**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

May 31, 2007

**[MEMORANDUM]{.underline}**

SUBJECT: Florasulam: Human Health Risk Assessment for Proposed Use on
Cereal Grains (Wheat, Oats, Barley, Rye, and Triticale). PC Code:
129108, Petition No: 56F7061, DP Barcode: D332983

Regulatory Action: Section 3 Registration Action

Risk Assessment Type: Single Chemical Aggregate

FROM: Karlyn J. Bailey, Toxicologist/Risk Assessor

Thurston Morton, Chemist

Margarita Collantes, ORE Assessor

Registration Action Branch 2

Health Effects Division (7509P)

THROUGH: Richard Loranger, Branch Senior Scientist

Christina Swartz, Branch Chief

Registration Action Branch 2

> Health Effects Division (7509P)
>
> And
>
> Risk Assessment Review Committee (RARC) Reviewers
>
> Ray Kent, Branch Chief

Reregistration Branch 4

Health Effects Division (7509P)

William Burnam, Senior Science Advisor

Immediate Office

Health Effects Division (7509P)

TO: Joanne Miller, PM 23

Herbicide Branch

Registration Division (7505P)

**Table of Contents**

**1.0** **Executive Summary** 4

**2.0 Ingredient Profile** 8

2.1 Summary of Registered/Proposed Uses 9

2.2 Structure and Nomenclature [9](#__RefHeading___Toc139000973)

2.3 Physical and Chemical Properties [10](#__RefHeading___Toc139000974)

**3.0** **Hazard Characterization/Assessment**
[10](#__RefHeading___Toc139000975)

3.1 Hazard and Dose-Response Characterization
[10](#__RefHeading___Toc139000976)

3.1.1 Database Summary 10

3.1.1.1 Sufficiency of studies/data 10

3.1.1.2 Mode of action, metabolism, toxicokinetic data 11

3.1.2 Toxicological Effects 11

3.1.3 Dose-response 12

3.1.4 FQPA 12

3.2 Absorption, Distribution, Metabolism, Excretion (ADME) 12

3.3 FQPA Considerations 13

3.3.1 Adequacy of the Toxicity Database 13

3.3.2 Evidence of Neurotoxicity 14

3.3.3 Developmental Toxicity Studies 14

3.3.4 Reproductive Toxicity Study 14

3.3.5 Additional Information from Literature Sources 15

3.3.6 Pre-and/or Postnatal Toxicity [15](#__RefHeading___Toc139000991)

3.3.6.1 Determination of Susceptibility 15

3.3.6.2 Degree of Concern Analysis and Residual Uncertainties 15

3.3.7 Recommendation for a Developmental Neurotoxicity Study 15

3.4 Safety Factor for Infants and Children 15

3.5 Hazard Identification and Toxicity Endpoint Selection 16

3.5.1 Acute Reference Dose (aRfD) - General Population 16

3.5.2 Acute Reference Dose (aRfD) - Females 13-49 16

3.5.3 Chronic Reference Dose (cRfD) 16

3.5.4 Incidental Oral Exposure (Short- and Intermediate-Term) 17

3.5.5 Dermal Absorption 17

3.5.6 Dermal Exposure (Short-, Intermediate- and Long-Term) 17

3.5.7 Inhalation Exposure (Short-, Intermediate- and Long-Term) 17

3.5.8 Level of Concern for Margin of Exposure
[18](#__RefHeading___Toc139001007)

3.5.9 Recommendation for Aggregate Exposure Risk Assessments 18

3.5.10 Classification of Carcinogenic Potential 18

3.5.11 Summary of Toxicological Doses and Endpoints for florasulam for
Use in Human Risk Assessments 19

3.6 Endocrine disruption 20

**4.0 Public Health and Pesticide Epidemiology Data** 20

**5.0 Dietary Exposure/Risk Characterization**
[20](#__RefHeading___Toc139001017)

5.1 Pesticide Metabolism and Environmental Degradation
[20](#__RefHeading___Toc139001018)

5.1.1 Metabolism in Primary Crops [20](#__RefHeading___Toc139001019)

5.1.2 Metabolism in Rotational Crops 21

5.1.3 Metabolism in Livestock 21

5.1.4 Analytical Methodology 23

5.1.5 Environmental Degradation 23

5.1.6 Comparative Metabolic Profile 24

5.1.7 Toxicity Profile of Major Metabolites and Degradates 25

5.1.8 Pesticide Metabolites and Degradates of Concern 25

5.1.9 Drinking Water Residue Profile 26

5.1.10 Food Residue Profile [27](#__RefHeading___Toc139001028)

5.1.11 International Residue Limits 27

5.2 Dietary Exposure and Risk 27

5.2.1 Acute Dietary Exposure/Risk 28

5.2.2 Chronic Dietary Exposure/Risk 28

5.2.3 Cancer Dietary Risk 29

5.3 Anticipated Residue and Percent Crop Treated (%CT) Information 29

**6.0** **Residential (Non-Occupational) Exposure/Risk
Characterization** 29

**7.0** **Aggregate Risk Assessments and Risk Characterization** 29

7.1 Acute Aggregate Risk 29

7.2 Short-Term Aggregate Risk 29

7.3 Intermediate-Term Aggregate Risk 29

7.4 Long-Term Aggregate Risk 30

7.5 Cancer Risk 30

**8.0** **Cumulative Risk Characterization/Assessment** 30

**9.0** **Occupational Exposure/Risk Pathway** 30

9.1 Short-Term Handler Risk 30

9.2 Short-Term Postapplication Risk 32

**10.0** **Data Needs and Label Requirements**
[33](#__RefHeading___Toc139001049)

10.1 Toxicology 33

10.2 Residue Chemistry 33

10.3 Occupational and Residential Exposure 33

**References:** 34

**Appendix A: Toxicology Assessment** 35

A.1 Toxicology Data Requirements 35

A.2 Toxicity Profiles 36

A.3 Executive Summaries 39

A.4 Toxicology References 55

**Appendix B: Metabolism Assessment** 57

B.1 Metabolism Guidance and Considerations 57

**Appendix C: Tolerance Reassessment Summary and Table** 59

**1.0 Executive Summary**

Florasulam is a selective triazolopyrimidine sulfonanilide post-emergent
herbicide. The mode of action for florasulam is through inhibition of
the plant enzyme acetolactate synthase (ALS). The inhibition of ALS
results in retardation of plant growth processes leading to death of the
plant. The registrant, Dow Agrosciences, is proposing this active
ingredient for selective control of a broad spectrum of annual broadleaf
weeds in cereal grain crops (wheat, oats, rye, barley, and triticale).
The proposed application rate for florasulam is low, 0.00446 pounds
(lbs) active ingredient (a.i.) per acre. Florasulam was first registered
in Israel in 1998. It has also been registered in Canada (2001) and
included in the European Annex Union Listing in 2002.

**HUMAN HEALTH RISK ASSESSMENT:**

**[Toxicology/Hazard]{.underline}**

Florasulam has low or minimal acute toxicity via the oral (Category IV),
dermal (Category III), and inhalation routes of exposure (Category IV).
It is non- irritating to the eye and skin (Category IV); it is not a
skin sensitizer.

Slight nephrotoxicity (increased kidney weights, hypertrophy, and
histopathology) was observed in the kidneys of rats after subchronic ( ≥
500 mg/kg/day) and chronic exposure ( ≥ 250 mg/kg/day) to florasulam.
Liver toxicity was observed in dogs (90-days) in the form of increased
liver weights and liver enzymes, hypertrophy, and histopathology;
adverse histopathology was also observed in the adrenal glands (1-year).
Other treatment-related effects noted were decreases in body weight and
body weight gain in rats and dogs and general malaise in rats. There
were no adverse treatment-related effects observed in mice.

There is no evidence of developmental or reproductive toxicity,
neurotoxicity, mutagenicity, or carcinogenicity. In addition, there is
no evidence of estrogen-, androgen-, or thyroid-mediated toxicity.

For chronic dietary exposure, the chronic toxicity study in dogs (NOAEL
of 5 mg/kg/day and LOAEL of 100/50 mg/kg/day) was used to calculate the
chronic reference dose (cRfD) of 0.05 mg/kg/day; endpoints for acute
dietary risk assessments (general population and females age 13-49) were
not selected. A 90-day oral toxicity study in dogs was used to select
the dose and endpoint for occupational short-term inhalation exposure
(NOAEL of 5 mg/kg/day and LOAEL of 50 mg/kg/day). A risk assessment was
not conducted for occupational dermal exposures (short-term) due to the
absence of adverse systemic effects in the dermal toxicity study (1000
mg/kg/day). There are no residential uses proposed for florasulam;
therefore, incidental oral and residential dermal and inhalation risk
assessments were not conducted.

HED recommends the FQPA SF be reduced to 1X because the toxicology
database is complete; there is no evidence of increased susceptibility
and no/low concerns and no residual uncertainties with regard to pre-
and/or postnatal toxicity. Additionally, the dietary food exposure
assessment is based on HED-recommended tolerance-level residues and
assumes 100% crop treated for all commodities, which results in upper
bound estimates of dietary exposure (95^th^ percentile of exposure).
Furthermore, the drinking water assessment is based on values generated
by model and associated modeling parameters which are designed to
provide conservative, health protective upper bound estimates of water
concentrations. Finally, there are no registered or proposed residential
uses.

**[Dietary Exposure (Food/Water)]{.underline}**

An acceptable wheat metabolism study using two radiolabels was submitted
for florasulam. Total radioactive residue (TRR) level in grain was
determined by combustion/LSC. The ^14^C-residues were too low to
elucidate the nature of the TRRs in mature wheat ears (up to 0.03 ppm)
and grain (up to 0.008 ppm). Therefore, no further attempts to
characterize/identify the ^14^C-residues in grain were carried out.
However, residues in immature whole wheat plants and mature wheat straw
were present at levels permitting adequate identification. Metabolites
detected in wheat matrices were 4-OH-(phenyl)-florasulam, the glucose
conjugate of 4-OH-(phenyl)-florasulam, and 2-sulfonamide. The metabolism
study was conducted at 10X the proposed label rate (5 g a.i./ha) and the
2-sulfonamide metabolite was detected only in winter wheat straw (0.059
ppm) and not in the grain. Based on the low level of residues observed
in wheat grain (0.008 ppm) at the exaggerated application rate (10X the
proposed application rate) in the wheat metabolism study, HED concludes
the residue of concern (ROC) in plants is the parent compound,
florasulam. This conclusion applies to cereal grains only. Additional
plant metabolism studies will be needed for any future uses on other
types of crops.

In confined rotational crops, the levels of TRRs were low (≤ 0.01 ppm)
and no residues were identified. Therefore, a residue of concern does
not need to be defined for rotational crops. Based on the results of the
confined rotational crop study, field rotational crop studies are not
needed, and a 30-day plant back interval (PBI) can be supported for all
crops.

The metabolism of florasulam in the laying hen and lactating goat were
similar. In both, the majority of the radioactivity was found in the
excreta. Most of the parent compound in goat and hen was eliminated
unchanged with minor unknown metabolites at unquantifiable levels. No
significant cleavage of the sulfonanilide bridge was observed.

Residues of florasulam as the N-methyl florasulam derivative were
determined by capillary gas chromatography with mass selective detection
(GC/MSD). This method has been forwarded to BEAD/ACB for a petition
method validation. The analytical methodology is acceptable as an
enforcement method pending validation by ACB. The limit of detection
(LOD) was calculated as three times the standard deviation (3s) which
was 0.0012 ppm in grain, 0.005 ppm in forage and immature green plant,
0.0036 ppm in hay and immature dried plant and 0.0074 ppm in straw. The
limit of quantitation (LOQ) for florasulam was established at 0.01 ppm
for grain over the concentration range of 0.01-0.10 ppm, and at 0.05 ppm
for forage, hay, straw, immature green plant and immature dried plant
over the concentration range of 0.05-0.50 ppm. The method of analysis
was independently validated at Enviro-Bio-Tech. Ltd. (Bernville, PA)
using wheat grain, forage, hay and straw. This ILV study successfully
validated the Dow AgroSciences method GRM 98.01 for the residues of the
florasulam in wheat matrices, indicating good reproducibility.

The proposed use of florasulam on cereal grains is considered to fall
under 40 CFR §180.6(a)3 (no expectation of finite residues in livestock
commodities). Therefore, feeding studies and tolerances for meat, milk,
poultry, and eggs are not needed for the purposes of this petition. HED
also concludes that residue analytical methods and storage stability
data for livestock commodities are not necessary.

[]{.mark}

There are adequate magnitude of the residue data for wheat, barley,
oats, and rye. The supervised field trials indicated that residues of
florasulam in grain, forage, hay, and straw of wheat, barley, rye, and
oats were non quantifiable (\<0.01 ppm for grain, \<0.05 ppm for forage,
hay, and straw), following a single foliar application at an exaggerated
rate (2x proposed maximum seasonal application rate). Florasulam
residues were greater than the proposed

tolerances in one wheat forage field trial. However, HED concludes the
proposed tolerance of 0.05 ppm for wheat forage would adequately cover
residues in wheat forage since field trials were conducted at a 2x
exaggerated rate.

[]{.mark}

Maximum residue levels (MRls) are established in Canada for residues of
florasulam in barley, oats, and wheat grain at 0.01 ppm. There are no
Codex MRLS and no harmonization issues exist since the same tolerance
level is recommended for the use in the U.S.

[]{.mark}

The chronic analysis incorporated 100% crop treated and proposed
tolerance values. The resulting DEEM-FCID food-only chronic exposure
estimates were below HED's level of concern for the US Population and
all population subgroups. Children 1-2 years of age (\<1 % cPAD) were
the most highly exposed population subgroup. When drinking water was
included in the dietary exposure analysis, the resulting DEEM-FCID
food-plus-water exposure estimates were below HED's level of concern for
all population subgroups, with Children 1-2 years of age (\<1 % cPAD)
being the most highly exposed population.

For drinking water, estimated drinking water concentrations (EDWCs) in
surface water were derived using the Environmental Fate and Effects
Division (EFED) Tier I aquatic model FIRST (FQPA Index Reservoir
Screening Tool, v.1.1.0; dated 12/12/2005). Estimated drinking water
concentrations (EDWCs) in groundwater were derived using EFED's Tier I
aquatic model SCI-GROW2 (Screening Concentration in Ground Water, v.2.3;
dated 11/12/1997). The residues of concern in drinking water are the
parent and 5-OH degradate.

**[Occupational Exposure/Risks]{.underline}**

Margins of Exposure (MOE) equal to or less than 100 are of concern to
HED. Since a dermal endpoint and dose were not selected a dermal
exposure assessment was not conducted. Inhalation MOEs were
significantly greater than 100 at baseline and are not of concern to
HED.

Since a dermal endpoint and dose were not selected a postapplication
dermal assessment was not conducted. As all scenarios are for outdoor
agricultural uses postapplication inhalation exposure is expected to be
negligible.

[Restricted Entry Interval]{.underline}

Since systemic toxicity was not evaluated for the dermal route (i.e. not
of concern), the restricted entry interval (REI) is based on the acute
toxicity of the technical active ingredient. Florasulam is classified as
Toxicity Category III for acute dermal and Category IV for acute oral,
inhalation, and eye exposure. Acute toxicity Category III and IV
chemicals require a 12 hour REI under the Worker Protection Standard
(WPS).

The product label for EF-1343 proposes an REI of 4 hours. Based on
review of the toxicological database for the active ingredient,
florasulam, EF-1343 is a candidate for a reduced risk active ingredient.
Therefore, florasulam is a candidate for a 4-hour REI. End-use products
must meet the criteria of PR Notice 95-3 to qualify for an REI of
4-hours.

The product labels for GF-1727, GF-184, and EF-1383 propose various REIs
ranging from 12 to 48 hours respectively. The REIs for these labels are
based on a second active ingredient (e.g. MCPA, fluroxpyr, and 2-4-D).
If products contain more than one active ingredient REI will be based on
the active ingredient which requires the longest REI. **HED recommends
that the Registration Division ensure that the proper REI be established
for each of the proposed labels**.

**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 Intakes 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. 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]{.underline}**

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 comprise the Pesticide Handlers Exposure
Database (PHED), have been determined to require a review of their
ethical conduct, and have received that review.

**[Additional Data Needs/Recommendations]{.underline}**

[Number range CHAPTERRegulatory Recommendations and Residue Chemistry
Deficiencies]{.underline}

-   A revised Section F should be submitted with correct raw
    agricultural commodity definitions along with the correct spelling
    of the chemical name for florasulam.

-   Successful completion of a petition method validation by BEAD/ACB is
    needed. The method has been sent to BEAD/ACB for validation.

-   Analytical standards for florasulam are not currently available in
    the National Pesticide Standards Repository. Analytical reference
    standards for florasulam need to be supplied and supplies need to be
    replenished as requested by the Repository. The reference standards
    should be sent to the Analytical Chemistry Branch, which is located
    at Fort Meade, to the attention of either Theresa Cole, Dallas
    Wright, or Frederic Siegelman at the following address:

> USEPA
>
> National Pesticide Standards Repository/Analytical Chemistry
> Branch/OPP
>
> 701 Mapes Road
>
> Fort George G. Meade, MD 20755-5350 (Note: mail will be returned if
> the extended zip code is not included).

-   The product labels for GF-1727, GF-184, and EF-1383 propose various
    REIs ranging from 12 to 48 hours respectively. The REIs for these
    labels are based on a second active ingredient (e.g. MCPA,
    fluroxpyr, and 2-4-D). If products contain more than one active
    ingredient, the REI will be based on the active ingredient which
    requires the longest REI. HED recommends that the Registration
    Division ensure that the proper REI is established for each of the
    proposed labels.

**Provided the above issues are addressed, HED recommends for the
establishment of the tolerances specified in Table C.1.**

**2.0 Ingredient Profile**

Florasulam is a triazolopyrimidine sulfonanilide post-emergent
herbicide. It is proposed for selective control of a broad spectrum of
annual broadleaf weeds in cereal grain crops (wheat, barley, oats, rye,
and triticale). The mode of action for florasulam is through inhibition
of the plant enzyme acetolactate synthase (ALS). The inhibition of ALS
results in a retardation of plant growth processes leading to death of
the plant.

**2.1 Summary of Registered/Proposed Uses**

+-------------+-------------+-------------+-------------+-------------+
| **Table     |             |             |             |             |
| 2.1:        |             |             |             |             |
| Proposed    |             |             |             |             |
| Use         |             |             |             |             |
| Patterns    |             |             |             |             |
| for the     |             |             |             |             |
| End-Use     |             |             |             |             |
| Products    |             |             |             |             |
| Containing  |             |             |             |             |
| F           |             |             |             |             |
| lorasulam** |             |             |             |             |
+=============+=============+=============+=============+=============+
| **          | **Method of | **Use       | **          | **Timing of |
| Formulation | Ap          | Sites**     | Application | Ap          |
| and         | plication** |             | Rate**      | plication** |
| Product**   |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| EF-1343     | Ground and  | Wheat,      | 0.00446 lb  | Po          |
|             | Aerial      | barley,     | ai/acre     | st-emergent |
| (4.84%      | equipment   | oats, rye,  |             | use, apply  |
| a.i.)       |             | and         |             | when weeds  |
|             |             | triticale   |             | are         |
| \#          |             |             |             | actively    |
| 62719-LAN   |             |             |             | growing     |
|             |             |             |             | between 2   |
|             |             |             |             | leaf and    |
|             |             |             |             | flag leaf   |
|             |             |             |             | emergence   |
|             |             |             |             | stage; do   |
|             |             |             |             | not apply   |
|             |             |             |             | more than   |
|             |             |             |             | 0.00446 lb  |
|             |             |             |             | ai/acre per |
|             |             |             |             | growing     |
|             |             |             |             | season      |
+-------------+-------------+-------------+-------------+-------------+
| EC-1383     |             |             |             |             |
|             |             |             |             |             |
| (0.58%      |             |             |             |             |
| a.i.)       |             |             |             |             |
|             |             |             |             |             |
| \#          |             |             |             |             |
| 62719-LL1   |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| GF-184      |             |             |             |             |
|             |             |             |             |             |
| (0.25%      |             |             |             |             |
| a.i.)       |             |             |             |             |
|             |             |             |             |             |
| #62719-LA6  |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| GF-1727     |             |             |             |             |
|             |             |             |             |             |
| (0.39%      |             |             |             |             |
| a.i.)       |             |             |             |             |
|             |             |             |             |             |
| 62719-LAE   |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+

**2.2 Structure and Nomenclature**

[[]{#__RefHeading___Toc139000973 .anchor}]{.mark}

+-------------------+--------------------------------------------------+
| **Table 2.2. Test |                                                  |
| Compound          |                                                  |
| Nomenclature**    |                                                  |
+===================+==================================================+
| **Compound**      | Chemical Structure                               |
|                   |                                                  |
|                   | ![](media/image2.wmf)                            |
+-------------------+--------------------------------------------------+
| **Common name**   | Florasulam                                       |
+-------------------+--------------------------------------------------+
| **Company         | DE-570 or EF-1343                                |
| experimental      |                                                  |
| name**            |                                                  |
+-------------------+--------------------------------------------------+
| **IUPAC name**    | 2\', 6\', 8-trifluoro-5-methoxy-*s*-triazolo     |
|                   | \[1,5-c\]pyrimidine-2-sulfonanilide              |
+-------------------+--------------------------------------------------+
| **CAS name**      | *N*-(2,6-difluorophenyl)-8-fluoro-5-methoxy(1,   |
|                   | 2, 4)triazolo(1, 5-c)pyrimidine-2-sulfonamide    |
+-------------------+--------------------------------------------------+
| **CAS \#**        | 145701-23-1                                      |
+-------------------+--------------------------------------------------+
| **End-use         | Florasulam Suspension Concentrate                |
| product/EP**      |                                                  |
+-------------------+--------------------------------------------------+
| **Molecular       | C~12~H~8~O~3~N~5~F~3~S                           |
| Formula**         |                                                  |
+-------------------+--------------------------------------------------+
| **Molecular       | 359.3                                            |
| Mass**            |                                                  |
+-------------------+--------------------------------------------------+

**2.3 Physical and Chemical Properties**[]{#__RefHeading___Toc139000974
.anchor}

[]{.mark}

+--------------------------+--------------------------+-----------------+
| **TABLE 2.3.             |                          |                 |
| Physicochemical          |                          |                 |
| Properties**             |                          |                 |
+==========================+==========================+=================+
| **Parameter**            | **Value**                | **Reference**   |
+--------------------------+--------------------------+-----------------+
| **Physical State**       | Solid                    | PMRA Lab        |
|                          |                          | Services        |
+--------------------------+--------------------------+-----------------+
| **Melting point/range**  | 193.5-230.5°C            |                 |
+--------------------------+--------------------------+-----------------+
| **Specific gravity**     | 1.53 at 22°C             |                 |
+--------------------------+--------------------------+-----------------+
| **Water solubility**     | [Medium]{.underline}     |                 |
|                          | [Solubility              |                 |
|                          | (g/L)]{.underline}       |                 |
|                          |                          |                 |
|                          | water 0.121              |                 |
|                          |                          |                 |
|                          | pH 5 0.084               |                 |
|                          |                          |                 |
|                          | pH 7 6.36                |                 |
|                          |                          |                 |
|                          | pH 9 94.2                |                 |
+--------------------------+--------------------------+-----------------+
| **Solvent solubility**   | [Solvent]{.underline}    |                 |
|                          | [Solubility              |                 |
|                          | (g/L)]{.underline}       |                 |
|                          |                          |                 |
|                          | acetone 123              |                 |
|                          |                          |                 |
|                          | acetonitrile 72.1        |                 |
|                          |                          |                 |
|                          | ethyl acetate 15.9       |                 |
|                          |                          |                 |
|                          | methanol 9.81            |                 |
|                          |                          |                 |
|                          | dichloromethane 3.75     |                 |
|                          |                          |                 |
|                          | xylene 0.227             |                 |
|                          |                          |                 |
|                          | n-octanol 0.184          |                 |
|                          |                          |                 |
|                          | n-heptane 0.000019       |                 |
+--------------------------+--------------------------+-----------------+
| **Vapor pressure**       | 1 x 10^-5^ Pa at 25°C    |                 |
+--------------------------+--------------------------+-----------------+
| **Dissociation constant  | 4.54                     |                 |
| (pK~a~)**                |                          |                 |
+--------------------------+--------------------------+-----------------+
| **Octanol/water          | [pH]{.underline} [Log    |                 |
| partition coefficient    | K~ow~]{.underline}       |                 |
| (K~ow~) at 22°C**        |                          |                 |
|                          | 4 1.00                   |                 |
|                          |                          |                 |
|                          | 7 -1.22                  |                 |
|                          |                          |                 |
|                          | 10 -2.06                 |                 |
+--------------------------+--------------------------+-----------------+
| **UV/visible absorption  | [Form]{.underline} [λmax |                 |
| spectrum**               | (nm)]{.underline}        |                 |
|                          |                          |                 |
|                          | Acidic 259.8             |                 |
|                          |                          |                 |
|                          | > 203.8                  |                 |
|                          |                          |                 |
|                          | Basic 262.4              |                 |
|                          |                          |                 |
|                          | > 209.7                  |                 |
|                          |                          |                 |
|                          | Methanolic 204.1         |                 |
|                          |                          |                 |
|                          | No absorbance above 300  |                 |
|                          | nm.                      |                 |
+--------------------------+--------------------------+-----------------+

[]{#__RefHeading___Toc139000975 .anchor}

**3.0 Hazard Characterization/Assessment for Florasulam**

**3.1 Hazard and Dose-Response Characterization**

**3.1.1 Database Summary**[]{#__RefHeading___Toc139000976 .anchor}

**3.1.1.1 Sufficiency of studies/data**

Based on the proposed use pattern, the toxicology database for
florasulam is complete and adequate for risk assessment. There are
acceptable studies available for endpoint selection that include: 1)
subchronic oral toxicity studies in rats, mice, and dogs; 2) a chronic
oral toxicity

study in dogs and carcinogenicity studies in rats and mice; 3)
developmental and reproduction studies in rats and a developmental study
in rabbits; and 4) a subchronic dermal toxicity study in rats. There is
also a complete mutagenicity battery, acute LD50, and neurotoxicity
studies (acute and chronic), as well as a metabolism study in the rat.

2.  **Mode of action, metabolism, toxicokinetic data**

Florasulam is a selective triazolopyrimidine sulfonanilide post-emergent
herbicide. The pesticidal mode of action (MOA) is through inhibition of
acetolactate synthase (ALS) in plants. ALS is found in the chloroplast
where it catalyses branch chained amino acid biosynthesis. Inhibition of
ALS results in inhibition of plant cell division, decreased plant
growth, and ultimately, plant death.

1.  **Toxicological effects**

Florasulam has low or minimal acute toxicity via the oral (Category IV),
dermal (Category III), and inhalation routes of exposure (Category IV).
It is non-irritating to the eye and skin (Category IV); it is not a skin
sensitizer.

Slight nephrotoxicity (increased kidney weights, hypertrophy, and
degeneration/regeneration and inflammation of the descending portion of
proximal tubules) was observed in the kidneys of rats (both sexes) after
subchronic exposure to florasulam (90 days) at ≥ 500 mg/kg/day. Chronic
exposure in rats led to slight nephrotoxicity (increased kidney weights,
hypertrophy, and slight multi-focal mineralization of the papilla) at
250 and 500 mg/kg/day in males only. Additionally at 500 mg/kg/day,
papillary necrosis and hyperplasia of the transitional epithelium
(papilla) were observed in the kidney (males). Decreases in body weight
and body weight gain were also observed in females after subchronic (500
mg/kg/day) and chronic exposure (250 mg/kg/day). Liver toxicity was
observed in dogs (both sexes) in the form of increased alkaline
phosphatase activity (59-127%), increased liver weights, hypertrophy,
and hepatic vacuolation at 50 mg/kg/day after 90 days. After 1 year,
there were increases in alkaline phosphatase (233-783%) in dogs (both
sexes) but no changes in liver weights or gross or microscopic pathology
at 50 mg/kg/day. Additionally, there were decreases in body weight, body
weight gain and food consumption, as well as vacuolation of the zona
reticularis and zona fasciculate in the adrenal gland (consistent with
fatty change) in both sexes. There were no adverse effects noted after
subchronic/chronic exposure to florasulam in mice up to the limit dose
of 1000 mg/kg/day.

There was no evidence of teratogenicity or indications of neonatal
sensitivity in the developmental and reproduction toxicity studies (rats
and rabbits). In the rat developmental toxicity study (750 mg/kg/day)
body weights were decreased by 4-6% during GD 6-19, resulting in a 16%
decrease in body weight gains during treatment (GD 6-16); food
consumption was also decreased (not statistically analyzed) by 6-13%
during the treatment period. Additionally at this dose, absolute and
relative (to body weight) kidney weights were increased (p\<=0.05) by 8
and 12%, respectively. At 250 and 750 mg/kg/day, slight decreases (3-4%)
were observed in fetal body weight. Additionally, there were delays in
ossification observed in fetuses at 750 mg/kg/day. However, the minor
differences were not considered adverse since there was no clear
dose-response and the values (both findings) fell within historical
control values. Furthermore, the findings were attributed to the
associated decreases in maternal body weights. There were no
treatment-related effects observed in dams or offspring in the
developmental toxicity study in rabbits. In the reproduction toxicity
study in rats, there were decreased body weights, body weight gains, and
food consumption, as well as increased kidney weights and hypertrophy in
both sexes at 500 mg/kg/day. Additionally at 500 mg/kg/day, transient
decreases in pup body weights were observed on PND 4 pre-culling (F1 and
F2 males) and PND 7 (F1 females and F2 males and females); however, by
PND 21, all treated groups were similar to controls. The decreases
observed were associated with decreased maternal body weight and food
consumption and were transient in nature; thus, they were not considered
adverse.

Dermal exposure to florasulam did not result in systemic toxicity up to
the limit dose of 1000 mg/kg/day.

There is no evidence of neurotoxicity, mutagenicity, or carcinogenicity
after exposure to florasulam. In addition, there is no evidence of
estrogen-, androgen-, and/or thyroid-mediated toxicity.

**3.1.3 Dose-response**

For chronic dietary exposure, the chronic study in dogs was used to
calculate the chronic reference dose (cRfD) of 0.05 mg/kg/day. The NOAEL
of 5 mg/kg/day and the LOAEL of 50 mg/kg/day were based on changes in
body weight, body weight gain and food consumption in females, and
adverse liver alterations, as well as slight vacuolation of the zona
reticularis and zona fasciculata in the adrenal gland (consistent with
fatty change) in both sexes; endpoints for acute dietary risk
assessments (general population and females age 13-49) were not
selected. A 90-day toxicity study in dogs was used to select the dose
and endpoint for occupational short- and intermediate-term inhalation
exposure. The NOAEL of 5 mg/kg/day and the LOAEL of 50 mg/kg/day were
based on adverse liver alterations (increased liver weights and alkaline
phosphatase activity, hypertrophy, and histopathology) in both sexes. A
risk assessment was not conducted for occupational dermal exposures
(short-term) due to the absence of adverse systemic effects in the
dermal toxicity study. There are no residential uses proposed for
florasulam; therefore, incidental oral and residential dermal and
inhalation risk assessments were not conducted.

**3.1.4 FQPA**

HED recommends the FQPA SF be reduced to 1X because there is no evidence
of increased susceptibility, there are no/low concerns and no residual
uncertainties with regard to pre- and/or postnatal toxicity.
Additionally, the toxicological database is complete (see Section 3.4).

**3.2. Absorption, Distribution, Metabolism, Excretion (ADME)**

In a metabolism study, \[^14^C\]-Florasulam in a suspension of 0.5%
Methocel™ cellulose ethers was administered to Fischer 344 rats as a
single gavage dose at 10 or 500 mg/kg. Additional rats were treated with
14 daily doses at 10 mg/kg/day of non-labeled Florasulam followed by a
single oral dose of \[^14^C\]-Florasulam on Day 15. To examine biliary
excretion, male rats were fitted with indwelling bile-duct cannulas
prior to dosing. Bile was periodically sampled, and urine and feces were
collected for a 24 h interval. Absorption was rapid and extensive.
Approximately

90-93% of the dose was absorbed in the 10 mg/kg rats, and 82-86% was
absorbed in the 500 mg/kg rats (based on the sum of radioactivity
detected in the urine, tissues/carcass, and cage rinse). Peak plasma
concentrations (C~max~) were achieved within 0.5-1 h following dose
administration. C~max~ in the plasma did not increase proportionally
with dose, possibly indicating a saturation of the absorption and/or
excretion mechanisms at the high dose. The apparent volume of
distribution was increased at the high dose, possibly indicative of
increased tissue binding. Total recoveries at 168 h post-dose were
95.9-100.2% of the administered dose. Elimination was rapid. The
administered dose was mostly eliminated within 12 h in the urine (\>80%
of the dose at 10 mg/kg and \>60% of the dose at 500 mg/kg). Total
radioactivity found in the urine was approximately 90-92% of the dose
following single or repeated low-dose treatment, and 81-85% of the dose
following treatment at 500 mg/kg. Radioactivity in the feces accounted
for another 5‑7% at 10 mg/kg and 14-17% at 500 mg/kg. Thus, compared to
the low dose, excretion of the high dose was slightly slower, and more
of the compound was excreted in the feces. At 24 h, \<0.5% of the dose
was found in expired air. By 24 h post-dose, plasma levels had declined
to \<0.1 µg eq/g plasma in both sexes at 10 mg/kg and \<5.0 µg eq/g
plasma in both sexes at 500 mg/kg. The highest residue levels were
observed in the skin (single dose) and carcass (repeated dose), but the
mean recovery of radioactivity in the tissues/carcass at sacrifice was
\<0.6% of the dose. Total recovery was 98.7% in the bile duct cannulated
group. The highest concentration of radioactivity was found in the
kidney (570 µg-eq/g). On a percentage-of-the dose basis, excluding the
carcass and GIT/ingesta, the blood, kidneys, liver, and skin had
relatively high amounts of radioactivity; however, the radioactivity
isolated in the skin may have been due to urinary contamination.
Excluding the skin, the amount (% dose) isolated was generally highest
in the blood, but all amounts were low (0.5-5.0% dose), regardless of
dose, time point, or sex. Parent accounted for \>91% of the
radioactivity in the kidney, liver, and blood for each dose, time point,
and sex. At 24 h postdose, biliary excretion accounted for only 1.0% of
the administered dose, while urinary excretion (81.0% dose) accounted
for the majority of the dose in this test group. The remaining
administered radioactivity in the bile duct cannulated test group was
isolated in the feces (3.9% dose), tissues, GIT/ingesta, and carcass
(8.3% dose), and final cage wash (4.6% dose). There were no sex-related
differences in the metabolism or pharmacokinetics of the test compound.
Identified compounds accounted for 87.6-91.6% of the administered dose
in each group. In each group, the following compounds were isolated:
parent accounted for 77.7-85.0% dose, OH-phenyl-XR-570 (exact position
of hydroxyl group not determined) accounted for 3.1-9.0% dose,
OH-phenyl-XR-570 sulfate conjugate accounted for 2.8-3.7% dose, and 2
unidentified metabolites accounted for ≤ 0.32% dose. In the high dose,
more of the parent was isolated in the feces and less in the urine
compared to the low dose. Similarly, the number of doses or the position
of the radiolabel generally made no difference in the metabolism and
pharmacokinetic profile.

**3.3 FQPA Considerations**

**3.3.1 Adequacy of the Toxicity Database**

The database is adequate to characterize potential pre- and/or
post-natal risk for infants and children. Acceptable/guideline studies
for developmental toxicity studies in rats and rabbits, a reproduction
study in rats, and acute and subchronic neurotoxicity studies in rats
were available for FQPA assessment.

2.  **Evidence of Neurotoxicity**

There was no evidence of neurotoxicity observed in the toxicology
database. In the acute neurotoxicity study, there was a slight transient
decrease in motor activity, increased incidence of minimal activity
(open-field), and decreased reactivity to sharp noise (Day 1) at 2000
mg/kg/day. However, the differences from control values did not exceed
the historical controls and complete recovery occurred by the next test
session (Day 8). When the FOB and motor activity findings were combined
they were considered to be a treatment-related high dose effect. As
there were no corroborative gross or neurological pathology, this
pattern of decreased activity was considered to be likely due to general
malaise. In the chronic neurotoxicity study, there were no
compound-related effects on mortality, clinical signs, food consumption,
FOB parameters, motor activity, or gross or neurological pathology
observed at any dose. Organ weights were not provided; however, in the
concurrently performed 2-year dietary chronic toxicity/carcinogenicity
study, brain weight was unaffected after 12 and 24 months of treatment.
There were no other potential signs of neurotoxicity noted in the
toxicology database.

3.  **Developmental Toxicity Studies**

There were no treatment-related effects observed in dams or offspring in
the developmental toxicity study in rabbits. In the rat developmental
toxicity study, at 750 mg/kg/day, body weights were decreased by 4-6%
during GD 6-19, resulting in a 16% decrease in body weight gains during
treatment (GD 6-16); food consumption was also decreased (not
statistically analyzed) by 6-13% during the treatment period.
Additionally at this dose, absolute and relative (to body weight) kidney
weights were increased (p\<=0.05) by 8 and 12%, respectively. At ≥ 250
mg/kg/day, slight decreases (3-4%) were observed in fetal body weight,
accompanied by delayed ossification (not significant) of the skull,
ribs, and sternebrae at 750mg/kg/day. However, both findings were within
the historical control range and attributed to the decreased maternal
body weights also seen in this dose group.

**3.3.4 Reproductive Toxicity Study**

In the 2-generation reproduction study, at 500 mg/kg/day, there were
decreases in pre-mating body weights and food consumption (Weeks 3-10),
resulting in decreased overall body weight gains (Weeks 0-10) in the F1
males and in the P and F1 females. During gestation, body weights and
food consumption were decreased during gestation days (GD) 0-21,
resulting in decreased overall (GD 0-21) body weight gains in the P and
F1 females. During lactation, body weights were decreased during
lactation days (LD) 1-14; however, food consumption and overall (LD
1-21) body weight gains were not adversely affected. Additionally at 500
mg/kg/day, there were increases in kidney weights and hypertrophy. In
the offspring, there were no adverse treatment-related effects observed
on birth index, live birth index, viability indices, clinical signs,
developmental landmarks, kidney weights, or gross pathology. Transient
decreases in pup body weights (500 mg/kg/day) were observed on PND 4
pre-culling (F1 and F2 males) and PND 7 (F1 females and F2 males and
females); however, by PND 21, all treated groups were similar to
controls. The decreases observed were associated with decreased maternal
body weight and food consumption and were transient in nature; thus,
they were not considered adverse. There were no other treatment-related
effects noted.

**3.3.5 Additional Information from Literature Sources**

A literature search did not reveal information that would impact the
risk assessment.

**3.3.6 Pre-and/or Postnatal Toxicity**

[]{#__RefHeading___Toc139000991 .anchor}

1.  **Determination of Susceptibility**

There is no concern for increased quantitative and/or qualitative
susceptibility after *in utero* or postnatal exposure to florasulam in
developmental toxicity studies in rats and rabbits, or a reproduction
study in rats.

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

The purposes of the Degree of Concern analysis are: (1) to determine the
level of concern for the effects observed when considered in the context
of all available toxicity data; and (2) to identify any residual
uncertainties after establishing toxicity endpoints and traditional
uncertainty factors to be used in the risk assessment. If residual
uncertainties are identified, then HED determines whether these residual
uncertainties can be addressed by a FQPA safety factor and, if so, the
size of the factor needed.

There is no evidence (quantitative or qualitative) of increased
susceptibility and no residual uncertainties with regard to pre- and/or
postnatal toxicity following *in utero* exposure to rats or rabbits and
pre and/or post-natal exposures to rats. Therefore, it is recommended
that the FQPA safety factor be reduced to 1X and no additional safety
factors are needed (section 3.4).

6.  **Recommendation for a Developmental Neurotoxicity Study**

There was no evidence of neurotoxicity observed following acute,
subchronic, or chronic exposure to florasulam, and no clinical signs of
neurotoxicity were observed following pre-natal or postnatal exposure;
therefore, a developmental neurotoxicity study is not warranted at this
time.

**3.4 Safety Factor for Infants and Children**

HED recommends the FQPA SF be reduced to 1x because there is no evidence
of increased susceptibility; there are no residual uncertainties with
regard to pre- and/or postnatal toxicity; and the toxicological database
for florasulam is complete. After evaluating the toxicological and
exposure data, the florasulam risk assessment team recommends that the
FQPA SF be reduced to 1x based on the following:

-   The toxicity data showed no increase in susceptibility in fetuses
    and pups with *in utero* and post-natal exposure.

-   The dietary food exposure assessment is based on HED-recommended
    tolerance- level residues and assumes 100% crop treated for all
    commodities, which results in upper bound estimates of dietary
    exposure.

-   The dietary drinking water assessment is based on values generated
    by model and associated modeling parameters which are designed to
    provide conservative, health protective, upper bound estimates of
    water concentrations.

-   There are no registered or proposed residential uses.

**3.5 Hazard Identification and Toxicity Endpoint Selection**

1.  **Acute Reference Dose (aRfD) -- General Population**

> In an acute neurotoxicity study, there was a slight transient decrease
> in motor activity, an increased incidence of minimal activity
> (open-field), and decreased reactivity to sharp noise (Day 1) at 2000
> mg/kg/day. However, the differences observed did not exceed the
> historical controls and complete recovery occurred by the next test
> session (Day 8). As there were no corroborative gross or neurological
> pathology to suggest a neurotoxic effect, this pattern of decreased
> activity was considered to be likely due to general malaise
> (treatment-related) and not frank neurotoxicity. Since the effects
> were observed at a very high dose considered non-applicable to human
> exposure, a risk assessment for acute dietary exposure (general
> population) was not conducted. There were no other studies with
> effects resulting from single dose exposure.

**3.5.2 Acute Reference Dose (aRfD) - Females age 13-49**

> No appropriate endpoint identified for this population.

**3.5.3 Chronic Reference Dose (cRfD)**

> **Study Selected:** Chronic Toxicity-Dog
>
> **MRID No:** 46808229
>
> **Dose and Endpoint for Risk Assessment**: NOAEL= 5 mg/kg/day
>
> **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x
> intraspecies variability)

  -------------------------------------------------------------------------------------
  **Chronic RfD** =
  $\frac{5\ \frac{\frac{\text{mg}}{\text{kg}}}{\text{day}}}{\text{100}\ (\text{UF})}$ =
  **0.05 mg/kg/day**

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

> **[Comments about Study/Endpoint/Uncertainty Factors:]{.underline}**
>
> A chronic toxicity study in dogs was used to select the dose and
> endpoint for establishing the cRfD of 0.05 mg/kg/day. This study is
> the appropriate route and duration to establish a chronic dietary
> endpoint. The NOAEL of 5 mg/kg/day and the LOAEL of 50 mg/kg/day were
> based on decreased body weights, body weight gains, and food
> consumption in females, adverse liver alterations, and slight
> vacuolation of the zona reticularis and zona fasciculata in the
> adrenal gland (consistent with fatty change) in both
>
> sexes. Uncertainty factors (100x) include: 10x interspecies
> extrapolation, 10x intraspecies variability.

4.  **Incidental Oral Exposure**

> There are no residential uses proposed; therefore, a risk assessment
> was not conducted for incidental oral exposure.

5.  **Dermal Absorption**

> In a dermal absorption study in rats, recovery of the applied dose
> (mass balance) was 100-103%. The majority of the dose was recovered in
> the skin swab (71-90% of the applied dose). Dermal absorption (based
> on the sum of residues in urine, feces, cage wash, tissues, residual
> carcass, and untreated skin) was only 0.13-0.45% of the applied dose
> and only 10-22% of the applied dose remained in the skin at the
> application site (considered potentially absorbable). Increasing the
> dose 200-fold resulted in only approximately 2-fold increase in
> absorption. Absorption increased 44% at 48 h and 61% at 72 h compared
> to 24 h in the low dose groups; however, a time-dependent increase in
> absorption was not evident in the high dose groups. The absorbed dose
> was almost completely excreted in the urine at the low dose, but was
> found primarily in the urine, cage wash, and untreated skin at the
> high dose. The amount of radioactivity at the treatment site increased
> at 48 hours in the low dose, but did not decrease within 72 hours at
> either dose, suggesting that the compound in the skin was not readily
> absorbable. This study is supported by a 28-day repeated dose dermal
> toxicity study, in which no compound-related effects in mortality,
> clinical signs, body weight, body weight gain, food consumption,
> hematology, clinical chemistry, urinalysis, organ weights, and gross
> or microscopic pathology parameters were observed in either sex up to
> the limit dose (1000 mg/kg/day). At 1000 mg/kg/day, very slight
> (grade 1) edema and erythema at the treatment site were noted in 4/5
> males beginning on Day 23. Dermal irritation was resolved by Day 28.

6.  **Occupational Dermal Exposure (Short-Term)**

> There were no systemic effects observed up to the limit dose of 1000
> mg/kg/day in a 28-day dermal toxicity study in rats; therefore, a
> quantitative dermal assessment was not conducted.

**3.5.7 Occupational Inhalation Exposure (Short-Term)**

> **Study Selected:** 90-Day Dog
>
> **MRID No:** 46808223

**Dose and Endpoint for Risk Assessment:** NOAEL= 5 mg/kg/day

**Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x
intraspecies variability)

> **[Comments about Study/Endpoint/Uncertainty Factors:]{.underline}** A
> 90-day oral toxicity study in dogs was used to select the dose and
> endpoint for short-term inhalation exposure. The study is the
> appropriate duration for selecting short-term endpoints. The NOAEL of
> 5 mg/kg/day and the LOAEL of 50 mg/kg/day were based on increased
> liver weights and alkaline phosphatase activity, hypertrophy, and
> histopathology. Inhalation studies were not available; thus,
> inhalation absorption was assumed to be 100% (default value).
> Uncertainty factors (100x) include: 10x interspecies extrapolation,
> and 10x intraspecies variability.

**3.5.8 Level of Concern for Margin of
Exposure**[]{#__RefHeading___Toc139001007 .anchor}

+-----------------------+-----------+-----------------+--------------+
| **Table 3.5.8 Summary |           |                 |              |
| of Levels of Concern  |           |                 |              |
| for Risk              |           |                 |              |
| Assessment.**         |           |                 |              |
+-----------------------+-----------+-----------------+--------------+
| **Route**             | **Sho     | **Inte          | *            |
|                       | rt-Term** | rmediate-Term** | *Long-Term** |
|                       |           |                 |              |
|                       | **(1 - 30 | **(1 - 6        | **(\> 6      |
|                       | Days)**   | Months)**       | Months)**    |
+-----------------------+-----------+-----------------+--------------+
| **Occupational        |           |                 |              |
| (Worker) Exposure**   |           |                 |              |
+-----------------------+-----------+-----------------+--------------+
| **Dermal**            | N/A       | N/A             | N/A          |
+-----------------------+-----------+-----------------+--------------+
| **Inhalation**        | 100       | N/A             | N/A          |
+-----------------------+-----------+-----------------+--------------+

**3.5.9 Recommendation for Aggregate Exposure Risk Assessments**

> As per FQPA, 1996, when there are potential residential exposures to a
> pesticide, aggregate risk assessment must consider exposures from
> three major routes: oral, dermal, and inhalation exposures. However,
> an aggregate risk assessment across the three routes of exposure was
> not conducted for florasulam since there are no registered or proposed
> residential uses.

10. **Classification of Carcinogenic Potential**

> There were no treatment-related increases in tumors in rat and mouse
> carcinogenicity studies after exposure to florasulam. Additionally,
> there was no evidence of mutagenicity noted. Therefore, according to
> *EPA's Final Guidelines for Carcinogen Risk Assessment* (March, 2005),
> florasulam is classified as "Not Likely to be Carcinogenic to Humans."

**Summary of Toxicological Doses and Endpoints for Florasulam for Use in
Human Risk Assessments.**

+----------+---------+----------+-------------+-----------------------+
| **Table  |         |          |             |                       |
| 3.5a     |         |          |             |                       |
| Toxic    |         |          |             |                       |
| ological |         |          |             |                       |
| Doses    |         |          |             |                       |
| and      |         |          |             |                       |
| E        |         |          |             |                       |
| ndpoints |         |          |             |                       |
| for      |         |          |             |                       |
| Fl       |         |          |             |                       |
| orasulam |         |          |             |                       |
| for Use  |         |          |             |                       |
| in       |         |          |             |                       |
| Dietary  |         |          |             |                       |
| and      |         |          |             |                       |
| Non-Occu |         |          |             |                       |
| pational |         |          |             |                       |
| Human    |         |          |             |                       |
| Health   |         |          |             |                       |
| Risk     |         |          |             |                       |
| Asses    |         |          |             |                       |
| sments** |         |          |             |                       |
+==========+=========+==========+=============+=======================+
| **Exp    | **Point | **Uncert | **RfD, PAD, | **Study and           |
| osure/** | of      | ainty/** | Level of    | Toxicological         |
|          | Depa    |          | Concern for | Effects**             |
| **Sc     | rture** | **FQPA   | Risk        |                       |
| enario** |         | Safety   | A           |                       |
|          |         | F        | ssessment** |                       |
|          |         | actors** |             |                       |
+----------+---------+----------+-------------+-----------------------+
| Acute    | N/A     | N/A      | N/A         | **[The risk           |
| Dietary  |         |          |             | assessment was not    |
| (General | []      | [        | []{.mark}   | cond                  |
| Pop      | {.mark} | ]{.mark} |             | ucted]{.underline}**. |
| ulation, |         |          |             | The effects observed  |
| i        |         |          |             | in an acute           |
| ncluding |         |          |             | neurotoxicity study   |
| Infants  |         |          |             | were seen at a very   |
| and      |         |          |             | high dose (2000       |
| C        |         |          |             | mg/kg/day) that is    |
| hildren) |         |          |             | considered not        |
|          |         |          |             | applicable to human   |
|          |         |          |             | exposure.             |
+----------+---------+----------+-------------+-----------------------+
| Acute    | N/A     | N/A      | N/A         | **[No appropriate     |
| Dietary  |         |          |             | endpoint              |
|          | []      | [        | []{.mark}   | ident                 |
| (Females | {.mark} | ]{.mark} |             | ified]{.underline}.** |
| 13-49    |         |          |             |                       |
| years of |         |          |             |                       |
| age)     |         |          |             |                       |
+----------+---------+----------+-------------+-----------------------+
| Chronic  | NOAEL = | UF~A~ =  | Chronic RfD | **[Chronic toxicity   |
| Dietary  | 5       | 10X      | = 0.05      | --                    |
| (All     | mg      |          | mg/kg/day   | dogs]{.underline}**   |
| Popu     | /kg/day | UF~H~ =  |             |                       |
| lations) |         | 10X      | cPAD = 0.05 | LOAEL = 50 mg/kg/day, |
|          |         |          | mg/kg/day   | based on decreased    |
|          |         | FQPA SF  |             | body weights (17%),   |
|          |         | = 1X     |             | body weight gains     |
|          |         |          |             | (68%), and food       |
|          |         |          |             | consumption in the    |
|          |         |          |             | females; adverse      |
|          |         |          |             | liver alterations;    |
|          |         |          |             | slight vacuolation of |
|          |         |          |             | the zona reticularis  |
|          |         |          |             | and zona fasciculata  |
|          |         |          |             | in the adrenal gland  |
|          |         |          |             | (fatty change) in     |
|          |         |          |             | both sexes.           |
+----------+---------+----------+-------------+-----------------------+
| Cancer   | "Not    |          |             |                       |
| (oral,   | Likely  |          |             |                       |
| dermal,  | to be   |          |             |                       |
| inh      | Carci   |          |             |                       |
| alation) | nogenic |          |             |                       |
|          | to      |          |             |                       |
|          | Humans" |          |             |                       |
+----------+---------+----------+-------------+-----------------------+

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. N/A = not applicable.

+----------+---------+----------+-------------+-----------------------+
| **Table  |         |          |             |                       |
| 3.5b     |         |          |             |                       |
| Summary  |         |          |             |                       |
| of       |         |          |             |                       |
| Toxic    |         |          |             |                       |
| ological |         |          |             |                       |
| Doses    |         |          |             |                       |
| and      |         |          |             |                       |
| E        |         |          |             |                       |
| ndpoints |         |          |             |                       |
| for      |         |          |             |                       |
| Fl       |         |          |             |                       |
| orasulam |         |          |             |                       |
| for Use  |         |          |             |                       |
| in       |         |          |             |                       |
| Occu     |         |          |             |                       |
| pational |         |          |             |                       |
| Human    |         |          |             |                       |
| Health   |         |          |             |                       |
| Risk     |         |          |             |                       |
| Asses    |         |          |             |                       |
| sments** |         |          |             |                       |
+==========+=========+==========+=============+=======================+
| **Exp    | **Point | **Unc    | **Level of  | **Study and           |
| osure/** | of      | ertainty | Concern for | Toxicological         |
|          | Depa    | F        | Risk        | Effects**             |
| **Sc     | rture** | actors** | A           |                       |
| enario** |         |          | ssessment** |                       |
+----------+---------+----------+-------------+-----------------------+
| Dermal   | N/A     | N/A      | N/A         | **[The risk           |
|          |         |          |             | assessment was not    |
| Sh       |         |          |             | con                   |
| ort-term |         |          |             | ducted]{.underline}** |
| (1-30    |         |          |             |                       |
| days)    |         |          |             | 28-day dermal         |
|          |         |          |             | toxicity study --     |
|          |         |          |             | rats                  |
|          |         |          |             |                       |
|          |         |          |             | LOAEL = not           |
|          |         |          |             | determined, no        |
|          |         |          |             | systemic effect up to |
|          |         |          |             | the limit dose of     |
|          |         |          |             | 1000 mg/kg/day.       |
+----------+---------+----------+-------------+-----------------------+
| In       | NOAEL = | UF~A~ =  | Residential | **[90-day oral        |
| halation | 5mg     | 10X      | LOC for MOE | toxicity --           |
| Short-t  | /kg/day |          | = 100       | dogs]{.underline}**   |
| erm(1-30 |         | UF~H~ =  |             |                       |
| days     | I       | 10X      |             | LOAEL = 50 mg/kg/day, |
|          | AF=100% |          |             | based on increased    |
|          |         | FQPA SF  |             | alkaline phosphatase  |
|          |         | = 1X     |             | activity and          |
|          |         |          |             | increased             |
|          |         |          |             | incidence/severity of |
|          |         |          |             | hepatic vacuolation   |
|          |         |          |             | in both sexes.        |
+----------+---------+----------+-------------+-----------------------+
| Cancer   | "Not    |          |             |                       |
| (oral,   | Likely  |          |             |                       |
| dermal,  | to be   |          |             |                       |
| inh      | Carci   |          |             |                       |
| alation) | nogenic |          |             |                       |
|          | to      |          |             |                       |
|          | Humans" |          |             |                       |
+----------+---------+----------+-------------+-----------------------+

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.
IAF=inhalation absorption factor.

**3.6 Endocrine Disruption**

EPA is required under the 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 its Endocrine Disruptor and Screening 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 system. EPA
also adopted EDSTAC's recommendation that the Program include
evaluations of potential effects in wildlife. For pesticide chemicals,
EPA will use FIFRA and, to the extent that effects in wildlife may help
determine whether a substance may have an effect in humans, FFDCA
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, florasulam may
be subjected to further screening and/or testing to better characterize
effects related to endocrine disruption.

**4.0 Public Health and Pesticide Epidemiology Data**

No public health/epidemiology data were used in developing this risk
assessment.

**5.0 Dietary Exposure/Risk
Characterization**[]{#__RefHeading___Toc139001017 .anchor}

**5.1 Pesticide Metabolism and Environmental
Degradation**[]{#__RefHeading___Toc139001018 .anchor}

**5.1.1 Metabolism in Primary Crops**[]{#__RefHeading___Toc139001019
.anchor}

[]{.mark}

In the metabolism study, \[^14^C\]-DE-570 (\>98%) formulated with EF
1343 blank formulation, radiolabeled as \[^14^C\]-phenyl-XDE-570 and
\[^14^C\]-TP-XDE-570 was applied to winter wheat at crop growth stages
of BBCH30 (stem elongation-early application) and BBCH49 (postflag leaf
emergence/first awns visible-late application) at 50 g a.i./ha. The rate
used was equivalent to 10x the proposed label rate of 5 g a.i./ha.

Total radioactive residue (TRR) level in grain was determined by
combustion/LSC. The ^14^C-residues were too low to elucidate the nature
of the TRRs in mature wheat ears (up to 0.03 ppm) and grain (up to 0.008
ppm). Therefore, no further attempts to characterize/identify the
^14^C-residues in grain were carried out. However, residues in immature
whole wheat plants and mature wheat straw were present at levels
permitting adequate identification.

The metabolism of florasulam in wheat proceeded via hydroxylation in the
4-position of the phenyl ring with subsequent glucose conjugation.
Additional degradation was followed by tentative cleavage of the
sulfonamide bridge. The metabolites detected in wheat matrices were
4-OH-(phenyl)-florasulam, the glucose conjugate of
4-OH-(phenyl)-florasulam, and 2-sulfonamide. The metabolism study was
conducted at 10X the proposed label rate (5 g a.i./ha) and the
2-sulfonamide metabolite was detected only in winter wheat straw (0.059
ppm) and not in the grain.

Based on the low level of residues observed in wheat grain (0.008 ppm)
at the exaggerated application rate (10X the proposed application rate)
in the wheat metabolism study, HED concludes the residue of concern
(ROC) in plants is the parent compound, florasulam. This conclusion
applies to cereal grains only. Additional plant metabolism studies will
be needed for any future uses on other types of crops.

[]{.mark}

**5.1.2 Metabolism in Rotational Crops**

[]{.mark}

In the confined rotational crop study, XDE-570 (florasulam), \> 97%
a.i., E-1343 Suspension Concentrate labeled either as the
\[UL-phenyl-^14^C\]XDE-570 or the \[9-triazolopyrimidine-^14^C\]XDE-570,
was applied to sandy loam soil at an application rate of 7.5 g a.i./ha
(1.5X the maximum proposed postemergent application rate). Spring wheat,
sunflower, cabbage and carrots were planted at 30 days after treatment
(DAT) of soil.

Spring wheat, sunflowers, cabbage and carrots were harvested at
maturity, 168 DAT (spring wheat and sunflowers), 195 DAT (cabbage), and
156 DAT (carrots). Each crop was separated into fractions as spring
wheat (ears and straw), sunflower (heads and stems), cabbage (shoots)
and carrot (leaves and roots). The samples were subjected to three
sequential surface washes (an aqueous wash, a dichloromethane wash and a
methanol wash). Each wash was analyzed to determine total ^14^C-residues
(TRRs) using combustion/liquid scintillation counting. In addition,
tissue samples were combusted and TRRs determined. None of the fractions
from rotational crops had TRRs greater than 0.01 ppm. Therefore, no
further attempt was made to profile TRRs.

Because levels of TRRs in the rotational crops were low (≤ 0.01 ppm), no
residues were identified. Therefore, the confined rotational crop study
supports the definition of ROC as parent only as defined in the plant
and livestock metabolism studies.

Based on the results of the confined rotational crop study, field
rotational crop studies are not required, and a 30-day plant back
interval (PBI) can be supported for all crops. The label has a plant
back interval of greater than 30 days for barley, canola, forage
grasses, oats, peas, rye and wheat.

**5.1.3 Metabolism in Livestock**

[]{.mark}

In the lactating goat metabolism study, XDE-570, radiolabeled as either
\[UL-aniline-^14^C\]XDE-570, or \[triazolopyrimidine-9- ^14^C\]XDE-570
was administered to two lactating goats (one per treatment) at a dose
level of approximately 0.48 mg/kg bw/day. The dose was administered
orally once daily in the morning for five consecutive days using a bolus
gun and was equivalent to approximately 11 ppm (\~100X the XDE-570
dietary burden) at an average feed consumption of 2 kg/day.

The results indicated that the total radioactive residues (TRRs) were
almost comparable between two labeling positions for urine, feces,
muscle and fat. But a slight difference in TRR was noted for kidney,
liver and milk. Recoveries of the administered dose in goat were 89% of
the aniline label (A-label) and 83% for the triazolopyrimidine label
(TP-label). The majority of the radioactivity was excreted in the urine
and feces, accounting for a total of 99.8% of the recovered
radioactivity. Total residues in tissues were very low. These residues
in the tissues, milk and blood samples were below 0.1% of the
administered dose. The highest concentration of residues in tissues was
found in the kidneys, 0.069 ppm and 0.039 ppm from the A-label and
TP-label experiments, respectively. Total radioactive residue in liver
was 0.033 ppm and 0.023 ppm from the A-label and TP-label experiments,
respectively. Total radioactive residue in muscle was 0.0016 ppm and
0.0009 ppm from the A-label and TP-label experiments, respectively.
Total radioactive residue in fat was 0.0016 ppm and 0.0017 ppm from the
A-label and TP-label experiments, respectively. Total radioactive
residue in milk was 0.016 ppm and 0.033 ppm from the A-label and
TP-label experiments, respectively. The predominant radioactive
component extracted from urine, milk, liver and kidney samples was
parent. One minor metabolite representing up to 1.5% of TRR was
tentatively identified as 5-OH-florasulam in urine, liver and kidney
samples.

In the laying hen metabolism study, XDE-570, radiolabeled as either
\[UL-aniline-^14^C\]XDE-570, or \[triazolopyrimidine-9- ^14^C\]XDE-570
was administered to two groups of 10 laying hens at a dose level of 0.76
± 0.01 mg/kg bw/day. The dose was equivalent to 11 ppm (\~1300X the
XDE-570 dietary burden) at an average feed consumption of 0.13 kg/day.
Samples of eggs and excreta were collected throughout the study. The
test hens were sacrificed approximately 24 hours after the final dose.
The tissue samples of fat, composite muscle (light and dark), skin, and
liver were collected for analysis.

The results indicated that the TRRs were comparable between two labeling
positions for excreta, muscle, fat, liver, and egg. TRR in muscle, fat
and liver were less than limit of quantification (\< LOQ). TRR in skin
and eggs were very low (0.013%, \< 0.007 ppm). Almost 100% of the
recovered radioactivity that was administered to hen was found in
excreta. The highest concentration of residues in tissues was found in
the skin, 0.0066 ppm and 0.005 ppm in A-label and TP-label,
respectively. The concentrations of residues in egg were about 0.004 ppm
for both the A-label and TP-label, respectively. Total radioactive
residue in liver was 0.0014 ppm and 0.001 ppm from the A-label and
TP-label experiments, respectively. Total radioactive residue in
composite muscle was 0.0005 ppm and 0.0008 ppm from the A-label and
TP-label experiments, respectively. Total radioactive residue in
composite fat was 0.0004 ppm and 0.0006 ppm from the A-label and
TP-label experiments, respectively.

The metabolism of florasulam in the laying hen and lactating goat were
similar. In both, the majority of the radioactivity was found in the
excreta. Most of the parent compound in goat and hen was eliminated
unchanged with minor unknown metabolites at unquantifiable levels. No
significant cleavage of the sulfonanilide bridge was observed.

**5.1.4 Analytical Methodology**

[]{.mark}

Residues of florasulam were extracted from wheat, barley and oat matrix
with acidified acetone. An aliquot of the extract was purified by
filtration through a graphitized carbon solid-phase extraction (SPE)
column. The extract was concentrated to remove acetone, diluted with
0.01 N hydrochloric acid and partitioned onto an octadecyl (C~18~) SPE
column. The florasulam was eluted with a 30% acetonitrile in 0.01 N
hydrochloride acid solution. Florasulam is partitioned, after salting,
into methyl *t*-butyl ether (MTBE). The MTBE was concentrated to
dryness. Residues of florasulam were dissolved in acetone and
derivatized at room temperature with iodomethane and triethylamine. The
acetone solution was concentrated to dryness and *N*-methyl florasulam
residues were dissolved in a 5% sodium thiosulfate solution and
partitioned into toluene containing the internal standard *N*-propyl
florasulam. Residues of florasulam as the N-methyl florasulam derivative
were determined by capillary gas chromatography with mass selective
detection (GC/MSD). This is a specific method that identifies/quantifies
florasulam, the parent compound only.

The limit of detection (LOD) was calculated as three times the standard
deviation (3s) which was 0.0012 ppm in grain, 0.005 ppm in forage and
immature green plant, 0.0036 ppm in hay and immature dried plant and
0.0074 ppm in straw. The limit of quantitation (LOQ) for florasulam was
established at 0.01 ppm for grain over the concentration range of
0.01-0.10 ppm, and at 0.05 ppm for forage, hay, straw, immature green
plant and immature dried plant over the concentration range of 0.05-0.50
ppm.

Representative chromatograms of control matrices of wheat, barley and
oat showed no interferences from crop components or from reagents,
solvents and glassware. The chromatographic peaks were sharp and free of
interferences in the retention areas of internal standard or *N*-methyl
florasulam derivative. The registrant stated no radiovalidation of the
analytical method was performed since residue levels were below LOQ.

The method of analysis was independently validated at Enviro-Bio-Tech.
Ltd. (Bernville, PA) using wheat grain, forage, hay and straw. This ILV
study successfully validated the Dow AgroSciences method GRM 98.01 for
the residues of the florasulam in wheat matrices, indicating good
reproducibility.

The GC/MSD method will be forwarded to BEAD/ACB for a petition method
validation. The analytical methodology is acceptable as an enforcement
method pending validation by ACB.

5.  **Environmental Degradation**

Florasulam does not hydrolyze at acidic or neutral pHs, but hydrolyzes
slowly (half-life of 99 days) at pH 9. The major hydrolysis degradates
at pH 9 are 5-OH-XDE-570 and a second hydrolysis product for which the
structure was not confirmed. In water, florasulam photodegrades slowly
(adjusted half-life of 46 days), the only major degradate is
triazolopyrimidine sulphonic acid of florasulam (TSPA). Florasulam is
stable to photodegradation on soil. Abiotic degradation (by hydrolysis
or photolysis) is not expected to be a significant route of dissipation
in the environment.

Florasulam is not persistent in aerobic soil, degrading rapidly with
half-lives of 0.7-8.3 days. The major degradates are
N-(2,6-difluorphenyl)-8-fluoro-5-hydroxy (1,2,4)triazolo (1,5c)
pyrimidine-2-sulphonamide (5-OH-XDE-570;
N-(2,6-difluorophenyl)-5-aminosulphonyl-1H-1,2,4-triazole-3-carboxylic
acid (DFP-ASTCA), 5-(aminosulphonyl)-1H-1,2,4-triazole-3-carboxylic acid
(ASTCA), and 1H-1,2,4-triazole-3-sulphonamide (TSA). Based on the study
results and the chemical structures, florasulam appears to biotransform
rapidly to 5-OH-XDE-570, which is then further biotransformed to
DFP-ASTCA, DFP-TSA, and polar compounds, eventually forming CO2 and
bound residues. The major degradate 5-OH-XDE-570 degrades more slowly
than the parent in aerobic soil, with half-lives ranging from 10 to 56
days in 11 soils, and is labile to moderately persistent.
Biotransformation of florasulam is a significant route of dissipation in
aerobic soils. Data for anaerobic soils were not submitted.

In aquatic systems, florasulam degrades with half-lives of 3-18 days in
aerobic systems and half-lives of 2-13 days in anaerobic systems. In
aerobic aquatic systems, florasulam is biotransformed to 5-OH-XDE-570,
which is then further biotransformed to DFP-ASTCA and STCA (tentative
identification). However, 5-OH-XDE-570 degrades much more slowly than
the parent, degrading with a half-life of 169 days in one aerobic system
and remaining stable in another aerobic system. In anaerobic aquatic
systems, 5-OH-XDE-570 is stable. Thus, 5-OH-XDE-570 is expected to be
persistent in both aerobic and anaerobic aquatic systems.

Based on the results from the laboratory batch equilibrium studies and
column leaching studies, as supported by the results of multiple
terrestrial field dissipation studies in which leaching was observed,
both florasulam and 5-OH-XDE-570 are very mobile in soil and, thus, have
the potential to leach. All measured Kds are less than 1. For the parent
compound, the potential to leach will be somewhat reduced by the fairly
rapid biotransformation of the parent in aerobic soil. For 5-OH-XDE-570,
the potential to leach is enhanced (relative to the parent) by slower
biotransformation in aerobic soil and by a much higher solubility in
water. For either compound, both of which partition mainly to the water
phase, the potential to leach will be greater when there is excessive
rainfall or irrigation.

Based on bioconcentration in fish (BCF) values of 0.9-2.0X, florasulam
is not expected to bioaccumulate in aquatic organisms.

6.  **Comparative Metabolic Profile**

Data depicting the metabolism of florasulam in plants and animals, as
well as data on environmental degradates, have been submitted to the
Agency. The nature of the residue for the use in/on cereal grains is
adequately understood based on acceptable metabolism studies in wheat,
rotational crops (spring wheat, sunflower, cabbage, and carrot),
ruminants (goat), and poultry (hen). Major metabolites (\> 10%) observed
include: parent (all matrices), 5-OH florasulam (rotational crops),
4-OH-(phenyl)-florasulam (wheat), the glucose conjugate of
4-OH-(phenyl)-florasulam (wheat), and 2-sulfonamide (wheat).

The metabolism of florasulam in wheat proceeded via hydroxylation in the
4-position of the phenyl ring with subsequent glucose conjugation.
Additional degradation was followed by tentative cleavage of the
sulfonamide bridge.

In rats, metabolism is limited to hydroxylation of the phenyl ring
without affecting the sulfonamide bond. The parent compound accounted
for 80% of the administered dose. The major metabolite observed was
OH-phenyl-florasulam (exact position of hydroxyl group not determined)
at 3-10%; 2-4% of a sulfate conjugate of OH-phenyl-florasulam was also
seen.

For the purposes of this petition, the ROC in plant and livestock
commodities for risk assessment and tolerance expression is the parent
compound. A metabolite summary table (Table B.1.2) is located in
Appendix B.

7.  **Toxicity Profile of Major Metabolites and Degradates of Concern**

[]{.mark}

Per correspondence with Alberto Protzel (Toxicology Branch, HED,
5/1/07), the major florasulam metabolites (4-OH phenyl florasulam,
glucose conjugate of 4-OH phenyl florasulam, 5-OH florasulam, TPSA,
ASTCA, and DFP-ASTCA) observed in the rat and primary crops, and as
environmental degradates in drinking water, are unlikely to be more
toxic than the parent compound.

8.  **Pesticide Metabolites and Degradates of Concern**

Since residues in grain were too low to identify, the decision for the
residue of concern in cereal grains is based on the results for the
whole wheat plants (30 days after application) and wheat straw. The
wheat metabolism study was conducted at a 10x rate (50 g ai/ha; 0.045 lb
ai/A). Parent was identified in all but one of these samples at levels
of 0.02-0.12 ppm (7-32% TRR). The only metabolites consistently observed
were the 4-OH phenyl florasulam and its glucose conjugate. The conjugate
was present at 0.0018-0.088 ppm (2.5-41.5% TRR) and the free 4-OH
metabolite at 0.0012-0.06 ppm (5.5-15% TRR). In the absence of
toxicology data for the OH metabolite and its conjugate, HED is not able
to consider these residues to be significantly less toxic than parent
florasulam. Since these residues are present at comparable or higher
levels than the parent, one would normally include them as residues of
concern. However, in this case due to the very low application rate,
residues of both the parent and metabolites are likely to be below the
LOQ of an analytical method from the proposed use. Based on the 10x rate
metabolism study, the parent or the metabolite with its conjugate could
serve as a marker of serious misuse for tolerance enforcement purposes.
Considering that total radioactivity in wheat grain from the 10x rate
was only 0.008 ppm, use of the parent compound LOQ of 0.01 ppm is a
conservative measure of exposure for dietary risk purposes. Taking into
account all of these factors, HED concludes that the residue of concern
in cereal grains is the parent compound florasulam.

The 5-OH degradate formed by demethylation of florasulam is by far the
predominant environmental residue reaching maximum levels of 70% of
applied material in the hydrolysis and metabolism (soil, aquatic)
studies. As with the 4-OH metabolite in plants, it is assumed to be of
comparable toxicity to the parent. Although several other degradates do
occur at levels \>10% applied, they do so in only one or two studies and
their maximum levels do not approach those of the 5-OH degradate. On
this basis, the residues of concern in drinking water are the parent and
5-OH degradate. EFED has supplied separate estimate drinking water
concentrations for these two compounds.

[]{.mark}

  ------------------------------------------------------------------------
  **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    Parent Florasulam    Parent Florasulam

                 Rotational Crop N/A                  N/A

  Livestock      Ruminant        N/A                  N/A

                 Poultry         N/A                  N/A

  Drinking Water                 Parent Florasulam &  Not Applicable
                                 5-OH florasulam      
  ------------------------------------------------------------------------

[]{.mark}

9.  **Drinking Water Residue Profile**

Estimated drinking water concentrations (EDWCs) in surface water were
derived using the Environmental Fate and Effects Division (EFED) Tier I
aquatic model FIRST (FQPA Index Reservoir Screening Tool, v.1.1.0; dated
12/12/2005). Estimated drinking water concentrations (EDWCs) in
groundwater were derived using EFED's Tier I aquatic model SCI-GROW2
(Screening Concentration in Ground Water, v.2.3; dated 11/12/1997).

+-----------------+-----------------+------------+---------------------+
| **Table 5.1.9a. |                 |            |                     |
| Maximum Tier I  |                 |            |                     |
| Estimated       |                 |            |                     |
| Drinking Water  |                 |            |                     |
| Concentrations  |                 |            |                     |
| (EDWCs) of      |                 |            |                     |
| parent          |                 |            |                     |
| florasulam for  |                 |            |                     |
| drinking water  |                 |            |                     |
| risk assessment |                 |            |                     |
| based on aerial |                 |            |                     |
| and ground      |                 |            |                     |
| applications of |                 |            |                     |
| florasulam.     |                 |            |                     |
| Results are     |                 |            |                     |
| reported in     |                 |            |                     |
| parts per       |                 |            |                     |
| trillion.**     |                 |            |                     |
+-----------------+-----------------+------------+---------------------+
| **Drinking      | **Use/Rate      | **Maximum  |                     |
| Water Source    | Modeled (lb     | Estimated  |                     |
| (Model Used)**  | ai/A)**         | Drinking   |                     |
|                 |                 | Water      |                     |
|                 |                 | Con        |                     |
|                 |                 | centration |                     |
|                 |                 | (EDWC;     |                     |
|                 |                 | ppTr)**    |                     |
+-----------------+-----------------+------------+---------------------+
| Groundwater     | 0.0045          | Acute and  | 1.35 x 10^-2^       |
|                 |                 | Chronic    |                     |
| (SCI-GROW)      |                 |            |                     |
+-----------------+-----------------+------------+---------------------+
| Surface Water   | Aerial          | Chronic    | **16.8**            |
| (FIRST)         | spray/0.0045    |            |                     |
+-----------------+-----------------+------------+---------------------+
| Surface Water   | Ground          | Chronic    | 16.7                |
| (FIRST)         | spray/0.0045    |            |                     |
+-----------------+-----------------+------------+---------------------+

+-----------------+-----------------+------------+---------------------+
| **Table 5.1.9 b |                 |            |                     |
| Maximum Tier I  |                 |            |                     |
| Estimated       |                 |            |                     |
| Drinking Water  |                 |            |                     |
| Concentrations  |                 |            |                     |
| (EDWCs) of      |                 |            |                     |
| 5-OH-XDE-570    |                 |            |                     |
| for drinking    |                 |            |                     |
| water risk      |                 |            |                     |
| assessment      |                 |            |                     |
| based on aerial |                 |            |                     |
| and ground      |                 |            |                     |
| applications of |                 |            |                     |
| florasulam.     |                 |            |                     |
| Results are     |                 |            |                     |
| reported in     |                 |            |                     |
| parts per       |                 |            |                     |
| trillion.**     |                 |            |                     |
+=================+=================+============+=====================+
| **Drinking      | **Use/Rate      | **Maximum  |                     |
| Water Source    | Modeled (lb     | Estimated  |                     |
| (Model Used)**  | ai/A)**         | Drinking   |                     |
|                 |                 | Water      |                     |
|                 |                 | Con        |                     |
|                 |                 | centration |                     |
|                 |                 | (EDWC;     |                     |
|                 |                 | ppTr)**    |                     |
+-----------------+-----------------+------------+---------------------+
| Groundwater     | 0.0045          | Acute and  | 7.44                |
|                 |                 | Chronic    |                     |
| (SCI-GROW)      |                 |            |                     |
+-----------------+-----------------+------------+---------------------+
| Surface Water   | Aerial          | Chronic    | 217.3               |
| (FIRST)         | spray/0.0045    |            |                     |
+-----------------+-----------------+------------+---------------------+
| Surface Water   | Ground          | Chronic    | **217.5**           |
| (FIRST)         | spray/0.0045    |            |                     |
+-----------------+-----------------+------------+---------------------+

**5.1.10 Food Residue Profile**[]{#__RefHeading___Toc139001028 .anchor}

[]{.mark}

There are adequate storage stability data for wheat forage, hay, straw,
and grain. These data indicate residues of florasulam were relatively
stable at -20 ^o^C for 524, 410, 313 and 459 days in spiked forage,
grain, straw and hay, respectively.

The proposed use of florasulam on cereal grains is considered to fall
under 40 CFR §180.6(a)(3) (no expectation of finite residues in
livestock commodities). Therefore, feeding studies and tolerances for
meat, milk, poultry, and eggs are not necessary for the purposes of this
petition. HED also concludes that residue analytical methods and storage
stability data for livestock commodities are not needed. This
determination is based on the results of the wheat, barley, oats, and
rye field trials treated at a 2x application rate. The decision is also
based on the low florasulam dietary burdens for dairy and beef cattle
(0.1 ppm), poultry (0.008 ppm), and swine (0.007 ppm), and the low
transfer of residues to tissues, milk, and eggs seen in the metabolism
studies. HED reserves the right to require these waived studies if the
petitioner seeks to register additional feed crops in the future.

There are adequate magnitude of the residue data for wheat, barley,
oats, and rye. The supervised field trials indicated that residues of
florasulam in grain, forage, hay, and straw of wheat, barley, rye, and
oats were non quantifiable (\<0.01 ppm for grain, \<0.05 ppm for forage,
hay, and straw), following a single foliar application at an exaggerated
rate (2x proposed maximum seasonal application rate). Florasulam
residues were greater than the proposed

tolerances in one wheat forage field trial. However, HED concludes the
proposed tolerance of 0.05 ppm for wheat forage would adequately cover
residues in wheat forage since field trials were conducted at a 2x
exaggerated rate. No processing studies on wheat were submitted;
however, the metabolism studies in wheat treated with ^14^C-DE-570 at
the exaggerated rate of 50 g a.i./ha (10x the proposed maximum season
rate) indicated very low radioactive residue levels in grain (maximum of
0.002 ppm). HED concludes that it is unlikely that residues of
florasulam in processed food/feed items will concentrate to quantifiable
levels when treated according to the proposed use pattern. A wheat
processing study is also not needed to support the proposed use.

For the proposed use on cereal grains, field rotational crop studies and
tolerances on rotational crops are not needed. Based on the results of
the confined rotational crop studies, it is permissible to rotate to any
crop after 30 days.

**5.1.11 International Residue Limits**

Maximum residue levels (MRLs) are established in Canada for residues of
florasulam in barley, oats, and wheat grain at 0.01 ppm. There are no
Codex MRLS. No harmonization issues exist since the same tolerance level
is recommended for the use in the U.S.

1.  **Dietary Exposure and Risk**

The chronic dietary risk assessment was conducted using the Dietary
Exposure Evaluation Model (DEEM-FCID, Version 2.03), which uses food
consumption data from the USDA's Continuing Survey of Food Intakes by
Individuals (CSFII) from 1994-1996 and 1998. The drinking water residues
used in the dietary risk assessment were provided by EFED (see Table
5.1.9a and b). Water residues were incorporated in the DEEM-FCID into
the food categories "water, direct, all sources" and "water, indirect,
all sources." To arrive at the total EDWC, the maximum surface water
value for the parent was added to the maximum surface water value for
the major degradate. For the parent, the chronic aerial spray value
(16.8 ppTr) was higher than the ground spray value. For the degradate,
the ground spray value was the higher of the two (217.5 ppTr). Adding
the 2 values (16.8 + 217.5) results in the total EDWC of 234 ppTr, or
0.00023 ppm.

**5.2.1 Acute Dietary Exposure/Risk**

No acute dietary endpoint was identified; therefore, an acute dietary
risk assessment was not conducted.

**5.2.2 Chronic Dietary Exposure/Risk**

The chronic analyses assumed tolerance level residues, 100% crop
treated, and DEEM (ver. 7.81) default processing factors for proposed
commodities. For those processed commodities in the DEEM-FCID residue
list which were not in DEEM (ver 7.81) e.g. (flour, bran, etc.), a
processing factor of 1 was assumed.

+---------------------------+------------+------------+---------------+
| **Table 5.2.3.1. Results  |            |            |               |
| of Chronic Dietary        |            |            |               |
| Exposure Analysis (Food   |            |            |               |
| Only)**                   |            |            |               |
+===========================+============+============+===============+
| **Population Subgroup**   | **cPAD**   | **Exposure | **% cPAD**    |
|                           |            | (mg        |               |
|                           | **(mg      | /kg/day)** |               |
|                           | /kg/day)** |            |               |
+---------------------------+------------+------------+---------------+
| General U.S. Population   | 0.05       | 0.000019   | \<1           |
+---------------------------+------------+------------+---------------+
| All Infants (\< 1 year    | 0.05       | 0.000013   | \<1           |
| old)                      |            |            |               |
+---------------------------+------------+------------+---------------+
| Children 1-2 years old    | 0.05       | 0.000047   | \<1           |
+---------------------------+------------+------------+---------------+
| Children 3-5 years old    | 0.05       | 0.000046   | \<1           |
+---------------------------+------------+------------+---------------+
| Children 6-12 years old   | 0.05       | 0.000031   | \<1           |
+---------------------------+------------+------------+---------------+
| Youth 13-19 years old     | 0.05       | 0.000018   | \<1           |
+---------------------------+------------+------------+---------------+
| Adults 20-49 years old    | 0.05       | 0.000016   | \<1           |
+---------------------------+------------+------------+---------------+
| Females 13-49 years old   | 0.05       | 0.000014   | \<1           |
+---------------------------+------------+------------+---------------+
| Adults 50+ years old      | 0.05       | 0.000013   | \<1           |
+---------------------------+------------+------------+---------------+

+---------------------------+------------+------------+---------------+
| **Table 5.2.3.2. Results  |            |            |               |
| of Chronic Dietary        |            |            |               |
| Exposure Analysis (Food   |            |            |               |
| Plus Water)**             |            |            |               |
+===========================+============+============+===============+
| **Population Subgroup**   | **cPAD**   | **Exposure | **% cPAD**    |
|                           |            | (mg        |               |
|                           | **(mg      | /kg/day)** |               |
|                           | /kg/day)** |            |               |
+---------------------------+------------+------------+---------------+
| General U.S. Population   | 0.05       | 0.000024   | \<1           |
+---------------------------+------------+------------+---------------+
| All Infants (\< 1 year    | 0.05       | 0.000029   | \<1           |
| old)                      |            |            |               |
+---------------------------+------------+------------+---------------+
| Children 1-2 years old    | 0.05       | 0.000054   | \<1           |
+---------------------------+------------+------------+---------------+
| Children 3-5 years old    | 0.05       | 0.000053   | \<1           |
+---------------------------+------------+------------+---------------+
| Children 6-12 years old   | 0.05       | 0.000036   | \<1           |
+---------------------------+------------+------------+---------------+
| Youth 13-19 years old     | 0.05       | 0.000022   | \<1           |
+---------------------------+------------+------------+---------------+
| Adults 20-49 years old    | 0.05       | 0.000020   | \<1           |
+---------------------------+------------+------------+---------------+
| Females 13-49 years old   | 0.05       | 0.000019   | \<1           |
+---------------------------+------------+------------+---------------+
| Adults 50+ years old      | 0.05       | 0.000018   | \<1           |
+---------------------------+------------+------------+---------------+

**5.2.3 Cancer Dietary Risk**

There were no treatment-related tumors observed in carcinogenicity
studies in rats and mice. As a result, a cancer assessment was not
conducted.

**5.3 Anticipated Residue and Percent Crop Treated (%CT) Information**

[]{.mark}

The chronic analyses assumed tolerance level residues, 100% crop
treated, and DEEM (ver. 7.81) default processing factors for all
registered and proposed commodities. For those processed commodities in
the DEEM-FCID residue list which were not in DEEM (ver 7.81) e.g.
(flour, bran, etc.), a processing factor of 1 was assumed.

**6.0 Residential (Non-Occupational) Exposure/Risk Characterization**

Currently, there are no registered or proposed residential uses for
florasulam; thus, there is no exposure via this pathway and an
assessment was not conducted.

7.  **Aggregate Risk Assessments and Risk Characterization**

    1.  **Acute Aggregate Risk**

No acute dietary endpoint was identified; therefore, an acute aggregate
risk assessment was not conducted.

**7.2 Short-Term Aggregate Risk**

As there are no residential uses for florasulam, short-term aggregate
risk assessments were not conducted.

**7.3 Intermediate-Term Aggregate Risk**

As there are no residential uses for florasulam, intermediate-term
aggregate risk assessments were not conducted.

**7.4 Long-Term Aggregate Risk**

The chronic dietary exposure analysis included both food and drinking
water. As a result, the chronic aggregate risk assessment is equivalent
to the chronic dietary risk assessment. Refer to Section 5.2.2 for a
discussion of the dietary exposure analysis. The general U.S. population
and all population subgroups have risk estimates that are below HED's
level of concern. The most highly exposed population subgroup is
Children (1-2 years) which utilizes \< 1% of the cPAD. The general U.S.
population utilizes \<1% of the cPAD.

[]{.mark}

**7.5 Cancer Risk**

[]{.mark}

Exposure to florasulam did not result in a treatment-related increase in
tumor formation in rats or mice; therefore, a cancer risk assessment was
not conducted.

**8.0 Cumulative Risk Characterization/Assessment**

Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency consider
\"available information concerning the cumulative effects" of a
particular pesticide\'s residues and \"other substances that have a
common mechanism of toxicity."

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to florasulam and any other
substances, and florasulam does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this tolerance action,
EPA has not assumed that florasulam has a common mechanism of toxicity
with other substances. For information regarding EPA's efforts to
determine which chemicals have a common mechanism of toxicity and to
evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA's Office of Pesticide Programs concerning
common mechanism determinations and procedures for cumulating effects
from substances found to have a common mechanism on EPA's website at
http://www.epa.gov/pesticides/cumulative/.

**9.0 Occupational Exposure/Risk Pathway**

**9.1 Short-Term Handler Risk**

The following agricultural products have been assessed for occupational
exposure: EF1343, EF1383, GF-184 and GF-1727. The end-use products are
formulated as a liquid with the following respective concentrations of
the a.i.: 4.84% a.i., 0.58% a.i., 0.25% a.i., and 0.39% a.i. It may be
applied by either ground or aerial equipment, at an application rate of
0.00446 pounds a.i. per acre. Based on the number of seasonal
applications indicated on the product labels, handler exposures are
expected to be short-term in duration.

A quantitative risk assessment for the dermal exposure route was not
conducted. There were no adverse systemic or dermal effects seen up to
the limit dose tested (1,000 mg/kg/day) in the 28-day dermal toxicity
study. The quantitative exposure/risk assessment developed for handlers
is based on the following exposure scenarios:

-   Mixing/loading liquid for groundboom

-   Applying liquid for groundboom to wheat, barley, rye, oats, and
    triticale

-   Mixing/loading liquid for aerial application

-   Applying liquid for aerial application to wheat, barley, rye, oats,
    and triticale

-   Flagger

**9.1.1 Data and Assumptions for Handler Exposure Scenarios**

The following assumptions, parameters, and factors were used in the
exposure and risk assessment:

**Unit Exposures:**

Chemical-specific data for assessing exposure during pesticide handling
activities were not submitted to the Agency in support of this Section 3
application. It is HED policy to use data from the Pesticide Handlers
Exposure Database (PHED) Version 1.1 to assess handler exposures for
regulatory actions when chemical-specific data are not available (HED
Science Advisory Council for Exposure, SOP Number .007, January 1999).

**Area Treated:**

(HED Exposure Science Advisory Committee SOP Number 9.1)

-   200 acres of wheat, barley, rye, oats, and triticale were treated
    per day with groundboom sprayer

-   1200 acres of wheat, barley, rye, oats, and triticale were treated
    per day with aerial spray equipment

-   350 acres assessed for flaggers

    **Application Rate**:

```{=html}
<!-- -->
```
-   The maximum application rate is 0.00446 lb ai/acre

    **Body Weight:**

```{=html}
<!-- -->
```
-   The average adult body weight of 70 kg was used for estimating both
    inhalation exposure and risk.

**Dermal Absorption Factor**:

-   Since a dermal endpoint was not selected, there was no need to use a
    dermal absorption factor to determine dermal exposure and risk.

    2.  **Handlers Exposure and Risk**

Since a dermal endpoint and dose were not selected, a dermal exposure
assessment was not conducted. Inhalation MOEs were significantly greater
than 100 at baseline and are not of concern to HED (MOEs of equal to or
less then 100 are of concern to HED).

+----------+---------+---------+---------+--------+---------+---------+
| **Table  |         |         |         |        |         |         |
| 5.1.2:   |         |         |         |        |         |         |
| Handler  |         |         |         |        |         |         |
| In       |         |         |         |        |         |         |
| halation |         |         |         |        |         |         |
| Exposure |         |         |         |        |         |         |
| and      |         |         |         |        |         |         |
| Risk**   |         |         |         |        |         |         |
+----------+---------+---------+---------+--------+---------+---------+
| **Sc     | **Mitig | **Inh   | **Appl  | *      | **Daily | **Inh   |
| enario** | ation** | alation | ication | *Acres | Dose    | alation |
|          |         | Unit    | Rate**  | T      | ^a^     | MOE     |
|          |         | Exp     |         | reated | (mg/kg  | ^b^**   |
|          |         | osure** | **(lb   | (A/    | /day)** |         |
|          |         |         | ai/A)** | Day)** |         |         |
|          |         | *       |         |        |         |         |
|          |         | *(mg/lb |         |        |         |         |
|          |         | ai)**   |         |        |         |         |
+----------+---------+---------+---------+--------+---------+---------+
| **Mixer/ |         |         |         |        |         |         |
| Loader** |         |         |         |        |         |         |
+----------+---------+---------+---------+--------+---------+---------+
| **Grou   | B       | 0.0012  | 0.00446 | 200    | 0.0     | 330,000 |
| ndboom** | aseline |         |         |        | 0001529 |         |
+----------+---------+---------+---------+--------+---------+---------+
| **       |         |         |         | 1200   | 0.      | 54,000  |
| Aerial** |         |         |         |        | 0000917 |         |
+----------+---------+---------+---------+--------+---------+---------+
| **Appl   |         |         |         |        |         |         |
| icator** |         |         |         |        |         |         |
+----------+---------+---------+---------+--------+---------+---------+
| **Grou   | B       | 0.00074 | 0.00446 | 200    | 0.      | 530,000 |
| ndboom** | aseline |         |         |        | 0000094 |         |
+----------+---------+---------+---------+--------+---------+---------+
| **       | Eng.    | 0       |         | 1200   | 0.      | 960,000 |
| Aerial** | Cont.   | .000068 |         |        | 0000052 |         |
|          | ^c^     |         |         |        |         |         |
+----------+---------+---------+---------+--------+---------+---------+
| **F      |         |         |         |        |         |         |
| lagger** |         |         |         |        |         |         |
+----------+---------+---------+---------+--------+---------+---------+
| **       | B       | 0.011   | 0.00446 | 350    | 0       | 20,000  |
| Aerial** | aseline |         |         |        | .000245 |         |
+----------+---------+---------+---------+--------+---------+---------+

a\. Inhalation Dose (mg/kg/day) =\[ Rate (lb ai/A) x UE (mg /lb ai ) x
Acres Treated (A/day)\] / BW (70 kg)

b\. Inhalation MOE = \[Inhalation NOAEL (5 mg/kg/day)\] / Inhalation
Dose (mg/kg/day)

**9.2 Short-Term Postapplication Risk**

A dermal non-cancer agricultural postapplication exposure assessment was
not conducted due to the absence of systemic toxicity in the dermal
toxicity study. Postapplication inhalation exposures are expected to be
minimal and less than the application exposures. As all scenarios are
for outdoor agricultural uses, inhalation postapplication exposure is
expected to be negligible.

[Restricted Entry Interval]{.underline}

The restricted entry interval (REI) is based on the acute toxicity of
the technical active ingredient. Florasulam is classified as Toxicity
Category III for acute dermal and Category IV for acute oral,
inhalation, and eye exposure. Acute toxicity Category III and IV
chemicals require a 12 hour REI.

The proposed label for EF-1343 proposes an REI of 4 hours. Based on
review of the toxicological database for florasulam, EF-1343 is a
candidate for a reduced risk active ingredient; therefore, HED does not
object to the proposed 4-hour REI.

The product labels for GF-1727, GF-184, and EF-1383 propose various REIs
ranging from 12 to 48 hours respectively. The REIs for these labels are
based on a second active ingredient (e.g. MCPA, fluroxpyr, and 2-4-D).
If products contain more than one active ingredient, the REI will be
based on the active ingredient which requires the longest REI. **HED
recommends that the Registration Division ensure that the proper REI is
established for each of the proposed labels**.

**10.0 Data Needs and Label
Recommendations**[]{#__RefHeading___Toc139001049 .anchor}

**10.1 Toxicology**

There are no toxicology data gaps.

2.  **Residue Chemistry**

Number range CHAPTERRegulatory Recommendations and Residue Chemistry
Deficiencies

-   A revised Section F should be submitted with correct raw
    agricultural commodity definitions along with the correct spelling
    of the chemical name for florasulam.

-   Successful completion of a petition method validation by BEAD/ACB.
    The method has been sent to BEAD/ACB for validation.

-   Analytical standards for florasulam are not currently available in
    the National Pesticide Standards Repository. Analytical reference
    standards of florasulam need to be supplied and supplies need to be
    replenished as requested by the Repository. The reference standards
    should be sent to the Analytical Chemistry Branch, which is located
    at Fort Meade, to the attention of either Theresa Cole, Dallas
    Wright, or Frederic Siegelman at the following address:

> USEPA
>
> National Pesticide Standards Repository/Analytical Chemistry
> Branch/OPP
>
> 701 Mapes Road
>
> Fort George G. Meade, MD 20755-5350
>
> (Note that the mail will be returned if the extended zip code is not
> used.)

**10.3 Occupational and Residential Exposure**

-   The product labels for GF-1727, GF-184, and EF-1383 propose various
    REIs ranging from 12 to 48 hours respectively. The REI for these
    labels are based on a second active ingredient (e.g. MCPA,
    fluroxpyr, and 2-4-D). If products contain more than one active
    ingredient, the REI will be based on the active ingredient which
    requires the longest REI. **HED recommends that the Registration
    Division ensure that the proper REI is established for each of the
    proposed labels**.

**References:**

Florasulam: Occupational and Residential Exposure Assessment for Section
3 Registration

for use of Florasulam on Weeds in Wheat, Barley, Oats, Rye and
Triticale. M. Collantes. D333360.

Florasulam: First Food Use Petition for the Establishment of Tolerances
on the Raw Agricultural Commodities of Barley, Oats, Rye, Triticale, and
Wheat. Summary of Analytical Chemistry and Residue Data. T. Morton.
D333759.

Florasulam: Chronic Aggregate Dietary and Drinking Water Exposure and
Risk Assessment for the New Active Ingredient. T. Morton. D366694.

Tier I Drinking Water Assessment for the Florasulam Proposed Section 3
Registration for Use on Wheat (Including Durum), Barley, Oats, Rye and
Triticale. C. Sutton. D332069

**Appendix A: Toxicology Assessment**

**A.1 Toxicology Data Requirements**

The requirements (40 CFR 158.340) for a food use for florasulam 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 21/28-Day Dermal               | yes         | yes         |
|                                         |             |             |
| 870.3250 90-Day Dermal                  | no          | \-\--       |
|                                         |             |             |
| 870.3465 90-Day Inhalation              | no          | \-\--       |
+-----------------------------------------+-------------+-------------+
| 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           | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.5100 Mutagenicity---Gene Mutation - | yes         | yes         |
| bacterial                               |             |             |
|                                         | yes         | yes         |
| 870.5300 Mutagenicity---Gene Mutation - |             |             |
| mammalian                               | yes         | yes         |
|                                         |             |             |
| 870.5375 Mutagenicity---Structural      | yes         | yes         |
| Chromosomal Aberrations                 |             |             |
|                                         |             |             |
| 870.5395 Mutagenicity---Other Genotoxic |             |             |
| Effects                                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.6100a Acute Delayed Neurotox. (hen) | no          | \-\--       |
|                                         |             |             |
| 870.6100b 90-Day Neurotoxicity (hen)    | no          | \-\--       |
|                                         |             |             |
| 870.6200a Acute Neurotox. Screening     | no          | yes         |
| Battery (rat)                           |             |             |
|                                         | no          | yes         |
| 870.6200b Chronic Neurotox. Screening   |             |             |
| Battery (rat)                           | no          | \-\--       |
|                                         |             |             |
| 870.6300 Develop. Neuro                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.7485 General Metabolism             | yes         | yes         |
|                                         |             |             |
| 870.7600 Dermal Penetration             | no          | yes         |
+-----------------------------------------+-------------+-------------+

**A.2 Toxicity Profiles**

+---------+---------------------+--------+-------------+-------------+
| **Table |                     |        |             |             |
| A.2.1   |                     |        |             |             |
| Acute   |                     |        |             |             |
| T       |                     |        |             |             |
| oxicity |                     |        |             |             |
| Profile |                     |        |             |             |
| --      |                     |        |             |             |
| Flora   |                     |        |             |             |
| sulam** |                     |        |             |             |
+---------+---------------------+--------+-------------+-------------+
| **Gu    | **Study Type**      | **MRI  | **Results** | **Toxicity  |
| ideline |                     | D(s)** |             | Category**  |
| No.**   |                     |        |             |             |
+---------+---------------------+--------+-------------+-------------+
| 8       | Acute oral -- rat   | 46     | LD~50~ \>=  | IV          |
| 70.1100 |                     | 808209 | 5000 mg/kg  |             |
+---------+---------------------+--------+-------------+-------------+
| 8       | Acute oral -- mouse | 46     | LD~50~ \>=  | IV          |
| 70.1100 |                     | 827915 | 5000 mg/kg  |             |
+---------+---------------------+--------+-------------+-------------+
| 8       | Acute dermal --     | 46     | LD~50~ \>=  | III         |
| 70.1200 | rabbit              | 808211 | 2000 mg/kg  |             |
+---------+---------------------+--------+-------------+-------------+
| 8       | Acute inhalation -- | 46     | LC~50~ \>=  | IV          |
| 70.1300 | rat                 | 808212 | 5.0 mg/L    |             |
+---------+---------------------+--------+-------------+-------------+
| 8       | Acute eye           | 46     | Non-        | IV          |
| 70.2400 | irritation --       | 808213 | irritating  |             |
|         | rabbit              |        |             |             |
+---------+---------------------+--------+-------------+-------------+
| 8       | Acute dermal        | 46     | Non-        | IV          |
| 70.2500 | irritation --       | 808214 | irritating  |             |
|         | rabbit              |        |             |             |
+---------+---------------------+--------+-------------+-------------+
| 8       | Skin sensitization  | 46     | No          |             |
| 70.2600 | -- guinea pig       | 808215 | se          |             |
|         |                     |        | nsitization |             |
|         |                     | 46     |             |             |
|         |                     | 808216 |             |             |
+---------+---------------------+--------+-------------+-------------+

+---------------+--------------+--------------------------------------+
| **Table A.2.2 |              |                                      |
| Subchronic,   |              |                                      |
| Chronic, and  |              |                                      |
| Other         |              |                                      |
| Toxicity      |              |                                      |
| Profile for   |              |                                      |
| Florasulam    |              |                                      |
| Technical**   |              |                                      |
+===============+==============+======================================+
| **Guideline   | **MRID No.   | **Results**                          |
| No./Study     | (year)       |                                      |
| Type**        | Classifica   |                                      |
|               | tion/Doses** |                                      |
+---------------+--------------+--------------------------------------+
| 870.3100      | 46808219     | **NOAEL = 100 mg/kg/day**            |
|               | (1996)       |                                      |
| 90-Day oral   |              | **LOAEL = 500 mg/kg/day**, based on  |
| toxicity      | Acceptab     | decreased body weights (5-8%) and    |
| (rat)         | le/guideline | body weight gains (21%) in females,  |
|               |              | and evidence of slight               |
|               | 0, 20, 100,  | nephrotoxicity (increased kidney     |
|               | 500,         | weights, hypertrophy, and            |
|               | 1000/800     | degeneration/regeneration and        |
|               | mg/kg/day    | inflammation of the descending       |
|               |              | portion of proximal tubules) in both |
|               |              | sexes.                               |
+---------------+--------------+--------------------------------------+
| 870.3100      | 46808222     | **NOAEL = 1000 mg/kg/day**           |
|               | (1996)       |                                      |
| 90-Day oral   |              | **LOAEL = Not determined**           |
| toxicity      | Acceptab     |                                      |
| (mouse)       | le/guideline |                                      |
|               |              |                                      |
|               | 0, 20, 100,  |                                      |
|               | 500, 1000    |                                      |
|               | mg/kg/day    |                                      |
+---------------+--------------+--------------------------------------+
| 870.3150      | 46808223     | **NOAEL = 5 mg/kg/day**              |
|               | (1995)       |                                      |
| 90-Day oral   |              | **LOAEL = 50 mg/kg/day,** based on   |
| toxicity      | Acceptab     | increased alkaline phosphatase       |
| (dog)         | le/guideline | (59-127%) activity, increased liver  |
|               |              | weights, hypertrophy and increased   |
|               | 0, 5, 50,    | incidence/severity of hepatic        |
|               | 100          | vacuolation in both sexes.           |
|               | mg/kg/day    |                                      |
+---------------+--------------+--------------------------------------+
| 870.3200      | 46808225     | **Systemic NOAEL = 1000 mg/kg/day**  |
|               | (1997)       |                                      |
| 28-Day dermal |              | **Systemic LOAEL = Not determined**  |
| toxicity      | Acceptab     |                                      |
| (rat)         | le/guideline | **Dermal NOAEL = 500 mg/kg/day**     |
|               |              |                                      |
|               | 0, 100, 500, | **Dermal LOAEL = 1000 mg/kg/day**,   |
|               | 1000         | based on edema and erythema in males |
|               | mg/kg/day, 6 | ( 4/5)                               |
|               | h/day, 7     |                                      |
|               | days/week    |                                      |
|               | for 28 days  |                                      |
+---------------+--------------+--------------------------------------+
| 870.3700a     | 46808234     | **Maternal** **NOAEL = 250           |
|               | (1997)       | mg/kg/day**                          |
| Prenatal      |              |                                      |
| developmental | 46808231     | **LOAEL = 750 mg/kg/day** based on   |
| toxicity      | (1996)       | decreased body weights (4-6%, GD     |
| (rat)         |              | 6-16), body weight gains (16%, GD    |
|               | Acceptab     | 6-16%), food consumption (6-13%),    |
|               | le/guideline | and increased kidney weights.        |
|               |              |                                      |
|               | 0, 50, 250,  | **Developmental NOAEL = 750          |
|               | 750          | mg/kg/day**                          |
|               | mg/kg/day    |                                      |
|               | (GD 6-15)    | **Developmental LOAEL = Not          |
|               |              | determined**                         |
+---------------+--------------+--------------------------------------+
| 870.3700b     | 46808233     | **Maternal NOAEL = 500 mg/kg/day**   |
|               | (1997)       |                                      |
| Prenatal      |              | **Maternal LOAEL = Not determined**  |
| developmental | 46808232     |                                      |
| toxicity      | (1997)       | **Developmental NOAEL = 500          |
| (rabbit)      |              | mg/kg/day**                          |
|               | Acceptab     |                                      |
|               | le/guideline | **Developmental LOAEL = Not          |
|               |              | determined**                         |
|               | 0, 50, 250,  |                                      |
|               | 500          | Note: Study acceptable due to        |
|               | mg/kg/day    | findings of preliminary              |
|               | (GD 7-19)    | developmental toxicity study at 600  |
|               |              | mg/kg/day (mortality and decreased   |
|               |              | body weight gains and food           |
|               |              | consumption).                        |
+---------------+--------------+--------------------------------------+
| 870.3800      | 46808235     | **Parental/Systemic NOAEL = 100      |
|               | (1997)       | mg/kg/day**                          |
| Reproduction  |              |                                      |
| and fertility | Acceptab     | **Parental/Systemic LOAEL = 500      |
| effects (rat) | le/guideline | mg/kg/day**, based on decreased body |
|               |              | weights, body weight gains, and food |
|               | 0, 10, 100,  | consumption, as well as kidney       |
|               | 500          | alterations.                         |
|               | mg/kg/day    |                                      |
|               |              | **Offspring NOAEL = 500 mg/kg/day**  |
|               |              |                                      |
|               |              | **Offspring LOAEL = Not determined** |
|               |              |                                      |
|               |              | **Reproductive NOAEL = 500           |
|               |              | mg/kg/day**                          |
|               |              |                                      |
|               |              | **Reproductive LOAEL = Not           |
|               |              | determined**                         |
+---------------+--------------+--------------------------------------+
| 870.4100b     | 46808229     | **NOAEL = 5 mg/kg/day**              |
|               | (1997)       |                                      |
| Chronic       |              | **LOAEL =100/50 mg/kg/day**, based   |
| toxicity      | Acceptab     | on decreased body weights (17%),     |
| (dog)         | le/guideline | body weight gains (68%), and food    |
|               |              | consumption in females; increased    |
| []{.mark}     | 0, 0.5, 5,   | liver enzymes (alanine               |
|               | 100/50       | aminotransferase and alkaline        |
| []{.mark}     | mg/kg/day    | phosphatase) and slight vacuolation  |
|               |              | of the zona reticularis and zona     |
| []{.mark}     |              | fasciculata in the adrenal gland     |
|               |              | (consistent with fatty change) in    |
|               |              | both sexes.                          |
+---------------+--------------+--------------------------------------+
| 870.4200      | 46808230     | **NOAEL = 1000 mg/kg/day.**          |
|               | (1997)       |                                      |
| Ca            |              | **LOAEL = Not determined**           |
| rcinogenicity | Acceptab     |                                      |
| (mouse)       | le/guideline | **No evidence of carcinogenicity**   |
|               |              |                                      |
|               | 0, 50, 500,  |                                      |
|               | 1000         |                                      |
|               | mg/kg/day    |                                      |
+---------------+--------------+--------------------------------------+
| 870.4300      | 46808236     | **NOAEL = 10 mg/kg/day-males; 125    |
|               | (1997)       | mg/kg/day-females**                  |
| Combined      |              |                                      |
| chronic       | Acceptab     | **LOAEL = 250 mg/kg/day (males)**,   |
| toxicity/ca   | le/guideline | based on slight nephrotoxicity       |
| rcinogenicity |              | (increased kidney weights,           |
| (rat)         | M: 0, 10,    | hypertrophy, and slight multi-focal  |
|               | 250, 500     | mineralization in the papilla);      |
|               | mg/kg/day    | **250 mg/kg/day (females)**, based   |
|               |              | on decreased body weights (3-8%) and |
|               | F: 0, 10,    | body weight gains (14%).             |
|               | 125, 250     |                                      |
|               | mg/kg/day    | **No evidence of carcinogenicity**   |
+---------------+--------------+--------------------------------------+
| 870.5100      | 46808240     | **Negative**-No evidence of induced  |
|               | (1995)       | mutant colonies over background in   |
| Bacterial     |              | the presence or absence of           |
| gene          | Acceptab     | S9-induced activation                |
| mutat         | le/guideline |                                      |
| ion/mammalian |              |                                      |
| activation    | 0, 0.333, 1, |                                      |
| gene mutation | 3.33, 10,    |                                      |
| assay         | 33.3, 100    |                                      |
|               | µg/plate     |                                      |
|               | (*S.         |                                      |
|               | t            |                                      |
|               | yphimurium*) |                                      |
|               |              |                                      |
|               | 0, 10, 33.3, |                                      |
|               | 100, 333,    |                                      |
|               | 1000, 3330   |                                      |
|               | g/plate (*E. |                                      |
|               | coli*)       |                                      |
+---------------+--------------+--------------------------------------+
| 870.5300      | 46808238     | **Negative**-No evidence of induced  |
|               | (1995)       | mutant colonies over background in   |
| Gene mutation |              | the presence or absence of           |
| at the HGPRT  | Acceptab     | S9-activation                        |
| locus in      | le/guideline |                                      |
| Chinese       |              |                                      |
| hamster ovary | 0, 187.5,    |                                      |
| cells         | 375, 750,    |                                      |
|               | 1500, 3000   |                                      |
|               | µg/mL        |                                      |
+---------------+--------------+--------------------------------------+
| 870.5375      | 46808237     | **Negative**-No evidence of          |
|               | (1995)       | chromosome aberrations induced over  |
| Chromosomal   |              | background in the presence or        |
| aberration    | Acceptab     | absence of S9-activation             |
| assay in rat  | le/guideline |                                      |
| lymphocytes   |              |                                      |
|               | 0, 3, 10,    |                                      |
|               | 30, 100,     |                                      |
|               | 300, 1000,   |                                      |
|               | 3000 µg/mL   |                                      |
+---------------+--------------+--------------------------------------+
| 870.5395      | 46808239     | **Negative**-No significant increase |
|               | (1995)       | in the frequency of micronucleated   |
| Mouse bone    |              | polychromatic erythrocytes in bone   |
| marrow        | Acceptab     | marrow                               |
| micronucleus  | le/guideline |                                      |
| assay         |              |                                      |
|               | 0, 1250,     |                                      |
|               | 2500, 5000   |                                      |
|               | mg/kg        |                                      |
+---------------+--------------+--------------------------------------+
| 870.6200a     | 46808217     | **Systemic NOAEL = 1000 mg/kg**      |
|               | (1997)       |                                      |
| Acute         |              | **Systemic LOAEL = 2000 mg/kg**,     |
| neurotoxicity | Acceptab     | based on decreased body weight gain  |
| screening     | le/guideline | (21%) and general malaise (slight    |
| battery (rat) |              | transient decrease in motor          |
|               | 0, 200,      | activity, minimal activity in open   |
|               | 1000, 2000   | field, and reactivity) in males.     |
|               | mg/kg        |                                      |
|               |              | **Neurotoxicity NOAEL = 2000 mg/kg** |
|               |              |                                      |
|               |              | **Neurotoxicity LOAEL = Not          |
|               |              | determined**                         |
+---------------+--------------+--------------------------------------+
| 870.6200b     | 46808228     | **Systemic NOAEL = 250 mg/kg/day**   |
|               | (1996)       |                                      |
| Chronic       |              | **Systemic LOAEL = 500 mg/kg/day**,  |
| neurotoxicity | Acceptab     | based on decreased body weight       |
| screening     | le/guideline | (9-15% at 6, 9, and 12 months) and   |
| battery (rat) |              | body weight gain in males (61-67% at |
|               | 0, 10, 125   | 3-12 months; 27% at 0-12 months)     |
|               | (female      |                                      |
|               | only), 250,  | **Neurotoxicity NOAEL = 250 mg/kg**  |
|               | 500 (male    | (highest dose tested in females).    |
|               | only)        | **Neurotoxicity LOAEL= Not           |
|               | mg/kg/day    | determined.**                        |
+---------------+--------------+--------------------------------------+
| 870.7485      | 46808301     | Absorption was rapid and extensive   |
|               | (1996)       | (≈90-93% at 10 mg/kg; ≈82-86% at 500 |
| Metabolism    |              | mg/kg rats). Peak plasma             |
| and           | 46808303     | concentrations (Cmax) were achieved  |
| pha           | (1997)       | within 0.5-1 hour. Cmax in the       |
| rmacokinetics |              | plasma did not increase              |
| (rat)         | Acceptab     | proportionally with dose, possibly   |
|               | le/guideline | indicating a saturation of the       |
|               |              | absorption and/or excretion          |
|               | 10 and 500   | mechanisms at the high dose. The     |
|               | mg/kg        | apparent volume of distribution was  |
|               |              | increased at the high dose, possibly |
|               |              | indicative of increased tissue       |
|               |              | binding. Total recoveries at 168     |
|               |              | hours post-dose were 95.9-100.2%.    |
|               |              | Elimination was rapid. The           |
|               |              | administered dose was mostly         |
|               |              | eliminated within 12 hours in the    |
|               |              | urine (\>80% at 10 mg/kg; \>60% at   |
|               |              | 500 mg/kg). Total radioactivity      |
|               |              | found in the urine was approximately |
|               |              | 90-92% following single or repeated  |
|               |              | low-dose treatment, and 81-85%       |
|               |              | following treatment at 500 mg/kg.    |
|               |              | Radioactivity in the feces accounted |
|               |              | for another 5‑7% at 10 mg/kg and     |
|               |              | 14-17% at 500 mg/kg. Thus, compared  |
|               |              | to the low dose, excretion of the    |
|               |              | high dose was slightly slower, and   |
|               |              | more of the compound was excreted in |
|               |              | the feces. At 24 hours, \<0.5% of    |
|               |              | the dose was found in expired air.   |
|               |              | By 24 hours post-dose, plasma levels |
|               |              | had declined to \<0.1 µg eq/g plasma |
|               |              | in both sexes at 10 mg/kg and \<5.0  |
|               |              | µg eq/g plasma in both sexes at 500  |
|               |              | mg/kg. The highest residue levels    |
|               |              | were observed in the skin (single    |
|               |              | dose) and carcass (repeated dose),   |
|               |              | but the mean recovery of             |
|               |              | radioactivity in the tissues/carcass |
|               |              | at sacrifice was \<0.6% of the dose. |
|               |              | Identified compounds accounted for   |
|               |              | 87.6-91.6% of the administered dose  |
|               |              | in each group. In each group, the    |
|               |              | following compounds were isolated:   |
|               |              | parent accounted for 77.7-85.0%      |
|               |              | dose, OH-phenyl-XR-570 accounted for |
|               |              | 3.1-9.0% dose, OH-phenyl-XR-570      |
|               |              | sulfate conjugate accounted for      |
|               |              | 2.8-3.7% dose, and 2 unidentified    |
|               |              | metabolites accounted for \<=0.32%   |
|               |              | dose. In the high dose, more of the  |
|               |              | parent was isolated in the feces and |
|               |              | less in the urine compared to the    |
|               |              | low dose. There were no sex-related  |
|               |              | differences in the metabolism or     |
|               |              | pharmacokinetics of the test         |
|               |              | compound. Similarly, the number of   |
|               |              | doses or the position of the         |
|               |              | radiolabel generally made no         |
|               |              | difference in the metabolism and     |
|               |              | pharmacokinetic profile.             |
+---------------+--------------+--------------------------------------+
| 870.7600      | 46808304     | In a dermal absorption study in      |
|               | (1997)       | rats, recovery of the applied dose   |
| Dermal        |              | (mass balance) was 100-103%. The     |
| penetration   | Acceptab     | majority of the dose was recovered   |
| (rat)         | le/guideline | in the skin swab (71-90% of the      |
|               |              | applied dose). Dermal absorption     |
|               | 0.001 or 0.5 | (based on the sum of residues in     |
|               | mg/cm^2^     | urine, feces, cage wash, tissues,    |
|               |              | residual carcass, and untreated      |
|               |              | skin) was only 0.13-0.45% of the     |
|               |              | applied dose and only 10-22% of the  |
|               |              | applied dose remained in the skin at |
|               |              | the application site (considered     |
|               |              | potentially absorbable). Increasing  |
|               |              | the dose 200-fold resulted in only   |
|               |              | approximately 2-fold increase in     |
|               |              | absorption. Absorption increased 44% |
|               |              | at 48 h and 61% at 72 h compared to  |
|               |              | 24 h in the low dose groups;         |
|               |              | however, a time-dependent increase   |
|               |              | in absorption was not evident in the |
|               |              | high dose groups. The absorbed dose  |
|               |              | was almost completely excreted in    |
|               |              | the urine at the low dose, but was   |
|               |              | found primarily in the urine, cage   |
|               |              | wash, and untreated skin at the high |
|               |              | dose. The amount of radioactivity at |
|               |              | the treatment site increased at 48   |
|               |              | hours in the low dose, but did not   |
|               |              | decrease within 72 hours at either   |
|               |              | dose, suggesting that the compound   |
|               |              | in the skin was not readily          |
|               |              | absorbable.                          |
+---------------+--------------+--------------------------------------+

**A.3 Executive Summaries**

**A.3.1 Subchronic Toxicity**

3100. **90-Day Oral Toxicity -- Rat**

**[EXECUTIVE SUMMARY]{.underline}:** In a subchronic oral toxicity study
(MRID 46808219), XDE-570 (Florasulam; 99.2% a.i.; Lot No. 930910) was
administered in the diet to ten Fischer 344 rats/sex/dose at dose levels
of 0, 20, 100, 500, or 1000/800 (males/females) mg/kg/day (time-weighted
intake was 0/0, 22/21, 112/106, 550/528, and 1111/843 mg/kg/day
\[males/females\]) for 13 weeks. An additional ten rats/sex/dose were
fed test diets containing 0 or 1000/800 (males/females) mg/kg/day for 13
weeks, followed by a 4-week recovery period, during which time all rats
were fed control diet.

No adverse treatment-related effects were observed on mortality,
clinical signs, food consumption, food efficiency, ophthalmoscopic
examinations, hematology, clinical chemistry, or gross pathology.

At 500 mg/kg/day, body weights were decreased (p\<=0.05) in the females
by 5-8% during Weeks 6-13, contributing to a 21% decrease (p\<=0.05) in
overall (Weeks 0-13) body weight gains. At 1000 mg/kg/day, body weights
were decreased (p\<=0.05) in both sexes by 7-17% throughout treatment,
resulting in decreased (p\<=0.05) overall body weights gains (decr.
23-30%). Body weights and body weight gains remained decreased
(p\<=0.05) in the 1000 mg/kg/day males following recovery (decr. 11% and
17% at Week 17, respectively).

Slight nephrotoxicity was observed at 500 mg/kg/day and above. Absolute
and relative (to body weight) kidney weights were increased (p\<=0.05)
by 9-37% in both sexes. Urinary pH was decreased in both the males
(5.90-6.85 vs. 7.55 in controls) and females (6.65-7.10 vs. 8.20 in
controls). Very slight to slight hypertrophy of the epithelial cells of
the collecting ducts were observed in the males (10/10 at each dose vs.
0/10 controls) and females (8-9/10 vs. 0/10 controls); and
degeneration/regeneration and inflammation (with or without necrosis) of
the descending portion of the proximal tubules was noted in the females
(3/10 at each dose vs. 0/10 controls). Additionally, the specific
gravity of the urine was decreased (p\<=0.05) in the 1000 mg/kg/day
males (1.035 vs. 1.051 in controls), and very slight multifocal
mineralization of the kidney papilla was observed in the 800 mg/kg/day
females (9/10 vs. 0/10 controls). Following recovery, both very slight
mineralization of the tubules of the papilla (9/10 vs. 0/10 controls)
and very slight degeneration/regeneration of the cortical tubules (5/10
vs. 0.10 controls) were noted in the kidney of the 800 mg/kg/day
females.

**The LOAEL is 500 mg/kg/day, based on decreased body weights (5-8%) and
body weight gains (21%) in the females, and evidence of slight
nephrotoxicity (increased kidney weights, hypertrophy, and
degeneration/regeneration and inflammation of the descending portion of
proximal tubules) in both sexes. The NOAEL is 100 mg/kg/day.**

This study is classified as **acceptable/guideline** and satisfies the
guideline requirements (OPPTS 870.3100; OECD 408) for a subchronic oral
toxicity study in the rat.

3100. **90-Day Oral Toxicity -- Mouse**

**[EXECUTIVE SUMMARY]{.underline}:** In a subchronic oral toxicity study
(MRID 46808222), XDE-570 (Florasulam; 99.2% a.i.; Lot No. 930910) was
administered in the diet to ten B6C3F1 mice/sex/dose at dose levels of
0, 20, 100, 500, or 1000 mg/kg/day (time-weighted intake was 0/0, 22/20,
110/101, 549/503, and 1125/1007 mg/kg/day \[males/females\]) for 13
weeks.

No adverse treatment-related effects were observed on mortality,
clinical signs, body weights, body weight gains, food consumption, food
efficiency, ophthalmoscopic examination, hematology, clinical chemistry,
organ weights, or gross or microscopic pathology. Very slight
multi-focal bilateral hypertrophy was observed in the collecting ducts
of the kidney in 10/10 males at 500 and 1000 mg/kg/day and in 8/10
females at 1000 mg/kg/day. There were no significant clinical chemistry
or histopathological findings to corroborate the observed kidney
effects.

**The LOAEL is not determined and the NOAEL is 1000 mg/kg/day.**

This study is classified as **acceptable/guideline** and satisfies the
guideline requirements (OPPTS 870.3100; OECD 408) for a subchronic oral
toxicity study in mice.

3150. **90-Day Oral Toxicity -- Dog**

**[EXECUTIVE SUMMARY]{.underline} -** In a 90-day oral toxicity study
(MRID 46808223), XDE-570 (Florasulam; 99.3% a.i.; Lot \# 940714) was
administered to 4 Beagle dogs/sex/dose *ad libitum* in the diet at dose
levels of 0, 5, 50, or 100 mg/kg/day (time-weighted average test
substance intake was 0/0, 6/6, 56/55, and 104/94 mg/kg/day \[M/F\]) for
13 weeks.

There were no compound-related effects on mortality, clinical signs,
body weight, body weight gain, food consumption, ophthalmoscopy,
hematology, urinalysis, or gross pathology observed at any dose.

The target organ appeared to be the liver. At 50 mg/kg, alkaline
phosphatase activity was increased (p\<0.05) by 59-112% in the males and
91-127% in the females on Days 45 and 91, and there was a slight
increase in the incidence of hepatic vacuolation (3/4 treated \[very
slight to slight severity\] vs. 1/4 control \[moderate severity\]
females). At 100 mg/kg, the following liver effects were noted: (i)
alkaline phosphatase activity was increased (p\<0.05) by 213-451% in
both sexes on Days 45 and 91; (ii) increased incidence of very slight to
slight hepatic vacuolation (4/4 treated vs. 3/4 control males and 3/4
treated vs. 1/4 control females); and (iii) increased (p\<0.05) absolute
(incr. 22-29%) and relative (to body; incr. 26-27%) liver weight in both
sexes.

**The LOAEL is 50 mg/kg/day, based on increased alkaline phosphatase
(59-127%) activity and increased incidence/severity of hepatic
vacuolation in both sexes. The NOAEL is 5 mg/kg/day.**

This study is classified as **acceptable/guideline** and satisfies the
guideline requirement for Test Guideline OPPTS 870.3150; OECD 409 for a
90-day oral toxicity study in the dog.

3200. **21/28-Day Dermal Toxicity -- Rat**

**[EXECUTIVE SUMMARY]{.underline} -** In a repeated-dose dermal toxicity
study (MRID 46808225), XDE-570 (Florasulam; 99.3% a.i.; Lot \# 940714)
in aqueous 0.5% Methocel was applied to the shaved skin of 5 Fischer 344
rats/sex/dose at dose levels of 0, 100, 500, or 1000 mg/kg/day, 6
hours/day for 7 days/week during a 28-day period.

No compound related effects in mortality, clinical signs, body weight,
body weight gain, food consumption, hematology, clinical chemistry,
urinalysis, organ weights, and gross or microscopic pathology parameters
were observed in either sex.

At 1000 mg/kg/day, very slight (grade 1) edema and erythema at the
treatment site were noted in 4/5 males beginning on Day 23. Dermal
irritation was resolved by Day 28

.

**The systemic LOAEL is not determined and the systemic NOAEL is 1000
mg/kg/day.**

**The dermal LOAEL is 1000 mg/kg/day, based on edema and erythema
observed at the treatment site in males (4/5). The dermal NOAEL is 500
mg/kg/day.**

This study is classified as **acceptable/guideline** and satisfies the
guideline requirement for Test Guideline OPPTS 870.3200; OECD 410 for a
28-day dermal toxicity study in rats.

3465. **90-Day Inhalation -- Rat**

There are no inhalation studies available.

**A.3.2 Prenatal Developmental Toxicity**

**870.3700a Prenatal Developmental Toxicity Study -- Rat**

**[EXECUTIVE SUMMARY]{.underline}:** In a developmental toxicity study
(MRID 46808234), XDE-570 (Florasulam; 99.3% a.i.; Lot No. 940714) in
aqueous 0.5% methylcellulose was administered daily via oral gavage to
25-27 time-mated CD (Sprague Dawley) rats/group at a dose volume of 4
mL/kg at dose levels of 0, 50, 250, or 750 mg/kg/day from gestation day
(GD) 6-15. On GD 21, all surviving dams were killed and a limited
necropsy was performed. The kidneys and uterus were removed and weighed,
and the fetuses were delivered by cesarean section.

No adverse treatment-related effects were observed on mortality,
clinical signs, or gross pathology.

Four 750 mg/kg/day dams died on study. One female was found dead on GD
9; one female was killed for humane reasons on GD 10; and two females
were found dead on GD 13. These animals did not display clinical signs
of toxicity prior to death. In three of the dams, necropsy revealed dark
or firm lungs, with gavage error noted as the probable cause of death.

At 750 mg/kg/day, body weights were decreased (p\<=0.05) by 4-6% during
GD 6-19, resulting in decreased (p\<=0.05) body weight gains during
treatment (GD 6-16; decr. 16%). Food consumption was also decreased (not
statistically analyzed) by 6-13% during the treatment period.
Additionally at this dose, absolute and relative (to body weight) kidney
weights were increased (p\<=0.05) by 8 and 12%, respectively. The kidney
findings were considered treatment-related since adverse kidney effects
(increased kidney weights, hypertrophy, and histopathology) were
observed in several rat studies at ≥ 250 mg/kg/day.

**The maternal LOAEL is 750 mg/kg/day, based on decreased body weights
(4-6%), body weight gains (16%), food consumption (6-13%), and increased
kidney weights. The maternal NOAEL is 250 mg/kg/day.**

There were no effects of treatment on the numbers of implantations, live
or dead fetuses, litters, or resorptions, or post-implantation loss.

There were no treatment-related external, visceral, or skeletal
malformations.

At 750 mg/kg/day, a slight decrease (p\<=0.05) in fetal body weight (4%)
was observed; however, this finding was attributed to the decrease in
maternal body weight observed in this dose group. The delayed
ossification (not significant) of the skull, ribs, and sternebrae, also
seen at 750 mg/kg/day, was within normal range of the historical control
data.

**The developmental LOAEL is not determined and the developmental NOAEL
is 750 mg/kg/day.**

This study is classified **acceptable/ guideline** and satisfies the
guideline requirements (OPPTS 870.3700a; OECD 414) for a developmental
toxicity study in rats.

**[EXECUTIVE SUMMARY]{.underline}:** In a preliminary developmental
toxicity study (MRID 46808231), XDE-570 (Florasulam; 99.3% a.i.; Lot No.
940714) in aqueous 0.5% methylcellulose was administered daily via oral
gavage to ten time-mated CD rats/group at a dose volume of 4 mL/kg at
dose levels of 0, 100, 500, or 1000 mg/kg/day from gestation day (GD)
6-15. Excessive maternal toxicity was observed in the 1000 mg/kg/day
group, so two additional groups of ten rats were administered the test
compound as previously described at dose levels of 0 or 750 mg/kg/day in
order to more accurately determine the maximum tolerated dose. On GD 16,
all surviving does were killed and a detailed necropsy was performed.
The kidneys were removed and weighed, and the uterus and ovaries were
removed and examined grossly for numbers of implantations, resorptions,
and corpora lutea. Fetuses were not examined. Prior to death, two of
these dams were observed with excessive chromorhinorrhea; and one also
displayed decreased activity. Additionally at this dose, body weights
were decreased (p\<=0.05) by 7-8% on GD 9-12, resulting in a body weight
loss on GD 6-9 (-3.8 g vs. 13.9 g in controls; p\<=0.05) and decreased
(p\<=0.05) body weight gains on GD 9-12 (decr. 36%). Food consumption
was also decreased (not significant \[NS\]) by 27% on GD 6-12. For these
reasons, the surviving animals in this dose group were killed on GD 13
for humane reasons. No further data were collected or reported for this
dose group.

In the remaining groups, no treatment-related effects were observed on
mortality, clinical signs, or body weights. Gross pathology results were
not provided for the 750 mg/kg/day group.

One 750 mg/kg/day dam was found dead on GD 15. This animal had no prior
clinical signs of toxicity. At necropsy, this animal presented with
decreased amounts of body fat, perineal soiling, hemolyzed blood in the
digestive tract, erosions and/or ulcers in the stomach, and an enlarged
spleen. The cause of death was attributed to a probable lymphoreticular
tumor and uterine hemorrhage and was not considered treatment-related.

At 750 mg/kg/day, overall (GD 6-16) body weight gains were decreased
(NS) by 14%, and food consumption was decreased by 5-10% during the
treatment period. Additionally, absolute and relative (to body weight)
kidney weights were increased (p\<=0.05) by 12 and 16%, respectively.

**The maternal LOAEL is 750 mg/kg/day, based on decreased body weight
gains and food consumption, and increased kidney weights. The maternal
NOAEL is 500 mg/kg/day.**

There were no effects of treatment on the numbers of implantations,
litters, or resorptions, or post-implantation losses. Fetal evaluations
were not conducted.

**The developmental LOAEL and NOAEL are not determined.**

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

**[EXECUTIVE SUMMARY]{.underline}:** In a developmental toxicity study
(MRID 46808233), XDE-570 (Florasulam; 99.3% a.i.; Lot No. 940714) in
aqueous 0.5% methylcellulose was administered daily via oral gavage to
20 naturally mated New Zealand White rabbits/group at a dose volume of 4
mL/kg at dose levels of 0, 50, 250, or 500 mg/kg/day from gestation day
(GD) 7-19. On GD 28, all surviving does were killed and a limited
necropsy was performed. The liver, kidneys, and gravid uterus were
removed and weighed, and the fetuses were delivered by cesarean section
and examined.

One 250 mg/kg/day doe aborted on GD 22, and one 500 mg/kg/day doe
aborted on GD 17. Prior to aborting, both animals displayed decreased
fecal output, body weight loss, and markedly lower food consumption. At
necropsy, the 500 mg/kg/day doe was found to have findings indicative of
pneumonia, which was most likely due to deposition of the test substance
in the lungs. One 500 mg/kg/day doe was found dead on GD 19; the cause
of death was attributed to a ruptured esophagus with atelactic lungs,
with thoracic adhesions and hydrothorax present.

No treatment-related effects were observed on mortality, clinical signs,
body weights, body weight gains, food consumption, organ weights, or
gross pathologic examinations in the animals that survived to scheduled
termination.

**The maternal LOAEL is not determined and the maternal NOAEL is 500
mg/kg/day.**

There were no premature deliveries or complete litter resorptions, and
no effects of treatment on the numbers of litters, live fetuses, dead
fetuses, or resorptions (early), or on gestation index, fetal body
weights, sex ratio, post-implantation loss, or gravid uterine weights.
There were no treatment-related external, visceral, or skeletal
findings.

**The developmental LOAEL is not determined and the developmental NOAEL
is 500 mg/kg/day.**

This study is classified **acceptable/guideline (OPPTS 870.3700b)** and
satisfies the guideline requirements for a developmental toxicity study
in the rabbit. Although the animals were not dosed to the limit dose, a
preliminary developmental toxicity study in rabbits (MRID 46808232) was
performed and indicated that a dose of 600 mg/kg/day probably would have
exceeded the maximum tolerated dose and resulted in excessive maternal
death. Therefore, selection of the high dose (500 mg/kg/day) used in
this study was considered reasonable. Additionally, while this study did
not dose the animals for the recommended interval (implantation through
the day prior to cesarean section), it must be noted that this study was
performed prior to the adoption of the current guidelines (OPPTS
870.3700, August, 1998).

**[EXECUTIVE SUMMARY]{.underline}:** In a preliminary developmental
toxicity study (MRID 46808232), XDE-570 (Florasulam; 99.3% a.i.; Lot No.
940714) in aqueous 0.5% methylcellulose was administered daily via oral
gavage to seven naturally mated New Zealand White rabbits/group at a
dose volume of 4 mL/kg at dose levels of 0, 100, 300, 600, or 1000
mg/kg/day from gestation day (GD) 7-19. On GD 20, all surviving does
were killed and necropsied. The liver and kidneys were removed and
weighed, and a detailed examination of the uterus and ovaries was
performed.

One 600 mg/kg/day doe died on GD 19, and one 1000 mg/kg/day doe died on
each of GDs 10, 13, 17. These animals all exhibited decreased fecal
output, body weight loss, and markedly lower food consumption. At
necropsy, findings of congested, edematous lungs, decreased ingesta in
the digestive tract, a gastric hairball, slight hemorrhage in the
vaginal wall, and a distended bladder were noted. Due to increased
mortality (43%), the remaining does from the 1000 mg/kg/day group were
killed for humane reasons on GD 17, and no further data were collected
from this group.

No treatment-related effects were observed on organ weights or gross
pathological examinations of animals that survived to scheduled
termination.

At 600 mg/kg/day, body weight gains were decreased (not significantly
\[NS\]) during treatment (GD 7-19) by 16%, due to body weight loss
during GD 7-10 (-33.1 g vs. 53.1g in controls) and decreased (NS) body
weight gains during GD 13-16 (decr. 56%). Food consumption was decreased
(NS) during GD 10-19 (decr. 7-36%).

**The maternal LOAEL is 600 mg/kg/day, based on mortality and decreased
body weight gains and food consumption. The maternal NOAEL is 300
mg/kg/day.**

No treatment-related effects were observed on the numbers of
implantations or resorptions, or litter size at up to 600 mg/kg/day.
Cesarean section data were not reported for the 1000 mg/kg/day group.
Fetuses were not examined in any dose group.

**The developmental LOAEL and NOAEL are not determined.**

This study is classified as an **acceptable/non-guideline**
range-finding developmental toxicity study in rabbits.

.

**A.3.3 Reproductive Toxicity**

**870.3800 Reproduction and Fertility Effects -- Rat**

**[EXECUTIVE SUMMARY]{.underline}:** In a two-generation reproduction
toxicity study (MRID 46808235), XDE-570 (Florasulam; 99.3% a.i.; Lot No.
940714) was administered in the diet to 30 CD (Sprague Dawley)
rats/group at dose levels of 0, 10, 100, or 500 mg/kg/day. The P
generation parents were dosed for at least 70 days before they were
mated to produce the F1 litters. From the F1 weanlings, 30 rats/sex/dose
were selected to be parents and were fed the same test diet
concentrations as their parents for 70 days prior to mating to produce
the F2 litters.

No adverse treatment-related effects were observed on mortality,
clinical signs, or gross pathology.

Systemic toxicity was observed at 500 mg/kg. During pre-mating, body
weights (p\<=0.05) and food consumption (not significant \[NS\])
generally were decreased during Weeks 3-10, resulting in decreased (NS)
overall (Weeks 0-10) body weight gains in the F1 males and in the P and
F1 females. During gestation, body weights (p\<=0.05) and food
consumption (NS) were decreased during gestation days (GD) 0-21,
resulting in decreased (p\<=0.05) overall (GD 0-21) body weight gains in
the P and F1 females. During lactation, body weights were decreased
(p\<=0.05) during lactation days (LD) 1-14; however, food consumption
and overall (LD 1-21) body weight gains were not adversely affected.

Additionally at 500 mg/kg/day, relative (to body weight) kidney weights
were increased (p\<=0.05) in the F1 males (incr. 19%) and in the P and
F1 females (incr. 18-19%), and very slight multi-focal hypertrophy of
the collecting ducts was observed in both sexes in both generations
(70-83% treated vs. 0 controls). Although the kidney findings were not
associated with histopathological findings in this study (urinalysis and
clinical chemistry not measured) adverse kidney effects (increased
kidney weights, hypertrophy, and histopathology) were observed in
subchronic and chronic rat studies at ≥ 250 mg/kg/day. Therefore, these
findings are considered adverse.

**The LOAEL for parental toxicity is 500 mg/kg/day, based on decreased
body weights, body weight gains, and food consumption, as well as
increased relative kidney weights, and hypertrophy in both sexes. The
NOAEL is 100 mg/kg/day.**

No adverse treatment-related effects were observed on birth index, live
birth index, or viability indices, clinical signs, developmental
landmarks, kidney weights, or gross pathology.

Transient decreases (p\<=0.05) in the 500 mg/kg/day pup body weights
were observed on PND 4 pre-culling (F1 males) and PND 7 (F1 females and
F2 males and females); however, by PND 21, all treated groups were
similar to controls. These transient decreases were not considered
adverse.

**The LOAEL for offspring toxicity is not determined and the NOAEL is
500 mg/kg/day.**

There were no effects of treatment on any reproductive parameter in
either generation, including: estrous cycle length and periodicity;
mating, fertility, and gestation indices; and pre-coital and gestation
durations.

**The LOAEL for reproductive toxicity is not determined and the NOAEL is
500 mg/kg/day.**

This study is classified as **acceptable/guideline** and satisfies the
guideline requirements (OPPTS 870.3800; OECD 416) for a two-generation
reproduction study in the rat.

**A.3.4 Chronic Toxicity**

**870.4100b Chronic Toxicity -- Dog**

**[EXECUTIVE SUMMARY]{.underline}:** In a chronic toxicity study (MRID
46808229), XDE-570 (Florasulam; 99.3% a.i.; Lot No. 940714) was
administered in the diet to four purebred beagle dogs/sex/dose at dose
levels of 0, 0.5, 5, or 100 mg/kg/day for 52 weeks. Severe body weight
loss and reduced food consumption were observed in both sexes at 100
mg/kg/day during the first three months of the study; therefore, the
high dose was reduced to 50 mg/kg/day in both sexes beginning on Study
Day 105 (Week 15).

No adverse treatment-related effects were observed on mortality,
clinical signs, food efficiency, ophthalmoscopic examinations,
hematology, urinalysis, organ weights, or gross or microscopic
pathology.

At 100 mg/kg/day, both sexes exhibited loss of body weight accompanied
by reduced food consumption. Following reduction of the high dose to 50
mg/kg/day, the females continued to exhibit both decreased (not
significant \[NS\]) body weights (decr. 17% at Week 52) and food
consumption, resulting in decreased (NS) overall (Week 0-52) body weight
gains (decr. 68%). Male body weights and food consumption at Week 52,
and overall body weight gains were similar to controls.

Additionally at 100 mg/kg/day, males and females had increased
(p\<=0.05) alkaline phosphatase (incr. 233-783%) and alanine
aminotransferase (incr. 268-390%) after 3 months of dosing. Alkaline
phosphatase continued to be elevated (p\<=0.05) in both sexes through 12
months of dosing (incr. 141-354%). Slight vacuolation of the zona
reticularis and zona fasciculata was also observed in the adrenal gland
of both sexes; the findings were consistent with fatty change.

**The LOAEL is 100/50 mg/kg/day, based on decreased body weights (17%),
body weight gains (68%), and food consumption in the females; increased
liver enzymes (alanine aminotransferase and alkaline phosphatase), and
slight vacuolation of the zona reticularis and zona fasciculata in the
adrenal gland (consistent with fatty change) of both sexes. The NOAEL is
5 mg/kg/day.**

This study is classified as **acceptable/guideline** and satisfies the
guideline requirements (OPPTS 870.4100b, OECD 452) for a chronic
toxicity study in the dog.

**A.3.5 Carcinogenicity**

**870.4200a Combined Chronic/Carcinogenicity Study -- rat**

**[EXECUTIVE SUMMARY]{.underline}:** In a combined chronic
toxicity/carcinogenicity study (MRID 46808236), XDE-570 (Florasulam;
99.3% a.i.; Lot No. 940714) was administered in the diet for 104 weeks
to 50 Fischer 344 rats/sex/dose at dose levels of 0/0, 10/10, 250/125,
or 500/250 mg/kg bw/day nominally in males/females (actual intake was
0/0, 10/10, 254/127, and 506/254 mg/kg bw/day in males/females). An
additional 10 rats/sex/dose were treated in a similar manner and killed
after 52 weeks. A concurrent neuropathology group (5 rats/sex/dose) were
treated similarly and killed at 52 weeks; however, only body weights and
body weight gains were reported in this study.

No adverse treatment-related effects were observed on mortality,
clinical signs, food consumption, food efficiency, hematology, clinical
chemistry, or gross pathology.

In the 250 mg/kg/day females, body weight was decreased (p\<=0.05) by
approximately 3-8% after Week 52. Only a minor decrease of 6% was
observed in body weight gain for Weeks 0-52, but overall body weight
gain decreased by 14%. In the 500 mg/kg/day males, body weight was
decreased (p\<=0.05) by approximately 13-18% after Week 13. Body weight
gain was similar to controls at Weeks 0-13, but was decreased at Weeks
0-52 by 27% and overall (Weeks 0-104) by 23%.

Slight nephrotoxicity was observed in males. At 250 and 500 mg/kg/day,
increased absolute and relative kidney weights (5 and 3%, 8-9 and
22-24%, respectively), increased incidences of very slight to moderate
renal collecting duct hypertrophy (82-98% treated vs 0% controls) and
very slight to slight multi-focal mineralization in the papilla (28-78%
treated vs 4% controls) were observed. Renal collecting duct hypertrophy
was also observed at 12 months at 250 and 500 mg/kg/day (50-100% treated
vs 0% controls). Additionally, at 500 mg/kg/day, the incidence of
focal/multi-focal transitional cell hyperplasia in the papilla was
increased (22% treated vs 0% controls) at 24 months.

It was not clear if the following findings were adverse and
treatment-related. In the 250 mg/kg/day females, the incidence of cloudy
cornea was increased (57% treated vs 20% controls); however histological
examination did not corroborate an adverse effect. Urinary pH was
decreased in the 500 mg/kg/day males (5.3-6.1 treated vs 7.0-8.1
controls).

**The LOAEL is 250 mg/kg/day, based on decreased body weights (3-8%) and
body weight gains (14%) in the females; slight nephrotoxicity (increased
kidney weights, hypertrophy, and histopathology) in males. The NOAEL is
10 mg/kg/day in males; 125 mg/kg/day in females.**

At the doses tested, there were no treatment-related increases in tumor
incidence when compared to controls. Dosing was considered adequate
based on decreased body weights and body weight gains in both sexes and
slight nephrotoxicity in males.

This study is classified as **acceptable/guideline** and satisfies the
guideline requirements (OPPTS 870.4200b; OECD 451) for a carcinogenicity
study in mice.

**870.4200b Carcinogenicity (feeding) -- Mouse**

**[EXECUTIVE SUMMARY]{.underline}:** In a carcinogenicity study (MRID
46808230), XDE-570 (Florasulam; 99.3% a.i.; Lot No. 940714) was
administered in the diet to 50 B6C3F1 mice/sex/dose at dose levels of 0,
50, 500, or 1000 mg/kg bw/day nominally (actual intake was 0/0, 50/51,
505/497, and 1009/1019 mg/kg bw/day in males/females) for 104 weeks. An
additional 10 mice/sex/dose were treated in a similar manner and
sacrificed after 52 weeks.

No adverse treatment-related effects were observed on clinical signs,
body weight, food consumption, food efficiency, ophthalmoscopic
examinations, hematology, clinical chemistry, organ weights, or gross
pathology.

At 500 and 1000 mg/kg/day, mortality was increased in the females (42%
each dose vs 26% controls) at Week 106; however, a dose-related effect
was not observed at Week 96, and a statistically significant difference
was not found at either time point. Therefore, the effect on mortality
was considered equivocal. Increased (p\<=0.05) incidences of very slight
to slight renal collecting duct hypertrophy (82-96% treated vs 0%
controls) and decreased slight to moderate vacuolization in the renal
cortex tubule (94-96% treated vs 48% controls) were noted at 24 months
in males, and similar findings were also noted at 12 months. The
toxicological significance of these findings in the kidney was
considered equivocal.

**The LOAEL is not determined and the NOAEL is 1000 mg/kg/day.**

**At the doses tested, there was not a treatment related increase in
tumor incidence when compared to controls. Dosing was considered
adequate because the limit dose was tested.**

This study is classified as **acceptable/guideline** and satisfies the
guideline requirements (OPPTS 870.4200b; OECD 451) for a carcinogenicity
study in mice.

**A.3.6 Mutagenicity**

**870.5100 Bacterial Reverse Mutation Test**

**[EXECUTIVE SUMMARY]{.underline} --** In two independent trials of a
reverse gene mutation assay in bacteria (MRID 46808240), *Salmonella
typhimurium* strains TA98, TA100, TA1535, and TA1537, and *Escherichia
coli* strain WP2*uvr*A were exposed to XDE-570 (Florasulam; 99.2% a.i.;
Lot \# 930910) in dimethylsulfoxide (DMSO) at concentrations of 0,
0.333, 1, 3.33, 10, 33.3, or 100 µg/plate (*S. typhimurium*) and 0, 10,
33.3, 100, 333, 1000, or 3330 µg/plate (*E. coli*) both in the presence
and absence of S9-activation. The S9 fraction was derived from the
livers of male Sprague-Dawley rats induced with Aroclor 1254. The
pre-incubation method was used in both the initial and confirmatory
assays. Standard strain-specific mutagens served as positive controls.

XDE-570 was tested up to cytotoxic concentrations, as indicated by the
reduced numbers of revertants at 33.3 µg/plate and above in the *S.
typhimurium* strains and at 3333 µg/plate in the *E. coli* strain. There
were no marked increases in the mean number of revertants/plate in any
strain. The positive controls induced the appropriate response in all
strains in the presence and absence of S9-activation. **There was no
evidence of induced mutant colonies over background.**

The study is classified as **acceptable/guideline** and satisfies the
guideline requirement for Test Guideline OPPTS 870.5100; OECD 471 for
*in vitro* mutagenicity (bacterial reverse gene mutation) data.

**870.5300 *In Vitro* Mammalian Cell Gene Mutation Test**

**[EXECUTIVE SUMMARY]{.underline} -** In two independent trials of a
mammalian cell gene mutation assay at the HGPRT locus (MRID 46808238),
Chinese hamster ovary (CHO) cells cultured *in vitro* were exposed to
XDE-570 (Florasulam; 99.2% a.i.; Lot \# 930910) in dimethylsulfoxide
(DMSO) at concentrations of 0, 187.5, 375, 750, 1500, or 3000 µg/mL
(+/-S9) for 4 hours. The S9 fraction was derived from the livers of male
Sprague-Dawley rats induced with Aroclor 1254. The positive controls
were ethyl methanesulfonate (-S9) and 20-methylcholanthracene (+S9).

XDE-570 was tested up to the limit of solubility (3000 µg/mL). No
evidence of cytotoxicity was observed at any concentration in either
trial in the presence or absence of S9-activation. No marked increase in
mutant frequency was observed in any trial in the presence or absence of
S9-activation. The positive controls induced the appropriate response in
both trials (+/-S9). **There was no evidence of induced mutant colonies
over background in the presence or absence of S9-activation.**

This study is classified as **acceptable/guideline** and satisfies the
guideline requirement for Test Guideline OPPTS 870.5300; OECD 476 for
*in vitro* mutagenicity (mammalian forward gene mutation) data.

**870.5375 *In Vitro* Mammalian Chromosome Aberration Test**

**[EXECUTIVE SUMMARY]{.underline} -** In two independent trials of a
mammalian cell cytogenetics assay (chromosome aberration; MRID
46808237), primary rat lymphocyte cultures were exposed to XDE-570
(Florasulam; 99.2% a.i.; Lot \# 930910) in dimethylsulfoxide (DMSO) for
4 hours in the presence of S9 and 24 hours in the absence of S9 at
concentrations of 0, 3, 10, 30, 100, 300, 1000, or 3000 µg/mL (Trial 1,
+/-S9); 0, 30, 100, or 300 µg/mL (Trial 2, --S9); and 0, 300, 1000, or
3000 µg/mL (Trial 2, +S9). Cells were harvested at 24 hours after
initiation of treatment in Trial 1 and at 24 and 48 hours after
initiation of treatment in Trial 2. The S9 fraction was derived from the
livers of male Sprague-Dawley rats induced with Aroclor 1254. The
positive controls were mitomycin C (-S9) and cyclophosphamide (+S9).

It was stated that XDE-570 was tested up to the limit of solubility
(3000 µg/mL). Based on the observed cytotoxicity (as indicated by
reduced mitotic index), cultures at concentrations of 30, 100, and 300
µg/mL (-S9, both trials, 24 hours); 300, 1000, and 3000 µg/mL (+S9, both
trials, 24 hours); 300 µg/mL (-S9, Trial 2; 48 hours); and 3000 µg/mL
(+S9, Trial 2, 48 hours) were selected for evaluation of chromosomal
aberrations. No relevant increases in the number of metaphases with
aberrations (excluding gaps) were observed at any concentration at the
24 or 48 hour harvest time in either the presence or absence of S9. The
positive controls induced the appropriate response in the presence and
absence of S9. **There was no evidence of chromosome aberrations induced
over background in the presence or absence of S9-activation.**

This study is classified as **acceptable/guideline** and satisfies the
guideline requirement for Test Guideline OPPTS 870.5375; OECD 473 for
*in vitro* mutagenicity (chromosome aberration) data.

**870.5395 Bacterial Mutation Assay**

**[EXECUTIVE SUMMARY]{.underline} -** In a bone marrow micronucleus
assay (MRID 46808239), young adult CD-1 mice (5/sex/dose/harvest time)
were treated once via gavage (20 mL/kg) with XDE-570 (Florasulam; 99.2%
a.i.; Lot \# 930910) in corn oil at doses of 0, 1250, 2500, or 5000
mg/kg. Bone marrow cells were harvested at 24, 48, and 72 hours after
dosing. Cyclophosphamide (120 mg/kg) served as the positive control.

No treatment-related clinical signs of toxicity were observed during the
study. At 5000 mg/kg, two females died on Day 2; however, the cause of
death and association with the test substance was not established. Both
the MPCE frequency and the PCE:NCE ratio were comparable between vehicle
controls and all treated groups at all sampling times in both sexes.
Although there were no clinical signs and no apparent effect on marrow
toxicity, dosing was considered to be adequate as XDE-570 was tested up
to more than twice the limit dose of 2000 mg/kg. The positive control
induced the appropriate response. **There was no significant increase in
the frequency of micronucleated polychromatic erythrocytes in bone
marrow after any treatment time.**

This study is classified as **acceptable/guideline** and satisfies the
guideline requirement for Test Guideline OPPTS 870.5395; OECD 474 for
*in vivo* cytogenetic mutagenicity data.

**A.3.7 Neurotoxicity**

**870.6200a Acute Neurotoxicity Screening Battery**

**[EXECUTIVE SUMMARY]{.underline} -** In an acute neurotoxicity study
(MRID 46808217), groups of 10 fasted young adult Fischer 344
rats/sex/dose were given a single oral gavage dose of XDE-570
(Florasulam; 99.3% a.i.; Lot \# 940714) in aqueous methylcellulose at
dose levels of 0, 200, 1000, or 2000 mg/kg (limit dose) and were
observed for 15 days. Neurobehavioral assessment (functional
observational battery \[FOB\] and motor activity testing) was performed
in all rats at one week prior to dosing and on Days 1 (approximately 6-7
hours post-dosing), 8, and 15. At study termination, 5 rats/sex/dose
were euthanized and perfused *in situ* for neuropathological
examination. The brain and peripheral nervous system tissues collected
from the perfused animals in the control and 2000 mg/kg groups were
subjected to histopathological evaluation. Positive control data were
provided.

There were no compound-related effects on mortality, clinical signs,
body weight, and gross or neuropathology observed at any dose.

In the 2000 mg/kg males, overall (Days 0-15) body weight gain was
decreased by 21%, although body weight at termination was comparable to
controls. This was attributed to a lower body weight gain (decr. 33%) in
these animals during Week 1. Additionally in these animals, there was a
slight transient decrease in motor activity, increased incidence of
minimal activity in the open-field, and decreased reactivity to sharp
noise on Day 1. However, the differences from control values did not
exceed the historical controls and complete recovery occurred by the
next test session (Day 8). When the FOB and motor activity findings were
combined they were considered to be a treatment-related effect. As there
were no corroborative gross or neuropathological findings to suggest a
neurotoxic effect, this pattern of decreased activity was considered to
be likely due to general malaise.

No treatment-related effects were observed in the females at any dose
and the males at 1000 mg/kg or below.

**No evidence of neurotoxicity was observed at any dose in either sex.**

**The systemic LOAEL is 2000 mg/kg (limit dose), based on decreased body
weight gain (21%) and general malaise (slight transient decrease in
motor activity, minimal activity in open field, and reactivity) in the
males. The systemic NOAEL is 1000 mg/kg.**

**The neurotoxicity LOAEL is not determined. The neurotoxicity NOAEL is
2000 mg/kg (limit dose).**

This study is classified as **acceptable/guideline** and satisfies the
guideline requirement for Test Guideline OPPTS 870.6200a; OECD 424 for
an acute neurotoxicity study in the rat.

**870.6200b Chronic Neurotoxicity Screening Battery**

**[EXECUTIVE SUMMARY]{.underline} -** In a chronic neurotoxicity study
(MRID 46808228), XDE-570 (Florasulam; 99.3% a.i.; Lot \# 940714) was
administered to 10 young adult Fischer 344 rats/sex/dose in the diet at
dose levels of 0, 10, 125 (females only), 250, or 500 (males only)
mg/kg/day (time-weighted average test substance intake was 0, 8.6, 216,
and 460 mg/kg/day in males and 0, 9, 113, and 266 mg/kg/day in females)
for 12 months. Neurobehavioral assessment (functional observational
battery \[FOB\] and motor activity testing) was performed in all rats at
pre-dosing and at 3, 6, 9, and 12 month post-dosing. At study
termination, auditory function (auditory brainstem response) was
evaluated in 5 rats/sex/dose from the control and high-dose animals (500
mg/kg/day males and 250 mg/kg/day females). After completion of the
auditory function examination, a neuropathological examination of
perfusion-fixed central and peripheral nervous system tissues was
conducted using these control and high-dose animals. All animals were
subjected to a gross necropsy at termination. Positive control data were
provided.

There were no compound-related effects on mortality, clinical signs,
food consumption, FOB parameters, motor activity, and gross or
neuropathology observed at any dose. Organ weights were not provided;
however, in the concurrently performed 2-year dietary chronic toxicity/
oncogenicity study (MRID 46808236), brain weight was unaffected after 12
and 24 months of treatment.

At 500 mg/kg/day, body weights were decreased (p\<0.05) by 9-15% in the
males at 6, 9, and 12 months. Additionally, body weight gains were
decreased by 61-67% at 3-12 months and overall (0-12 months) gains were
decreased by 27% compared to controls. Food consumption was similar to
controls in these animals.

No treatment-related effects were observed at 250 mg/kg/day and below in
either sex.

**No evidence of neurotoxicity was observed at any dose in either sex.**

**The systemic LOAEL is 500 mg/kg/day, based on decreased body weight
(9-15%) and body weight gain in males (61-67%). The systemic NOAEL is
250 mg/kg/day.**

**The neurotoxicity LOAEL is not determined. The neurotoxicity NOAEL is
250 mg/kg/day, the highest dose tested in females.**

This study is classified as **acceptable/guideline** and satisfies the
guideline requirement for Test Guideline OPPTS 870.6200 for a chronic
neurotoxicity feeding study in the rat

**A.3.8 Metabolism**

7485. **Metabolism -- Rat**

**[EXECUTIVE SUMMARY]{.underline}:** In a metabolism study (MRID
46808301), \[^14^C\]-XDE-570 (Florasulam; 99.3-99.5% radiochemical
purity; Lot Nos. B463-145 and B844-08A) in a suspension of 0.5%
Methocel™ cellulose ethers was administered to 5 Fischer 344 rats/sex as
a single gavage dose at 10 or 500 mg/kg bw. Additionally, 5 rats/sex
were treated with 14 daily doses at 10 mg/kg bw/day of non-labeled
XDE-570 followed by a single oral dose of \[^14^C\]-XR-570 on Day 15.
\[^14^C\]-XDE-570 was uniformly labeled in the aniline ring for each of
these test groups. In addition, 5 males were treated with a single
gavage dose at 10 mg/kg bw with \[^14^C\]-XR-570 (labeled at the 9
position in the triazolo-pyrimidine ring). All animals were killed 168
hours after the administration of the radiolabeled dose.

Absorption was rapid and extensive. Approximately 90-93% of the dose was
absorbed in the 10 mg/kg rats, and 82-86% was absorbed in the 500 mg/kg
rats (based on the sum of radioactivity detected in the urine,
tissues/carcass, and cage rinse). Peak plasma concentrations (Cmax) were
achieved within 0.5-1 hour following dose administration at 10 or 500
mg/kg. Cmax in the plasma did not increase proportionally with dose,
possibly indicating a saturation of the absorption and/or excretion
mechanisms at the high dose. The apparent volume of distribution was
increased at the high dose, possibly indicative of increased tissue
binding.

Total recoveries at 168 hours post-dose were 95.9-100.2% of the
administered dose. Elimination was rapid. The administered dose was
mostly eliminated within 12 hours in the urine (\>80% of the dose at 10
mg/kg and \>60% of the dose at 500 mg/kg). Total radioactivity found in
the urine was approximately 90-92% of the dose following single or
repeated low-dose treatment, and 81-85% of the dose following treatment
at 500 mg/kg. Radioactivity in the feces accounted for another 5‑7% at
10 mg/kg and 14-17% at 500 mg/kg. Thus, compared to the low dose,
excretion of the high dose was slightly slower, and more of the compound
was excreted in the feces. At 24 hours, \<0.5% of the dose was found in
expired air. By 24 hours post-dose, plasma levels had declined to \<0.1
µg eq/g plasma in both sexes at 10 mg/kg and \<5.0 µg eq/g plasma in
both sexes at 500 mg/kg. The highest residue levels were observed in the
skin (single dose) and carcass (repeated dose), but the mean recovery of
radioactivity in the tissues/carcass at sacrifice was \<0.6% of the
dose.

Identified compounds accounted for 87.6-91.6% of the administered dose
in each group. In each group, the following compounds were isolated:
parent accounted for 77.7-85.0% dose, OH-phenyl-XR-570 (exact position
of hydroxyl group not determined) accounted for 3.1-9.0% dose,
OH-phenyl-XR-570 sulfate conjugate accounted for 2.8-3.7% dose, and 2
unidentified metabolites accounted for \<=0.32% dose. In the high dose,
more of the parent was isolated in the feces and less in the urine
compared to the low dose.

There were no sex-related differences in the metabolism or
pharmacokinetics of the test compound. Similarly, the number of doses or
the position of the radiolabel generally made no difference in the
metabolism and pharmacokinetic profile.

This study is classified as **acceptable/guideline** and satisfies the
guideline requirement for a metabolism study \[OPPTS 870.7485, OECD
417\] in rats.

7600. **Dermal Absorption -- Rat**

**[EXECUTIVE SUMMARY]{.underline}:** In a dermal penetration study (MRID
46808304), \[^14^C\]-XDE-570 (Florasulam; 98-99% radiochemical purity as
applied; Batch Nos. B463-145 and C237-7B) was applied to the skin (12
cm^2^) of Fischer 344 rats (4 males for each time point at each dose
level). Nominal doses were 0.001 or 0.5 mg/cm^2^ skin. The high dose
(EF-1343 commercial formulation) was included to assess exposure to
mixer/loaders. The low dose (spray dilution, using an EF-1343 blank as a
vehicle) represented a dose that was 2.39-fold more concentrated than
the highest anticipated spray concentration for use on field crops,
which was necessary in order to provide sufficient analytical
sensitivity. The exposure duration was 24 hours, after which one group
of 4 males for each dose level was sacrificed. The remaining 2
groups/dose were sacrificed at 48 or 72 hours post-application.

Recovery of the applied dose (mass balance) was 100-103%. The majority
of the dose was recovered in the skin swab (71-90% of the applied dose).
Dermal absorption (based on the sum of residues in urine, feces, cage
wash, tissues, residual carcass, and untreated skin) was only 0.13-0.45%
of the applied dose and only 10-22% of the applied dose remained in the
skin at the application site (considered potentially absorbable).
Increasing the dose 200-fold resulted in only approximately 2-fold
increase in absorption. Absorption increased 44% at 48 h and 61% at 72 h
compared to 24 h in the low dose groups; however, a time-dependent
increase in absorption was not evident in the high dose groups. The
absorbed dose was almost completely excreted in the urine at the low
dose, but was found primarily in the urine, cage wash, and untreated
skin at the high dose. The amount of radioactivity at the treatment site
increased at 48 hours in the low dose, but did not decrease within 72
hours at either dose, suggesting that the compound in the skin was not
readily absorbable.

The compound isolated in the treated skin after 72 hours (including the
24 hour exposure period) would be absorbed in negligible amounts. The
highest dermal absorption noted was 0.45% of the applied dose. This
value is considered appropriate for use in risk assessment, with the
appropriate uncertainty factors applied.

This study is classified as **acceptable/guideline** and satisfies the
guideline requirements (OPPTS 870.7600; OECD none) for a dermal
penetration study in rats.

**A. 4 Toxicology References**

  ---------- --------------------------------------------------------------
  46808209   Gilbert, K.; Yano, B. (1995) XDE-570: Acute Oral Toxicity
             Study in Fischer 344 Rats. Project Number: DR/0312/6565/012A.
             Unpublished study prepared by The Dow Chemical Co. 56 p.

  46808211   Gilbert, K. (1995) XDE-570: Acute Dermal Toxicity Study in New
             Zealand White Rabbits. Project Number: DR/0312/6565/012D.
             Unpublished study prepared by The Dow Chemical Co. 27 p.

  46808212   Clements, C.; Cieszlak, F. (1995) XDE-570: Acute Aerosol
             Inhalation Toxicity Study with Fischer 344 Rats. Project
             Number: DR/0312/6565/015. Unpublished study prepared by THe
             Dow Chemical Co. 34 p.

  46808213   Gilbert, K. (1995) XDE-570: Primary Eye Irritation Study in
             New Zealand White Rabbits. Project Number: DR/0312/6565/012C.
             Unpublished study prepared by Dow Chemical, USA. 16 p.

  46808214   Gilbert, K. (1995) XDE-570: Primary Dermal Irritation Study in
             New Zealand White Rabbits. Project Number: DR/0312/6565/012B.
             Unpublished study prepared by The Dow Chemical Co. 16 p.

  46808215   Gilbert, K. (1995) XDE-570: Dermal Sensitization Potential in
             the Hartley Albino Guinea Pig. Project Number:
             DR/0312/6565/012E. Unpublished study prepared by The Dow
             Chemical Co. 18 p.

  46808216   Johnson, I. (1996) XDE-570: Skin Sensitization in the Guinea
             Pig. Project Number: DWC/738/962306/SS, DWC/738. Unpublished
             study prepared by Huntingdon Life Sciences, Ltd. 43 p.

  46808217   Mattsson, J.; McGuirk, R.; Yano, B. (1997) XDE-570: Acute
             Neurotoxicity Study in Fischer 344 Rats. Project Number:
             DR/0312/6565/022. Unpublished study prepared by The Dow
             Chemical Co. 477 p.

  46808219   Redmond, J.; Johnson, K. (1996) XDE-570: 13-Week Dietary
             Toxicity and 4-Week Recovery Study in F344 Rats. Project
             Number: DR/0312/6565/011, DR/0312/6565/011A. Unpublished study
             prepared by The Dow Chemical Co. 509 p.

  46808222   Redmond, J.; Johnson, K. (1996) XDE-570: 13-Week Dietary
             Toxicity Study in B6C3F1 Mice. Project Number:
             DR/0312/6565/010. Unpublished study prepared by The Dow
             Chemical Co. 350 p.

  46808223   Stebbins, K. (1997) Amended Report for XDE-570: Thirteen-Week
             Dietary Toxicity Study in Beagles. Project Number:
             DR/0312/6565/021, TI94/069, 236. Unpublished study prepared by
             The Dow Chemical Co. 171 p.

  46808225   Scortichini, B.; Kociba, R. (1997) XDE-570: 28-Day Repeated
             Dose Dermal Toxicity Study in Fischer 344 Rats. Project
             Number: 971042. Unpublished study prepared by The Dow Chemical
             Co. 235 p.

  46808228   Shankar, M.; Johnson, K. (1996) XDE-570: Chronic Neurotoxicity
             Study in Fischer 344 Rats. Project Number: DR/0312/6565/019N.
             Unpublished study prepared by The Dow Chemical Co. 618 p.

  46808229   Stebbins, K.; Haut, K. (1997) XDE-570: One Year Dietary
             Toxicity Study in Beagle Dogs. Project Number: 960018.
             Unpublished study prepared by The Dow Chemical Co. 419 p.

  46808230   Quast, J.; Haut, K.; Kociba, R. (1997) XDE-570: Two Year
             Oncogenicity in B6C3F1 Mice. Project Number: 96006,
             DR/0312/6565/020, 33674. Unpublished study prepared by The Dow
             Chemical Co. 2220 p.

  46808231   Liberacki, A.; Breslin, W.; Stebbins, K. (1996) XDE-570: Oral
             Gavage Teratology Probe Study CD Rats. Project Number:
             DR/0312/6565/024, DR/0312/6565/024F, DR/0312/6565/024A.
             Unpublished study prepared by The Dow Chemical Co. 92 p.

  46808232   Zablotny, C.; Quast, J. (1996) XDE-570: Oral Gavage Teratology
             Probe Study in New Zealand White Rabbits. Project Number:
             DR/0312/6565/023, 960014. Unpublished study prepared by The
             Dow Chemical Co. 100 p.

  46808233   Zablotny, C.; Carney, E. (1997) XDE-570: Oral Gavage
             Teratology Study in New Zealand White Rabbits. Project Number:
             960022. Unpublished study prepared by The Dow Chemical Co. 263
             p.

  46808234   Liberacki, A.; Carney, E. (1997) XDE-570: Oral Gavage
             Teratology Study in CD Rats. Project Number: DR/0312/6565/027.
             Unpublished study prepared by The Dow Chemical Co. 258 p.

  46808235   Liberacki, A.; Carney, E.; Kociba, R. (1997) XDE-570:
             Two-Generation Dietary Reproduction Study in CD Rats. Project
             Number: 960030, DR/0312/6565/028P1, R550425. Unpublished study
             prepared by The Dow Chemical Co. 2234 p.

  46808236   Johnson, K.; Haut, K.; Stebbins, K. (1997) XDE-570: Two-Year
             Chronic Toxicity/Oncogenicity Study in Fischer 344 Rats.
             Project Number: 96004, DR/0312/6565/019. Unpublished study
             prepared by Dow Chemical, USA. 2896 p.

  46808237   Linscombe, V.; Okowit, D.; Kropscott, B. (1995) Evaluation of
             XDE-570 in an In Vitro Chromosomal Aberration Assay Utitlizing
             Rat Lymphocytes. Project Number: DR/0312/6565/007. Unpublished
             study prepared by The Dow Chemical Co. 43 p.

  46808238   Linscombe, V.; Okowitt, D.; Kropscott, B. (1995) Evaluation of
             XDE-570 in the Chinese Hamster Ovary
             Cell/Hypoxanthine-Guanine-Phosphoribosyl Transferase
             (CHO/HGPRT) Forward Mutation Assay. Project Number:
             DR/0312/6565/006, 33674. Unpublished study prepared by The Dow
             Chemical Co. 40 p.

  46808239   Lick, S.; Gollapudi, B.; Kropscott, B. (1995) Evaluation of
             XDE-570 in the Mouse Bone Marrow Micronucleus Test. Project
             Number: DR/0312/6565/013. Unpublished study prepared by Dow
             Chemical, USA. 45 p.

  46808240   Lawlor, T. (1995) Mutagenicity Test on XDE-570 in the
             Salmonella/Mammalian-Microsome Reverse Mutation Assay (AMES
             Test) Preincubation Method With A Confirmatory Assay. Project
             Number: 16246/0/422R, DR/0312/6565/016. Unpublished study
             prepared by Corning Hazleton, Inc. 39 p.

  46808301   Dryzga, M.; Stewart, H.; Hansen, S.; et. al. (1996) XR-570P:
             Tissue Distribution and Metabolism of (Carbon 14)-Labeled
             XR-570 in Fischer 344 Rats. Project Number: DR/0312/6565/014,
             HET/DR/0312/65665/014, 87/302. Unpublished study prepared by
             The Dow Chemical Co. 130 p.

  46808303   Hansen, S. (1997) XDE-570: Distribution and Metabolism of
             (Carbon 14)-Labeled XDE-570 in Selected Tissues at Plasma Cmax
             and C1/2max and in Bile Following Oral Administration in
             Fischer 344 Rats. Project Number: HET/DR/0312/6565/029,
             87/302. Unpublished study prepared by The Dow Chemical Co. 121
             p.

  46808304   Bounds, S. (1997) XDE-570: Dermal Absorption of \[(Carbon
             14)\]-XDE-570 in Male Fischer 344 Rats Following Exposure to
             Undiluted EF-1343 and a Spray Solution: Final Report. Project
             Number: DWC/891, DWC891/972958. Unpublished study prepared by
             Huntingdon Life Sciences, Ltd. 195 p.
  ---------- --------------------------------------------------------------

**Appendix B: Metabolism Assessment**

**B.1. Metabolism Guidance and Considerations**

  ---------------- ------------ ----------------- --------------------------
  **Table B1.2                                    
  Tabular Summary                                 
  of Metabolites**                                

  **Chemical Name  **Matrix**   **Percent TRR     
  (other names in               (PPM) ^1^**       
  parenthesis)**                                  

                                **Matrices -      **Structure**
                                Major Residue     
                                (\>10%TRR)**      

  Florasulam       Wheat straw  ≤14 % TRR         ![](media/image3.wmf)

                   Wheat forage ≤32 % TRR         

                   Ruminant     ≤98 % TRR         

                   Poultry      ≤95 % TRR         

                   Rotational   ≤92 % TRR         
                   crops                          

  4-OH-phenyl      Wheat straw  ≤14 % TRR         ![](media/image4.wmf)
  florasulam                                      

                   Wheat forage ≤15 % TRR         

  Glucose          Wheat straw  ≤22 % TRR         ![](media/image5.wmf)
  conjugate of                                    
  4-OH-phenyl                                     
  florasulam                                      

                   Wheat forage ≤42 % TRR         

  2-sulfonamide    Wheat straw  ≤18 % TRR         ![](media/image6.wmf)
  ---------------- ------------ ----------------- --------------------------

+---------+---------+---------+------+----------+---+-------+-------+
| **Table |         |         |      |          |   |       |       |
| B.1.3   |         |         |      |          |   |       |       |
| Summary |         |         |      |          |   |       |       |
| of      |         |         |      |          |   |       |       |
| Major   |         |         |      |          |   |       |       |
| Flo     |         |         |      |          |   |       |       |
| rasulam |         |         |      |          |   |       |       |
| Degr    |         |         |      |          |   |       |       |
| adation |         |         |      |          |   |       |       |
| Prod    |         |         |      |          |   |       |       |
| ucts.** |         |         |      |          |   |       |       |
+=========+=========+=========+======+==========+===+=======+=======+
| **Study | **De    |         |      |          |   |       | **So  |
| Type**  | gradate |         |      |          |   |       | urce/ |
|         | and     |         |      |          |   |       | Comme |
|         | Maximum |         |      |          |   |       | nts** |
|         | Concen  |         |      |          |   |       |       |
|         | tration |         |      |          |   |       |       |
|         | (% of   |         |      |          |   |       |       |
|         | a       |         |      |          |   |       |       |
|         | pplied, |         |      |          |   |       |       |
|         | day)**  |         |      |          |   |       |       |
+---------+---------+---------+------+----------+---+-------+-------+
|         | **      | **\     | **TP | **DFP    | * | **    |       |
|         | 5-OH-XD | ASTCA** | SA** | -ASTCA** | * | TSA** |       |
|         | E-570** |         |      |          | S |       |       |
|         |         |         |      |          | T |       |       |
|         |         |         |      |          | C |       |       |
|         |         |         |      |          | A |       |       |
|         |         |         |      |          | * |       |       |
|         |         |         |      |          | * |       |       |
+---------+---------+---------+------+----------+---+-------+-------+
|         | ![]     | !       | ![   | ![]      | \ | !     |       |
|         | (media/ | [](medi | ](me | (media/i | _ | [](me |       |
|         | image7. | a/image | dia/ | mage10.w |   | dia/i |       |
|         | wmf){wi | 8.wmf){ | imag | mf){widt |   | mage1 |       |
|         | dth="1. | width=" | e9.w | h="1.158 |   | 1.wmf |       |
|         | 0375in" | 1.08055 | mf){ | 33333333 |   | ){wid |       |
|         | he      | 5555555 | widt | 33334in" |   | th="0 |       |
|         | ight="0 | 5555in" | h="0 | height   |   | .8923 |       |
|         | .563888 | hei     | .767 | ="0.5361 |   | 61111 |       |
|         | 8888888 | ght="0. | 3611 | 11111111 |   | 11111 |       |
|         | 889in"} | 4298611 | 1111 | 1111in"} |   | 12in" |       |
|         |         | 1111111 | 1111 |          |   | heigh |       |
|         |         | 114in"} | 2in" |          |   | t="0. |       |
|         |         |         | he   |          |   | 48472 |       |
|         |         |         | ight |          |   | 22222 |       |
|         |         |         | ="0. |          |   | 22222 |       |
|         |         |         | 7048 |          |   | 2in"} |       |
|         |         |         | 6111 |          |   |       |       |
|         |         |         | 1111 |          |   |       |       |
|         |         |         | 1112 |          |   |       |       |
|         |         |         | in"} |          |   |       |       |
+---------+---------+---------+------+----------+---+-------+-------+
| Hyd     | 78% (7  | \_      | \_   | \_       | \ | \_    | MRIDs |
| rolysis | d, 50   |         |      |          | _ |       | 4680  |
| (pH 9   | C);    |         |      |          |   |       | 8130, |
| only)   | 32% (90 |         |      |          |   |       | 468   |
|         | d,      |         |      |          |   |       | 27909 |
|         | 25C)   |         |      |          |   |       |       |
+---------+---------+---------+------+----------+---+-------+-------+
| Aqueous | \_      | \_      | 17%  | \_       | \ | \_    | MRID  |
| Pho     |         |         | (32  |          | _ |       | 468   |
| tolysis |         |         | d)   |          |   |       | 08132 |
+---------+---------+---------+------+----------+---+-------+-------+
| Soil    | \_      | \_      | \_   | \_       | \ | \_    | MRID  |
| Pho     |         |         |      |          | _ |       | 468   |
| tolysis |         |         |      |          |   |       | 08134 |
|         |         |         |      |          |   |       | (     |
|         |         |         |      |          |   |       | there |
|         |         |         |      |          |   |       | were  |
|         |         |         |      |          |   |       | no    |
|         |         |         |      |          |   |       | phot  |
|         |         |         |      |          |   |       | oprod |
|         |         |         |      |          |   |       | ucts) |
+---------+---------+---------+------+----------+---+-------+-------+
| Aerobic | 41-72%  | 20%     | \_   | 17-18%   |   | 10%   | MRIDs |
| Soil    | (3-7    | (100    |      | (59 d);  |   | (14   |       |
| Met     | d);     | d);     |      | minor    |   | d);   | 468   |
| abolism |         | 25-40%  |      | deg. in  |   | 16%   | 08135 |
|         | 69-74%  | (59 d); |      | other    |   | (100  |       |
|         | (3-7    | minor   |      | soils    |   | d)    | 468   |
|         | d);     | deg. in |      |          |   |       | 08136 |
|         |         | other   |      |          |   |       |       |
|         | 54-70%  | soils   |      |          |   |       | 468   |
|         | (7-30   |         |      |          |   |       | 08137 |
|         | d);     |         |      |          |   |       |       |
|         |         |         |      |          |   |       | 468   |
|         | 44-50%  |         |      |          |   |       | 08138 |
|         | (14-29  |         |      |          |   |       |       |
|         | d)      |         |      |          |   |       |       |
+---------+---------+---------+------+----------+---+-------+-------+
| Aerobic | 90-99%  | \_      | \_   | 14.6%    | 1 | \_    | MRIDs |
| Aquatic | (60-100 |         |      | (100 d); | 6 |       | 4682  |
| Met     | d); 77% |         |      | 30% (1   | - |       | 7910, |
| abolism | (10 d)  |         |      | yr)      | 2 |       | 4680, |
|         |         |         |      |          | 1 |       | 8143, |
|         |         |         |      |          | % |       |       |
|         |         |         |      |          | ( |       | 462   |
|         |         |         |      |          | 1 |       | 87911 |
|         |         |         |      |          | y |       |       |
|         |         |         |      |          | r |       |       |
|         |         |         |      |          | ) |       |       |
+---------+---------+---------+------+----------+---+-------+-------+
| An      | 83-87%  | \_      | \_   | \_       | \ | \_    | MRID  |
| aerobic | (97 d)  |         |      |          | _ |       | 468   |
| Aquatic |         |         |      |          |   |       | 08140 |
| Met     |         |         |      |          |   |       |       |
| abolism |         |         |      |          |   |       |       |
+---------+---------+---------+------+----------+---+-------+-------+

5-OH-XDE-570 = N-(2,6-difluorphenyl)-8­fluoro-5-hydroxy (1,2,4)triazolo
(1,5c) pyrimidine ­2-sulphonamide; TPSA = (triazolopyrimidine sulphonic
acid) of florasulam; DFP-ASTCA =
N-(2,6-difluorophenyl)-5-aminosulphonyl-1H-1,2,4­triazole-3-carboxylic
acid; ASTCA = 5-(aminosulphonyl)-1H-1,2,4-triazole-3-carboxylic acid;
TSA = 1H-1,2,4-triazole-3-sulphonamide;

**Appendix C: Tolerance Reassessment Summary and Table**

  -------------------------------------------------------------------------
  **Table C.1.                                      
  Tolerance Summary                                 
  for Florasulam**                                  
  ----------------- --------------- --------------- -----------------------
  **Commodity**     **Proposed      **Recommended   **Comments (correct
                    Tolerance       Tolerance       commodity definition)**
                    (ppm)**         (ppm)**         

  Barley grain      0.01            0.01            Barley, grain

  Barley forage     0.05            None            Not a RAC per Table 1,
                                                    OPPTS 860 Guidelines.

  Barley hay        0.05            0.05            Barley, hay

  Barley straw      0.05            0.05            Barley, straw

  Oats grain        0.01            0.01            Oat, grain

  Oats forage       0.05            0.05            Oat, forage

  Oats hay          0.05            0.05            Oat, hay

  Oats straw        0.05            0.05            Oat, straw

  Rye grain         0.01            0.01            Rye, grain

  Rye forage        0.05            0.05            Rye, forage

  Rye hay           0.05            None            Not a RAC per Table 1,
                                                    OPPTS 860 Guidelines.

  Rye straw         0.05            0.05            Rye, straw

  Triticale grain   0.01            None            Triticale is covered by
                                                    wheat per 40CFR
                                                    180.1(g)

  Triticale forage  0.05            None            

  Triticale hay     0.05            None            

  Triticale straw   0.05            0.05            

  Wheat grain       0.01            0.01            Wheat, grain

  Wheat forage      0.05            0.05            Wheat, forage

  Wheat hay         0.05            0.05            Wheat, hay

  Wheat straw       0.05            0.05            Wheat, straw
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