UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
Date:
November
22,
2004
MEMORANDUM
SUBJECT:
[
Flumetsulam:]
Revised
Phase
2
HED
Chapter
of
the
Tolerance
Reassessment
Eligibility
Decision
Document
(
TRED).
PC
Code:
129016,
DP
Barcode:
D306238.

Regulatory
Action:
Tolerance
Reassessment,
Phase
2
Risk
Assessment
Type:
Single
Chemical
Aggregate
FROM:
Elissa
Reaves,
PhD.,
Toxicologist/
Risk
Assessor
Sam
Ary,
Product
and
Residue
Chemist,
Dietary
Risk
Assessor
Reregistration
Branch
II
Health
Effects
Division
(
7509C)

AND
James
Lin
and
Stephanie
Syslo,
Drinking
Water
Exposure
Assessors
Environmental
Risk
Branch
III
Environmental
Fate
and
Effects
Division
(
7507C)

THROUGH:
Alan
Nielsen,
Branch
Senior
Scientist
Reregistration
Branch
II
Health
Effects
Division
(
7509C)

TO:
Mika
Hunter,
Chemical
Review
Manager
Special
Review
Branch
Special
Review
and
Reregistration
Division
(
7508C)
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
November
22,
2004
Memorandum
Subject:
Flumetsulam:
Revised
Phase
2
HED
Risk
Assessment
for
the
Tolerance
Reassessment
Eligibility
Document
(
TRED).
[
PC
Code
129016,
DP
Barcode
306238].

From:
Elissa
Reaves,
Toxicologist
Reregistration
Branch
II
Health
Effects
Division
(
7509C)

Through:
Alan
Nielsen,
Branch
Senior
Scientist
Reregistration
Branch
II
Health
Effects
Division
(
7509C)

To:
Mika
Hunter,
Chemical
Review
Manager
Special
Review
Branch
Special
Review
and
Reregistration
Division
(
7508C)

Background:

Attached
is
Health
Effects
Division's
(
HED's)
revised
risk
assessment
of
flumetsulam
for
purposes
of
issuing
a
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
document
for
this
active
ingredient.
A
new
use
has
been
requested
by
Dow
AgroSciences
LLC
for
use
on
dry
beans
(
i.
e.,
kidney
bean,
navy
bean,
pinto
bean)
and
the
data
review
and
occupational
and
residential
exposure
assessment
for
this
new
use
will
be
addressed
in
a
separate
document.
However,
the
dietary
assessment
for
this
new
use
will
be
addressed
in
this
TRED.
This
document
was
reviewed
by
the
Risk
Assessment
Review
Committee
(
RARC),
an
expedited
process
used
for
lower
risk
chemicals.
Toxicity
endpoints
were
concurred
upon
and
the
document
has
been
revised
in
response
to
Review
Committee
comments.
HED
is
confident
that
this
analysis
does
not
underestimate
the
risk
associated
with
exposures
to
flumetsulam.
Residue
chemistry
and
dietary
analysis
was
performed
by
Samuel
Ary,
drinking
water
analysis
by
James
Lin
and
Stephanie
Syslo,
and
hazard
assessment
and
toxicological
profile
by
Elissa
Reaves.
Page
2
of
23
I.
Executive
Summary:

This
assessment
provides
information
to
support
the
issuance
of
a
Tolerance
Reassessment
Eligibility
Document
for
flumetsulam.
EPA's
pesticide
reregistration
process
provides
for
the
review
of
older
pesticides
(
those
initially
registered
prior
to
November
1984)
under
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
to
ensure
that
they
meet
current
scientific
and
regulatory
standards.
The
process
considers
the
human
health
and
ecological
effects
of
pesticides
and
incorporates
a
reassessment
of
tolerances
(
pesticide
residue
limits
in
food)
to
ensure
that
they
meet
the
safety
standard
established
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.

Flumetsulam
is
in
the
triazolopyrimidine
chemical
class
and
has
a
mode
of
action
similar
to
the
sulfonylurea
herbicides
that
are
acetolactate
synthase
inhibitors
(
regulate
plant
growth).
Flumetsulam
is
currently
registered
by
Dow
AgroSciences
LLC
for
use
as
a
herbicide
at
the
preplant
pre­
emergence,
or
post­
emergence
stage
to
control
broadleaf
weeds
in
field
corn
and
soybeans.
Flumetsulam
as
an
active
ingredient
ranges
in
formulations
from
2.1
to
80%
and
may
be
applied
alone
or
in
formulation
with
other
active
ingredients.
The
maximum
application
rate
for
flumetsulam
is
0.07
lb
a.
i./
acre
with
a
minimum
pre­
harvest
interval
range
of
70
to
85
days.

Flumetsulam
is
in
Toxicity
Category
III
or
IV
for
acute
oral,
dermal,
and
inhalation
exposure
and
for
dermal
and
ocular
irritation,
and
is
not
a
dermal
sensitizer.
The
kidney
appears
to
be
the
primary
target
organ
of
rats
and
dogs
following
subchronic
to
chronic
exposures.
There
was
no
indication
of
reproductive
or
neurotoxicant
effects
from
flumetsulam
in
the
reviewed
studies.
Flumetsulam
is
classified
as
Group
E
(
evidence
of
non­
carcinogenicity
for
humans)
and
is
not
mutagenic.
Flumetsulam
is
rapidly
excreted
mainly
in
the
urine
unchanged.
Therefore,
there
are
no
metabolites
of
toxicological
concern
for
flumetsulam.
The
chronic
reference
dose
is
based
on
a
chronic
dog
study
with
a
NOAEL
of
100
mg/
kg/
day
and
an
uncertainty
factor
(
UF)
of
100
for
inter­
species
extrapolation
and
intra­
species
variability.
There
are
no
studies
that
identify
an
acute
hazard
based
on
toxic
effects
observed
following
a
single
oral
exposure
(
dose)
of
flumetsulam.
No
effects
in
the
developmental
toxicity
studies
in
the
rabbit
or
rat
were
attributed
from
a
single
oral
exposure
during
gestation.
Therefore,
a
dose
and
endpoint
are
not
proposed
for
the
general
population
including
infants
and
children
or
females
13­
49
years
of
age.

Flumetsulam
is
soluble
in
water
and
is
stable
under
photolysis.
Degradation
studies
indicate
the
soil
half­
life
ranges
from
approximately
two
weeks
to
four
months
with
the
majority
degrading
in
less
than
two
months
(
mean
of
69.5
days).

Analyses
of
dietary
and
drinking
water
exposure
pathways
were
included
in
the
flumetsulam
risk
assessment.
Drinking
water
exposure
may
occur
due
to
run­
off
from
agricultural
uses
of
flumetsulam
to
regulate
plant
growth.
The
estimated
drinking
water
concentrations
of
flumetsulam
in
surface
water
indicate
the
highest
1­
in­
10
year
annual
mean
was
0.59

g/
L.
The
estimated
chronic
drinking
water
concentration
from
ground
water
sources
is
0.823
ppb.

Sources
of
dietary
exposure
include
food
crops
to
which
flumetsulam
is
applied
as
an
acetolactate
synthase
inhibitor.
A
conservative
dietary
(
food
and
water)
risk
assessment
concludes
that
for
all
supported
commodities
(
including
proposed
dry
bean),
the
chronic
dietary
exposure
estimates
are
below
the
HED's
level
of
concern
for
all
population
subgroups
at
less
than
1%
of
the
cPAD.
Page
3
of
23
N
S
F
F
N
N
N
N
CH
3
O
O
H
EPA
has
determined
that
flumetsulam
does
not
have
a
common
mechanism
of
toxicity
with
the
other
sulfonylurea
pesticides.
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
flumetsulam
and
any
other
substances,
and
flumetsulam
does
not
appear
to
produce
a
toxic
metabolite
produced
by
other
substances.

II.
Use
Information:
A
screening
level
estimate
of
flumetsulam
usage
performed
by
HED's
Biological
and
Economic
Analysis
Division
(
BEAD)
indicate
that
the
highest
usage
of
flumetsulam
is
on
corn.

Older
reports
on
use
of
flumetsulam
indicate
that
the
use
of
flumetsulam
has
increased
over
time.
A
Special
Chemical
Use
Report
by
the
Mississippi
Ag
Report
released
June
13,
2000
indicated
flumetsulam
was
estimated
to
be
applied
at
17%
of
the
total
area
in
one
application
at
a
rate
of
0.03
lbs
per
acre
and
0.04
lbs
per
crop
per
year
with
a
total
amount
applied
at
12,000
lbs
(
Mississippi
Ag
Report
available
at
www.
nass.
usda.
gov/
ms/
vol100­
09.
txt).
Estimates
for
flumetsulam
use
in
the
United
States
were
also
provided
by
the
Pesticide
National
Synthesis
Project
of
the
U.
S.
Geological
Survey's
National
Water
Quality
Assessment
Program.
A
map
of
use
indicated
that
flumetsulam
was
applied
to
corn
at
a
total
of
41,443
lbs
and
36,916
lbs
to
soybeans.
The
map
was
based
on
state­
level
estimates
of
pesticide
use
rates
for
individual
crops,
which
were
compiled
by
the
National
Center
for
Food
and
Agricultural
Policy
(
NCFAP)
for
1991­
1993
and
1995,
and
on
county­
based
crop
acreage
data
obtained
from
the
1992
Census
of
Agriculture
(
as
cited
on
FAN).

III.
Physical/
Chemical
Properties
Table
1.
Test
Compound
Nomenclature.

Chemical
Structure
Common
name
Flumetsulam
Company
experimental
name
DE­
498
and
TSN­
100986
Molecular
formula
C12H9F2N5O2S
Molecular
weight
325.30
IUPAC
name
2­(
2,6­
difluorophenylsulphamoyl)­
5­
methyl(
1,2,4)­
Triazolo(
1,5­
a)
pyrimidine
CAS
name
N­(
2,6­
difluorophenyl)­
5­
methyl­(
1,2,4)
triazolo(
1,5­
a)
pyrimidine­
2­
sulfonamide
CAS
number
98967­
40­
9
Current
food/
feed
site
registrations
Corn
and
soybean
(
a
petition
for
dry
beans
has
been
submitted)
Page
4
of
23
Table
2.
Physicochemical
Properties
of
the
Technical
Grade
Test
Compound.

Parameter
Value
Reference
Melting
point
252.9

C
N.
Dodd,
PP#
1G4006,
3/
27/
92
pH
3.44
at
24.4

C
for
a
10%
suspension
in
water
Density
1.77
g/
cm3
at
21

C
Water
solubility
49.1
±
0.5
mg/
L
at
25

C,
pH
2.5
5.65
±
0.01
g/
L
at
25

C,
pH
7.0
Solvent
solubility
17.0
g/
L
in
acetone
5.2
g/
L
in
acetonitrile
0.0016
g/
L
in
aromatic
100
9.0
g/
L
in
cyclohexanone
261.0
g/
L
in
dimethylformamide
Less
than
0.001
g/
L
in
hexane
3.3
g/
L
in
methanol
Less
than
0.001
g/
L
in
o­
xylene
0.06
g/
L
in
octanol
11.0
g/
L
in
tetrahydrofuran
N.
Dodd,
PP#
2F4036,
4/
14/
93
Vapor
pressure
1.0
x
10­
15
mm
Hg
at
25

C
N.
Dodd,
PP#
1G4006,
3/
27/
92
Dissociation
constant
pKa
=
4.6
Octanol­
water
partition
coefficient
Log(
KOW)
log
P
=
0.21
IV.
Hazard
Assessment:

A.
Hazard
Profile
The
Agency
based
its
hazard
assessment
upon
required
acute
toxicity
data,
subchronic
feeding
studies,
developmental
toxicity,
chronic
toxicity,
carcinogenic
toxicity,
reproduction
toxicity,
and
mutagenicity
studies.
Please
refer
to
Appendix
A
for
the
hazard
profile
table.

Flumetsulam
is
in
Toxicity
Category
III
or
IV
for
acute
oral,
dermal,
and
inhalation
exposure
and
for
dermal
and
ocular
irritation,
but
it
is
not
a
dermal
sensitizer.
The
kidney
appears
to
be
the
primary
target
organ
of
flumetsulam
following
exposure
of
rats
and
dogs
to
high
doses
of
the
test
material
in
subchronic
to
chronic
toxicity
studies.
Following
subchronic
oral
exposure,
rats
developed
bilateral
tubular
nephritis
at
concentrations
equal
to
the
limit
dose;
however,
no
renal
effects
were
found
in
mice
at
doses
five
times
the
limit
dose.
Decreased
kidney
weights
were
found
in
rat
dams,
and
anorexia,
moribundity,
and
decreased
body
weight
gain
in
rabbit
does,
but
no
developmental
effects
were
found.
Also,
no
reproductive
effects
attributable
to
flumetsulam
were
found
in
male
and
female
rats
treated
at
the
limit
dose.
In
chronic
dog
and
rat
studies,
renal
calculi,
inflammation,
and
atrophic
changes
were
found
in
the
kidney
of
male
animals.
These
effects
were
not
observed
in
female
rats
or
dogs,
nor
in
treated
male
and
female
mice.
In
addition,
no
systemic
toxicity
was
observed
in
rats
treated
with
dermal
doses
that
exceeded
the
limit
dose,
although
diffuse
epidermal
hyperplasia
was
present.
Page
5
of
23
Available
metabolism
and
pharmacokinetics
studies
in
mice
and
rats
indicate
that
flumetsulam
is
primarily
eliminated
within
48
hours
from
all
test
animals
following
oral
administration.
The
primary
route
was
urinary
excretion
of
unchanged
flumetsulam.
The
rapid
clearance
of
flumetsulam
demonstrated
little
potential
for
bioaccumulation.
Metabolic
studies
show
that
approximately
52­
63%
of
the
administered
test
material
was
absorbed
by
male
and
female
rats.
Plasma
pharmacokinetic
studies
suggest
that
increased
doses
were
associated
with
increased
clearance,
possibly
due
to
saturation
of
plasma
binding
sites.
In
addition,
there
was
a
dose­
dependant
decrease
in
the
rate
of
plasma
absorption
and
elimination
for
both
rats
and
mice.
Two
very
minor
metabolites
were
detected
in
the
urine
of
mice
(
not
identified).
At
the
limit
dose,
mice
showed
a
greater
capacity
for
absorption
and
elimination
than
rats.

Genotoxicity
studies
with
flumetsulam
were
negative
and
no
evidence
of
carcinogenicity
was
found
in
life­
time
rat
and
mouse
studies.

A
neurotoxicity
study
was
not
conducted,
however,
flumetsulam
showed
no
indication
of
being
a
neurotoxicant
in
the
reviewed
studies.
A
90­
day
inhalation
study
and
a
subchronic
dog
study
were
not
conducted,
but
it
is
doubtful
these
would
provide
any
additional
useful
information.

B.
Special
Considerations
for
Infants
and
Children
(
FQPA
Safety
Determination)

The
toxicology
database
for
flumetsulam
is
adequate
for
FQPA
considerations.
The
data
available
for
evaluation
suggest
that
there
is
no
evidence
of
increased
quantitative
or
qualitative
susceptibility
of
the
offspring
after
in
utero
or
post­
natal
exposure
to
flumetsulam.
Neither
acceptable
Developmental
Toxicity
Studies
in
rats
or
rabbits
revealed
increased
susceptibility
of
the
fetus
after
in
utero
exposure.
Similarly,
the
results
of
the
Two
Generation
Reproduction
Study
did
not
indicate
an
increased
susceptibility
to
the
test
article
in
utero
or
during
post­
natal
exposure.
Therefore,
no
special
FQPA
safety
factor
(
i.
e.
1X)
is
required
for
risk
assessments
for
this
chemical.
A
developmental
neurotoxicity
study
is
not
required
since
there
was
no
evidence
of
neurotoxicity
or
neuropathy
from
the
available
studies.

Based
on
the
hazard
data,
HED
recommended
the
special
FQPA
Safety
Factor
be
reduced
to
1X
because
there
are
low
concerns,
and
no
residential
uncertainties
with
regard
to
preand
or
post­
natal
toxicity.
Also,
based
on
the
quality
of
the
exposure
data,
the
flumetsulam
risk
assessment
team
recommended
that
the
special
FQPA
Safety
Factor
be
reduced
to
1X.
The
recommendation
is
based
on
the
following:
1)
the
dietary
food
exposure
assessment
utilizes
proposed
tolerance
level
residues
and
100%
crop
treatment
information
for
all
commodities,
2)
by
using
these
screening­
level
assessments
chronic
exposure
will
not
be
underestimated,
and
3)
the
dietary
drinking
water
assessment
utilizes
values
generated
by
model
and
associated
modeling
parameters
which
are
designed
to
provide
health
protective,
high­
end
estimates
of
water
concentrations.

C.
Endocrine
Disruption
Page
6
of
23
EPA
is
required
under
the
Federal
Food,
Drug,
and
Cosmetic
Act
(
FFDCA),
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
pesticide
active
and
other
ingredients)
"
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
recommendations
of
its
Endocrine
Disruptor
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
scientific
bases
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).
In
the
available
toxicity
studies
on
flumetsulam,
there
was
no
estrogen,
androgen,
and/
or
thyroid
mediated
toxicity.
When
additional
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
flumetsulam
may
be
subjected
to
further
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.

D.
Classification
of
Carcinogenic
Potential
The
Health
Effects
Division
RfD/
Peer
Review
Committee
determined
the
high
dose
tested
in
the
carcinogenicity
studies
in
rats
and
mice
were
considered
a
"
limit
dose".
Flumetsulam
did
not
alter
the
spontaneous
tumor
profile
in
these
strains
of
rats
and
mice
under
the
test
conditions.
Therefore,
on
the
basis
of
the
two
studies,
the
Committee
classified
flumetsulam
as
a
"
Group
E",
evidence
of
non­
carcinogenicity
for
humans
(
G.
Ghali
Memorandum,
3/
24/
93,
TXR
011039).

E.
Toxicological
Endpoint
for
Dietary
Exposure
The
doses
and
toxicological
endpoints
selected
for
various
exposure
scenarios
are
summarized
below.
There
are
no
residential
uses
listed
for
this
chemical,
therefore,
no
endpoints
were
identified
for
these
exposure
scenarios.

1.
Acute
Reference
Dose
(
aRfD)

There
are
no
studies
that
identify
an
acute
hazard
based
on
toxic
effects
observed
following
a
single
oral
exposure
(
dose)
of
flumetsulam.
No
effects
in
the
developmental
toxicity
studies
in
the
rabbit
or
rat
were
attributed
from
a
single
oral
exposure
during
gestation.
Therefore,
a
dose
and
endpoint
are
not
proposed
for
the
general
population
including
infants
and
children
or
females
13­
49
years
of
age
(
G.
Ghali
Memorandum,
3/
24/
93,
TXR
011039).

2.
Chronic
Reference
Dose
(
cRfD)

The
chronic
feeding
study
in
the
dog
(
MRID
41952103)
supports
the
toxicity
endpoint
Page
7
of
23
for
chronic
dietary
exposure
because
the
study
encompasses
the
appropriate
duration
of
exposure
and
has
the
most
conservative
NOAEL.
The
NOAEL
was
100/
500
mg/
kg/
day
[
M/
F]
and
LOAEL
500/
not
identified
mg/
kg/
day
[
M/
F],
based
on
renal
inflammatory
and
atrophic
changes
secondary
to
renal
calculi
and
hepatic
effects
consisting
of
inflammation,
focal
necrosis,
and
biliary
stasis.
Similar
renal
effects
were
found
in
male
rats
given
1000
mg/
kg/
day
for
2
years.
The
male
rats
had
increased
incidences
of
dilated
renal
pelvises
that
contained
renal
calculi,
and
atrophic
renal
papillae
along
with
renal
pelvic
epithelial
hyperplasia
and
mineralization
(
G.
Ghali
Memorandum,
3/
24/
93,
TXR
011039).
An
uncertainty
factor
(
UF)
of
100
(
10X
for
interspecies
extrapolation
and
10X
for
intraspecies
variability)
was
applied
to
the
chronic
toxicity
endpoint.

Chronic
RfD
=
100
mg/
kg/
day
(
NOAEL)
=
1.0
mg/
kg/
day
100
(
UF)

3.
Toxicological
Endpoint
for
Dermal
Exposure
A
21­
Day
dermal
toxicity
study
(
MRID
41931706)
in
New
Zealand
white
rabbits
exposed
dermally
at
0,
100,
500,
or
1000
mg/
kg/
day
for
3
weeks
caused
no
systemic
compound­
related
changes
in
males
or
females
at
any
dose
level
[
NOAEL
>
1000
mg/
kg/
day
(
HDT)].
The
only
treatment­
related
effect
was
epidermal
hyperplasia
at
the
application
site.

Since
the
limit
dose
was
achieved
in
the
21­
day
dermal
toxicity
study,
there
is
no
hazard
identified
for
dermal
exposure.
Quantification
of
dermal
risk
assessment
is
not
required
for
this
exposure
due
to
lack
of
dermal,
systemic,
neuro,
or
developmental
toxicity
concerns.

4.
Toxicological
Endpoint
for
Inhalation
Exposure
(
All
Durations)

Due
to
the
lack
of
repeated
dose
inhalation
toxicity
study,
oral
studies
were
selected
for
the
appropriate
duration
of
exposure.
Absorption
via
inhalation
is
assumed
to
be
equivalent
to
oral
absorption.

a.
Short­
term
(
1­
30
days)

The
chronic
feeding
dog
study
(
MRID
41952103)
encompasses
the
appropriate
exposure
duration
and
provides
a
screening
level
hazard
with
a
NOAEL
of
100/
500
mg/
kg/
day
[
M/
F]
and
LOAEL
of
500/
not
identified
mg/
kg/
day
[
M/
F],
based
on
renal
inflammatory
and
atrophic
changes
secondary
to
renal
calculi
and
hepatic
effects
consisting
of
inflammation,
focal
necrosis,
and
biliary
stasis.

b.
Intermediate­
and
Long
­
term
(
1­
6
months
and
>
6
months)

The
chronic
feeding
study
in
the
dog
(
MRID
41952103)
supports
the
toxicity
endpoint
for
intermediate
and
long­
term
dietary
exposure
because
the
study
Page
8
of
23
encompasses
the
appropriate
duration
of
exposure
and
has
the
most
conservative
NOAEL.
The
NOAEL
was
100/
500
mg/
kg/
day
[
M/
F]
and
LOAEL
500/
not
identified
mg/
kg/
day
[
M/
F],
based
on
renal
inflammatory
and
atrophic
changes
secondary
to
renal
calculi
and
hepatic
effects
consisting
of
inflammation,
focal
necrosis,
and
biliary
stasis.

5.
Incidental
Oral
Exposure
Flumetsulam
has
not
been
approved
for
residential
uses;
therefore,
toxicity
endpoint
selection
is
not
necessary
for
this
scenario.

6.
Margins
of
Exposure
Summary
of
target
Margins
of
Exposure
(
MOEs)
for
risk
assessment.

Route
Duration
Short­
Term
(
1­
30
Days)
Intermediate­
Term
(
1
­
6
Months)
Long­
Term
(>
6
Months)

Occupational
(
Worker)
Exposure
Inhalation
100
100
100
For
occupational
exposure
short­,
intermediate­,
and
long­
term
inhalation
exposure
risk
assessment,
a
MOE
of
100
is
adequate.
This
is
based
on
the
conventional
uncertainty
factor
of
100X,
which
includes
the
10X
for
intraspecies
extrapolation
and
10X
for
interspecies
variation.

Table
3.
Summary
of
Toxicological
Dose
and
Endpoints
for
Flumetsulam
Exposure
Scenario
Dose
(
mg/
kg/
day)
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Endpoint
for
Risk
Assessment
Acute
Dietary
(
Females
13­
50
years
of
age)
Not
applicable.
No
hazard
identified.

Acute
Dietary
(
General
population
including
infants
and
children)
Not
applicable.
No
hazard
identified.

Chronic
Dietary
(
All
populations)
NOAEL=
100
mg/
kg/
day
UF
=
100
Chronic
RfD
=
1.0
mg/
kg/
day
FQPA
SF
=
1
cPAD
=
chronic
RfD
FQPA
SF
=
1.0
mg/
kg/
day
Chronic
feeding,
dog
LOAEL
=
500
mg/
kg/
day
based
on
renal
inflammatory
and
atrophic
changes
secondary
to
renal
calculi
and
hepatic
effects
(
inflammation,
focal
necrosis,
biliary
stasis)
Table
3.
Summary
of
Toxicological
Dose
and
Endpoints
for
Flumetsulam
Exposure
Scenario
Dose
(
mg/
kg/
day)
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Endpoint
for
Risk
Assessment
Page
9
of
23
Incidental
Oral
No
Residential
uses
are
proposed
for
flumetsulam.

Dermal
Exposureall
time
periods
Not
applicable.
No
hazard
identified.

Short­
Term
Inhalation
(
1
to
30
days)
Oral
NOAEL=
100
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
Occupational
LOC
for
MOE
=
100
Chronic
feeding,
dog
LOAEL
=
500
mg/
kg/
day
based
on
renal
inflammatory
and
atrophic
changes
secondary
to
renal
calculi
and
hepatic
effects
(
inflammation,
focal
necrosis,
biliary
stasis)

Intermediate­
Term
Inhalation
(
1
to
6
months)
Oral
NOAEL
=
100
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
Occupational
LOC
for
MOE
=
100
Chronic
feeding,
dog
LOAEL
=
500
mg/
kg/
day
based
on
renal
inflammatory
and
atrophic
changes
secondary
to
renal
calculi
and
hepatic
effects
(
inflammation,
focal
necrosis,
biliary
stasis)

Long­
Term
Inhalation
(>
6
months)
Oral
NOAEL=
100
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
Occupational
LOC
for
MOE
=
100
Chronic
feeding,
dog
LOAEL
=
500
mg/
kg/
day
based
on
renal
inflammatory
and
atrophic
changes
secondary
to
renal
calculi
and
hepatic
effects
(
inflammation,
focal
necrosis,
biliary
stasis)

Cancer
(
oral,
dermal,
inhalation)
Flumetsulam
is
classified
as
Group
E
(
Evidence
of
non­
carcinogenicity
for
humans)
(
6/
23/
93).
Not
mutagenic.

UF
=
uncertainty
factor,
FQPA
SF
=
Special
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
©
=
chronic
RfD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
*
No
systemic
toxicity
was
found
in
21­
day
dermal
study
at
the
limit
dose.

V.
Exposure
Assessment:

The
residue
chemistry
data
submitted
in
support
of
the
proposed
petitions
were
reviewed
in
the
HED
memorandum
dated
8/
31/
04
(
S.
Ary,
D306242).
The
chronic
dietary
exposure
assessment
was
completed
in
the
HED
memorandum
dated
8/
30/
04
(
S.
Ary,
D306279).
The
drinking
water
assessment
was
completed
in
the
EFED
memorandum
dated
5/
19/
04
(
J.
Lin
and
S.
Syslo,
D301361).

A.
Summary
of
Registered
Food
Uses
Tolerances
have
been
established
under
40
CFR
§
180.468
for
residues
of
flumetsulam
in/
on
field
corn
(
forage,
grain,
and
stover)
and
soybean
at
0.05
ppm.
Available
residue
data
indicate
that
the
established
tolerances
for
these
commodities
are
adequate.
Dow
has
petitioned
for
the
establishment
of
a
tolerance
for
residues
of
flumetsulam
in/
on
dry
beans
at
0.05
ppm.
HED
recommends
that
the
tolerance
level
in/
on
dry
beans
be
established
at
the
Page
10
of
23
proposed
rate.
Table
7
presents
the
established/
proposed
and
recommended
tolerance
levels
for
all
commodities.

There
are
no
Codex,
Canadian,
or
Mexican
maximum
residue
limits
(
MRLs)
for
flumetsulam;
therefore,
no
questions
of
compatibility
with
U.
S.
tolerances
exist.

Table
4.
Tolerance
Summary
for
Flumetsulam.

Commodity
Established/
Propo
sed
Tolerance
(
ppm)
Recommended
Tolerance
(
ppm)
Comments
(
correct
commodity
definition)

Corn,
field,
forage
0.05
(
established)
0.05
None
Corn,
field,
grain
0.05
(
established)
0.05
None
Corn,
field,
stover
0.05
(
established)
0.05
None
Soybean
0.05
(
established)
0.05
None
Bean,
dry
0.05
(
proposed)
0.05
None
B.
Residue
Profile
1.
Nature
of
the
Residue­
Plants
and
Livestock
The
nature
of
residues
in
corn
and
soybeans
is
adequately
delineated
based
on
acceptable
plant
metabolism
studies.
The
Health
Effects
Division
(
HED)
Metabolism
Committee
concluded
that
the
residue
of
concern
resulting
from
the
uses
on
field
corn
and
soybeans
is
flumetsulam
per
se
(
N.
Dodd,
HED
Metabolism
Committee
Memo,
4/
26/
93).
Plant
metabolism
studies
for
dry
beans
have
not
been
submitted;
however,
metabolism
data
from
soybeans
may
be
translated
to
dry
beans
because
of
the
similarities
between
the
two
crops.

The
HED
Metabolism
Committee
has
not
determined
the
residue
of
concern
in
livestock;
however,
based
on
the
submitted
data,
the
nature
of
the
residue
in
livestock
(
goats
and
hens)
is
adequately
defined
because
no
detectable
residues
of
flumetsulam
per
se
were
found
in
feed
items.

2.
Residue
Analytical
Method
The
available
analytical
methodology
(
GC/
MS
method)
is
considered
adequate
for
tolerance
enforcement
of
flumetsulam
in/
on
plant
commodities.
The
method
is
available
and
has
been
submitted
for
inclusion
in
the
Pesticide
Analytical
Manual
(
PAM)
Volume
II;
however,
the
method
has
not
yet
been
included.
The
limit
of
quantitation
(
LOQ)
for
the
method
is
0.010
ppm
and
the
estimated
limit
of
detection
(
LOD)
is
0.005
ppm.
Using
the
analytical
method,
flumetsulam
is
extracted
from
the
crop
material
with
a
90%
Page
11
of
23
acetone/
10%
0.1
N
HCl
solution.
The
acetone
is
evaporated
from
an
aliquot
of
the
extract
and
the
residue
is
diluted
with
0.005
N
HCl
and
washed
with
hexane.
The
sample
is
cleaned
up
on
C
18
and
alumina
SPE
cartridges
and
derivatized
with
methyl
iodide.
The
resulting
N­
methyl
derivative
is
dissolved
in
N­
d
3­
methyl
flumetsulam
internal
standard
solution
and
quantitated
by
gas
chromatography.

3.
Meat,
Milk,
Poultry,
and
Eggs
The
dietary
burdens
of
beef
cattle,
dairy
cattle,
and
poultry
are
presented
in
Table
5.
Using
a
diet
containing
field
corn
forage,
field
corn
grain,
and
field
corn
milled
byproducts,
the
maximum
theoretical
dietary
burden
for
beef
cattle
is
0.07
ppm,
0.09
ppm
for
dairy
cattle,
and
0.05
ppm
for
poultry.

Table
5.
Calculation
of
Theoretical
Dietary
Burdens
of
Flumetsulam
to
Livestock.

Feedstuff
%
Dry
Matter1
Residue
(
ppm)
2
Beef
Cattle
Dairy
Cattle
Poultry
%
in
Diet
Dietary
Burden
(
ppm)
3
%
in
Diet
Dietary
Burden
(
ppm)
2
%
in
Diet
Dietary
Burden
(
ppm)
2
Corn,
field,
forage
40
0.05
30
0.04
50
0.06
0
0
Corn,
field,
grain
88
0.05
60
0.03
40
0.02
80
0.04
Corn,
field,
milled
byproducts
85
0.05
10
0.01
10
0.01
20
0.01
Total
100
0.07
100
0.09
100
0.05
1.
OPPTS
Guideline
860.1000,
Table
1.
2.
Established
tolerance
levels
of
0.05
ppm
on
field
corn
were
used.
3.
Dietary
Burden
=
%
in
diet
x
(
residue
/
percent
dry
matter).

Flumetsulam
is
not
presently
registered
for
use
as
a
direct
livestock
treatment
and
residues
of
flumetsulam
were
not
detected
in
the
feed
items.
The
nature
of
the
residue
in
animals
is
adequately
defined
for
the
current
and
proposed
uses.
HED
concludes
that
the
registered
uses
on
corn
and
soybeans
and
the
proposed
use
on
dry
beans
results
in
a
40
CFR
§
180.6(
a)(
3)
situation
for
ruminant
and
poultry
commodities;
i.
e.,
there
is
no
reasonable
expectation
of
finite
residues
in
ruminant
and
poultry
commodities.
Therefore,
additional
data
on
the
transfer
of
residues
to
meat,
milk,
and
poultry
are
not
required.
However,
for
uses
which
may
result
in
detectable
residues
in
feed
items,
additional
animal
metabolism
data
on
ruminants
and
poultry
may
be
required.
Such
data
may,
in
turn,
trigger
the
need
for
magnitude
of
the
residue
(
feeding)
studies
in
livestock.

4.
Confined
and
Field
Accumulation
in
Rotational
Crops
The
current
use
labels
for
flumetsulam
restricts
crop
rotation
after
treatment
to
four
months
or
greater
for
all
crops
except
soybean.
Feeding
of
soybean
forage,
hay,
or
straw
to
livestock
is
restricted.
Under
these
restrictions,
the
total
quantifiable
14C
residues
accumulated
in
crop
fractions
is
less
than
0.006
ppm
with
the
exception
of
Page
12
of
23
wheat
straw/
chaff.
The
highest
wheat
straw/
chaff
residue
occurred
for
the
30­
day
planting
at
0.060
ppm.
The
total
14C
residue
levels
in
wheat
straw/
chaff
samples
were
0.029
ppm
in
the
120­
day
study
and
0.010
ppm
in
the
365­
day
study.

The
results
of
the
30­
day,
120­
day,
and
365­
day
rotational
crop
studies
indicate
that
the
total
14C
residue
accumulation
in
lettuce,
carrot
roots
and
tops,
turnip
roots
and
tops,
wheat
grain,
and
soybeans
was
less
than
or
equal
to
0.01
ppm.
However,
total
14C
residues
reported
in
wheat
straw/
chaff
ranged
from
0.010
to
0.047
ppm
(
MRID
Nos.:
41263232
and
41931738).
In
a
separate
study
(
MRID
No.:
41931739),
wheat
forage,
soybean
forage,
soybean
trash,
and
wheat
straw/
chaff
had
reported
total
14C
residues
of
0.039,
0.056,
0.082,
0.060
ppm,
respectively.
Therefore,
for
leafy
and
root
crops,
a
30­
day
rotational
crop
interval
is
satisfactory.
For
cereal
grains,
a
120­
day
rotational
crop
interval
is
satisfactory.

C.
Dietary
Exposure
and
Risk
Assessment
A
chronic
dietary
(
food
and
water)
risk
assessment
was
conducted
using
the
Dietary
Exposure
Evaluation
Model
software
with
the
Food
Commodity
Intake
Database
(
DEEMFCID
 
,
Version
2.03),
which
uses
food
consumption
data
from
the
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.
The
analysis
was
performed
to
support
the
tolerance
reassessment
eligibility
decision
for
current
uses
and
to
support
the
proposed
tolerance
in/
on
dry
beans
(
Petition
Number:
7F4851).
No
acute
dietary
exposure
was
identified,
so
no
acute
dietary
assessment
was
performed.
The
chronic
dietary
exposure/
risk
analysis
was
conducted
using
current
and
proposed
tolerance
values
for
corn
(
forage,
grain,
and
stover),
soybean,
and
dry
beans.
Also,
default
processing
factors,
100%
crop
treated
for
all
commodities,
and
the
highest
estimated
chronic
drinking
water
concentration
were
used
to
conduct
this
Tier
1
(
unrefined)
assessment.

Dietary
risk
assessment
incorporates
both
exposure
and
toxicity
of
a
given
pesticide.
For
acute
and
chronic
assessments,
the
risk
is
expressed
as
a
percentage
of
a
maximum
acceptable
dose
(
i.
e.,
the
dose
which
HED
has
concluded
will
result
in
no
unreasonable
adverse
health
effects).
This
dose
is
referred
to
as
the
population­
adjusted
dose
(
PAD).
The
PAD
is
equivalent
to
the
reference
dose
(
RfD)
divided
by
the
special
Food
Quality
Protection
Act
(
FQPA)
Safety
Factor.

Dietary
risk
estimates
are
provided
for
the
general
U.
S.
population
and
various
population
subgroups.
This
assessment
concludes
that
for
all
supported
commodities,
the
chronic
dietary
exposure
estimates
are
below
the
Health
Effects
Division's
(
HED)
level
of
concern
for
all
population
subgroups
at
less
than
1%
of
the
cPAD.
Page
13
of
23
Table
6.
Summary
of
Chronic
Dietary
(
food
and
water)
Exposure
and
Risk
for
Flumetsulam.

Population
Subgroup
cPAD
(
mg/
kg/
day)
Exposure
(
mg/
kg/
day)
%
cPAD
General
U.
S.
Population
1
0.000113
less
than
1
All
Infants
(
less
than
1
year
old)
0.000219
less
than
1
Children
1­
2
years
old
0.000223
less
than
1
Children
3­
5
years
old
0.000244
less
than
1
Children
6­
12
years
old
0.000181
less
than
1
Youth
13­
19
years
old
0.000135
less
than
1
Adults
20­
49
year
old
0.000094
less
than
1
Adults
50+
years
old
0.000066
less
than
1
Females
13­
49
year
old
0.000092
less
than
1
(
S.
Ary
Memorandum,
8/
30/
04
D306279)

D.
Drinking
Water
Exposure
and
Risk
Assessment
Estimated
Drinking
Water
Environmental
Concentrations
Flumetsulam
is
soluble
in
water
and
is
stable
under
photolysis.
Degradation
studies
indicate
the
soil
half­
life
ranges
from
approximately
two
weeks
to
four
months
with
majority
degrading
in
less
than
two
months
(
mean
of
69.5
days)

The
Environmental
Fate
and
Effects
Division
(
EFED)
calculated
estimated
drinking
water
concentrations
(
EDWCs)
by
using
a
Tier
I
SCI­
GROW
model
for
ground
water
concentrations
and
Tier
II
PRZM
and
EXAMS
models
for
surface
water
concentrations.
The
highest
modeled
(
PRZM
and
EXAMS)
1­
in­
10
year
annual
mean
for
surface
water
was
0.59

g/
L
(
ppb),
based
on
application
on
corn.
The
modeled
EDWCs
(
SCIGROW
for
chronic
ground
water
was
0.823

g/
L
(
J.
Lin
and
S.
Syslo
Memorandum,
D301361,
5/
19/
04).

The
application
rate
for
the
proposed
new
use
on
dry
beans
is
the
same
as
for
corn
(
0.07
lb
a.
i./
acre).
The
2004
NASS
data
indicate
81
million
acres
of
corn
compared
with
only
1.4
million
acres
of
dry
edible
beans.
This
new
use
on
dry
bean
accounts
for
only
1.4%
of
the
acres
currently
estimated
in
the
EDWCs
based
on
corn.
Therefore,
the
EDWCs
are
not
expected
to
be
significantly
higher
when
dry
bean
is
included
than
the
presently
estimated
concentration
based
on
corn.

E.
Occupational
Exposure
and
Risk
Assessment
Occupational
exposure
scenarios
for
the
new
uses
of
flumetsulam
will
be
addressed
in
a
supplemental
document.
Therefore,
the
occupational
exposure
and
risk
assessment
will
not
be
discussed
in
this
TRED.
Page
14
of
23
G.
Aggregate
Exposure
and
Risk
Assessment
The
aggregate
risk
assessment
integrates
the
assessments
conducted
for
dietary,
drinking
water,
and
residential
exposure
if
applicable.
Since
there
is
potential
for
concurrent
exposure
via
the
food
and
water,
the
combined
exposures
from
both
water
and
dietary
risk
are
estimated
and
compared
with
modeling­
based
estimates
of
drinking
water
contamination
determined
by
EFED.

Taking
into
account
the
present
uses
in
this
action,
the
Agency
can
conclude
with
reasonable
certainty
that
residues
of
flumetsulam
in
food
and
drinking
water
would
not
likely
result
in
an
aggregate
chronic
dietary
risk
above
the
Agency's
level
of
concern,
particularly
to
infants
and
children.
The
estimates
of
flumetsulam
in
surface
waters
were
derived
from
a
refined
Tier
II
model.
Conservative
ground
water
concentrations
(
chronic
0.82

g/
L)
from
modeled
Tier
1
estimates
were
similar
to
refined
chronic
surface
waters
numbers
(
0.59

g/
L).

G.
Cumulative
Risk
Assessment
Section
408(
b)(
2)(
D)(
v)
of
FIFRA
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."

EPA
has
determined
that
flumetsulam
does
not
have
a
common
mechanism
of
toxicity
with
the
other
sulfonylurea
pesticides.
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
flumetsulam
and
any
other
substances,
and
flumetsulam
does
not
appear
to
produce
a
toxic
metabolite
produced
by
other
substances.
For
the
purposes
of
this
tolerance
action,
therefore,
EPA
has
not
assumed
that
flumetsulam
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/.

References:
G.
Ghali
Memorandum,
3/
24/
93.
RfD/
Peer
Review
Report
of
XRD­
498
(
flumetsulam),
TXR
011039.

J.
Lin
and
S.
Syslo
Memorandum.
5/
19/
04.
Drinking
Water
Assessment
for
Flumetsulam
for
Uses
on
Field
Corn
and
Soybeans.
D301361
N.
Dodd,
HED
Metabolism
Committee
Memo.
Flumetsulam
Metabolism
in
Soybeans
and
Field
Corn.
4/
26/
93.
Page
15
of
23
S.
Ary
Memorandum,
8/
30/
04.
Flumetsulam.
Chronic
Dietary
Exposure
Assessment
for
the
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
Document.
D306279.

S.
Ary
Memorandum,
8/
31/
04.
Flumetsulam.
Summary
of
Analytical
Chemistry
and
Residue
Data
for
the
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
Document.
D306242.
Page
16
of
23
Appendix
A:
Toxicological
Profile
and
Executive
Summaries
of
Key
studies
for
Flumetsulam
The
requirements
(
CFR
158.340)
for
a
food
use
for
flumetsulam
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
new
(
1998)
guideline
protocols
were
used.

Table
1:
Toxicology
data
requirements
for
a
food
use
pesticide
and
whether
or
not
they
have
been
satisfied.

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
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3250
90­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3465
90­
Day
Inhalation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
no
no
yes
yes
1
yes
no
no
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
yes1
yes
no
yes
yes
870.5100
Mutagenicity
 
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
870.5300
Mutagenicity
 
Gene
Mutation
­
mammalian
.
.
.
.
.
.
870.5xxx
Mutagenicity
 
Structural
Chromosomal
Aberrations
870.5xxx
Mutagenicity
 
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
yes
yes
yes
no
yes
yes
yes
no
870.6100a
Acute
Delayed
Neurotox.
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6100b
90­
Day
Neurotoxicity
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
.
.
870.6300
Develop.
Neuro
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no2
no2
no
no
no
­­

no
no
no
870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
no
yes
no
Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Subchronic
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Six­
month
Oral
(
dog)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
no
no
no
1Either
870.4300
or
870.4100
can
fulfil
this
requirement.
2Required
only
for
organophosphate
pesticides.
Page
17
of
23
Toxicological
Profile
of
Flumetsulam
TOXICOLOGY
PROFILE:
FLUMETSULAM
Type
of
Study/
Guide
line
Study
Title
MRID
Results
81­
1
870.1000
Acute
oral
LD50,
Rat
(
99.6%)
41263202
LD50
(
M/
F)
>
5000
mg/
kg
(
99.6%
a.
i.)
Tox
Category
IV
81­
2
870.1200
Acute
dermal
LD50,
Rabbit
(
99.6%)
41263203
LD50
(
M/
F)
>
2000
mg/
kg
(
99.6%
a.
i.)
Tox
Category
III
81­
3
870.1300
Acute
inhalation
toxicity,
Rat
(
99.8%)
41556501
(
41931703)
LC50
(
M/
F)
>
0.6
mg/
L
(
99.8%
a.
i.)
Tox
Category
III
81­
4
870.2400
Primary
eye
irritation,
Rabbit
(
99.6%)
41263204
Slight
conjunctival
reddening
and
chemosis
and
iridal
redness
at
1
hour
Tox
Category
IV
81­
5
870.2500
Primary
dermal
irritation,
Rabbit
(
99.6%)
41263205
No
irritation
Tox
Category
IV
81­
6
870.2600
Dermal
sensitization,
Guinea
Pig
(
99.6%)
41263206
Not
a
sensitizer
82­
1a
870.3100
90­
Day
oral
toxicity,
Rat
41263212
Levels
tested:
0,
250,
1000,
2000/
2500
[
M/
F]
mg/
kg/
day
NOAEL
(
M/
F)
250
mg/
kg/
day
LOAEL
(
M/
F)
1000
mg/
kg/
day
based
on
severe
bilateral
tubular­
interstitial
nephritis.

82­
1a
870.3100
90­
Day
oral
toxicity,
Mice
41931704
Levels
tested:
0,
100,
500,
1000,
5000
mg/
kg/
day
NOAEL
(
M/
F)
5000
mg/
kg/
day
(
98.6%
a.
i.)
LOAEL
(
M/
F)
Not
identified.
Statistically
increased
full
cecum
weights
and
decreased
kidney
weights
were
found
at
5000
mg/
kg/
day
but
were
considered
adaptive
and/
or
toxicologically
irrelevant.

82­
1b
870.3150
90­
Day
oral
toxicity,
Dog
See
guideline
870.4100b
82­
2
870.3200
21­
Day
Dermal,
Rabbit
41931706
Levels
tested:
0,
100,
500,
1000
mg/
kg/
day
Systemic
&
dermal
NOAEL
(
M/
F)
>
1000
mg/
kg/
day.
LOAEL
(
M/
F)
Not
identified
Diffuse
treatment­
related
epidermal
hyperplasia
observed
at
application
site.
TOXICOLOGY
PROFILE:
FLUMETSULAM
Type
of
Study/
Guide
line
Study
Title
MRID
Results
Page
18
of
23
83­
3a
870.3700a
Developmental
Toxicity,
Rat
(
GD
6­
15)
41263213
41615301
Levels
tested:
0,
100,
500,
1000,
mg/
kg/
day
Maternal
NOAEL
500
mg/
kg/
day
Maternal
LOAEL
1000
mg/
kg/
day,
based
on
statistically
increased
full
cecum
weights
and
decreased
kidney
weights,
but
considered
adaptive
and/
or
toxicologically
irrelevant.
Developmental
NOAEL
>
1000
mg/
kg/
day
Developmental
LOAEL
Not
identified.
No
developmental
toxicity
reported.

83­
3b
870.3700b
Developmental
Toxicity,
Rabbit
(
GD
7­
19)
41931709
Levels
tested:
0,
100,
500,
700
mg/
kg/
day
Maternal
NOAEL=
100
mg/
kg/
day
Maternal
LOAEL=
500
mg/
kg/
day
based
on
anorexia,
moribundity,
and
decreased
body
weight
gain
(
GD
10­
13
at
500
and
GD
7­
10
at
700
mg/
kg/
day)
Developmental
NOAEL>
700
mg/
kg/
day
Developmental
LOAEL=
Not
identified
83­
4
870.3800
Reproduction
(
2­
Generation),
Rat
41931710
(
42474001)
Levels
tested:
0,
100,
500,
1000
mg/
kg/
day
Reproductive
NOAEL
>
1000
mg/
kg/
day
Reproductive
LOAEL
Not
identified
Offspring
NOAEL
>
1000
mg/
kg/
day
Offspring
LOAEL
Not
identified
Parental
NOAEL
>
1000
mg/
kg/
day
Parental
LOAEL
Not
identified
83­
1a
870.4100a
Chronic
Feeding,
Rodent
See
guideline
870.4300
(
83­
5)

83­
1b
870.4100b
Chronic
Feeding,
Dog
41952103
Levels
tested:
0,
20,
100,
500
mg/
kg/
day
Systemic
NOAEL
(
M)
=
100
mg/
kg/
day
Systemic
NOAEL
(
F)
>
500
mg/
kg/
day
Systemic
LOAEL
(
M)
=
500
mg/
kg/
day
based
on
renal
inflammatory
and
atrophic
changes
secondary
to
renal
calculi
and
hepatic
effects
consisting
of
inflammation,
focal
necrosis,
and
biliary
stasis
LOAEL
(
F)
Not
identified
83­
2b
870.4200b
Carcinogenicity,
Mouse
41931708
Levels
tested:
0,
100,
500,
1000
mg/
kg/
day
Systemic
NOAEL
(
M/
F)
>
1000
mg/
kg/
day
LOAEL
(
M/
F)
Not
identified
Not
evidence
for
carcinogenicity
in
M/
F
TOXICOLOGY
PROFILE:
FLUMETSULAM
Type
of
Study/
Guide
line
Study
Title
MRID
Results
Page
19
of
23
83­
5
870.4300
Chronic/
Oncogenicity,
2­
Year­
Rat
41931707
Levels
tested:
0,
100,
500,
1000
mg/
kg/
day
NOAEL
(
M)
=
500
mg/
kg/
day
NOAEL
(
F)
>
1000
mg/
kg/
day
LOAEL
(
M)
=
1000
mg/
kg/
day
based
on
dilated
renal
pelvises
containing
renal
calculi,
atrophy
of
renal
papillae,
renal
pelvic
epithelial
hyperplasia,
and
mineralization
of
pelvic
epithelium
LOAEL
(
F)
Not
identified
Not
evidence
for
carcinogenicity
in
M/
F
84­
2
870.5100
Ames
bacterial
mutagenicity
test
41263214
Salmonella
­
Negative
in
strains
TA98,
TA100,
TA1535,
TA1537,
and
TA1538
with
and
without
metabolic
activation
at
concentrations
of
0.01­
1.0
mg/
plate
84­
2
870.5300
In
vitro
mammalian
cell
gene
mutation
test
(
Chinese
hamster
ovary
cells)
41263217
The
study
was
negative
at
concentrations
from
500
to
3000

g/
mL
with
and
without
metabolic
activation
with
Arochlor
1254
induced
rat
liver
S­
9
84­
2
870.5395
In
Vivo
Micronucleus
Assay
41263216
Negative
for
micronucleus
induction
in
bone
marrow
cells
of
male
and
female
CD­
1
mice
at
24
hrs
after
oral
gavage
administration
of
500
to
5000
mg/
kg.

84­
2
870.5550
Unscheduled
DNA
Synthesis
41263215
Negative
at
concentrations
from
3.16
x
10­
6
to
3.16
x
10­
4
M
85­
1
870.7485
General
Metabolism,
rats
and
mice
41931711
41993801
Absorbed
test
material
(
52­
63%)
excreted
unchanged
in
urine.
Unabsorbed
test
material
eliminated
unchanged
in
feces.
Test
material
essentially
eliminated
within
48
hours
by
male
and
female
rats.
Plasma
14C
exhibited
a
dosedependant
increase
in
absorption
and
elimination.
Increasing
dose
associated
with
increasing
clearance
possibly
due
to
saturation
of
plasma
binding
sites.
Male
mice
exhibited
faster
absorption
and
elimination
at
1000
mg/
kg
than
male
rats.
Urine
primary
elimination
route
in
both
male
and
female
rats
and
mice.
Two
minor
metabolites
identified
in
urine
in
mice.

85­
2
870.7600
Dermal
Absorption
Study
not
available
Page
20
of
23
Executive
Summaries
of
Key
Studies
in
the
Flumetsulam
Hazard
Assessment
1.
MRID
41952103­
Chronic
Feeding
Study,
Dog
CITATION:
Yano
BL.,
Cosse
PF.,
and
Corley
RA.
(
1991).
XRD­
498:
One­
year
dietary
toxicity
study
in
beagle
dogs.
The
Toxicology
Research
Laboratory,
Health
and
Environmental
Sciences,
Dow
Chemical
Company,
Midland,
MI
48674.
Laboratory
project
study
ID:
DR­
0238­
5651­
024
MRID
41952103.
Unpublished
EXECUTIVE
SUMMARY:

In
a
chronic
toxicity
study
(
MRID
41952103)
flumetsulam
[
99.0%
a.
i.
by
HPLC
and
99.2%
a.
i.
by
DSC,
batch/
lot
#
not
provided]
was
administered
to
4
Beagle
dog/
sex/
dose
in
diet
at
dose
levels
of
0,
20,
100,
or
500
mg/
kg
bw/
day
for
up
to
one
year
(
369
days).

In
the
high­
dose
group,
3
of
4
male
dogs
had
pale
looking
mucous
membranes
and
2/
4
appeared
icteric
and
thin.
Because
of
its
deteriorating
condition,
one
male
high­
dose
dog
was
euthanized
on
Day
81.
At
termination
(
day
369),
the
surviving
dogs
showed
no
signs
of
icterus
or
pale
mucous
membranes.
All
four
females
in
the
high­
dose
group
had
pale
mucous
membranes,
but
by
the
end
of
the
study,
this
was
present
in
only
one
female.
No
clinical
signs
were
observed
in
dogs
from
the
other
dose
groups.

There
was
no
compound­
related
effects
on
ophthalmological
examination
or
urinalysis.

Body
weights
of
male
and
females
dogs
were
decreased
in
the
high­
dose
group
only.
Food
consumption
was
also
decreased
in
the
high­
dose
group,
which
indicates
the
decreased
body
weights
were
likely
due
to
the
unpalatability
of
the
test
diets
at
this
dose.

The
male
high­
dose
dog
that
was
euthanized
on
Day
81
of
the
study
had
significant
decreases
in
glucose,
albumin,
total
protein,
cholesterol,
creatinine,
calcium,
sodium,
potassium
and
chloride
and
a
significant
increase
in
alanine
aminotransferase
activity,
alkaline
phosphatase
(
ALP)
activity,
aspartate
aminotransferase
activity,
creatine
phosphokinase
activity,
triglycerides
and
total
bilirubin,
when
compared
to
control
males
at
3
months.

At
12
months,
alkaline
phosphatase
(
ALP)
activities
of
both
male
and
female
dogs
in
the
mid­
dose
group
were
within
or
close
in
proximity
to
concurrent
and
historical
control
values
for
each
sex.
ALP
activities
of
both
male
and
female
dogs
in
the
high­
dose
group
were
increased
compared
to
concurrent
and
historical
controls
(
M:
339
mu/
ml
vs.
range
32­
61;
F:
482
mu/
ml
vs.
36­
55).
Albumin
levels
at
12
months
in
high­
dose
dogs
were
lower
than
concurrent
and
historical
controls
(
M:
2.9
g/
dl
vs
range
3.4­
3.8;
F:
2.3
g/
dl
vs.
range
3.3­
3.7).
Cholesterol
and
triglycerides
in
the
high­
dose
group
were
decreased
throughout
the
study.
Aspartate
aminotransferase
(
at
3
and
6
months)
and
total
bilirubin
values
(
at
3
months)
of
both
male
and
female
dogs
of
the
high­
dose
group
were
statistically
significantly
increased.
However,
at
12
months
these
previous
elevated
levels
appeared
more
normal.
The
alterations
in
the
chemistry
parameters
in
the
high­
dose
dogs
was
likely
attributable
to
decreased
body
weight
and
food
consumption
seemingly
due
to
palatability
problems.
Clinical
chemistry
parameters
were
normal
for
all
of
the
other
dose
groups
Page
21
of
23
compared
to
controls.

After
12
months,
2/
4
female
dogs
from
the
high­
dose
group
had
calculi
in
the
renal
pelvis
of
both
kidneys
and
a
rough
cortical
surface
of
the
kidneys.
Microscopically,
kidneys
of
these
females
shoed
signs
of
inflammation,
atrophy
of
the
renal
papillae,
and
distension
and
atrophy
of
tubules.
One
of
three
surviving
high­
dose
males
had
pale
foci
in
the
cortex
of
both
kidneys.
Microscopically,
kidneys
of
the
high­
dose
male
had
multifocal
tubular
atrophic
lesions.
Histopathology
of
all
other
animals
were
normal
compared
with
controls.

Therefore,
the
LOAEL
is
500
mg/
kg/
day,
based
on
renal
effects
(
inflammatory
and
atrophic
changes
secondary
to
renal
calculi),
and
hepatic
effects
(
significantly
elevated
alkaline
phosphatase,
inflammation
and
necrosis
of
individual
hepatocytes,
and
bile
duct
stasis.
The
NOAEL
is
100
mg/
kg/
day.

2.
MRID
41931709­
Prenatal
Developmental
Toxicity
Study­
Rabbit
CITATION:
Hanley,
TR
(
1989)
XRD­
498:
Gavage
teratology
study
in
new
zealand
white
rabbits.
Toxicology
Research
Lab;
Health
and
Environmental
Sciences;
Dow
Chemical
Co.,
Midland,
MI
48674.
Lab
Project
No.:
DR­
0238­
5651­
023.
MRID
41931709.
Unpublished.

EXECUTIVE
SUMMARY:

In
a
developmental
toxicity
study
(
MRID
41931709)
flumetsulam
(
99.8%
a.
i.,
batch
#
/
ARG
240043)
was
administered
to
64
inseminated
female
New
Zealand
white
rabbits
by
gavage
at
dose
levels
of
0,
100,
500,
or
700
mg/
kg
nominal
(
dosage
volume
2
ml/
kg/
day
was
adjusted
daily
for
each
rabbits
body
weight)
from
days
7
through
19
of
gestation.
Dams
were
sacrificed
on
day
28
of
gestation
and
all
fetuses
were
weighed,
sexed,
and
examined
externally.

Six
of
16
rabbits
of
the
mid­
dose
group
showed
signs
of
anorexia.
Four
of
these
6
exhibited
prolonged
periods
of
anorexia
from
days
5­
11
associated
with
abortion
in
2
rabbits
(
GD
20
and
26)
and
moribundity
in
a
third
(
GD
20).
Eight
of
16
high­
dose
dams
also
showed
signs
of
anorexia
and
4/
16
died.
Two
of
these
deaths
were
determined
to
be
treatment­
related
(
GD
13
and
16)
and
the
other
two
that
died
were
due
to
technical
errors.
In
the
low­
dose
group,
one
animal
aborted
on
Day
25
of
gestation.
The
non­
specific
signs
of
toxicity
included
perineal
soiling,
fresh
blood
in
the
pan,
stomach
erosions
or
ulcers
and
were
considered
to
be
consistent
with
the
deteriorated
clinical
condition
of
the
rabbits.

High­
dose
animals
had
significantly
decreased
body
weight
on
days
16
and
20
of
gestation
(

11%
vs.
controls).
In
the
mid­
dose
group,
maternal
body
weight
was
lower,
but
not
statistically
significant
compared
to
controls
on
days
7­
20.
Feed
consumption
was
not
reported.

There
were
no
significant
differences
in
absolute
or
relative
organ
weights
after
cesarean
section.
There
were
no
dose­
related
trends
in
the
number
of
corpora
lutea
or
gravid
uterine
weights
or
significant
differences
in
the
incidence
of
fetal
alteration,
or
the
degree
of
skeletal
ossification
to
suggest
any
fetotoxic
effect
at
the
low­,
mid­,
or
high­
dose
groups.
Page
22
of
23
The
maternal
LOAEL
is
500
mg/
kg
bw/
day,
based
on
anorexia,
moribundity,
and
decreased
body
weight
gain.
The
maternal
NOAEL
is
100
mg/
kg
bw/
day.

There
were
no
fetal
malformations
or
variations
associated
with
administration
of
the
test
substance
in
pregnant
rabbits.

The
developmental
LOAEL
is
not
established.
The
developmental
NOAEL
is
700
mg/
kg
bw/
day.

3.
MRID
41263212­
Subchronic
Oral
Toxicity
(
90
days)­
Rat
CITATION:
Zempel,
JA,
Grandjean
M,
and
Szabo
JR.
(
1988)
XRD­
498:
Results
of
a
13­
week
dietary
toxicity
study
in
Fischer­
344
Rats.
Health
and
Environmental
Sciences,
Texas,
Dow
Chemical
Company,
Lake
Jackson
Research
Center,
Freeport,
Texas
77541
Study
No.:
DR­
0238­
5651­
007,
July
29,
1989.
MRID
41263212.
Unpublished.

In
a
90­
day
oral
toxicity
study
(
MRID
41263212)
flumetsulam
(
97.8­
98.1%
a.
i.,
batch/
lot
#
AGR
229750)
was
administered
to
10
Fischer­
344
rats/
sex/
dose
in
diet
at
dose
levels
of
0,
250,
1000,
or
2000
[
M]
and
2500
[
F]
mg/
kg
bw/
day.
Ten
males
and
10
females
from
each
dose
group
were
sacrificed
at
91
days.
The
remaining
animals
in
the
control
and
high­
dose
group
(
10/
sex/
group)
were
continued
on
to
day
199
as
a
recovery
group.

Animals
were
subjected
to
the
following
(
1)
observed
daily
and
handled
once
weekly,
(
2)
body
weights
measured
weekly,
(
3)
food
consumption
measured
weekly,
(
4)
hematology,
clinical
chemistry,
urinalysis
at
scheduled
necropsy,
(
5)
functional
observational
battery,
and
(
6)
at
day
of
sacrifice,
recorded
organ
weights
and
gross
examination
and
microscopic
examination
of
selected
tissues
and
organs.

No
treatment
related
clinical
signs
from
flumetsulam.
High­
dose
animals
displayed
clinical
signs
related
to
feed
refusal.
Two
high­
dose
males
were
found
dead
on
days
35
and
37
and
one
female
on
day
50.
All
other
rats
survived
to
scheduled
sacrifice.

High­
dose
males
and
females
had
significantly
decreased
body
weights
from
controls
beginning
on
day
7
in
males
(
8%)
and
day
35
in
females
(
6%)
and
continuing
to
termination
of
the
study
(
16%
and
5%,
respectively).
Absolute
body
weights
were
similar
to
the
control
until
day
35
at
which
time
the
difference
from
the
control
became
statistically
significant.
Food
wastage
during
this
period
may
have
contributed
to
this
loss
in
body
weights,
especially
in
high­
dose
males.
Body
weight
gain
was
similarly
reduced
beginning
on
day
7
and
continuing
until
day
91
sacrifice.
Body
weights
in
the
low­
and
mid­
dose
animals
were
not
affected
by
treatment.
Feed
consumption
was
significantly
(
not
statistically)
lower
in
high­
dose
males
during
the
period
from
day
1
to
day
64.
After
day
64,
feed
consumption
was
similar
for
all
groups.

High­
dose
males
has
significantly
and
statistically
reduced
RBC
(
12%),
HGB
(
6.5%),
and
PCV
Page
23
of
23
(
packed
cell
volume,
8%)
relative
to
controls.
Platelet
counts
were
significantly
increased
in
the
mid­
and
high­
dose
males
(
8%
and
16%,
respectively).
High­
dose
females
had
statistically
increased
platelet
concentrations
relative
to
control
(
11%).
No
other
treatment
related
hematological
effects
were
reported
in
female
rats.

High­
dose
males
had
increased
alkaline
phosphatase
(
29%),
BUN
(
186%),
creatinine
(
140%),
cholesterol
(
63%)
and
calcium
(
7%).
Decreased
values
were
reported
for
high­
dose
males
in
albumin
(
5%),
SGOT
(
10%),
SGPT
(
16%),
total
protein
(
7%),
and
globulin
(
10%).
A
dose­
related
decrease
was
reported
for
glucose
in
the
mid­
and
high­
dose
groups,
a
dose
related
increase
for
potassium
in
all
treated
groups
and
for
sodium
in
the
mid­
and
high­
dose
groups,
and
reduced
triglycerides
in
all
treated
groups
relative
to
controls.
The
recovery
animals
in
the
high­
dose
group
retained
the
differences
in
clinical
chemistries
reported
at
the
13
week
sacrifice.

Female
rats
exhibited
dose­
related
increases
in
SGOT
and
SGPT
in
all
treated
groups.
BUN
was
increased
in
high­
dose
females
only
(
63%).
At
recovery
sacrifice,
all
values
in
females
were
comparable
to
the
control.
Increased
BUN
levels
in
the
high­
dose
males
and
females
and
creatinine
levels
reported
in
high­
dose
males
indicate
reduced
renal
function.

Urinalysis
profiles
of
low­
dose
males
and
low­
and
mid­
dose
females
were
similar
to
control.
High­
dose
males
had
significantly
reduced
urinary
specific
gravity
to
control.
Recovery
males
persisted
in
having
reduced
urinary
specific
gravity
and
decreased
levels
of
ketones
and
blood.
In
females,
only
urinary
specific
gravity
was
affected
by
treatment.
The
data
presented
indicated
more
severe
effects
in
males
than
females,
and
only
limited
recovery
in
high­
dose
males.

All
measured
organ
weights
of
high­
dose
males
except
brain
were
affected
by
treatment.
At
the
119
days
sacrifice,
high­
dose
males
demonstrated
recovery
with
respect
to
organ
weights
except
for
kidney
weights
which
remained
significantly
lower
than
control
and
at
similar
levels
as
on
day
91.
High­
dose
females
were
less
severely
affected
than
high­
dose
males.

High­
dose
males
had
kidneys
that
were
notable
smaller
in
size
with
rough
and
pitted
surfaces
upon
examination.
Microscopic
pathology
revealed
severe
bilateral
tubule­
interstitial
nephritis
in
all
highdose
males,
6/
10
high­
dose
females,
and
1/
10
mid­
dose
males.
This
condition
was
described
by
marked
interstitial
and
peritubular
fibrosis,
variable
interstitial
edema
of
the
renal
papillae,
focal
necrosis
of
the
tubular
epithelium,
interstitial
suppurative
inflammatory
microfocal
and
microfocal
dystrophic,
and
interstitial
mineralization.

Necropsy
of
the
three
rats
that
died
during
the
study
indicate
the
death
were
likely
due
to
severe
renal
disease
which
appeared
to
become
more
extensive
with
increasing
time
on
treatment.

The
LOAEL
is
1000
mg/
kg/
day
for
males
and
females,
based
on
kidney
pathology,
clinical
chemistries,
and
organ
weights.
The
NOAEL
is
250
mg/
kg/
day
in
males
and
females.
