chromosome aberrations induced over background in the presence or
absence of S9-activation.

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

870.5395 Bacterial Mutation Assay

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

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

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

A.3.7	Neurotoxicity

870.6200a Acute Neurotoxicity Screening Battery

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

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

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

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

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

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

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

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

870.6200b Chronic Neurotoxicity Screening Battery

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

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

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

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

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

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

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

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

A.3.8	Metabolism

Metabolism – Rat

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

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

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

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

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

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

Dermal Absorption – Rat

EXECUTIVE SUMMARY:  In a dermal penetration study (MRID 46808304),
[14C]-XDE-570 (Florasulam; 98-99% radiochemical purity as applied; Batch
Nos. B463-145 and C237-7B) was applied to the skin (12 cm2) of Fischer
344 rats (4 males for each time point at each dose level).  Nominal
doses were 0.001 or 0.5 mg/cm2 skin.  The high dose (EF-1343 commercial
formulation) was included to assess exposure to mixer/loaders.  The low
dose (spray dilution, using an EF-1343 blank as a vehicle) represented a
dose that was 2.39-fold more concentrated than the highest anticipated
spray concentration for use on field crops, which was necessary in order
to provide sufficient analytical sensitivity.  The exposure duration was
24 hours, after which one group of 4 males for each dose level was
sacrificed.  The remaining 2 groups/dose were sacrificed at 48 or 72
hours post-application.

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

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

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

A. 4	Toxicology References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Appendix B:  Metabolism Assessment

B.1. Metabolism Guidance and Considerations

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   Tabular Summary of Metabolites

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

	Matrices - Major Residue (>10%TRR)	Structure

Florasulam

Table B.1.3  Summary of Major Florasulam Degradation Products.

Study Type	Degradate and Maximum Concentration (% of applied, day)
Source/ Comments

	5-OH-XDE-570

	  Hydrolysis (pH 9 only)	78% (7 d, 50 (C); 32% (90 d, 25(C)	_	_	_	_	_
MRIDs 46808130, 46827909

  Aqueous Photolysis	_	_	17% (32 d)	_	_	_	MRID 46808132

  Soil Photolysis 	_	_	_	_	_	_	MRID 46808134 (there were no
photoproducts)

  Aerobic Soil Metabolism	41-72% (3-7 d);

 69-74% (3-7 d);

54-70% (7-30 d);

44-50% (14-29 d)	20% (100 d); 25-40% (59 d); minor deg.  in other soils
_	17-18% (59 d); minor deg. in other soils

10% (14 d); 16% (100 d)	MRIDs

46808135

46808136

46808137

46808138

  Aerobic Aquatic Metabolism	90-99% (60-100 d); 77% (10 d)	_	_	14.6%
(100 d); 30% (1 yr)	16-21% (1 yr)	_	MRIDs 46827910, 4680,8143,

46287911

 Anaerobic Aquatic Metabolism

	83-87% (97 d)	_	_	_	_	_	MRID 46808140

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

Appendix C:  Tolerance Reassessment Summary and Table

Table C.1.  Tolerance Summary for Florasulam

Commodity

Proposed Tolerance (ppm)

Recommended Tolerance (ppm)

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Oats forage	0.05	0.05	Oat, forage

Oats hay	0.05	0.05	Oat, hay

Oats straw	0.05	0.05	Oat, straw

Rye grain	0.01	0.01	Rye, grain

Rye forage	0.05	0.05	Rye, forage

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

Rye straw	0.05	0.05	Rye, straw

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

Triticale forage	0.05	None

	Triticale hay	0.05	None

	Triticale straw	0.05	0.05

	Wheat grain	0.01	0.01	Wheat, grain

Wheat forage	0.05	0.05	Wheat, forage

Wheat hay	0.05	0.05	Wheat, hay

Wheat straw	0.05	0.05	Wheat, straw

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