UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

                         WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

May 31, 2007

MEMORANDUM

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

  TOC \f  1.0	Executive Summary	4

2.0	Ingredient Profile	8

2.1	Summary of Registered/Proposed Uses	9

2.2	Structure and Nomenclature	  PAGEREF _Toc139000973 \h  9

2.3	Physical and Chemical Properties	  PAGEREF _Toc139000974 \h  10

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc139000975 \h  10

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc139000976 \h
 10

3.1.1	Database Summary	10

<IP_ADDRESS>	Sufficiency of studies/data	10

<IP_ADDRESS>	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	  PAGEREF _Toc139000991 \h  15

<IP_ADDRESS>	Determination of Susceptibility	15

<IP_ADDRESS>	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	  PAGEREF _Toc139001007 \h
 18

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	  PAGEREF _Toc139001017 \h
20

5.1  Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc139001018 \h  20

5.1.1	Metabolism in Primary Crops	  PAGEREF _Toc139001019 \h  20

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	  PAGEREF _Toc139001028 \h  27

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	  PAGEREF _Toc139001049 \h  33

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

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 (95th 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)

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 14C-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 14C-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.

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.

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.

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

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

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"   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf"
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures.
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food 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

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

  SEQ CHAPTER \h \r 1 Regulatory 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 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.

  TC \l1 "1.0	Ex

ecutive Summary 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
Florasulam

Formulation and Product	Method of Application	Use Sites	Application Rate
Timing of Application

EF-1343

 (4.84% a.i.)

# 62719-LAN	Ground and Aerial  equipment	Wheat, barley, oats, rye, and
triticale	0.00446 lb ai/acre	Post-emergent use, apply when weeds are
actively 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

  TC \l2 "2.2	Structure and Nomenclature

Table 2.2.	Test Compound Nomenclature

Compound

Chemical Structure

Common name

Florasulam

Company experimental name

DE-570 or EF-1343

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 product/EP

Florasulam Suspension Concentrate

Molecular Formula

C12H8O3N5F3S

Molecular Mass

359.3

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

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		Solubility (g/L)

water		0.121

pH 5		0.084

pH 7		6.36

pH 9		94.2

Solvent solubility

Solvent		Solubility (g/L)

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 (pKa)

4.54

Octanol/water partition coefficient (Kow) at 22(C

pH			Log Kow

4			1.00

7			-1.22

10			-2.06

UV/visible absorption spectrum

λmax (nm)

Acidic			259.8

203.8

Basic			262.4

209.7

Methanolic		204.1

No absorbance above 300 nm.

	  TC \l1 "3.0	Hazard Characterization/Assessment

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

3.1	Hazard and Dose-Response Characterization

3.1.1	Database Summary  TC \l2 "3.1	Hazard and Dose-Response
Characterization

	<IP_ADDRESS>	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.

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.

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)

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
[14C]-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

≤ 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  TC \l2 "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.

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.

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

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

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.

<IP_ADDRESS>	Degree of Concern Analysis and Residual Uncertainties  TC \l4
"<IP_ADDRESS>	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).

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

  TC \l2 "3.4	Safety Factor for Infants and Children

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.

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

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)

  = 0.05 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors:

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.

Incidental Oral Exposure

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

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.

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)

  TC \l3 "3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)

Comments about Study/Endpoint/Uncertainty Factors:  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.

  TC \l3 "3.5.7	Inhalation Exposure (Short-, Intermediate- and
Long-Term)

3.5.8	Level of Concern for Margin of Exposure  TC \l3 "3.5.8	Level of
Concern for Margin of Exposure

Table 3.5.8   Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	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   TC \l3 "3.5.9	Recommendation for
Aggregate Exposure Risk Assessments there are no registered or proposed
residential uses.

  TC \l3 "3.5.9	Recommendation for Aggregate Exposure Risk Assessments

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  Toxicological Doses and Endpoints for Florasulam for Use in
Dietary and Non-Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty/

FQPA Safety Factors	RfD, PAD, Level of Concern for Risk Assessment	Study
and Toxicological Effects

Acute Dietary (General Population, including Infants and Children)	N/A

	N/A

	N/A

	The risk assessment was not conducted. The effects observed in an acute
neurotoxicity study were seen at a very high dose (2000 mg/kg/day) that
is considered not applicable to human exposure.

Acute Dietary

(Females 13-49 years of age)	N/A

	N/A

	N/A

	No appropriate endpoint identified.

Chronic Dietary (All Populations)	NOAEL = 5 mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF = 1X	Chronic RfD = 0.05 mg/kg/day

cPAD = 0.05 mg/kg/day	Chronic toxicity – dogs

LOAEL = 50 mg/kg/day, based on decreased body weights (17%), 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 (oral, dermal, inhalation)	“Not Likely to be Carcinogenic to
Humans”

  TC \l3 "3.5.10	Classification of Carcinogenic Potential NOAEL = no
observed adverse effect level.  LOAEL = lowest observed adverse effect
level.  UF = uncertainty factor.  UFA = extrapolation from animal to
human (interspecies).  UFH = potential variation in sensitivity among
members of the human population (intraspecies).  FQPA SF = FQPA Safety
Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD =
reference dose.  N/A = not applicable.

Table 3.5b  Summary of Toxicological Doses and Endpoints for Florasulam
 for Use in Occupational Human Health Risk Assessments

Exposure/

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

Dermal

Short-term (1-30 days)	N/A	N/A

	N/A 	The risk assessment was not conducted

28-day dermal toxicity study – rats

LOAEL = not determined, no systemic effect up to the limit dose of 1000
mg/kg/day.

Inhalation Short-term(1-30 days 	NOAEL = 5mg/kg/day

IAF=100%	UFA = 10X

UFH = 10X

FQPA SF = 1X	Residential LOC for MOE = 100	90-day oral toxicity – dogs

LOAEL = 50 mg/kg/day, based on increased alkaline phosphatase activity
and increased incidence/severity of hepatic vacuolation in both sexes.

Cancer (oral, dermal, inhalation)	“Not Likely to be Carcinogenic to
Humans”

NOAEL = no observed adverse effect level.  LOAEL = lowest observed
adverse effect level.  UF = uncertainty factor.  UFA = extrapolation
from animal to human (interspecies).  UFH = potential variation in
sensitivity among members of the human population (intraspecies).  MOE =
margin of exposure.  LOC = level of concern.  N/A = not applicable.
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.

  TC \l2 "3.6	Endocrine disruption 4.0	Public Health and Pesticide
Epidemiology Data

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

  TC \l2 "4.4	Other Pesticide Epidemiology Published Literature 5.0
Dietary Exposure/Risk Characterization  TC \l1 "5.0	Dietary
Exposure/Risk Characterization

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

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

In the metabolism study, [14C]-DE-570 (>98%) formulated with EF 1343
blank formulation, radiolabeled as [14C]-phenyl-XDE-570 and
[14C]-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 14C-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
14C-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.

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

In the confined rotational crop study, XDE-570 (florasulam), > 97% a.i.,
E-1343 Suspension Concentrate labeled either as the
[UL-phenyl-14C]XDE-570 or the [9-triazolopyrimidine-14C]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 14C-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  TC \l3 "5.1.3	Metabolism in Livestock

In the lactating goat metabolism study, XDE-570, radiolabeled as either
[UL-aniline-14C]XDE-570, or [triazolopyrimidine-9- 14C]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-14C]XDE-570, or [triazolopyrimidine-9- 14C]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  TC \l3 "5.1.4	Analytical Methodology

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 (C18) 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.

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.

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.

Toxicity Profile of Major Metabolites and Degradates of Concern

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.

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.

 TC \l3 "5.1.8	Pesticide Metabolites and Degradates of Concern

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

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants

	Primary Crop	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 & 5-OH florasulam	Not Applicable

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 Water Source (Model Used)	Use/Rate Modeled (lb ai/A)	Maximum
Estimated Drinking Water Concentration (EDWC; ppTr)

Groundwater

(SCI-GROW)	0.0045	Acute and Chronic	1.35 x 10-2

Surface Water (FIRST)	Aerial spray/0.0045	Chronic	16.8

Surface Water (FIRST)	Ground spray/0.0045	Chronic	16.7

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 Water Source (Model Used)	Use/Rate Modeled (lb ai/A)	Maximum
Estimated Drinking Water Concentration (EDWC; ppTr)

Groundwater

(SCI-GROW)	0.0045	Acute and Chronic	7.44

Surface Water (FIRST)	Aerial spray/0.0045	Chronic	217.3

Surface Water (FIRST)	Ground spray/0.0045	Chronic	217.5

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

There are adequate storage stability data for wheat forage, hay, straw,
and grain.  These data indicate residues of florasulam were relatively
stable at -20 oC 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 14C-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.

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  TC \l3 "5.2.2  Chronic 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  TC \l3 "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 <IP_ADDRESS>.  Results of Chronic Dietary Exposure Analysis (Food Only)

Population Subgroup

cPAD

(mg/kg/day)	Exposure (mg/kg/day)	% cPAD

General U.S. Population

0.05

0.000019	<1

All Infants (< 1 year old)

0.05	0.000013	<1

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 <IP_ADDRESS>.  Results of Chronic Dietary Exposure Analysis (Food Plus
Water)

Population Subgroup

cPAD

(mg/kg/day)	Exposure (mg/kg/day)	% cPAD

General U.S. Population

0.05	0.000024	<1

All Infants (< 1 year old)

0.05	0.000029	<1

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  TC \l3 "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 TC
\l2 "5.3 Anticipated Residue and Percent Crop Treated (%CT) Information

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.

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

Aggregate Risk Assessments and Risk Characterization

Acute Aggregate Risk

 TC \l2 "7.1	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 TC \l2 "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 TC \l2 "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.

7.5	Cancer Risk

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:

The maximum application rate is 0.00446 lb ai/acre

Body Weight:

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.

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 Inhalation Exposure and Risk

Scenario	Mitigation	Inhalation Unit Exposure

(mg/lb ai)	Application Rate

 (lb ai/A)	Acres Treated (A/Day)	Daily Dose a (mg/kg/day)	Inhalation MOE
 b

Mixer/Loader

Groundboom	Baseline	0.0012	0.00446	200	0.00001529	330,000

Aerial

1200	0.0000917	54,000

Applicator

Groundboom	Baseline	0.00074	0.00446	200	0.0000094	530,000

Aerial	Eng. Cont. c	0.000068

1200	0.0000052	960,000

Flagger

Aerial	Baseline	0.011	0.00446	350	0.000245	20,000

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

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  TC \l1 "10.0	Data Needs and
Label Requirements

10.1	Toxicology

There are no toxicology data gaps.

Residue Chemistry

  SEQ CHAPTER \h \r 1 Regulatory 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.)

  TC \l2 "10.1	Toxicology 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.

  TC \l2 "10.3	Occupational and Residential Exposure

References:  TC \l1 "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  TC \l1 "Appendix A:  Toxicology
Assessment

A.1	Toxicology Data Requirements TC \l2 "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

870.1200	Acute Dermal Toxicity

870.1300	Acute Inhalation Toxicity

870.2400	Primary Eye Irritation

870.2500	Primary Dermal Irritation

870.2600	Dermal Sensitization

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100	Oral Subchronic (rodent)

870.3150	Oral Subchronic (nonrodent)

870.3200	21/28-Day Dermal

870.3250	90-Day Dermal

870.3465	90-Day Inhalation

yes

yes

yes

no

no

yes

yes

yes

---

---

870.3700a	Developmental Toxicity (rodent)

870.3700b	Developmental Toxicity (nonrodent)

870.3800	Reproduction

yes

yes

yes

yes

yes

yes

870.4100a	Chronic Toxicity (rodent)

870.4100b	Chronic Toxicity (nonrodent)

870.4200a	Oncogenicity (rat)

870.4200b	Oncogenicity (mouse)

870.4300	Chronic/Oncogenicity

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100	Mutagenicity—Gene Mutation - bacterial

870.5300	Mutagenicity—Gene Mutation - mammalian

870.5375	Mutagenicity—Structural Chromosomal Aberrations

870.5395	Mutagenicity—Other Genotoxic Effects

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a	Acute Delayed Neurotox. (hen)

870.6100b	90-Day Neurotoxicity (hen)

870.6200a	Acute Neurotox. Screening Battery (rat)

870.6200b	Chronic Neurotox. Screening Battery (rat)

870.6300	Develop. Neuro

no

no

no

no

no

---

---

yes

yes

---

870.7485	General Metabolism

870.7600	Dermal Penetration

yes

no

yes

yes

A.2  Toxicity Profiles

Table A.2.1	Acute Toxicity Profile – Florasulam

Guideline No.	Study Type	MRID(s)	Results	Toxicity Category

870.1100	Acute oral – rat	46808209	LD50 >= 5000 mg/kg	IV

870.1100	Acute oral – mouse	46827915	LD50 >= 5000 mg/kg	IV

870.1200	Acute dermal – rabbit	46808211	LD50 >= 2000 mg/kg	III

870.1300	Acute inhalation – rat	46808212	LC50 >= 5.0 mg/L	IV

870.2400	Acute eye irritation – rabbit	46808213	Non- irritating	IV

870.2500	Acute dermal irritation – rabbit	46808214	Non- irritating	IV

870.2600	Skin sensitization – guinea pig	46808215

46808216	No sensitization

Table A.2.2	Subchronic, Chronic, and Other Toxicity Profile for
Florasulam Technical

Guideline No./Study Type	MRID No. (year) Classification/Doses	Results

870.3100

90-Day oral toxicity (rat)	46808219 (1996)

Acceptable/guideline

0, 20, 100, 500, 1000/800 mg/kg/day	NOAEL = 100 mg/kg/day

LOAEL = 500 mg/kg/day, based on decreased body weights (5-8%) and body
weight gains (21%) in 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.

870.3100

90-Day oral toxicity (mouse)	46808222 (1996)

Acceptable/guideline

0, 20, 100, 500, 1000 mg/kg/day	NOAEL = 1000 mg/kg/day

LOAEL = Not determined

870.3150

90-Day oral toxicity (dog)	46808223 (1995)

Acceptable/guideline

0, 5, 50, 100 mg/kg/day	NOAEL = 5 mg/kg/day

LOAEL = 50 mg/kg/day, based on increased alkaline phosphatase (59-127%)
activity, increased liver weights, hypertrophy and increased
incidence/severity of hepatic vacuolation in both sexes.

870.3200

28-Day dermal toxicity (rat)	46808225 (1997)

Acceptable/guideline

0, 100, 500, 1000 mg/kg/day, 6 h/day, 7 days/week for 28 days	Systemic
NOAEL = 1000 mg/kg/day

Systemic LOAEL = Not determined

Dermal NOAEL = 500 mg/kg/day

Dermal LOAEL = 1000 mg/kg/day, based on edema and erythema in males (
4/5)

870.3700a

Prenatal developmental toxicity (rat)	46808234 (1997)

46808231 (1996)

Acceptable/guideline

0, 50, 250, 750 mg/kg/day (GD 6-15)	Maternal NOAEL = 250 mg/kg/day

LOAEL = 750 mg/kg/day based on decreased body weights (4-6%, GD 6-16),
body weight gains (16%, GD 6-16%), food consumption (6-13%), and
increased kidney weights.

Developmental NOAEL = 750 mg/kg/day

Developmental LOAEL = Not determined

870.3700b

Prenatal developmental toxicity (rabbit)	46808233 (1997)

46808232 (1997)

Acceptable/guideline

0, 50, 250, 500 mg/kg/day (GD 7-19)	Maternal NOAEL = 500 mg/kg/day

Maternal LOAEL = Not determined

Developmental NOAEL = 500 mg/kg/day

Developmental LOAEL = Not determined

Note: Study acceptable due to findings of preliminary developmental
toxicity study at 600 mg/kg/day (mortality and decreased body weight
gains and food consumption).

870.3800

Reproduction and fertility effects (rat)	46808235 (1997)

Acceptable/guideline

0, 10, 100, 500 mg/kg/day 	Parental/Systemic NOAEL = 100 mg/kg/day

Parental/Systemic LOAEL = 500 mg/kg/day, based on decreased body
weights, body weight gains, and food consumption, as well as kidney
alterations.

Offspring NOAEL = 500 mg/kg/day

Offspring LOAEL = Not determined

Reproductive NOAEL = 500 mg/kg/day

Reproductive LOAEL = Not determined

870.4100b

Chronic toxicity (dog)

	46808229 (1997)

Acceptable/guideline

0, 0.5, 5, 100/50 mg/kg/day	NOAEL = 5 mg/kg/day

LOAEL =100/50 mg/kg/day, based on decreased body weights (17%), body
weight gains (68%), and food consumption in 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) in both sexes.

870.4200

Carcinogenicity (mouse)	46808230 (1997)

Acceptable/guideline

0, 50, 500, 1000 mg/kg/day	NOAEL = 1000 mg/kg/day.

LOAEL = Not determined

No evidence of carcinogenicity

870.4300

Combined chronic toxicity/carcinogenicity (rat)	46808236 (1997)

Acceptable/guideline

M:  0, 10, 250, 500 mg/kg/day

F:  0, 10, 125, 250 mg/kg/day	NOAEL = 10 mg/kg/day-males; 125
mg/kg/day-females

LOAEL = 250 mg/kg/day (males), based on slight nephrotoxicity (increased
kidney weights, hypertrophy, and slight multi-focal mineralization in
the papilla); 250 mg/kg/day (females), based on decreased body weights
(3-8%) and body weight gains (14%).

No evidence of carcinogenicity

870.5100

Bacterial gene mutation/mammalian activation gene mutation assay
46808240 (1995)

Acceptable/guideline

0, 0.333, 1, 3.33, 10, 33.3, 100 µg/plate (S. typhimurium)

0, 10, 33.3, 100, 333, 1000, 3330 g/plate (E. coli)	Negative-No evidence
of induced mutant colonies over background in the presence or absence of
S9-induced activation

870.5300

Gene mutation at the HGPRT locus in Chinese hamster ovary cells	46808238
(1995)

Acceptable/guideline

0, 187.5, 375, 750, 1500, 3000 µg/mL	Negative-No evidence of induced
mutant colonies over background in the presence or absence of
S9-activation

870.5375

Chromosomal aberration assay in rat lymphocytes	46808237 (1995)

Acceptable/guideline

0, 3, 10, 30, 100, 300, 1000, 3000 µg/mL	Negative-No evidence of
chromosome aberrations induced over background in the presence or
absence of S9-activation

870.5395

Mouse bone marrow micronucleus assay	46808239 (1995)

Acceptable/guideline

0, 1250, 2500, 5000 mg/kg	Negative-No significant increase in the
frequency of micronucleated polychromatic erythrocytes in bone marrow

870.6200a

Acute neurotoxicity screening battery (rat)	46808217 (1997)

Acceptable/guideline

0, 200, 1000, 2000 mg/kg	Systemic NOAEL = 1000 mg/kg

Systemic LOAEL = 2000 mg/kg, based on decreased body weight gain (21%)
and general malaise (slight transient decrease in motor activity,
minimal activity in open field, and reactivity) in  males.

Neurotoxicity NOAEL = 2000 mg/kg

Neurotoxicity LOAEL = Not determined

870.6200b

Chronic neurotoxicity screening battery (rat)	46808228 (1996)

Acceptable/guideline

0, 10, 125 (female only), 250, 500 (male only) mg/kg/day	Systemic NOAEL
= 250 mg/kg/day

Systemic LOAEL = 500 mg/kg/day, based on decreased body weight (9-15% at
6, 9, and 12 months) and body weight gain in males (61-67% at 3-12
months; 27% at 0-12 months)

Neurotoxicity NOAEL = 250 mg/kg (highest dose tested in females).
Neurotoxicity LOAEL= Not determined.

870.7485

Metabolism and pharmacokinetics (rat)

	46808301 (1996)

46808303 (1997)

Acceptable/guideline

10 and 500 mg/kg	Absorption was rapid and extensive (≈90-93% at 10
mg/kg; ≈82-86% at 500 mg/kg rats).  Peak plasma concentrations (Cmax)
were achieved within 0.5-1 hour.  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%.  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

Dermal penetration (rat)	46808304 (1997)

Acceptable/guideline

0.001 or 0.5 mg/cm2

	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.

A.3  	Executive Summaries TC \l2 "A.3  Executive Summaries

A.3.1	Subchronic Toxicity

90-Day Oral Toxicity – Rat

EXECUTIVE SUMMARY:  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.

90-Day Oral Toxicity – Mouse

EXECUTIVE SUMMARY:  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.

 90-Day Oral Toxicity – Dog

EXECUTIVE SUMMARY - 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.

21/28-Day Dermal Toxicity – Rat

EXECUTIVE SUMMARY - 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.

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:  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:  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:  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:  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:  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.

≥ 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:  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:  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:  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 – 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
WP2uvrA 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 - 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 - 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