loss on the days preceding death, they had a wasted
appearance and exhibited clinical signs related to a poor health
condition on one or more occasions prior to death.

At 3500 ppm:

The mortality incidence in males was higher than in the control group
after 12 and 18 months of treatment (20.0% and 58.1%, respectively,
compared to 5.0% and 24.4% in the respective control group). The higher
mortality rate was largely due to the presence of stones within the
urinary tract, causing acute or chronic renal failure or due to
secondary treatment-related nephropathy following product
administration. Treatment-related clinical signs were confined to males
and consisted of clinical observations which were, on most occasions,
recorded on the days preceding the death or early sacrifice of the
animals and reflecting their general poor health condition. During the
first week of treatment, mean body weight of males was reduced by 4%,
whilst mean body weight gain was reduced by 33%, compared to the
controls. Thereafter, starting from Day 92, mean body weight was
slightly reduced, compared to controls, at most time points, resulting
in a reduction of 5% at the end of the treatment period (Day 540). An
overall mean cumulative body weight gain reduction of 12% was observed
by Day 540, when compared to controls. In females, mean cumulative body
weight gain was reduced by between 29 and 71% at most time points during
the last 6 months of treatment (week period 55-77), resulting in a mean
body weight reduction of 3% on Day 540, compared to controls. During the
last 6 months of treatment, mean food consumption was reduced by between
2 and 10% in females, when compared to controls.

At the 18-month haematology determination, a tendency towards lower red
blood cell count was noted in both sexes. This change was associated
with slightly lower haemoglobin concentration, haematocrit and mean
corpuscular haemoglobin concentration and slightly higher mean
corpuscular volume.

At the 12-month interim sacrifice, macroscopic findings consisted of
thickening of the mucosa and stones in the urinary bladder of 4/9 and
1/9 males, respectively. Pale kidneys and gritty content were seen in
the urinary bladder in a prematurely sacrificed male allocated to the
chronic phase. At the microscopic examination, a higher incidence of
renal cortical basophilic tubules was noted in the kidney of males. In
the urinary bladder, urothelial hyperplasia, interstitial oedema,
induced arteritis/periarteritis, suburothelial mixed cell infiltrate and
intramuscular inflammatory cell infiltrates were observed in one male.

For males allocated to the carcinogenicity phase of the study, 21/30
premature deaths were attributed to the presence of urinary stones or to
treatment-related nephropathy. In females, 2/11 deaths was attributed to
the presence of urinary stones or to treatment-related nephropathy.
Treatment-related macroscopic findings at unscheduled sacrifice
consisted of stones found in the urinary bladder of both sexes,
thickening of the mucosa in the urinary bladder and dilatation of
ureters in males. A higher incidence of enlarged kidney, renal pelvic
dilatation, pale kidney or kidney with irregular surface was observed in
males and/or females, compared to controls. The incidence of gritty
content in the kidney was increased in males and stones were observed in
the kidney of one male and one female. An increased incidence of dark
liver was noted in males. This finding was often associated with
hepatocellular hypertrophy at the microscopic examination.

At the carcinogenicity phase (18-month) sacrifice, mean terminal body
weight of males and females was 5% lower than the controls. At the
macroscopic examination, kidneys with an irregular surface were observed
in 6/20 males, compared to 1/37 males in the control group, and stones
were found in the kidney of 1/20 males, compared to no cases in the
control group. At the microscopic examination, treatment-related effects
were found in the liver and the urinary tract including kidney, urinary
bladder, prostatic urethra and ureters. In the liver, minimal to slight
centrilobular to panlobular hepatocellular hypertrophy and an increased
incidence of hepatocellular single cell necrosis were observed in males.

In the urinary bladder, stones were noted in both sexes,
hyperplastic/metaplastic changes and secondary changes due to
stones-induced irritation or urinary blockage (muscular
degeneration/hemorrhage(s) and interstitial oedema, inflammatory cell
infiltrate, mixed cell infiltrate and arteritis/periarteritis) were
noted in males and/or females. In the kidney, stones were observed in
the pelvis in both sexes and in the collecting ducts in males only, and
a higher incidence of concretions was found in the collecting ducts in
males. Induced hyperplastic changes (collecting duct and
papillary/pelvic epithelium hyperplasia) and changes resulting from
chronic inflammation or urinary blockage (atrophy/fibrosis/scar,
perirenal inflammation, glomerular chamber and cortical or
cortex/medulla tubular dilatation, parenchymal cysts and pelvic
dilatation) were observed mostly in males. In addition in males alone, a
higher incidence and severity of bilateral cortical basophilic tubules
was noted and a higher incidence of cortical and medullar tubular
mineralization was found. The incidence of cellular casts was also
increased. Stones were found in the prostatic urethra and ureter.
Urothelial hyperplasia and interstitial mixed cell infiltrate were also
observed.

All the effects seen in the urinary tract were considered to be due to a
single and chronic irritative mechanism, resulting from the formation of
stones or crystals. In addition, indirect treatment-related findings
were observed in the lymphoid system in males (apoptotic bodies in the
spleen and mesenteric lymph nodes, and lymphoid atrophy in the spleen)
and were considered to be secondary to the stress induced by the stone
deposition and/or the treatment-related nephropathy. In the heart, a
higher incidence of epicardial mixed cell infiltrate was noted in 5/50
males, when compared to no cases in controls. This minimal change only
observed in males was considered to be an indirect and non-adverse
response to the treatment.

Neoplastic changes comprised transitional cell papilloma in the urinary
bladder of 2/49 females. This finding was considered to be secondary to
the chronic hyperplastic changes due to the presence of calculi.
Analysis of urinary bladder stones taken from one male and one female at
terminal sacrifice revealed that the composition of the stones consisted
of approximately 90 to 95% of test material.

At 2000 ppm:

There was no treatment-related change in females. Mortality rate, body
weight or food consumption parameters were not affected in males. At the
12-month interim sacrifice there were no treatment-related organ weight
changes and no macroscopic or microscopic findings.

For animals allocated to the carcinogenicity phase of the study, 1/13
premature deaths in males was attributed to the presence of urinary
stones. Treatment-related macroscopic findings at unscheduled sacrifice
consisted of gritty content found in the urinary bladder of 1/13 males
and in the kidney of 2/13 males, compared to no cases in the control
group.

At the carcinogenicity phase (18-month) sacrifice, treatment-related
findings were confined to males. Stones were observed in the urinary
bladder of 1/37 males and gritty content was found in the kidney of 1/37
males at the macroscopic examination, compared to no cases in the
control group. At the microscopic examination, treatment-related effects
were found in the liver, kidney, urinary bladder, prostatic urethra and
ureters. In the liver, minimal centrilobular to panlobular
hepatocellular hypertrophy was observed in a few males. In the urinary
bladder, stones were noted in 2/49 males. Simple hyperplasia and
interstitial oedema were observed in 1/49 males and intraluminal mixed
cell infiltrate was observed in another male. In the kidney, stones were
noted in the pelvis and collecting ducts in males. Hyperplasia was
observed in the collecting ducts and papillary/pelvic epithelium in 2/50
males. In the prostatic urethra, urothelial hyperplasia was observed in
1/50 males. All the effects seen in the urinary tract were considered to
be due to a single and chronic irritative mechanism, resulting from the
formation of stones or crystals.

There was no neoplastic change in either sex.

Analysis of urinary bladder stones taken from one male at terminal
sacrifice revealed that the composition of the stones consisted of
approximately 90 to 95% of test material.

At 350 ppm:

No treatment-related changes were observed in either sex.

In conclusion, dietary administration of AE 0001789 over an 18-month
period to the C57BL/6J mouse, at dose levels up to 3500 ppm
(corresponding to 506 mg/kg/day in males and 616 mg/kg/day in females),
produced transitional cell papilloma in the urinary bladder of females.
The incidence of these tumours was very low and was considered to be
secondary to the chronic hyperplastic changes resulting from chronic
irritation due to the presence of calculi. Thus AE 0001789 was
considered not to be directly carcinogenic in the mouse. The No Observed
Effect Level (NOEL) was 350 ppm for males (equivalent to 50 mg/kg/day)
and 2000 ppm for females (equivalent to 354 mg/kg/day).

<table>
<colgroup>
<col style="width: 23%" />
<col style="width: 18%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="10"><strong>EVALUATION, SUMMARY AND CONCLUSION BY
REGULATORY AUTHORITY</strong></td>
</tr>
<tr class="even">
<td><strong>Name of authority</strong></td>
<td colspan="9">Pesticides Safety Directorate, UK</td>
</tr>
<tr class="odd">
<td><strong>Reviewer’s Comments</strong></td>
<td colspan="9"><p>Reliability rating: Totally reliable</p>
<p>The study (M-281276-01-2) is fully compliant with OECD 451</p>
<p>There was marked toxicity at the top dose (7000 ppm) which exceeded
the MTD in both sexes, clearly demonstrated by marked individual body
weight loss and mortality in both sexes. This resulted in early
termination of this group of males on Day 320 and females on Day 40. Due
to the poor condition of the animals at 7000 ppm, only data pertaining
to mortality, clinical signs, body weight parameters and food
consumption (in-life phase), which reflected the poor condition of the
animals, were included in the study report</p>
<p>There was a treatment related increase in mortality in males at 3500
ppm was higher than controls after both 12 and 18 months of treatment
(20.0% and 58.1%, respectively). The deaths were a result of the
presence of stones within the urinary tract, causing acute or chronic
renal failure or due to secondary treatment-related nephropathy. This
finding together with the clear treatment related effects on bodyweights
at 3500 ppm (by the end of the study mean cumulative bodyweight gain in
males was 12% lower than controls) indicates this dose demonstrated
sufficient toxicity.</p></td>
</tr>
<tr class="even">
<td rowspan="11"></td>
<td rowspan="3"><strong>Week</strong></td>
<td colspan="8"><strong>Survival in carcinogenicity group (50
animals/sex/group)</strong></td>
</tr>
<tr class="odd">
<td colspan="4"><strong>M</strong></td>
<td colspan="4"><strong>F</strong></td>
</tr>
<tr class="even">
<td><strong>0</strong></td>
<td><strong>350</strong></td>
<td><strong>2000</strong></td>
<td><strong>3500</strong></td>
<td><strong>0</strong></td>
<td><strong>350</strong></td>
<td><strong>2000</strong></td>
<td><strong>3500</strong></td>
</tr>
<tr class="odd">
<td rowspan="2"><strong>54</strong></td>
<td>47</td>
<td>48</td>
<td>49</td>
<td>39</td>
<td>44</td>
<td>47</td>
<td>42</td>
<td>48</td>
</tr>
<tr class="even">
<td>94%</td>
<td>96%</td>
<td>98%</td>
<td>78%</td>
<td>88%</td>
<td>94%</td>
<td>84%</td>
<td>96%</td>
</tr>
<tr class="odd">
<td rowspan="2"><strong>65</strong></td>
<td>46</td>
<td>42</td>
<td>47</td>
<td>32</td>
<td>44</td>
<td>46</td>
<td>41</td>
<td>45</td>
</tr>
<tr class="even">
<td>92%</td>
<td>84%</td>
<td>94%</td>
<td>64%</td>
<td>88%</td>
<td>92%</td>
<td>82%</td>
<td>90%</td>
</tr>
<tr class="odd">
<td rowspan="2"><strong>75</strong></td>
<td>40</td>
<td>35</td>
<td>41</td>
<td>27</td>
<td>42</td>
<td>44</td>
<td>39</td>
<td>41</td>
</tr>
<tr class="even">
<td>80%</td>
<td>70%</td>
<td>82%</td>
<td>54%</td>
<td>84%</td>
<td>88%</td>
<td>78%</td>
<td>82%</td>
</tr>
<tr class="odd">
<td rowspan="2"><strong>80</strong></td>
<td>19</td>
<td>11</td>
<td>21</td>
<td>21</td>
<td>22</td>
<td>25</td>
<td>20</td>
<td>39</td>
</tr>
<tr class="even">
<td>38%</td>
<td>29%</td>
<td>42%</td>
<td>42%</td>
<td>44%</td>
<td>50%</td>
<td>40%</td>
<td>78%</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="9"><p>At 3500 ppm at the 18-month haematology
determination, a tendency towards lower RBC count was noted in both
sexes. This change was associated with a slightly lower haemoglobin
concentration, haematocrit and mean corpuscular haemoglobin
concentration and a slightly higher mean corpuscular volume. This
corresponds to similar effects seen in the short terms studies in the
rat and dog, although not in the 90 day mouse study.</p>
<p>Apart from the effects on the urinary system long term dosing in the
mouse resulted in treatment-related effects in the males specifically
centrilobular to panlobular hepatocellular hypertrophy doses <u>&gt;</u>
2000 pp and an increased incidence of hepatocellular single cell
necrosis was observed at 3500 ppm. Another notable change was observed
in the lymphoid system (apoptotic bodies and/or lymphoid atrophy) at
3500 ppm which was considered stress induced. In the heart, a higher
incidence of epicardial mixed cell infiltrate was noted in 5/50 males at
3500 ppm, when compared to no cases in controls. This minimal change
only observed in males was considered to be an indirect response to the
treatment.</p>
<p>Two treatment related tumours were observed in this study both in top
dose females, and both transitional cell papillomas in the urinary
bladder. These tumours were very likely to be a consequence of the
chronic irritation/hyperplasia due to the presence of calculi. Analysis
of urinary bladder stones taken from one male and one female at terminal
sacrifice revealed that the composition of the stones consisted of
approximately 90 to 95% of test material.</p>
<p>The only other statistically significant neoplastic change was an
increased incidence of histiocytic sarcoma was noted in females at 3500
ppm (5/50) cf. 0/50 in controls. Single histiocytic sarcomas were also
noted at 350 ppm (females) and 2000 ppm (males). The Notifier has
provided some published historical control data from the early and late
1990’s; this study was conducted 2004-6 so the relevance of these data
is questionable. The HC data indicate incidence of histiocytic sarcoma
in the C57BL/6J mouse for a 19 months study, similar in length to this
study ranged between 6-42%.</p>
<p>Overall the HC data do show that there is a high backgrounds
incidence of histiocytic sarcoma in the C57BL/6J mouse. The tumours seen
at 3500 ppm in females have an equivocal relationship to treatment at
worst.</p></td>
</tr>
<tr class="even">
<td><strong>Conclusions</strong></td>
<td colspan="9"><p>Cyprosulfamide was carcinogenic in the mouse although
the occurrence of tumours (transitional cell papilloma in the urinary
bladder of females) was considered to be secondary to the chronic
hyperplastic changes resulting from chronic irritation due to the
presence of calculi.</p>
<p>In males a NOAEL of 350 ppm (equivalent to 50 mg/kg bw/day) was based
on the effects seen in the urinary tract (combination of hyperplastic
and inflammatory changes) resulting from the presence of stones and/or
crystals at 2000 ppm and some evidence of hepatotoxicity.</p>
<p>In females a NOAEL of 2000 ppm for females (equivalent to 345 mg/kg
bw/day) was based on the effects seen in the urinary tract (combination
of hyperplastic and inflammatory changes, and tumours) resulting from
the presence of stones and/or crystals at 3500 ppm.</p></td>
</tr>
</tbody>
</table>

+-----------------------------------------------------------------------+
| **SUMMARY OF LONG-TERMTOXICITY AND CARCINOGENICITY DATA BY REGULATORY |
| AUTHORITY**                                                           |
+-----------------------------------------------------------------------+
| **Name of authority:** Pesticides Safety Directorate, UK              |
+-----------------------------------------------------------------------+
| Cyprosulfamide was investigated in two guideline studies in the rat   |
| and mouse. Treatment related tumours were seen in both species        |
+-----------------------------------------------------------------------+
| In the rat there was a slight treatment related increase in mortality |
| in top dose females where half of the unscheduled deaths were         |
| attributed to treatment-related nephropathy. A concerning aspect of   |
| the study was poor survival rates in males- across all groups         |
| (survival rates at 104 weeks falling to 41.1%, 49.2%, 27.4%, and      |
| 34.4% at 0, 1000, 4000 and 8000 ppm respectively). Survival in males  |
| at doses of 4000 ppm and 8000 ppm drop below 50% at around week 94.   |
| It was considered that this weakens the carcinogenicity assessment at |
| these dose levels                                                     |
|                                                                       |
| Sulphonamide-like crystals were observed at 8000 and 4000 ppm in both |
| sexes. This finding was dose-related in terms of incidence and/or     |
| severity on most occasions, the effect being more pronounced in       |
| females than in males. Urinalysis revealed slightly lower urinary     |
| protein levels throughout most the study in both sexes at 8000 and    |
| 4000 ppm compared to controls. A statistically significant increase   |
| in urinary volume was noted at 8000 ppm in females during the         |
| toxicity phase of the study (59% higher than controls), although this |
| was not observed during the second year of the study.                 |
|                                                                       |
| Gross necropsy of both premature decedents and at terminal sacrifice  |
| revealed treatment related changes in the kidneys and urinary bladder |
| at doses \>4000 ppm. Findings in the kidneys included abnormal shape, |
| pelvic dilatation, irregular surface, gritty content and stones. In   |
| the urinary bladder stones were observed.                             |
|                                                                       |
| At 24 months treatment-related non-neoplastic effects were observed   |
| in the urinary tract, i.e. kidney, urinary bladder and ureter,        |
| including a combination of hyperplastic and inflammatory changes      |
| associated with the presence of stones. Treatment-induced nephropathy |
| was observed at a higher incidence in both sexes in the kidney at     |
| 8000 ppm, with an increased severity in females, and at 4000 ppm in a |
| higher incidence in females only. Treatment-induced nephropathy is a  |
| general term which incorporates some or all of the following          |
| findings: stones, papillary necrosis/loss/scarring, collecting duct   |
| hyperplasia, bilateral cortico-medullary scarring, pelvic dilatation  |
| and bilateral cortex/medulla tubular dilatation. In addition, an      |
| increased incidence of pelvic dilatation was noted at 4000 ppm in     |
| males.                                                                |
|                                                                       |
| A slight increase in severity of simple pelvic epithelium hyperplasia |
| was observed in both sexes at 8000 and 4000 ppm. Nodular pelvic       |
| epithelium hyperplasia and a higher incidence of intrapelvic mineral  |
| deposit was observed in females at 8000 ppm. Intraluminal stones and  |
| multifocal/diffuse urothelial hyperplasia were observed in the        |
| urinary bladder in both sexes at 8000 ppm and in females at 4000 ppm. |
| Suburothelial mononuclear cell infiltrate and mixed cell infiltrate   |
| were considered to be associated lesions                              |
|                                                                       |
| An increased incidence of the commonly occurring lesion diffuse       |
| bilateral tubular degeneration of the testis (associated with diffuse |
| interstitial oedema and/or focal/multifocal mineralization in most    |
| cases) and bilateral oligospermia of the epididymis (associated with  |
| epithelial degenerative change) was observed at 8000 ppm, which was   |
| considered to be treatment-related.                                   |
|                                                                       |
| Indirect systemic changes commonly associated with induced            |
| nephropathy, including compensatory hyperplasia of the parathyroid    |
| glands associated with mineralization, especially involving lungs and |
| the gastric mucosa, were observed at 8000 ppm mainly in females.      |
|                                                                       |
| At 24 months treatment-related neoplastic changes were seen at 8000   |
| ppm, a transitional cell carcinoma was observed in the kidney in one  |
| male and a transitional cell carcinoma was observed in the urinary    |
| bladder in one female. These two single tumours were considered to be |
| secondary to the combination of hyperplastic and inflammatory changes |
| associated with the presence of stones                                |
+-----------------------------------------------------------------------+
| In the mouse mortality was higher in males at 3500 ppm than in the    |
| control group after 12 and 18 months of treatment, largely due to the |
| presence of stones within the urinary tract, causing acute or chronic |
| renal failure or due to secondary treatment-related nephropathy       |
| following product administration. At 3500 ppm at the 18-month         |
| haematology determination, a tendency towards lower RBC count was     |
| noted in both sexes. This change was associated with a slightly lower |
| haemoglobin concentration, haematocrit and mean corpuscular           |
| haemoglobin concentration and a slightly higher mean corpuscular      |
| volume. This corresponds to similar effects seen in the short terms   |
| studies in the rat and dog, although not in the 90 day mouse study.   |
|                                                                       |
| Histopathological treatment-related changes were mainly attributed to |
| the presence of urinary stones or to treatment-related nephropathy.   |
| These changes were located in the urinary bladder and to a less       |
| extent to the kidney at the 12-month interim sacrifice. At the        |
| carcinogenicity phase (18-month) sacrifice, changes due to            |
| treatment-related nephropathy were seen in the kidney, urinary        |
| bladder, prostatic urethra and ureters. In the liver, minimal to      |
| slight centrilobular to panlobular hepatocellular hypertrophy and an  |
| increased incidence of hepatocellular single cell necrosis were       |
| observed in males. All the effects seen in the urinary tract were     |
| considered to be due to a single and chronic irritative mechanism,    |
| resulting from the formation of stones or crystals. In addition,      |
| indirect treatment-related findings were observed in the lymphoid     |
| system in males (apoptotic bodies in the spleen and mesenteric lymph  |
| nodes, and lymphoid atrophy in the spleen) and were considered to be  |
| secondary to the stress induced by the stone deposition and/or the    |
| treatment-related nephropathy. In the heart, a higher incidence of    |
| epicardial mixed cell infiltrate was noted in 5/50 males at 3500 ppm, |
| when compared to no cases in controls. This minimal change only       |
| observed in males was considered to be an indirect and non-adverse    |
| response to the treatment.                                            |
|                                                                       |
| Neoplastic changes comprised transitional cell papilloma in the       |
| urinary bladder of 2/49 females at 3500 ppm. This finding was         |
| considered to be secondary to the chronic hyperplastic changes due to |
| the presence of calculi. Analysis of urinary bladder stones taken     |
| from one male and one female at terminal sacrifice revealed that the  |
| composition of the stones consisted of approximately 90 to 95% of     |
| test material.                                                        |
|                                                                       |
| A NOAEL of 1000 ppm for both sexes (equivalent to mean achieved       |
| dietary intakes of 147 and 185 mg/kg bw/d in males and females        |
| respectively) was determined for this study.                          |
|                                                                       |
| [Relevance of tumours to the human risk assessment]{.underline}       |
|                                                                       |
| Cyprosulfamide was shown to be carcinogenic in rats and mice. In the  |
| rat there was a low incidence of transitional cell carcinoma in the   |
| kidney and transitional cell carcinoma in the urinary bladder. In the |
| mouse a low incidence of transitional cell papilloma in the urinary   |
| bladder. In both species the formation of these tumours was a result  |
| of a non-genotoxic threshold mechanism involving chronic irritation   |
| secondary to the formation of calculi. The Notifier has proposed a    |
| mechanism these tumours see IIA 5.5.4 below. The proposed mechanism   |
| is considered to be plausible and fulfils the critical criteria of    |
| the IPCS conceptual framework for analysis of the relevance of a      |
| cancer mode of action for humans (IPCS, 2001). While there is little  |
| in the way of mechanistic data, key aspects of the IPCS criteria      |
| including a dose-response relationship with a clear threshold,        |
| biological plausibility and coherence, temporal association are       |
| satisfied. Cyprosulfamide is considered to be non-genotoxic. The lack |
| of relevance of the mode of carcinogenesis for the human risk         |
| assessment means that classification of cyprosulfamide for            |
| carcinogenicity (current EC criteria) is not proposed.                |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| HED Reviewer Comments:                                                |
|                                                                       |
| **Classification: Acceptable/Guideline.** This study satisfies the    |
| guideline requirement for a series 870.4200 carcinogenicity study in  |
| mice.                                                                 |
+-----------------------------------------------------------------------+

**A.3.6 Mutagenicity**

+---------------+---+-------------+---+----------------+---+-----------------+
| **C           |   |             |   |                |   |                 |
| yprosulfamide |   |             |   |                |   |                 |
| and           |   |             |   |                |   |                 |
| metabolites   |   |             |   |                |   |                 |
| --            |   |             |   |                |   |                 |
| mutagenicity  |   |             |   |                |   |                 |
| studies**.    |   |             |   |                |   |                 |
+===============+===+=============+===+================+===+=================+
| Study         |   | MRID        | R |                |   | Classification: |
|               |   |             | e |                |   |                 |
|               |   |             | s |                |   | UK/HED\*        |
|               |   |             | u |                |   |                 |
|               |   |             | l |                |   |                 |
|               |   |             | t |                |   |                 |
|               |   |             | s |                |   |                 |
+---------------+---+-------------+---+----------------+---+-----------------+
| **Cyp         |   |             |   |                |   |                 |
| rosulfamide** |   |             |   |                |   |                 |
+---------------+---+-------------+---+----------------+---+-----------------+
| 870.5100.     | 4 |             | N |                | \ |                 |
| Bacterial --  | 7 |             | o |                | [ |                 |
| Ames test     | 0 |             | t |                | R |                 |
|               | 6 |             | a |                | e |                 |
|               | 9 |             | n |                | l |                 |
|               | 8 |             | t |                | i |                 |
|               | 2 |             | i |                | a |                 |
|               | 1 |             | b |                | b |                 |
|               | 9 |             | a |                | l |                 |
|               |   |             | c |                | e |                 |
|               | \ |             | t |                | w |                 |
|               | ( |             | e |                | i |                 |
|               | 2 |             | r |                | t |                 |
|               | 0 |             | i |                | h |                 |
|               | 0 |             | a |                | r |                 |
|               | 6 |             | l |                | e |                 |
|               | \ |             | , |                | s |                 |
|               | ) |             | N |                | t |                 |
|               |   |             | o |                | r |                 |
|               | P |             | t |                | i |                 |
|               | a |             | m |                | c |                 |
|               | r |             | u |                | t |                 |
|               | e |             | t |                | i |                 |
|               | n |             | a |                | o |                 |
|               | t |             | g |                | n |                 |
|               | ( |             | e |                | s |                 |
|               | 9 |             | n |                | \ |                 |
|               | 6 |             | i |                | ] |                 |
|               | . |             | c |                | / |                 |
|               | 0 |             | a |                |   |                 |
|               | % |             | t |                | A |                 |
|               | ) |             | u |                | c |                 |
|               |   |             | p |                | c |                 |
|               |   |             | t |                | e |                 |
|               |   |             | o |                | p |                 |
|               |   |             | 5 |                | t |                 |
|               |   |             | 0 |                | a |                 |
|               |   |             | 0 |                | b |                 |
|               |   |             | 0 |                | l |                 |
|               |   |             | μ |                | e |                 |
|               |   |             | g |                | / |                 |
|               |   |             | / |                | G |                 |
|               |   |             | p |                | u |                 |
|               |   |             | l |                | i |                 |
|               |   |             | a |                | d |                 |
|               |   |             | t |                | e |                 |
|               |   |             | e |                | l |                 |
|               |   |             | . |                | i |                 |
|               |   |             |   |                | n |                 |
|               |   |             |   |                | e |                 |
+---------------+---+-------------+---+----------------+---+-----------------+
| 870.5100.     | 4 |             | N |                | \ |                 |
| Bacterial --  | 7 |             | o |                | [ |                 |
| Ames test     | 0 |             | t |                | R |                 |
|               | 6 |             | m |                | e |                 |
|               | 9 |             | u |                | l |                 |
|               | 8 |             | t |                | i |                 |
|               | 2 |             | a |                | a |                 |
|               | 0 |             | g |                | b |                 |
|               | ( |             | e |                | l |                 |
|               | 2 |             | n |                | e |                 |
|               | 0 |             | i |                | w |                 |
|               | 0 |             | c |                | i |                 |
|               | 4 |             |   |                | t |                 |
|               | / |             |   |                | h |                 |
|               | 2 |             |   |                | r |                 |
|               | 0 |             |   |                | e |                 |
|               | 0 |             |   |                | s |                 |
|               | 5 |             |   |                | t |                 |
|               | ) |             |   |                | r |                 |
|               |   |             |   |                | i |                 |
|               | P |             |   |                | c |                 |
|               | a |             |   |                | t |                 |
|               | r |             |   |                | i |                 |
|               | e |             |   |                | o |                 |
|               | n |             |   |                | n |                 |
|               | t |             |   |                | s |                 |
|               | ( |             |   |                | \ |                 |
|               | 9 |             |   |                | ] |                 |
|               | 7 |             |   |                | / |                 |
|               | . |             |   |                |   |                 |
|               | 4 |             |   |                | A |                 |
|               | % |             |   |                | c |                 |
|               | ) |             |   |                | c |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | p |                 |
|               |   |             |   |                | t |                 |
|               |   |             |   |                | a |                 |
|               |   |             |   |                | b |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | / |                 |
|               |   |             |   |                | G |                 |
|               |   |             |   |                | u |                 |
|               |   |             |   |                | i |                 |
|               |   |             |   |                | d |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | i |                 |
|               |   |             |   |                | n |                 |
|               |   |             |   |                | e |                 |
+---------------+---+-------------+---+----------------+---+-----------------+
| 870.5300.     | 4 |             | N |                | \ |                 |
| Forward       | 7 |             | e |                | [ |                 |
| mutation      | 0 |             | g |                | R |                 |
|               | 6 |             | a |                | e |                 |
|               | 9 |             | t |                | l |                 |
|               | 8 |             | i |                | i |                 |
|               | 2 |             | v |                | a |                 |
|               | 3 |             | e |                | b |                 |
|               | ( |             | i |                | l |                 |
|               | 2 |             | n |                | e |                 |
|               | 0 |             | t |                | w |                 |
|               | 0 |             | h |                | i |                 |
|               | 6 |             | e |                | t |                 |
|               | ) |             | V |                | h |                 |
|               |   |             | 7 |                | r |                 |
|               | P |             | 9 |                | e |                 |
|               | a |             | / |                | s |                 |
|               | r |             | H |                | t |                 |
|               | e |             | P |                | r |                 |
|               | n |             | R |                | i |                 |
|               | t |             | T |                | c |                 |
|               |   |             | f |                | t |                 |
|               |   |             | o |                | i |                 |
|               |   |             | r |                | o |                 |
|               |   |             | w |                | n |                 |
|               |   |             | a |                | s |                 |
|               |   |             | r |                | \ |                 |
|               |   |             | d |                | ] |                 |
|               |   |             | m |                | / |                 |
|               |   |             | u |                |   |                 |
|               |   |             | t |                | A |                 |
|               |   |             | a |                | c |                 |
|               |   |             | t |                | c |                 |
|               |   |             | i |                | e |                 |
|               |   |             | o |                | p |                 |
|               |   |             | n |                | t |                 |
|               |   |             | t |                | a |                 |
|               |   |             | e |                | b |                 |
|               |   |             | s |                | l |                 |
|               |   |             | t |                | e |                 |
|               |   |             |   |                | / |                 |
|               |   |             |   |                | G |                 |
|               |   |             |   |                | u |                 |
|               |   |             |   |                | i |                 |
|               |   |             |   |                | d |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | i |                 |
|               |   |             |   |                | n |                 |
|               |   |             |   |                | e |                 |
+---------------+---+-------------+---+----------------+---+-----------------+
| 870.5375. *In | 4 |             | N |                | \ |                 |
| vitro*        | 7 |             | o |                | [ |                 |
| chromosome    | 0 |             | c |                | T |                 |
|               | 6 |             | l |                | o |                 |
| aberration    | 9 |             | a |                | t |                 |
| test in V79   | 8 |             | s |                | a |                 |
|               | 2 |             | t |                | l |                 |
|               | 6 |             | o |                | l |                 |
|               | ( |             | g |                | y |                 |
|               | 2 |             | e |                | r |                 |
|               | 0 |             | n |                | e |                 |
|               | 0 |             | i |                | l |                 |
|               | 4 |             | c |                | i |                 |
|               | / |             | e |                | a |                 |
|               | 2 |             | f |                | b |                 |
|               | 0 |             | f |                | l |                 |
|               | 0 |             | e |                | e |                 |
|               | 6 |             | c |                | \ |                 |
|               | ) |             | t |                | ] |                 |
|               |   |             | a |                | / |                 |
|               | P |             | t |                |   |                 |
|               | a |             | u |                | A |                 |
|               | r |             | p |                | c |                 |
|               | e |             | t |                | c |                 |
|               | n |             | o |                | e |                 |
|               | t |             | 1 |                | p |                 |
|               |   |             | 6 |                | t |                 |
|               |   |             | 0 |                | a |                 |
|               |   |             | 0 |                | b |                 |
|               |   |             | μ |                | l |                 |
|               |   |             | g |                | e |                 |
|               |   |             | / |                | / |                 |
|               |   |             | m |                | G |                 |
|               |   |             | l |                | u |                 |
|               |   |             | . |                | i |                 |
|               |   |             |   |                | d |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | i |                 |
|               |   |             |   |                | n |                 |
|               |   |             |   |                | e |                 |
+---------------+---+-------------+---+----------------+---+-----------------+
| 870.5395.     | 4 |             | N |                | \ |                 |
|               | 7 |             | o |                | [ |                 |
| Micronucleus  | 0 |             | e |                | T |                 |
| test *in      | 6 |             | v |                | o |                 |
| vivo*         | 9 |             | i |                | t |                 |
|               | 8 |             | d |                | a |                 |
|               | 2 |             | e |                | l |                 |
|               | 9 |             | n |                | l |                 |
|               | ( |             | c |                | y |                 |
|               | 2 |             | e |                | r |                 |
|               | 0 |             | o |                | e |                 |
|               | 0 |             | f |                | l |                 |
|               | 4 |             | a |                | i |                 |
|               | / |             | c |                | a |                 |
|               | 2 |             | l |                | b |                 |
|               | 0 |             | a |                | l |                 |
|               | 0 |             | s |                | e |                 |
|               | 6 |             | t |                | \ |                 |
|               | ) |             | o |                | ] |                 |
|               |   |             | g |                | / |                 |
|               | P |             | e |                |   |                 |
|               | a |             | n |                | A |                 |
|               | r |             | i |                | c |                 |
|               | e |             | c |                | c |                 |
|               | n |             | e |                | e |                 |
|               | t |             | f |                | p |                 |
|               |   |             | f |                | t |                 |
|               |   |             | e |                | a |                 |
|               |   |             | c |                | b |                 |
|               |   |             | t |                | l |                 |
|               |   |             | a |                | e |                 |
|               |   |             | f |                | / |                 |
|               |   |             | t |                | G |                 |
|               |   |             | e |                | u |                 |
|               |   |             | r |                | i |                 |
|               |   |             | t |                | d |                 |
|               |   |             | w |                | e |                 |
|               |   |             | o |                | l |                 |
|               |   |             | d |                | i |                 |
|               |   |             | o |                | n |                 |
|               |   |             | s |                | e |                 |
|               |   |             | e |                |   |                 |
|               |   |             | s |                |   |                 |
|               |   |             | u |                |   |                 |
|               |   |             | p |                |   |                 |
|               |   |             | t |                |   |                 |
|               |   |             | o |                |   |                 |
|               |   |             | 2 |                |   |                 |
|               |   |             | 0 |                |   |                 |
|               |   |             | 0 |                |   |                 |
|               |   |             | 0 |                |   |                 |
|               |   |             | m |                |   |                 |
|               |   |             | g |                |   |                 |
|               |   |             | / |                |   |                 |
|               |   |             | k |                |   |                 |
|               |   |             | g |                |   |                 |
|               |   |             | ( |                |   |                 |
|               |   |             | i |                |   |                 |
|               |   |             | p |                |   |                 |
|               |   |             | ) |                |   |                 |
+---------------+---+-------------+---+----------------+---+-----------------+
| **Metabolite: |   |             |   |                |   |                 |
| Sul           |   |             |   |                |   |                 |
| famoylbenzoic |   |             |   |                |   |                 |
| acid**        |   |             |   |                |   |                 |
+---------------+---+-------------+---+----------------+---+-----------------+
| 870.5         | 4 |             | N |                | \ |                 |
| 100.Bacterial | 7 |             | o |                | [ |                 |
| -- Ames test  | 0 |             | t |                | R |                 |
|               | 6 |             | m |                | e |                 |
|               | 9 |             | u |                | l |                 |
|               | 8 |             | t |                | i |                 |
|               | 2 |             | a |                | a |                 |
|               | 1 |             | g |                | b |                 |
|               | ( |             | e |                | l |                 |
|               | 2 |             | n |                | e |                 |
|               | 0 |             | i |                | w |                 |
|               | 0 |             | c |                | i |                 |
|               | 6 |             |   |                | t |                 |
|               | ) |             |   |                | h |                 |
|               |   |             |   |                | r |                 |
|               | S |             |   |                | e |                 |
|               | u |             |   |                | s |                 |
|               | l |             |   |                | t |                 |
|               | f |             |   |                | r |                 |
|               | a |             |   |                | i |                 |
|               | m |             |   |                | c |                 |
|               | o |             |   |                | t |                 |
|               | y |             |   |                | i |                 |
|               | l |             |   |                | o |                 |
|               | b |             |   |                | n |                 |
|               | e |             |   |                | s |                 |
|               | n |             |   |                | \ |                 |
|               | z |             |   |                | ] |                 |
|               | o |             |   |                | / |                 |
|               | i |             |   |                |   |                 |
|               | c |             |   |                | A |                 |
|               | a |             |   |                | c |                 |
|               | c |             |   |                | c |                 |
|               | i |             |   |                | e |                 |
|               | d |             |   |                | p |                 |
|               |   |             |   |                | t |                 |
|               |   |             |   |                | a |                 |
|               |   |             |   |                | b |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | / |                 |
|               |   |             |   |                | G |                 |
|               |   |             |   |                | u |                 |
|               |   |             |   |                | i |                 |
|               |   |             |   |                | d |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | i |                 |
|               |   |             |   |                | n |                 |
|               |   |             |   |                | e |                 |
+---------------+---+-------------+---+----------------+---+-----------------+
| 870.5300.     | 4 |             | N |                | \ |                 |
| Forward       | 7 |             | e |                | [ |                 |
| mutation      | 0 |             | g |                | T |                 |
|               | 6 |             | a |                | o |                 |
|               | 9 |             | t |                | t |                 |
|               | 8 |             | i |                | a |                 |
|               | 2 |             | v |                | l |                 |
|               | 4 |             | e |                | l |                 |
|               | ( |             | i |                | y |                 |
|               | 2 |             | n |                | r |                 |
|               | 0 |             | t |                | e |                 |
|               | 0 |             | h |                | l |                 |
|               | 6 |             | e |                | i |                 |
|               | ) |             | V |                | a |                 |
|               |   |             | 7 |                | b |                 |
|               | S |             | 9 |                | l |                 |
|               | u |             | / |                | e |                 |
|               | l |             | H |                | \ |                 |
|               | f |             | P |                | ] |                 |
|               | a |             | R |                | / |                 |
|               | n |             | T |                |   |                 |
|               | o |             | f |                | A |                 |
|               | y |             | o |                | c |                 |
|               | l |             | r |                | c |                 |
|               | b |             | w |                | e |                 |
|               | e |             | a |                | p |                 |
|               | n |             | r |                | t |                 |
|               | z |             | d |                | a |                 |
|               | o |             | m |                | b |                 |
|               | i |             | u |                | l |                 |
|               | c |             | t |                | e |                 |
|               |   |             | a |                | / |                 |
|               | A |             | t |                | G |                 |
|               | c |             | i |                | u |                 |
|               | i |             | o |                | i |                 |
|               | d |             | n |                | d |                 |
|               |   |             | t |                | e |                 |
|               |   |             | e |                | l |                 |
|               |   |             | s |                | i |                 |
|               |   |             | t |                | n |                 |
|               |   |             |   |                | e |                 |
+---------------+---+-------------+---+----------------+---+-----------------+
| 870.5375. *In | 4 |             | N |                | \ |                 |
| vitro*        | 7 |             | e |                | [ |                 |
| chromosome    | 0 |             | g |                | T |                 |
|               | 6 |             | a |                | o |                 |
| aberration    | 9 |             | t |                | t |                 |
| test in V79   | 8 |             | i |                | a |                 |
|               | 2 |             | v |                | l |                 |
|               | 7 |             | e |                | l |                 |
|               | ( |             |   |                | y |                 |
|               | 2 |             |   |                | r |                 |
|               | 0 |             |   |                | e |                 |
|               | 0 |             |   |                | l |                 |
|               | 6 |             |   |                | i |                 |
|               | ) |             |   |                | a |                 |
|               |   |             |   |                | b |                 |
|               | s |             |   |                | l |                 |
|               | u |             |   |                | e |                 |
|               | l |             |   |                | \ |                 |
|               | f |             |   |                | ] |                 |
|               | a |             |   |                | / |                 |
|               | m |             |   |                |   |                 |
|               | o |             |   |                | A |                 |
|               | y |             |   |                | c |                 |
|               | l |             |   |                | c |                 |
|               | b |             |   |                | e |                 |
|               | e |             |   |                | p |                 |
|               | n |             |   |                | t |                 |
|               | z |             |   |                | a |                 |
|               | o |             |   |                | b |                 |
|               | i |             |   |                | l |                 |
|               | c |             |   |                | e |                 |
|               | a |             |   |                | / |                 |
|               | c |             |   |                | G |                 |
|               | i |             |   |                | u |                 |
|               | d |             |   |                | i |                 |
|               |   |             |   |                | d |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | i |                 |
|               |   |             |   |                | n |                 |
|               |   |             |   |                | e |                 |
+---------------+---+-------------+---+----------------+---+-----------------+
| **Metabolite: |   |             |   |                |   |                 |
| Cyclop        |   |             |   |                |   |                 |
| ropyl-sulfamo |   |             |   |                |   |                 |
| ylbenzamide** |   |             |   |                |   |                 |
+---------------+---+-------------+---+----------------+---+-----------------+
| 870.5         |   | 47069822    |   | Not mutagenic  | \ |                 |
| 100.Bacterial |   | (2006)      |   |                | [ |                 |
| -- Ames test  |   | C           |   |                | T |                 |
|               |   | yclopropyl- |   |                | o |                 |
|               |   | sulfamo     |   |                | t |                 |
|               |   | ylbenzamide |   |                | a |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | y |                 |
|               |   |             |   |                | r |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | i |                 |
|               |   |             |   |                | a |                 |
|               |   |             |   |                | b |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | \ |                 |
|               |   |             |   |                | ] |                 |
|               |   |             |   |                | / |                 |
|               |   |             |   |                |   |                 |
|               |   |             |   |                | A |                 |
|               |   |             |   |                | c |                 |
|               |   |             |   |                | c |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | p |                 |
|               |   |             |   |                | t |                 |
|               |   |             |   |                | a |                 |
|               |   |             |   |                | b |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | / |                 |
|               |   |             |   |                | G |                 |
|               |   |             |   |                | u |                 |
|               |   |             |   |                | i |                 |
|               |   |             |   |                | d |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | i |                 |
|               |   |             |   |                | n |                 |
|               |   |             |   |                | e |                 |
+---------------+---+-------------+---+----------------+---+-----------------+
| 870.5300.     |   | 47069825    |   | Negative in    | \ |                 |
| Forward       |   | (2006)      |   | the V79/HPRT   | [ |                 |
| mutation      |   |             |   | forward        | T |                 |
|               |   | C           |   | mutation test  | o |                 |
|               |   | yclopropyl- |   |                | t |                 |
|               |   | sulfamo     |   |                | a |                 |
|               |   | ylbenzamide |   |                | l |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | y |                 |
|               |   |             |   |                | r |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | i |                 |
|               |   |             |   |                | a |                 |
|               |   |             |   |                | b |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | \ |                 |
|               |   |             |   |                | ] |                 |
|               |   |             |   |                | / |                 |
|               |   |             |   |                |   |                 |
|               |   |             |   |                | A |                 |
|               |   |             |   |                | c |                 |
|               |   |             |   |                | c |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | p |                 |
|               |   |             |   |                | t |                 |
|               |   |             |   |                | a |                 |
|               |   |             |   |                | b |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | / |                 |
|               |   |             |   |                | G |                 |
|               |   |             |   |                | u |                 |
|               |   |             |   |                | i |                 |
|               |   |             |   |                | d |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | i |                 |
|               |   |             |   |                | n |                 |
|               |   |             |   |                | e |                 |
+---------------+---+-------------+---+----------------+---+-----------------+
| 870.5375. *In |   | 47069828    |   | Negative       | \ |                 |
| vitro*        |   | (2006)      |   |                | [ |                 |
| chromosome    |   |             |   |                | T |                 |
|               |   | Cyclopro    |   |                | o |                 |
| aberration    |   | pyl-sulfamo |   |                | t |                 |
| test in V79   |   | ylbenzamide |   |                | a |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | y |                 |
|               |   |             |   |                | r |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | i |                 |
|               |   |             |   |                | a |                 |
|               |   |             |   |                | b |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | \ |                 |
|               |   |             |   |                | ] |                 |
|               |   |             |   |                | / |                 |
|               |   |             |   |                |   |                 |
|               |   |             |   |                | A |                 |
|               |   |             |   |                | c |                 |
|               |   |             |   |                | c |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | p |                 |
|               |   |             |   |                | t |                 |
|               |   |             |   |                | a |                 |
|               |   |             |   |                | b |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | / |                 |
|               |   |             |   |                | G |                 |
|               |   |             |   |                | u |                 |
|               |   |             |   |                | i |                 |
|               |   |             |   |                | d |                 |
|               |   |             |   |                | e |                 |
|               |   |             |   |                | l |                 |
|               |   |             |   |                | i |                 |
|               |   |             |   |                | n |                 |
|               |   |             |   |                | e |                 |
+---------------+---+-------------+---+----------------+---+-----------------+

**A.3.7 Neurotoxicity**

**870.6100 Delayed Neurotoxicity Study - Hen**

**No study available and not required.**

**870.6200 Acute Neurotoxicity Screening Battery - MRID No\>;
47069830.**

**Executive summary:**

Technical grade AE 0001789 (batch number 08466/0013, 97.4% purity) was
administered by gavage in a single dose to non fasted young-adult Wistar
rats. Four dose groups (12 rats/sex/dose level) were administered the
test substance at nominal doses of 0 (vehicle), 125, 500 or 2000 mg/kg
for both sexes. The test substance was administered in 0.5%
methylcellulose / 0.4% Tween 80 in deionized water, at a dosing volume
of 10 ml/kg. Dose concentrations, as well as the homogeneity and
stability of AE 0001789 in the dosing suspensions, were confirmed. All
12 rats/sex/dose level were used for neurobehavioural evaluation, with
six/sex/dose level used for micropathology. Body weight was measured
weekly as a component of the functional observational battery (FOB).
Detailed clinical observations for each animal were performed daily
throughout the study. Observations for moribundity and mortality were
performed at least once daily. Automated measurements of activity
(figure-eight maze) and a functional observational battery (FOB) were
conducted during the week prior to treatment and on days 0 (the day of
treatment, at the time of peak effect), 7 and 14. All animals placed on
study were subjected to a gross necropsy. Selected animals (six/sex/dose
level) were perfused, the brain was weighed in order to calculate the
brain/body weight ratio and skeletal muscle, peripheral nerves, eyes
(with optic nerves) and tissues from the central nervous system were
examined microscopically for lesions.

Based on analytical results, the actual doses of AE 0001789 used in the
study were 0, 126, 508 and 2060 mg/kg for males and females.

Findings attributed to exposure to AE 0001789 were as follows:

**2060 mg/kg:** Urine staining was evident in both sexes on day 0 and
resolved by the following day.

**508 mg/kg:** There were no signs related to treatment in either sex.

**126 mg/kg:** There were no signs related to treatment in either sex.

**In conclusion,** compound-related effects following a single oral dose
of the test substance were limited to the high dose (2060 mg/kg) males
and females. Effects in high-dose males and females consisted of urine
staining, which resolved the following day after treatment. Based on
these findings, a NOEL of 508 mg AE 0001789/kg body weight was
established in both sexes. There was no evidence of neurotoxicity at any
dose level and there were no compound-related gross or microscopic
lesions at the high dose of 2060 mg/kg.

  ----------------- -------------------------------------------------------
  **EVALUATION,     
  SUMMARY AND       
  CONCLUSION BY     
  REGULATORY        
  AUTHORITY**       

  **Name of         Pesticides Safety Directorate, UK
  authority**       

  **Reviewer's      Reliability rating: Reliable with restrictions
  comments**        

                    The study is compliant with OECD 424 (1997) with the
                    exception of the following deviations:

                    The guideline states that 'dosing should normally begin
                    as soon as possible after weaning, preferably not later
                    than when the animals are six weeks, and, in any case,
                    before the animals are nine weeks of age'. The study
                    report states that the animals in this study were 'at
                    least nine weeks' old at the time of dosing. This
                    deviation is not considered to affect the integrity of
                    the study in this case. It is noted that there was no
                    indication of neurotoxicity in any of the standard
                    toxicity studies (required under Directive 91/414/EEC),
                    including the neurotoxicity assessment in the 90-day
                    toxicity study. A study of neurotoxicity is therefore
                    not a specific data requirement for this compound
                    according to EU legislation, based on the absence of
                    findings in the other studies and the mode of action of
                    the compound.

                    Food consumption was not measured in this study,
                    whereas the guideline specifies that food consumption
                    should be measured at least weekly. This deviation is
                    not considered to be critical and does not affect the
                    integrity of the study. Food consumption was not
                    affected in most of the other studies in the rat (or
                    other species).

  **Conclusions**   No evidence of neurotoxicity or neuropathology was seen
                    following the administration of a single oral limit
                    dose of 2060 mg/kg bw under the conditions of this
                    study. A NOAEL of 508 mg/kg bw can be determined, based
                    on urine staining at the top dose level of 2060 mg/kg
                    bw
  ----------------- -------------------------------------------------------

+-----------------------------------------------------------------------+
| HED Reviewer Comments:                                                |
|                                                                       |
| This study is classified as ACDEPTABLE/GUIDELINE and satisfies the    |
| requirement for a series 870.6200 acute neurotoxicity screen study.   |
| HED concurs with the NOAEL and LOAEL.                                 |
+-----------------------------------------------------------------------+

**870.6200 Subchronic Neurotoxicity Screening Battery - MRID No.:
47069831**

Technical grade AE 0001789 (batch number 08466/0013, 97.4 to 97.5%
purity) was administered in the diet for 13 weeks to young-adult Wistar
rats (12/sex/dietary level), using nominal concentrations of 0, 1000,
3000 and 9000 ppm for males and females. The top dose level for this
study was chosen based on mortality observed in a 90-day toxicity study
(M-105691-01-2) at a higher dietary level (i.e., 12,000 ppm). All test
diets (including control) were provided for *ad libitum* consumption
throughout the study except during neurobehavioural testing. All 12
rats/sex/dietary level were used for neurobehavioural evaluation, with
micropathology performed on selected tissues from 6 rats/sex from
control and high-dose groups. Body weight and food consumption
determinations, as well as a detailed clinical observation for each
animal, were conducted weekly throughout the study. Observations for
moribundity and mortality were performed at least once daily. Automated
measurements of activity (figure-eight maze) and a functional
observational battery (FOB) were conducted the week prior to treatment
and during weeks 2, 4, 8 and 13. Ophthalmologic examinations were
conducted on all animals prior to shipment release and then again on all
study animals during week 12. All animals placed on study were subjected
to a gross necropsy. For selected animals, the brain was weighed in
order to calculate the brain:body weight ratio and skeletal muscle,
peripheral nerves, eyes (with optic nerves) and tissues from the central
nervous system were also examined microscopically for lesions.Number
range CHAPTER

The mean daily intake of the test substance (mg AE 0001789/kg body
wt/day) over approximately 13 weeks at nominal dietary concentrations of
1000, 3000 or 9000 ppm, respectively, was 65.2, 193 and 592 mg/kg/day
for males and 84.5, 251 and 748 mg/kg/day for females.

There were no treatment-related effects attributed to exposure to AE
0001789 at any dietary level in either sex.

***Conclusions***. Through approximately 13 weeks of continuous dietary
exposure to the test substance, there were no treatment-related findings
apparent at any dietary level in either sex. Based on these findings, a
NOEL of 9000 ppm was established for the rat (equating to 592 and 748 mg
AE 0001789/kg body wt/day for males and females, respectively).

+---------------+------------------------------------------------------+
| **EVALUATION, |                                                      |
| SUMMARY AND   |                                                      |
| CONCLUSION BY |                                                      |
| REGULATORY    |                                                      |
| AUTHORITY**   |                                                      |
+---------------+------------------------------------------------------+
| **Name of     | Pesticides Safety Directorate, UK                    |
| authority**   |                                                      |
+---------------+------------------------------------------------------+
| **Reviewer's  | Reliability rating: Totally reliable                 |
| comments**    |                                                      |
|               | The study is fully compliant with OECD 424.          |
|               |                                                      |
|               | The animals in this study stated in the study report |
|               | to be approximately eight weeks old on Study Day 0,  |
|               | and not 'at least 9 weeks' as stated in the          |
|               | Notifier's summary. The age of the animals is        |
|               | therefore compliant with that specified in the OECD  |
|               | guideline (see comments for the acute neurotoxicity  |
|               | study, above).                                       |
|               |                                                      |
|               | It is noted that there was no indication of          |
|               | neurotoxicity in any of the standard toxicity        |
|               | studies (required under Directive 91/414/EEC),       |
|               | including the neurotoxicity assessment in the 90-day |
|               | toxicity study or in the acute neurotoxicity study.  |
|               | A study of neurotoxicity is therefore not a specific |
|               | data requirement for this compound according to EU   |
|               | legislation, based on the absence of findings in the |
|               | other studies and the mode of action of the          |
|               | compound..                                           |
|               |                                                      |
|               | No treatment-related findings were apparent in this  |
|               | study, based on the 90-day toxicity study in the rat |
|               | (Mc Elligott A. 2003, SA 02352) as higher dose could |
|               | have been employed however based on the absence of   |
|               | any evidence of neurotoxicity in other study this is |
|               | not considered a concern.                            |
+---------------+------------------------------------------------------+
| **            | No evidence of neurotoxicity or neuropathology was   |
| Conclusions** | seen under the conditions of this study.             |
|               |                                                      |
|               | A NOAEL of 9000 ppm (equivalent to mean achieved     |
|               | dietary intakes of 592 and 748 mg/kg bw/d in males   |
|               | and females respectively) can be determined, in the  |
|               | absence of any treatment-related findings at the top |
|               | dose level.                                          |
+---------------+------------------------------------------------------+

+-----------------------------------------------------------------------+
| HED Reviewer Comments:                                                |
|                                                                       |
| This study is classified as ACCEPTABLE/GUIDELINE and satisfies the    |
| requirement for a series 870.6200 subchronic neurotoxicity screen     |
| study in rats. HED concurs with the NOAEL and LOAEL setting.          |
+-----------------------------------------------------------------------+

**870.6300 Developmental Neurotoxicity Study**

**No study available and not required.**

**A.3.8 Metabolism**

**870.7485 Metabolism - Rat**

**Study 1. MRID No. 47069832. (sulfonylbenzamide label -
pharmacokinetics)**

The biokinetic behaviour and metabolism of
\[sulfonylbenzamide-UL-^14^C\] AE 0001789 was investigated in the rat
following a single oral dose. Groups of four animals each received a
single dose per gavage at a dose level of 2 and 200 mg/kg b.w\... The
absorption kinetic of the test item was followed by the time-dependent
level of radioactivity in blood plasma. The distribution of the
radioactivity in organs and tissues was studied after sacrifice, 96
hours of administration. The metabolism was could be derived from the
observed metabolites in urine and faeces. The elimination of radioactive
residues was determined by time-dependent determination of the
radioactivity in urine and faeces.

The gastro-intestinal absorption of the test item started immediately
after dosing. The maximum plasma levels were reached already after 10 --
60 minutes. The absorption was complete at the low dose (2 mg/kg b.w.)
in both sexes; more than 90 % of the dose recovered was renally excreted
or remained in the body at sacrifice, 96 hours after dosing (without
GIT). The excretion was fast and almost complete after 72 hours as more
than 84 % of the administered dose (corresponding to \> 98 % of the
recovered radioactivity) was excreted 72 hours after administration. The
predominant route of excretion was via urine, accounting for 69 to 90 %
of the dose administered.

In the high dose group, a certain saturation of the absorption process
could be observed as shown via the maximum dose-normalized plasma
levels. They were lower in the high-dose than in the low-dose animals
and the faecal excretion was increased in the high-dose animals by a
factor of 2 -- 3 compared to the low-dose animals.

Insignificant of radioactive residues remained in the organs, tissue and
carcass at sacrifice, 96 hours after administration; the sum of the
total residues amounted to \< 0.06 % of the administered dose in all
animals. Particular increase of radioactivity in certain organs and
tissues could not be observed. Therefore, it can be concluded that
residues of AE 0001789 did not accumulate in any of the organs, tissues
or glands.

A delayed gastric emptying was observed with some of the high-dose
animals, resulting in a double peak in the plasma concentration-time
curves and in a late excretion of significant portions of the
administered dose between 24 and 72 hours after the administration.
These double peak phenomena in plasma profiles already have been
described in the pharmacokinetic literature as effects caused by
discontinuous absorption and/or delayed gastric emptying of a portion of
the dose.

From the metabolites identified in urine and faeces three metabolic
steps can be derived.

> \(1\) Elimination of the cyclopropylamine moiety by hydrolysis of
> carboxamide bond in the sulfonylbenzamide part forming AE
> 0001789-descyclopropylamino.
>
> \(2\) Desmethylation of the methoxybenzoyl moiety leading to AE
> 0001789-desmethyl
>
> \(3\) Hydrolytic cleavage of carboxamide bond in the methoxybenzoyl
> group of the parent molecule or of AE 0001789-desmethyl resulting in
> AE 0001789-cyclopropyl-sulfamoylbenzamide.

Sex-specific differences were not observed with the absorption,
distribution, metabolism and excretion of AE 0001789.

**Study No.: 2 - MRID No.: 47069832 - (sulfonylbenzamide label - tissue
distribution).**

The distribution of radioactive residue in organs and tissues of male
rats were investigated following oral administration of
\[sulfonylbenzamide-ring-UL-^14^C\]AE 0001789 at an actual dose rate of
4.95 mg/kg b.w in Tragacanth as vehicle. Eight animals were employed in
the test and were sacrificed at the following time intervals: 1, 4, 8,
24, 48, 72, 120 and 168 hours after administration. After sacrifice,
they were fixed in a metal template in a stretched position and
immediately shock-frozen at approximately -- 70°C in a
dichloromethane/dry ice bath. After removal of the template, the
animal's body was embedded in a slurry of carboxymethyl-cellulose (7 --
8 %) together with radioactively spiked blood standards on the platform
of a microtome. The slurry with the rat's body and the blood standard
was deep-frozen in a block. Sections with a thickness of 50 µm from
different depths of the body were cut from the block, attached to an
adhesive tape and freeze-dried overnight in the cooled microtome.
Sections with relevant organs and tissues were used for exposure of
imaging plates to scan the radioactivity contained in these organs and
tissues.

The radioactivity contained in the sections excited sensitive material
of the imaging plates at a high spatial resolution. The excitation was
scanned as photostimulated luminescence by an image analyser providing
autoradiography pictures and digital scans. With use of the
radioactively spiked blood standards a linear correlation could be
derived between the photostimulated luminescence counts per square
millimetre and the radioactivity per mass (dpm/g) of the freeze-dried
animal matrix and square millimetre after subtraction of the background
luminescence. Self-absorbing quenching effects of the animal matrix were
compensated by measuring the transmission of ^14^C-radioactivity
homogenously distributed over a basis foil through sections originating
from a non-radioactive control animal overlaid over the radioactive
basis foil. For each organ and tissue the transmission ratio between
matrix and blood and its reciprocal as correction factor could be
determined according to a publication of Klein, Binder and Steinke
(2000). Integration of the unit area (square millimetre) to the total
area of the organ or tissue yielded the radioactivity concentration of
this organ or tissue. Division by the specific radioactivity of the
administered test item finally resulted in the equivalent concentration
(µg parent equivalents per gram organ or tissue).

Using this technique it was shown that radiolabeled AE 0001789 was very
quickly absorbed from the gastrointestinal tract. The maxima of the
radioactivity levels were observed already one hour after administration
in almost all organs and tissues. Normalization of the maximum residue
levels by division through the dose rate resulted in dose normalized
concentration that was generally less than unity indicating that
bioaccumulation is very unlikely. With particular reference to the
organs of the endocrine system no accumulation of AE 0001789 occurred.
Residues from glandular organs or tissues responsible for hormonal
regulation (such as adrenal, testis, or thyroid gland) were rapidly
depleted in parallel with depletion from the other organs and tissues.

The absorption process was apparently interrupted, likely due to a delay
gastric emptying occurring between 4 and 48 hours after administration.
This phenomenon could be deduced from the high amounts of radioactivity
remaining in the gastro-intestinal tract in concurrence with an inflated
stomach until 48 hours after dosing, and from the slight increase in the
radioactive residues observed in most organs and tissues 48 h after the
administration.

At all intervals of sacrifice the highest radioactivity levels were
detected in blood and the excretory organs kidney and liver. Radioactive
residues in all organs and tissues decreased rapidly between 1 and 72
hours. Between 120 and 168 hours of dosing all organ and tissue levels
were below LOQ or LOD.

From additional monitoring of the radioactivity excreted with urine and
faeces it was shown that excretion with urine was the predominant
excretion route. This excretion was very fast with high radioactivity
levels in urine already 8 hours after dosing. Excretion was complete at
the end of the test period, 168 hours after administration.

**Study No.: 3 - MRID No.: 47069833** (methoxybenzoyl-ring label -
pharmacokinetics).

The biokinetic behaviour and metabolism of
\[methoxybenzoyl-ring-UL-^14^C\]AE 0001789 was investigated in four male
rats following a single oral dose of 2 mg/kg b.w. given per gavage. The
absorption kinetic of the test item was followed by the time-dependent
radioactivity level in blood plasma. The distribution of the
radioactivity in organs and tissues was studied after sacrifice, 96
hours of administration. The metabolism was could be derived from the
observed metabolites in urine and faeces. The elimination of radioactive
residues was determined by time-dependent determination of the
radioactivity in urine and faeces.

The gastro-intestinal absorption of the test item started immediately
after dosing. The maximum plasma levels were reached already after 40
minutes. The absorption was nearly complete, approximately 82 % of the
dose recovered was renally excreted or remained in the body at
sacrifice, 96 hours after administration (without GIT). Excretion via
urine (82 % or the radioactivity recovered) was determined as
predominant route of excretion. A total of 18 % were excreted with the
faeces.

Consequently, residues in tissues and organs at sacrifice were very low.
Between \<0.001 % and 0.029 % of the administered radioactivity were
found in the individual organs and tissues of the rats. In total,
approximately 0.07 % of the administered dose was found in the body of
the rats (inclusive GIT).

From the metabolites identified in urine and faeces three metabolic
steps can be derived.

> \(1\) Elimination of the cyclopropylamine moiety by hydrolysis of
> carboxamide bond in the sulfonylbenzamide part forming AE
> 0001789-descyclopropylamino (AE 0893016).
>
> \(2\) Desmethylation of the methoxybenzoyl moiety leading to AE
> 0001789-desmethyl (AE 01448796)
>
> \(3\) Hydrolytic cleavage of carboxamide bond in the methoxybenzoyl
> group of the parent substance or the primary metabolite AE
> 0001789-descyclopropylamino resulting in AE 0001789-anisic acid
> (AE 0854787).

**Study No.: 4. - MRID No.: 47069833 - (methoxybenzoyl-ring label -
tissue distribution).**

The distribution of radioactive residue in organs and tissues of male
rats were investigated following oral administration of
\[methoxybenzoyl-ring-UL-^14^C\]AE 0001789 at an actual dose rate of
4.94 mg/kg b.w in Tragacanth as vehicle. Eight animals were employed in
the test and were sacrificed at the following time intervals: 1, 4, 8,
24, 48, 72, 120 and 168 hours after administration. After sacrifice,
they were fixed in a metal template in a stretched position and
immediately shock-frozen at approximately -- 70°C in a
dichloromethane/dry ice bath. After removal of the template, the
animal's body was embedded in a slurry of carboxymethyl-cellulose (7 --
8 %) together with radioactively spiked blood standards on the platform
of a microtome. The slurry with the rat's body and the blood standard
was deep-frozen in a block. Sections with a thickness of 50 µm from
different depths of the body were cut from the block, attached to an
adhesive tape and freeze-dried overnight in the cooled microtome.
Sections with relevant organs and tissues were used for exposure of
imaging plates to scan the radioactivity contained in these organs and
tissues.

The radioactivity contained in the sections excited sensitive material
of the imaging plates at a high spatial resolution. The excitation was
scanned as photostimulated luminescence by an image analyser providing
autoradiography pictures and digital scans. With use of the
radioactively spiked blood standards a linear correlation could be
derived between the photostimulated luminescence counts per square
millimetre and the radioactivity per mass (dpm/g) of the freeze-dried
animal matrix and square millimetre after subtraction of the background
luminescence. Self-absorbing quenching effects of the animal matrix were
compensated by measuring the transmission of ^14^C-radioactivity
homogenously distributed over a basis foil through sections originating
from a non-radioactive control animal overlaid over the radioactive
basis foil. For each organ and tissue the transmission ratio between
matrix and blood and its reciprocal as correction factor could be
determined according to a publication of Klein, Binder and Steinke
(2000). Integration of the unit area (square millimetre) to the total
area of the organ or tissue yielded the radioactivity concentration of
this organ or tissue. Division by the specific radioactivity of the
administered test item finally resulted in the equivalent concentration
(µg parent equivalents per gram organ or tissue).

Using this technique it was shown that radiolabeled AE 0001789 was very
quickly absorbed from the gastrointestinal tract. The maxima of the
radioactivity levels were observed already one hour after administration
in almost all organs and tissues. Normalization of the maximum residue
levels by division through the dose rate resulted in dose normalized
concentration that was in almost all organs and tissues less than unity
indicating that bioaccumulation is very unlikely. Only kidney (renal
medulla) as a main excretory organ showed a higher dose normalized
radioactivity level than unity. In addition, blood was slightly above
unity.

With particular reference to the organs of the endocrine system no
accumulation of AE 0001789 occurred. Residues from glandular organs or
tissues responsible for hormonal regulation (such as adrenal, testis, or
thyroid gland) were rapidly depleted in parallel with depletion from the
other organs and tissues

The absorption process was apparently interrupted, likely due to a delay
gastric emptying occurring between 4 and 24 hours after administration.
This phenomenon could be deduced from the high amounts of radioactivity
remaining in the gastro-intestinal tract in concurrence with an inflated
stomach until 24 hours after dosing, and from the slight increase in the
radioactive residues observed in most organs and tissues 24 h after the
administration.

AE 0001789 was quickly and efficiently eliminated from the body. A fast
decline of the radioactive residues in all organs and tissues could be
observed between 1 and 48 hours after the administration, residues
dropped by two orders of magnitude in all organs and tissues. At the end
of the test period, 168 hours after administration, residues in all
organs and tissues were \< LOD or \< LOQ (liver).

From additional monitoring of the radioactivity excreted with urine and
faeces it was shown that excretion via urine was the predominant
excretion route. This excretion was very fast with high radioactivity
levels in urine already 4 hours after dosing. Excretion was complete at
the end of the test period, 168 hours after administration. An
insignificant amount of radioactivity was expired as radiolabeled carbon
dioxide or organic volatiles

+---------------+------------------------------------------------------+
| **SUMMARY OF  |                                                      |
| T             |                                                      |
| OXICOKINETICS |                                                      |
| STUDIES BY    |                                                      |
| REGULATORY    |                                                      |
| AUTHORITY**   |                                                      |
+---------------+------------------------------------------------------+
| **Name of     | Pesticides Safety Directorate, UK                    |
| authority**   |                                                      |
+---------------+------------------------------------------------------+
| The           |                                                      |
| t             |                                                      |
| oxicokinetics |                                                      |
| of            |                                                      |
| c             |                                                      |
| yprosulfamide |                                                      |
| following     |                                                      |
| oral gavage   |                                                      |
| were          |                                                      |
| investigated  |                                                      |
| in four       |                                                      |
| studies in    |                                                      |
| the rat, with |                                                      |
| the parent    |                                                      |
| substance     |                                                      |
| uniformly     |                                                      |
| 14C-labelled  |                                                      |
| in the        |                                                      |
| sulf          |                                                      |
| onylbenzamide |                                                      |
| and the       |                                                      |
| m             |                                                      |
| ethoxybenzoyl |                                                      |
| ring. These   |                                                      |
| studies       |                                                      |
| included two  |                                                      |
| quantitative  |                                                      |
| whole body    |                                                      |
| au            |                                                      |
| toradiography |                                                      |
| studies (each |                                                      |
| label). All   |                                                      |
| the studies   |                                                      |
| employed      |                                                      |
| single oral   |                                                      |
| gavage doses. |                                                      |
| The Notifier  |                                                      |
| considered    |                                                      |
| that a study  |                                                      |
| with repeated |                                                      |
| a             |                                                      |
| dministration |                                                      |
| was not       |                                                      |
| needed as the |                                                      |
| single-dose   |                                                      |
| studies       |                                                      |
| demonstrated  |                                                      |
| that          |                                                      |
| accumulation  |                                                      |
| does not      |                                                      |
| occur in any  |                                                      |
| organ or      |                                                      |
| tissues based |                                                      |
| on a very     |                                                      |
| rapid         |                                                      |
| excretion and |                                                      |
| extremely low |                                                      |
| organ and     |                                                      |
| tissue levels |                                                      |
| 96 hours      |                                                      |
| after dosing. |                                                      |
| In addition,  |                                                      |
| no indication |                                                      |
| of enzyme     |                                                      |
| induction was |                                                      |
| observed in   |                                                      |
| long-term     |                                                      |
| toxicity      |                                                      |
| studies.      |                                                      |
|               |                                                      |
| Overall it is |                                                      |
| considered    |                                                      |
| that the      |                                                      |
| t             |                                                      |
| oxicokinetics |                                                      |
| have been     |                                                      |
| adequately    |                                                      |
| c             |                                                      |
| haracterised. |                                                      |
+---------------+------------------------------------------------------+
| [Absorption   |                                                      |
| ]{.underline} |                                                      |
|               |                                                      |
| C             |                                                      |
| yprosulfamide |                                                      |
| was found to  |                                                      |
| be rapidly    |                                                      |
| absorbed      |                                                      |
| following     |                                                      |
| a             |                                                      |
| dministration |                                                      |
| (plasma       |                                                      |
| t~max~        |                                                      |
| reached       |                                                      |
| [ca           |                                                      |
| ]{.underline} |                                                      |
| 10-40 and     |                                                      |
| 40-60 minutes |                                                      |
| at 2 and 200  |                                                      |
| mg/kg bw      |                                                      |
| doses         |                                                      |
| r             |                                                      |
| espectively). |                                                      |
| At the high   |                                                      |
| dose the      |                                                      |
| plasma        |                                                      |
| decline       |                                                      |
| curves were   |                                                      |
| bimodal, a    |                                                      |
| discontinuous |                                                      |
| excretion     |                                                      |
| pattern       |                                                      |
| indicating    |                                                      |
| delayed       |                                                      |
| absorption of |                                                      |
| some of the   |                                                      |
| dose.         |                                                      |
| Absorption    |                                                      |
| was found to  |                                                      |
| be high and   |                                                      |
| ranged        |                                                      |
| between       |                                                      |
| 70-90%.       |                                                      |
| Toxicokinetic |                                                      |
| parameters    |                                                      |
| were          |                                                      |
| independent   |                                                      |
| of sex.       |                                                      |
+---------------+------------------------------------------------------+
| [Distribution |                                                      |
| ]{.underline} |                                                      |
|               |                                                      |
| Distribution  |                                                      |
| was           |                                                      |
| extensive,    |                                                      |
| although      |                                                      |
| overall very  |                                                      |
| low dose      |                                                      |
| normalised    |                                                      |
| c             |                                                      |
| oncentrations |                                                      |
| were detected |                                                      |
| in all organs |                                                      |
| and tissues,  |                                                      |
| with mean     |                                                      |
| values,       |                                                      |
| ranging from  |                                                      |
| \<LOD to      |                                                      |
| 0.004 µg      |                                                      |
| parent        |                                                      |
| equivalent/µg |                                                      |
| (excluding    |                                                      |
| carcass) with |                                                      |
| no clear      |                                                      |
| indication of |                                                      |
| accumulation  |                                                      |
| in any of the |                                                      |
| tissues,      |                                                      |
| organs or     |                                                      |
| glands        |                                                      |
+---------------+------------------------------------------------------+
| [Metabolism   |                                                      |
| ]{.underline} |                                                      |
|               |                                                      |
| Metabolism of |                                                      |
| \[c           |                                                      |
| yprosulfamide |                                                      |
| was limited,  |                                                      |
| with          |                                                      |
| approximately |                                                      |
| 80-90% of the |                                                      |
| administered  |                                                      |
| dose excreted |                                                      |
| as unchanged  |                                                      |
| parent        |                                                      |
| compound.     |                                                      |
| Based on the  |                                                      |
| metabolites   |                                                      |
| found the     |                                                      |
| following     |                                                      |
| pathway has   |                                                      |
| been          |                                                      |
| postulated.   |                                                      |
| Elimination   |                                                      |
| of the        |                                                      |
| cyc           |                                                      |
| lopropylamine |                                                      |
| moiety by     |                                                      |
| hydrolysis of |                                                      |
| carboxamide   |                                                      |
| bond in the   |                                                      |
| sulfo         |                                                      |
| nyl-benzamide |                                                      |
| part forming  |                                                      |
| c             |                                                      |
| yprosulfamide |                                                      |
| -descycl      |                                                      |
| opropylamino. |                                                      |
| D             |                                                      |
| esmethylation |                                                      |
| of the        |                                                      |
| m             |                                                      |
| ethoxybenzoyl |                                                      |
| moiety        |                                                      |
| leading to    |                                                      |
| c             |                                                      |
| yprosulfamide |                                                      |
| -desmethyl.   |                                                      |
| Hydrolytic    |                                                      |
| cleavage of   |                                                      |
| carboxamide   |                                                      |
| bond in the   |                                                      |
| m             |                                                      |
| ethoxybenzoyl |                                                      |
| group of the  |                                                      |
| parent        |                                                      |
| molecule      |                                                      |
| resulting in  |                                                      |
| c             |                                                      |
| yprosulfamide |                                                      |
| cycl          |                                                      |
| opropyl-sulfa |                                                      |
| moylbenzamide |                                                      |
| and           |                                                      |
| cyprosul      |                                                      |
| famide-anisic |                                                      |
| acid.         |                                                      |
|               |                                                      |
| The           |                                                      |
| characterised |                                                      |
| metabolites   |                                                      |
| were:         |                                                      |
|               |                                                      |
| M04, AE       |                                                      |
| 1448796 (AE   |                                                      |
| 00017         |                                                      |
| 89-desmethyl) |                                                      |
|               |                                                      |
| M01, AE       |                                                      |
| 0893016 (AE   |                                                      |
| 00            |                                                      |
| 01789-descycl |                                                      |
| opropylamino) |                                                      |
|               |                                                      |
| M02, AE       |                                                      |
| 0852999 (AE   |                                                      |
| 0001789-cyclo |                                                      |
| propyl-sulfam |                                                      |
| oylbenzamide) |                                                      |
|               |                                                      |
| M07, AE       |                                                      |
| 0854787 (AE   |                                                      |
| 0             |                                                      |
| 001789-anisic |                                                      |
| acid)         |                                                      |
|               |                                                      |
| M06, AE       |                                                      |
| 2300015       |                                                      |
| (cyc          |                                                      |
| lopropylamine |                                                      |
| (postulated)) |                                                      |
+---------------+------------------------------------------------------+
| [Excretion    |                                                      |
| ]{.underline} |                                                      |
|               |                                                      |
| Excretion was |                                                      |
| rapid (79-98% |                                                      |
| of the        |                                                      |
| administered  |                                                      |
| dose at 24    |                                                      |
| hours) and    |                                                      |
| mostly via    |                                                      |
| the urine     |                                                      |
| (70-90% of    |                                                      |
| the           |                                                      |
| administered  |                                                      |
| dose) at the  |                                                      |
| low dose. At  |                                                      |
| the high dose |                                                      |
| excretion was |                                                      |
| much slower   |                                                      |
| reflecting    |                                                      |
| the delayed   |                                                      |
| absorption    |                                                      |
| (50% and 94%  |                                                      |
| of the        |                                                      |
| administered  |                                                      |
| dose at 48    |                                                      |
| hours in      |                                                      |
| males and     |                                                      |
| females       |                                                      |
| r             |                                                      |
| espectively). |                                                      |
| Excretion of  |                                                      |
| radioactivity |                                                      |
| via exhaled   |                                                      |
| air was found |                                                      |
| to be         |                                                      |
| negligible.   |                                                      |
| Biliary       |                                                      |
| excretion was |                                                      |
| not assessed. |                                                      |
| No sex        |                                                      |
| difference    |                                                      |
| was apparent  |                                                      |
| in the faecal |                                                      |
| excretion     |                                                      |
| rate.         |                                                      |
+---------------+------------------------------------------------------+

+-----------------------------------------------------------------------+
| HED Comments:                                                         |
|                                                                       |
| These four studies when taken together are classified as              |
| ACCEPTABLE/GUIDELINE and satisfy the requirement for a series         |
| 870.7485 metabolism and pharmacokinetics study. HED considers that    |
| these studies demonstrate the absorption, excretion, distribution and |
| metabolism with identification of metabolites.                        |
+-----------------------------------------------------------------------+

**870.7600 Dermal Absorption - Rat**

**No study available and not required.**

**A.3.9 Special/Other Studies -**

**There are no special studies with cyprosulfamide.**

[]{#__RefHeading___Toc200865336 .anchor}**Appendix B: Metabolism
Assessment**

The table below was copied, with minor formatting alterations, from
"Tier 2 Summary of the Metabolism and Residues Data for Cyprosulfamide
(AE 0001789)" prepared by Bayer CropScience (Document Number
M-286420-01-1).

+---+----------------------------------+--------------+---------------+
| * |                                  |              |               |
| * |                                  |              |               |
| T |                                  |              |               |
| a |                                  |              |               |
| b |                                  |              |               |
| l |                                  |              |               |
| e |                                  |              |               |
| B |                                  |              |               |
| . |                                  |              |               |
| 1 |                                  |              |               |
| C |                                  |              |               |
| h |                                  |              |               |
| e |                                  |              |               |
| m |                                  |              |               |
| i |                                  |              |               |
| c |                                  |              |               |
| a |                                  |              |               |
| l |                                  |              |               |
| N |                                  |              |               |
| a |                                  |              |               |
| m |                                  |              |               |
| e |                                  |              |               |
| s |                                  |              |               |
| a |                                  |              |               |
| n |                                  |              |               |
| d |                                  |              |               |
| S |                                  |              |               |
| t |                                  |              |               |
| r |                                  |              |               |
| u |                                  |              |               |
| c |                                  |              |               |
| t |                                  |              |               |
| u |                                  |              |               |
| r |                                  |              |               |
| e |                                  |              |               |
| s |                                  |              |               |
| o |                                  |              |               |
| f |                                  |              |               |
| C |                                  |              |               |
| y |                                  |              |               |
| p |                                  |              |               |
| r |                                  |              |               |
| o |                                  |              |               |
| s |                                  |              |               |
| u |                                  |              |               |
| l |                                  |              |               |
| f |                                  |              |               |
| a |                                  |              |               |
| m |                                  |              |               |
| i |                                  |              |               |
| d |                                  |              |               |
| e |                                  |              |               |
| a |                                  |              |               |
| n |                                  |              |               |
| d |                                  |              |               |
| M |                                  |              |               |
| e |                                  |              |               |
| t |                                  |              |               |
| a |                                  |              |               |
| b |                                  |              |               |
| o |                                  |              |               |
| l |                                  |              |               |
| i |                                  |              |               |
| t |                                  |              |               |
| e |                                  |              |               |
| s |                                  |              |               |
| . |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+===+==================================+==============+===============+
|   | **Report name**                  | **Molecular  | *             |
|   |                                  | formula**    | *Occurrence** |
|   | **Structure**                    |              |               |
|   |                                  | **molar      |               |
|   | **IUPAC name**                   | mass**       |               |
|   |                                  |              |               |
|   | **CAS name**                     | **Other      |               |
|   |                                  | names /      |               |
|   | **\[CAS number\]**               | codes**      |               |
+---+----------------------------------+--------------+---------------+
| * | **AE 0001789 (parent             |              |               |
| * | substance)**                     |              |               |
| a |                                  |              |               |
| . |                                  |              |               |
| s |                                  |              |               |
| . |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image3.wmf)            | C~18~ H~18~  | Rat,          |
|   |                                  | N~2~ O~5~ S  |               |
|   |                                  |              | Goat,         |
|   |                                  | 374.4 g/mol  |               |
|   |                                  |              | Hen           |
|   |                                  |              |               |
|   |                                  |              | Corn,         |
|   |                                  |              |               |
|   |                                  |              | Soil,         |
|   |                                  |              |               |
|   |                                  |              | W             |
|   |                                  |              | ater-Sediment |
+---+----------------------------------+--------------+---------------+
|   | N-cyclopropyl-4                  | **Cypr       |               |
|   | -\[(2-methoxybenzoyl)sulfamoyl\] | osulfamide** |               |
|   | benzamide (IUPAC)                |              |               |
|   |                                  | (common      |               |
|   | Benzamide,                       | name)        |               |
|   | N-\[\[4-\[(cycl                  |              |               |
|   | opropylamino)-carbonyl\]phenyl\] |              |               |
|   | sulfonyl\]-2-methoxy- (CAS, 9CI) |              |               |
|   |                                  |              |               |
|   | \[CAS-no: 221667-31-8\]          |              |               |
+---+----------------------------------+--------------+---------------+
| * | **AE                             |              |               |
| * | 0001789-descyclopropylamino**    |              |               |
| M |                                  |              |               |
| 0 |                                  |              |               |
| 1 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image4.wmf)            | C~15~ H~13~  | Rat (minor),  |
|   |                                  | N O~6~ S     |               |
|   |                                  |              | Soil, aerobic |
|   |                                  | 335.3 g/mol  | and anaerobic |
|   |                                  |              | (major),      |
|   |                                  |              |               |
|   |                                  |              | W             |
|   |                                  |              | ater-Sediment |
|   |                                  |              | (major)       |
+---+----------------------------------+--------------+---------------+
|   | 4-\[(2-m                         | **AE         |               |
|   | ethoxybenzoyl)sulfamoyl\]benzoic | 0893016**    |               |
|   | acid (IUPAC)                     |              |               |
|   |                                  |              |               |
|   | 4-\[\[(2-Methoxy                 |              |               |
|   | benzoyl)amino\]sulfonyl\]benzoic |              |               |
|   | acid (CAS)                       |              |               |
+---+----------------------------------+--------------+---------------+
| * | **AE                             |              |               |
| * | 0001789-                         |              |               |
| M | cyclopropyl-sulfamoylbenzamide** |              |               |
| 0 |                                  |              |               |
| 2 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image5.wmf)            | C~10~ H~12~  | Rat (minor),  |
|   |                                  | N~2~ O~3~ S  |               |
|   |                                  |              | Goat (major   |
|   |                                  | 240.3 g/mol  | in milk,      |
|   |                                  |              | liver,        |
|   |                                  |              | kidney, also  |
|   |                                  |              | present as    |
|   |                                  |              | conjugates),  |
|   |                                  |              |               |
|   |                                  |              | Hen (major)   |
|   |                                  |              |               |
|   |                                  |              | Corn (major   |
|   |                                  |              | in forage and |
|   |                                  |              | stover, not   |
|   |                                  |              | present in    |
|   |                                  |              | grain)        |
|   |                                  |              |               |
|   |                                  |              | Soil, aerobic |
|   |                                  |              | and anaerobic |
|   |                                  |              | (major),      |
|   |                                  |              |               |
|   |                                  |              | Succeeding    |
|   |                                  |              | crops         |
|   |                                  |              | (major),      |
|   |                                  |              |               |
|   |                                  |              | W             |
|   |                                  |              | ater-Sediment |
|   |                                  |              | (major)       |
+---+----------------------------------+--------------+---------------+
|   | N-                               | **AE         |               |
|   | cyclopropyl-4-sulfamoylbenzamide | 0852999**    |               |
|   | (IUPAC)                          |              |               |
|   |                                  |              |               |
|   | 4-(Amino                         |              |               |
|   | sulfonyl)-N-cyclopropylbenzamide |              |               |
|   | (CAS)                            |              |               |
+---+----------------------------------+--------------+---------------+
| * | **AE 0001789-sulfamoylbenzoic    |              |               |
| * | acid**                           |              |               |
| M |                                  |              |               |
| 0 |                                  |              |               |
| 3 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image6.wmf)            | C~7~ H~7~ N  | Goat (minor   |
|   |                                  | O~4~ S       | in milk),     |
|   |                                  |              |               |
|   |                                  | 201.2 g/mol  | Soil, aerobic |
|   |                                  |              | and anaerobic |
|   |                                  |              | (major),      |
|   |                                  |              |               |
|   |                                  |              | W             |
|   |                                  |              | ater-Sediment |
|   |                                  |              | (minor)       |
+---+----------------------------------+--------------+---------------+
|   | 4-sulfamoylbenzoic acid (IUPAC)  | **AE         |               |
|   |                                  | 0467398**    |               |
|   | Benzoic acid, 4-(aminosulfonyl)- |              |               |
|   | (CAS, 9CI)                       |              |               |
|   |                                  |              |               |
|   | \[CAS no.: 138-41-0\]            |              |               |
+---+----------------------------------+--------------+---------------+
| * | **AE 0001789-desmethyl**         |              |               |
| * |                                  |              |               |
| M |                                  |              |               |
| 0 |                                  |              |               |
| 4 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image7.wmf)            | C~17~ H~16~  | Rat (minor),  |
|   |                                  | N~2~ O~5~ S  |               |
|   |                                  |              | Goat (minor   |
|   |                                  | 360.39 g/mol | in milk and   |
|   |                                  |              | liver),       |
|   |                                  |              |               |
|   |                                  |              | Soil aerobic  |
|   |                                  |              | (major),      |
|   |                                  |              |               |
|   |                                  |              | W             |
|   |                                  |              | ater-Sediment |
|   |                                  |              | (aerobic:     |
|   |                                  |              | minor;        |
|   |                                  |              | anaerobic:    |
|   |                                  |              | major)        |
+---+----------------------------------+--------------+---------------+
|   | N-cy                             | **AE         |               |
|   | clopropyl-4-\[(2-hydroxybenzoyl) | 1448796**    |               |
|   | sulfamoyl\]benzamide (IUPAC)     |              |               |
+---+----------------------------------+--------------+---------------+
| * | **AE 0001789-descyclopropyl**    |              |               |
| * |                                  |              |               |
| M |                                  |              |               |
| 0 |                                  |              |               |
| 5 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](med                          | C~15~ H~14~  | Soil          |
|   | ia/image8.wmf){width="2.18125in" | N~2~ O~5~ S  | photolysis    |
|   | height="1.0944444444444446in"}   |              | (major),      |
|   |                                  | 334.35 g/mol |               |
|   |                                  |              | Corn (minor   |
|   |                                  |              | in forage,    |
|   |                                  |              | stover and    |
|   |                                  |              | grain)        |
+---+----------------------------------+--------------+---------------+
|   | N-{\[4-(aminocarbonyl)phen       | **AE         |               |
|   | yl\]sulfonyl}-2-methoxybenzamide | 1272799**    |               |
|   | (IUPAC)                          |              |               |
|   |                                  |              |               |
|   | N-\[\[4-(Aminocarbonyl)pheny     |              |               |
|   | l\]sulfonyl\]-2-methoxybenzamide |              |               |
|   | (CAS)                            |              |               |
+---+----------------------------------+--------------+---------------+
| * | **AE 0001789-cyclopropylamine**  |              |               |
| * |                                  |              |               |
| M |                                  |              |               |
| 0 |                                  |              |               |
| 6 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image9.wmf)            | C~3~ H~7~ N  | Soil and      |
|   |                                  |              | water         |
|   |                                  | 57.1 g/mol   | (postulated   |
|   |                                  |              | major         |
|   |                                  |              | metabolite),  |
|   |                                  |              |               |
|   |                                  |              | Rat           |
|   |                                  |              | (postulated   |
|   |                                  |              | minor         |
|   |                                  |              | metabolite)   |
+---+----------------------------------+--------------+---------------+
|   | Cyclopropylamine (9Cl) (IUPAC)   | **AE         |               |
|   |                                  | 2300015**    |               |
|   | Cyclopropaneamine (9Cl, CAS)     |              |               |
|   |                                  | cycl         |               |
|   | \[CAS no.: 765-30-0\]            | opropylamine |               |
+---+----------------------------------+--------------+---------------+
| * | **AE 0001789-anisic acid**       |              |               |
| * |                                  |              |               |
| M |                                  |              |               |
| 0 |                                  |              |               |
| 7 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image10.wmf)           | C~8~ H~8~    | Rat (minor),  |
|   |                                  | O~3~         |               |
|   |                                  |              | Goat (major   |
|   |                                  | 152.2 g/mol  | in liver),    |
|   |                                  |              |               |
|   |                                  |              | Hen (major in |
|   |                                  |              | eggs and      |
|   |                                  |              | liver)        |
|   |                                  |              |               |
|   |                                  |              | Aquatic       |
|   |                                  |              | photolysis    |
|   |                                  |              | (major)       |
+---+----------------------------------+--------------+---------------+
|   | 2-methoxybenzoic acid (IUPAC)    | **           |               |
|   |                                  | AE 0854787** |               |
|   | Benzoic acid, 2-methoxy- (CAS,   |              |               |
|   | 9CI)                             | O-met        |               |
|   |                                  | hylsalicylic |               |
|   | \[CAS no.: 579-75-9\]            | acid,        |               |
|   |                                  |              |               |
|   |                                  | anisic acid, |               |
|   |                                  |              |               |
|   |                                  | salicylic    |               |
|   |                                  | acid methyl  |               |
|   |                                  | ether        |               |
+---+----------------------------------+--------------+---------------+
|   |                                  |              |               |
+---+----------------------------------+--------------+---------------+
| * | **AE                             |              |               |
| * | 0001789-cyclopropyl-sulfonic     |              |               |
| M | acid**                           |              |               |
| 0 |                                  |              |               |
| 8 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image11.wmf)           | C~10~ H~11~  | Aquatic       |
|   |                                  | N O~4~ S     | photolysis    |
|   |                                  |              | (major)       |
|   |                                  | 241.3 g/mol  |               |
|   |                                  |              | Corn (minor   |
|   |                                  |              | in forage,    |
|   |                                  |              |               |
|   |                                  |              | not present   |
|   |                                  |              | in grain)     |
+---+----------------------------------+--------------+---------------+
|   | 4-\[(cyclopropy                  | **AE         |               |
|   | lamino)carbonyl\]benzenesulfonic | 2158927**    |               |
|   | acid (IUPAC)                     |              |               |
|   |                                  |              |               |
|   | 4-\[(cyclopropy                  |              |               |
|   | lamino)carbonyl\]benzenesulfonic |              |               |
|   | acid (CAS)                       |              |               |
+---+----------------------------------+--------------+---------------+
| * | **AE 0001789-salicylic acid**    |              |               |
| * |                                  |              |               |
| M |                                  |              |               |
| 0 |                                  |              |               |
| 9 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image12.wmf)           | C~7~ H~6~    | Soil (major   |
|   |                                  | O~3~         | in anaerobic  |
|   |                                  |              | soil          |
|   |                                  | 138.12 g/mol | metabolism)   |
+---+----------------------------------+--------------+---------------+
|   | 2-methoxybenzoic acid (IUPAC)    | **           |               |
|   |                                  | AE 0171385** |               |
|   | 2-hydroxy benzoic acid (CAS,     |              |               |
|   | 9CI)                             | o-hy         |               |
|   |                                  | droxybenzoic |               |
|   | \[CAS n.: 69-72-7\]              | acid,        |               |
|   |                                  |              |               |
|   |                                  | salicylic    |               |
|   |                                  | acid         |               |
+---+----------------------------------+--------------+---------------+
| * | **AE                             |              |               |
| * | 0001789-sulfonamide-lactate**    |              |               |
| M |                                  |              |               |
| 1 |                                  |              |               |
| 0 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image13.wmf)           | C~13~ H~16~  | Corn (major   |
|   |                                  | N~2~ O~6~ S  | in forage and |
|   |                                  |              | stover;       |
|   |                                  | 328.3 g/mol  |               |
|   |                                  |              | not present   |
|   |                                  | lactic acid  | in grain)     |
|   |                                  | conjugate of |               |
|   |                                  | AE 0852999   |               |
+---+----------------------------------+--------------+---------------+
|   | 3-\[({4-\[(cy                    | **AE         |               |
|   | clopropylamino)carbonyl\]phenyl} | 2300002**    |               |
|   | sul                              |              |               |
|   | fonyl)amino\]-2-hydroxypropanoic |              |               |
|   | acid (IUPAC)                     |              |               |
+---+----------------------------------+--------------+---------------+
| * | **AE                             |              |               |
| * | 0001789-sulfonamide-alanine**    |              |               |
| M |                                  |              |               |
| 1 |                                  |              |               |
| 1 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image14.wmf)           | C~13~ H~17~  | Corn (major   |
|   |                                  | N~3~ O~5~ S  | in forage and |
|   |                                  |              | stover;       |
|   |                                  | 327.36 g/mol |               |
|   |                                  |              | not present   |
|   |                                  | alanine      | in grain)     |
|   |                                  | conjugate of |               |
|   |                                  | AE 0852999   |               |
+---+----------------------------------+--------------+---------------+
|   | 3-\[({4-\[(cy                    | **AE         |               |
|   | clopropylamino)carbonyl\]phenyl} | 2300003**    |               |
|   | sulfonyl)amino\]alanine (IUPAC)  |              |               |
+---+----------------------------------+--------------+---------------+
| * | **AE                             |              |               |
| * | 0001789-sulfonamide-acetate**    |              |               |
| M |                                  |              |               |
| 1 |                                  |              |               |
| 2 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image15.wmf)           | C~12~ H~14~  | Corn (minor   |
|   |                                  | N~2~ O~4~ S  | in forage and |
|   |                                  |              | stover;       |
|   |                                  | 282.32 g/mol |               |
|   |                                  |              | not present   |
|   |                                  | acetic acid  | in grain),    |
|   |                                  | conjugate of |               |
|   |                                  | AE 0852999   | Goat (major   |
|   |                                  |              | in milk)      |
+---+----------------------------------+--------------+---------------+
|   | 4-\[(acetylamino)s               |              |               |
|   | ulfonyl\]-N-cyclopropylbenzamide |              |               |
|   | (IUPAC)                          |              |               |
+---+----------------------------------+--------------+---------------+
| * | **AE 0001789-sulfonamide         |              |               |
| * | aspartate**                      |              |               |
| M |                                  |              |               |
| 1 |                                  |              |               |
| 3 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image16.wmf)           | C~14~ H~17~  | Corn (major   |
|   |                                  | N~3~ O~6~ S  | in stover,    |
|   |                                  |              | minor in      |
|   |                                  | 355.37 g/mol | forage,       |
|   |                                  |              |               |
|   |                                  | aspartic     | not present   |
|   |                                  | acid         | in grain)     |
|   |                                  | conjugate of |               |
|   |                                  | AE 0852999   |               |
+---+----------------------------------+--------------+---------------+
|   | N-({4-\[(cy                      |              |               |
|   | clopropylamino)carbonyl\]phenyl} |              |               |
|   | sulfonyl)-alpha-asparagine       |              |               |
|   | (IUPAC)                          |              |               |
+---+----------------------------------+--------------+---------------+
| * | **AE 0001789-sulfonamide         |              |               |
| * | oxalate**                        |              |               |
| M |                                  |              |               |
| 1 |                                  |              |               |
| 4 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image17.wmf)           | C~12~ H~12~  | Corn (minor   |
|   |                                  | N~2~ O~6~ S  | in forage and |
|   |                                  |              | stover,       |
|   |                                  | 312.30 g/mol |               |
|   |                                  |              | not present   |
|   |                                  | oxalic acid  | in grain)     |
|   |                                  | conjugate of |               |
|   |                                  | AE 0852999   |               |
+---+----------------------------------+--------------+---------------+
|   | \[({4-\[(cy                      |              |               |
|   | clopropylamino)carbonyl\]phenyl} |              |               |
|   | sulfonyl)amino\] (oxo)acetic     |              |               |
|   | acid (IUPAC)                     |              |               |
+---+----------------------------------+--------------+---------------+
| * | **AE                             |              |               |
| * | 0001789                          |              |               |
| M | -sulfonamide-alanine-conjugate** |              |               |
| 1 |                                  |              |               |
| 5 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image18.wmf)           | i            | Corn (major   |
|   |                                  | ndeterminate | in forage and |
|   |                                  | alanine      | stover;       |
|   |                                  | conjugate of |               |
|   |                                  | AE 0852999   | not present   |
|   |                                  |              | in grain)     |
+---+----------------------------------+--------------+---------------+
|   | 3-\[({4-\[(cy                    |              |               |
|   | clopropylamino)carbonyl\]phenyl} |              |               |
|   | sulfonyl)amino\]alanine,         |              |               |
|   | conjugate                        |              |               |
+---+----------------------------------+--------------+---------------+
| * | **AE 0001789-glucoside**         |              |               |
| * |                                  |              |               |
| M |                                  |              |               |
| 1 |                                  |              |               |
| 6 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image19.wmf)           | C~24~ H~18~  | Corn (major   |
|   |                                  | N~2~ O~10~ S | in stover;    |
|   |                                  |              |               |
|   |                                  | 536.6 g/mol  | minor in      |
|   |                                  |              | grain)        |
|   |                                  | glucose      |               |
|   |                                  | conjugate of |               |
|   |                                  | AE 0001789,  |               |
|   |                                  |              |               |
|   |                                  | linkage of   |               |
|   |                                  | glucose in   |               |
|   |                                  | 4-position   |               |
|   |                                  | of the       |               |
|   |                                  | methoxy      |               |
|   |                                  | benzoyl ring |               |
+---+----------------------------------+--------------+---------------+
|   | glucose conjugate of parent      |              |               |
|   | substance                        |              |               |
+---+----------------------------------+--------------+---------------+
| * | **AE                             |              |               |
| * | 0001789-sulfonamide-pyruvate**   |              |               |
| M |                                  |              |               |
| 1 |                                  |              |               |
| 7 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image20.wmf)           | C~13~ H~14~  | Goat (minor   |
|   |                                  | N~2~ O~5~ S  | in milk)      |
|   |                                  |              |               |
|   |                                  | 310.33 g/mol |               |
|   |                                  |              |               |
|   |                                  | pyruvic acid |               |
|   |                                  | conjugate of |               |
|   |                                  | AE 0852999   |               |
+---+----------------------------------+--------------+---------------+
|   | N-cycloprop                      |              |               |
|   | yl-4-\[(pyruvoylamino)sulfonyl\] |              |               |
|   | benzamide (IUPAC)                |              |               |
+---+----------------------------------+--------------+---------------+
| * | **AE 0001789-methoxyhippuric     |              |               |
| * | acid**                           |              |               |
| M |                                  |              |               |
| 1 |                                  |              |               |
| 8 |                                  |              |               |
| * |                                  |              |               |
| * |                                  |              |               |
+---+----------------------------------+--------------+---------------+
|   | ![](media/image21.wmf)           | C~10~ H~11~  | Goat (minor   |
|   |                                  | N O~4~       | in milk,      |
|   |                                  |              | liver,        |
|   |                                  | 209.2 g/mol  | kidney)       |
|   |                                  |              |               |
|   |                                  | glycine      | Corn (minor   |
|   |                                  | conjugate of | in stover,    |
|   |                                  | AE 0854787   |               |
|   |                                  |              | not present   |
|   |                                  | (AE          | in grain)     |
|   |                                  | 00           |               |
|   |                                  | 01789-anisic |               |
|   |                                  | acid)        |               |
+---+----------------------------------+--------------+---------------+
|   | N-(2-methoxybenzoyl)glycine      |              |               |
|   | (IUPAC)                          |              |               |
|   |                                  |              |               |
|   | Glycine, N-(2-methoxybenzoyl)-   |              |               |
|   | (CAS, 9CI)                       |              |               |
|   |                                  |              |               |
|   | (2-methoxy-benzoylamino)-acetic  |              |               |
|   | acid                             |              |               |
|   |                                  |              |               |
|   | \[CAS no.: 13443-58-8\]          |              |               |
+---+----------------------------------+--------------+---------------+
| * | **AE                             | C~12~H~      |               |
| * | 0001789-sulfonamide-glycine**    | 14~N~2~O~5~S |               |
| M |                                  |              |               |
| 1 | ![](media/image22.wmf)           | 298.3 g/mol  |               |
| 9 |                                  |              |               |
| * | \[((4-\[(cyc                     | glycine      |               |
| * | lopropylamino)-carbonyl\]phenyl) | conjugate of |               |
|   | sulfonyl)amino\] acetic acid     | AE 0852999   |               |
+---+----------------------------------+--------------+---------------+
|   |                                  |              | Corn (minor   |
|   |                                  |              | in stover,    |
|   |                                  |              |               |
|   |                                  |              | not present   |
|   |                                  |              | in grain)     |
+---+----------------------------------+--------------+---------------+
|   |                                  |              |               |
+---+----------------------------------+--------------+---------------+

[]{#__RefHeading___Toc200865337 .anchor}**Appendix C: EPA 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 (which compose PHED, listed below) were
determined to require a review of their ethical conduct, have received
that review and have been determined to be ethical.

> *The PHED Task Force, 1995. The Pesticide Handlers Exposure Database,
> Version 1.1. Task Force members Health Canada, U.S. Environmental
> Protection Agency, and the National Agricultural Chemicals
> Association, released February, 1995.*