UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
TXR
No:
0050924
October
2,
2003
Memorandum
SUBJECT:
TRIFLURALIN
(
PC
Code:
036101)
Toxicology
Disciplinary
Chapter
for
the
Tolerance
Reassessment
Eligibility
Decision
Document
FROM:
Robert
Fricke,
Toxicologist
Reregistration
Branch
2
Health
Effects
Division
(
7509C)

THRU:
Alan
Nielsen,
Branch
Senior
Scientist
Reregistration
Branch
2
Health
Effects
Division
(
7509C)

TO:
Richard
Griffin,
Risk
Assessor
Reregistration
Branch
2
Health
Effects
Division
(
7509C)

DP
Barcode:
D284395
Submission
No:
S618837
Action
Requested:
Review
toxicology
studies
submitted
by
the
registrant
and
prepare
the
toxicology
chapter
to
support
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
for
trifluralin.

Attached
is
the
updated
toxicology
chapter
summarizing
the
findings
of
the
toxicology
studies.
ii
TRIFLURALIN
PC
Code:
036101
Toxicology
Disciplinary
Chapter
for
the
Tolerance
Reassessment
Eligibility
Decision
Document
Date
completed:
October
2,
2003
Prepared
by:

Robert
F.
Fricke,
Ph.
D.
Reregistration
Branch
2
Health
Effects
Division
Reviewed
by:

Linda
Taylor,
Ph.
D.
Reregistration
Branch
1
Health
Effects
Division
form:
FINAL
June
21,
2000
iii
1
HAZARD
CHARACTERIZATION
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1
2
REQUIREMENTS
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3
3
DATA
GAP(
S)
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4
4
HAZARD
ASSESSMENT
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4
4.1
Acute
Toxicity
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4
4.2
Subchronic
Toxicity
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6
4.2.1
Subchronic
Oral
Toxicity
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6
4.2.1.1
870.3100
90­
Day
Oral
Toxicity
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Rat
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6
4.2.1.2
870.3100
90­
Day
Oral
Toxicity
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Mouse
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4.2.1.3
870.3150
90­
Day
Oral
Toxicity
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Dog
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7
4.2.2
Subchronic
Dermal
Toxicity
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4.2.2.1
870.3200
31­
day
Dermal
Toxicity
Study
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Rat
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9
4.2.2.2
870.3200
21­
Day
Dermal
Toxicity
B
Rabbit
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4.2.2.3
870.3200
21­
Day
Dermal
Toxicity
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Rabbit
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10
4.2.3
870.3465
30­
Day
Inhalation
B
Rat
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11
4.3
Prenatal
Developmental
Toxicity
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12
4.3.1
870.3700a
Prenatal
Developmental
Toxicity
Study
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Rat
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4.3.2
870.3700a
Prenatal
Developmental
Toxicity
Study
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Rat
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4.3.3
870.3700b
Prenatal
Developmental
Toxicity
Study
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Rabbit
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4.3.4
870.3700b
Prenatal
Developmental
Toxicity
Study
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Rabbit
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15
4.4
Reproduction
and
Fertility
Effects
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16
4.4.1
870.3800
Reproduction
and
Fertility
Effects
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Rat
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4.4.2
870.3800
Reproduction
and
Fertility
Effects
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Rat
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4.4.3
870.3800
Reproduction
and
Fertility
Effects
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Rat
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19
4.5
Chronic
Toxicity
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20
4.5.1
870.4300
Chronic
Toxicity/
Carcinogenicity
B
Rat
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21
4.5.2
870.4100b
Chronic
Toxicity
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Dog
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22
4.5.3
870.4100b
Chronic
Toxicity
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Dog
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23
4.6
Carcinogenicity
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23
4.6.1
870.4200a
Carcinogenicity
Study
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Rat
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24
4.6.4
870.4200a/
b
Carcinogenicity
Study
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Rat
and
Mouse
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25
4.7
Mutagenicity
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25
4.7.1
Gene
Mutation
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25
4.7.2
Cytogenetics
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27
4.7.3
Other
Genotoxicity
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29
4.8
Neurotoxicity
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29
4.8.1
870.6100
Delayed
Neurotoxicity
Study
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Hen
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30
4.8.2
870.6200
Acute
Neurotoxicity
Screening
Battery
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30
4.8.3
870.6200
Subchronic
Neurotoxicity
Screening
Battery
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30
4.8.4
870.6300
Developmental
Neurotoxicity
Study
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30
4.9
Metabolism
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30
iv
4.9.1
Adequacy
of
data
base
for
metabolism:
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30
4.9.2
870.7485
Metabolism
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31
4.9.3
870.7600
Dermal
Absorption
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Rat
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31
4.10
Other
Studies
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32
4.10.1
Urinary
Tract
Effects
(
Range
Finding)
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Rat
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32
4.10.2
Urinary
Tract
Effects
in
Male
Rats
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33
5
TOXICITY
ENDPOINT
SELECTION
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5.1
Endpoint
Selection
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34
5.2Acute
Reference
Dose
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aRfD)
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5.3
Chronic
Reference
Dose
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cRfD)
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34
5.4Occupational/
Residential
Exposure
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35
5.4.1
Incidental
Oral
Exposure
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5.4.1.1
Short­
Term
(
1
­
30
days)
Incidental
Oral
Exposure
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5.4.1.2
Incidental
Oral
Exposure:
Intermediate­
Term
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1
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6
Months)
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35
5.4.2
Dermal
Exposure
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36
5.4.2.1
Dermal
Exposure:
Short
Term
(
1
­
30
Days)
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36
5.4.2.2
Dermal
Exposure:
Intermediate­
Term
(
1
­
6
Months)
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36
5.4.2.3
Dermal
Exposure
Long­
Term
(>
6
Months)
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37
5.5
Dermal
Absorption
.
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38
5.6
Classification
and
Quantification
of
Carcinogenic
Potential
.
.
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38
5.6.1
Classification
of
Carcinogenic
Potential
.
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38
5.6.2
Quantification
of
Carcinogenic
Potential
.
.
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38
6
FQPA
CONSIDERATIONS
.
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39
6.1
Special
Sensitivity
to
Infants
and
Children
.
.
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.
39
6.1.1
Determination
of
Susceptibility
.
.
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39
6.1.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
.
.
.
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.
39
6.1.3
Special
FQPA
Safety
Factor(
s)
.
.
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39
6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
.
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39
7
REFERENCES
.
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39
8
APPENDICES
.
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48
8.1
Toxicity
Profile
Summary
Tables
.
.
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49
8.1.1
Acute
Toxicity
Table
.
.
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49
8.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
.
.
.
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49
8.2
Summary
of
Toxicological
Dose
and
Endpoints
.
.
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62
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
1
1
HAZARD
CHARACTERIZATION
The
toxicity
database
for
trifluralin
is
adequate
for
the
selection
of
endpoints
for
use
in
risk
assessment.
The
Health
Effects
Division
[
HED]
Hazard
Identification
Assessment
Review
Committee
[
HIARC]
evaluated
all
the
available
studies
in
the
database
and
established
an
acute
and
a
chronic
reference
dose
[
RfD],
as
well
as
doses
and
endpoints
for
incidental
oral
exposure,
residential,
and
short­
term,
intermediate­
term,
and
long­
term
dermal
and
inhalation
exposure
scenarios.
The
HIARC
also
evaluated
available
studies
to
determine
if
there
is
a
special
sensitivity
for
infants
and
children.

Technical
trifluralin
shows
low
acute
toxicity
via
the
oral,
dermal
and
inhalation
routes
of
exposure,
toxicity
categories
IV,
III,
and
IV,
respectively.
Technical
trifluralin
showed
some
irritation
in
the
eye
(
toxicity
category
III),
but
not
the
skin
(
toxicity
category
IV);
in
the
dermal
sensitization
assay
trifluralin
was
found
to
be
a
dermal
sensitizer.
Although
not
required,
an
acute
delayed
neurotoxicity
study
was
also
performed
with
negative
results.

In
the
subchronic
oral
rat
toxicity
study,
minor
decreases
in
overall
body
weight
gains
and
food
consumption
in
males
and
females,
decreased
hemoglobin,
alkaline
phosphatase,
and
alanine
aminotransferase
in
the
males,
and
increased
absolute
and
relative
(
to
body)
liver
weights
in
males
and
females
were
observed.
In
a
6­
month
oral
(
capsule)
study
in
the
dog,
increased
absolute
and
relative
(
to
body)
liver
weights,
liver
enlargement,
discolored
kidneys,
decreased
red
cell
indices,
increased
platelets
in
males;
and
increased
alkaline
phosphatase
were
observed.
In
dermal
toxicity
studies
with
technical
trifluralin
and
a
formulation,
no
systemic
toxicity
was
observed
at
the
limit
dose;
dermal
effects
included
sub­
epidermal
inflamation
and
ulcerations.
In
a
30­
day
inhalation
study
in
rats,
increased
methemoglobin
and
bilirubin,
as
well
as
dyspnea
and
ruffled
fur
were
observed.

Chronic
toxicity
to
trifluralin
was
evaluated
in
the
rat,
mouse,
and
dog.
Systemic
toxicity
in
rats
included
decreases
in
body
weight
and
body
weight
gains;
no
systemic
toxicity
was
observed
at
the
highest
dose
tested
in
a
2­
year
oncogenicity
study
in
the
mouse.
Two
12­
month
oral
(
capsule)
toxicity
studies
were
performed
in
the
dog.
In
one
study,
increased
frequency
of
abnormal
stool,
decreased
body
weights
and
body
weight
gains,
decreased
erythrocytes
and
hemoglobin,
and
increased
thrombocytes
in
males
were
observed,
while
increased
absolute
liver
weights
were
observed
in
the
other.

In
the
developmental
toxicity
studies,
maternal
toxicity
consisted
of
decreased
body
weight
gain
and
food
consumption,
increased
liver
and
spleen
weights,
increased
incidence
of
resorptions
and
litters
with
total
resorptions
in
the
rat;
and
increased
number
of
abortions,
macroscopic
changes
in
the
liver
and
lungs,
and
decreased
food
consumption
in
the
rabbit.
Reduced
ossification
of
vertebrae
and
ribs
were
observed
in
both
the
rat
and
rabbit.
In
the
reproduction
studies
kidney
toxicity
(
acute
renal
failure,
lesions
of
renal
proximal
tubule,
increased
relative
liver)
and
uterine
atrophy
in
females
were
observed.
Offspring
toxicity
consisted
of
decreased
pup
weight
and
increased
number
of
runts.
Decreased
fetal,
neonatal,
and
litter
viability,
and
decreased
lactation
index
were
also
observed.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
2
Extensive
testing
showed
trifluralin
is
neither
mutagenic
nor
genotoxic.
These
tests
showed
that
trifluralin
does
not
inhibit
the
polymerization
of
microtubules
in
mammalian
cells.

The
oncogenic
potential
of
trifluralin
was
addressed
by
the
Agency
Special
Review,
Carcinogenicity
Peer
Review
Committee
(
CPRC)
in
1986,
as
well
as
an
IARC
Monograph
in
1991.
Two
NCI
oncogenicity
studies
in
the
rat
and
mouse
revealed
hepatocellular
carcinomas
in
both
studies;
these
tumors
were
attributed
to
nitrosamine
(
N­
dinitroso­
di­
n­
propylamine,
NDPA);
contamination.
Oncogenicity
studies
with
purified
trifluralin
revealed
malignant
neoplasms
of
the
renal
pelvis
and
benign
urinary
bladder
neoplasms
in
the
rat.
Based
on
the
available
data,
the
CPRC
concluded
that
trifluralin
is
a
"
Group
C"
(
limited
evidence
of
carcinogenicity)
carcinogen
with
a
Q1*
of
0.0077
(
mg/
kg/
day)­
1.
Recalculation
of
the
Q1*
with
3/
4s
interspecies
scaling
factor
resulted
in
a
Q1*
of
0.00579
(
mg/
kg/
day)­
1
(
TXR
0051890).

The
kidney
appears
to
be
a
target
organ
for
trifluralin.
In
a
special
urinalysis
study
in
the
rat
tubular
cytoplasmic
hyaline
droplets,
increased
total
protein,
aspartate
aminotransferase
(
AST),
and
lactate
dehydrogenase
(
LDH)
were
observed
in
the
urine.
Following
electrophoresis,
albumin,


1­
globulin
and

2­
globulin
were
identified
in
the
urine.
Histopathological
findings
included
increased
incidences
of
lesions
of
the
renal
proximal
tubules,
decreased
corticomedullary
mineralization,
hyaline
droplets
in
the
tubular
epithelium
in
the
rat;
in
the
dog,
multifocal
cortical
tubular
cytoplasmic
pigment
deposition
was
observed.

Trifluralin
does
not
appear
to
be
an
immunotoxicant.
Effects
suggestive
of
immunotoxicity
include
thymic
hypoplasia
and
decreased
relative
thymus
weights
in
the
rabbit
developmental
toxicity
study
and
rat
reproduction
study,
respectively,
and
increased
spleen
weights
in
a
rat
developmental
toxicity
study.
No
other
indications
of
possible
immunotoxicity
were
observed
in
the
trifluralin
data
base.

In
the
rat
and
dog
absolute
and
relative
liver
weights
were
increased,
but
this
response
was
considered
to
be
adaptive
since
serum
alanine
aminotransferase
(
ALT),
AST,
gamma
glutamyl
transferase
(
GGT)
and
alkaline
phosphatase
(
AP)
activities
were
unaffected
by
treatment.
In
a
30­
day
inhalation
study
in
the
rat,
liver
weights
were
increased,
but
again,
were
considered
to
be
adaptive
since
no
changes
in
clinical
chemistry
or
histopathological
findings
were
observed.

In
a
rat
metabolism
study,
14C­
trifluralin
in
the
rat,
many
non­
conjugated
(
20­
30)
and
conjugated
(
10­
20)
urinary
metabolites
were
observed,
the
majority
of
the
metabolites
were
present
at
1­
2%
of
the
total
urinary
radioactivity.
One
metabolite,
found
at
8.2­
8.9%
of
the
total
urinary,
was
partially
characterized
as
retaining
the
trifluoromethyl
groups,
the
two
equivalent
aromatic
protons,
and
the
two
nitro
groups,
but
the
propyl
groups
were
lost.
Another
metabolite,
identified
as
N­[(
3­(
acetylamino)­
2­
amino­
5­(
trifluoromethyl)
phenyl]
acetamide,
was
found
at
4.0­
5.2%.
Based
on
the
metabolic
profile,
four
metabolic
pathways
were
identified
(
1)
oxidative
Ndealkylation
of
one
or
both
propyl
groups
and
metabolites
which
were
hydroxylated
on
the
propyl
side
chain,
(
2)
reduction
of
one
or
both
nitro
groups
to
the
corresponding
amine,
(
3)
cyclization
reactions
to
give
a
variety
of
substituted
and
unsubstituted
benzimidazole
metabolites,
and
(
4)
conjugation
reactions,
including
acetylation
of
the
reduced
nitro
groups,
sulfate,
and
glucuronic
acid
conjugates.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
3
2
REQUIREMENTS
The
requirements
(
CFR
158.340)
for
food
and
non
food
for
trifluralin
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.

Table
1:
Data
Requirements
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
Yes
Yes
Yes
Yes
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
870.5xxx
Mutagenicity
C
Gene
Mutation
­
Bacterial
.
.
.
.
.
.
.
.
870.5xxx
Mutagenicity
C
Gene
Mutation
­
Mammalian
.
.
.
.
.
.
870.5xxx
Mutagenicity
C
Structural
Chromosomal
Aberrations
870.5xxx
Mutagenicity
C
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
870.6100a
Acute
Delayed
Neurotoxicity
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6100b
90­
Day
Neurotoxicity
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6200a
Acute
Neurotoxicity
Screening
Battery
(
rat)
.
.
.
.
.
.
.
870.6200b
90
Day
Neurotoxicity
Screening
Battery
(
rat)
.
.
.
.
.
.
870.6300
Developmental
Neurotoxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
No
No
No
No
No
Yes
B
B
B
B
870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Yes
Yes
Yes
No
a
Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
.
.
.
.
.
.
.
.
.
Subchronic
Oral
(
rat)
.
.
.
.
.
Six­
month
Oral
(
dog)
.
.
.
.
.
No
No
No
B
B
­­

a
The
requirement
for
a
dermal
penetration
study
has
been
satisfied
with
a
dermal
absorption
study
with
14Cethalfluralin
(
a
close
structural
analog
of
trifluralin)
in
monkeys
(
MRID
132820,
92062028;
TXR
004090,
004235).
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
4
3
DATA
GAP(
S)

None
4
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
data
base
for
acute
toxicity:
The
data
base
for
acute
toxicity
is
considered
complete;
no
additional
studies
are
required
at
this
time.
The
acute
toxicity
of
trifluralin
is
summarized
in
Table
2a;
acute
toxicity
of
formulation
is
summarized
in
Tables
2b
and
2c.
Technical
trifluralin
shows
low
acute
toxicity
via
the
oral,
dermal
and
inhalation
routes
of
exposure,
with
toxicity
categories
III,
IV,
and
IV,
respectively.
Technical
trifluralin
was
found
to
be
an
eye
irritant
(
Toxicity
Category
II)
and
showed
some
skin
irritation
(
Toxicity
Category
III);
in
the
dermal
sensitization
assay
trifluralin
was
found
to
be
a
dermal
sensitizer.
Although
not
required,
an
acute
delayed
neurotoxicity
study
was
also
performed
with
negative
results
Table
2a:
Acute
Toxicity
of
Trifluralin,
Technical
Guideline
No.
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
Oral
(
Rat)
00157486
(
1985)
TXR
006174
Acceptable/
Guideline
LD50
>
5000
mg/
kg
IV
870.1200
Acute
Dermal
(
Rat)
00157482
(
1985)
TXR
006174
Acceptable/
Guideline
LD50
>
2000
mg/
kg
III
870.1300
Acute
Inhalation
(
Rat)
00155261
(
1982)
TXR
006174
Acceptable/
guideline
LC50
>
4660
mg/
m3,
4.66
mg/
L
IV
870.2400
Primary
Eye
Irritation
(
Rabbit)
00157483
(
1985)
TXR
006174
Acceptable/
Guideline
Conjunctival
redness
at
24hr,
cleared
by
4
d
III
870.2500
Primary
Skin
Irritation
00157485
(
1985)
TXR
006174
Acceptable/
Guideline
Not
an
irritant
IV
870.2600
Dermal
Sensitization
00157484
(
1985)
TXR
006174
Acceptable/
Guideline
Sensitizing
agent
N/
A
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
5
Table
2
(
b)
Acute
Toxicity
of
Trific
10G
(
10%
Trifluralin)

Guideline
No.
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
Oral
(
Rat)
43447301
(
1994)
TXR
5000582
Acceptable/
Guideline
LD50
>
5050
mg/
kg
IV
870.1200
Acute
Dermal
(
Rat)
43447302
(
1994)
TXR5000582
Acceptable/
Guideline
LD50
>
2020
mg/
kg
III
870.1300
Acute
Inhalation
(
Rat)
43447303
(
1994)
TXR
5000582
Acceptable/
guideline
LC50
>
1.21
mg/
L
(
analytical)
>
5.60
mg/
L
(
nom)
IV
870.2400
Primary
Eye
Irritation
(
Rabbit)
43447304
(
1994)
TXR
5000582
Acceptable/
guideline
Conjunctival
redness
at
24hr,
cleared
by
4
d
III
870.2500
Primary
Skin
Irritation
(
Rabbit)
43447305
(
1994)
TXR
5000582
Acceptable/
guideline
Not
an
irritant
IV
870.2600
Dermal
Sensitization
43447306
(
1994)
TXR
5000582
Acceptable/
guideline
Sensitizing
agent
N/
A
Table
2(
c)
Acute
Toxicity
of
Trilin
5
(
50.8%
Trifluralin)

Guideline
No.
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
Oral
(
Rat)
42972701
(
1993)
TXR5000675
Acceptable/
Guideline
LD50
>
5000
mg/
kg
IV
870.1200
Acute
Dermal
(
Rat)
42972702
(
1993)
TXR
5000675
Acceptable/
Guideline
LD50
>
5000
mg/
kg
(
both
sexes)
IV
870.1300
Acute
Inhalation
(
Rat)
42972703
(
1983)
TXR
5000675
Acceptable/
guideline
LC50
=
4.3
4.15­
4.46)
mg/
L(
male)
5.0
mg/
L
(
female)
IV
870.2400
Primary
Eye
Irritation
(
Rabbit)
42972704
(
1993)
TXR
5000675
Acceptable/
Guideline
Ocular
opacity
in
1/
6
on
day
21
II
870.2500
Primary
Skin
Irritation
(
Rabbit)
42972705
(
1993)
TXR
5000675
Acceptable/
Guideline
Erythema
at
72
hr
Moderate
to
severe
1/
6
Well­
defined
3/
6
Very
slight
2/
6
III
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
6
870.2600
Dermal
Sensitization
42972706
(
1993)
TXR
5000675
Acceptable/
Guideline
Sensitizing
agent
N/
A
4.2
Subchronic
Toxicity
Adequacy
of
data
base
for
subchronic
toxicity:
The
data
base
for
subchronic
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
In
the
subchronic
oral
rat
toxicity
study,
minor
decreases
in
overall
body
weight
gains
and
food
consumption
in
males
and
females,
decreased
hemoglobin
and
alkaline
phosphatase
in
the
males,
and
increased
absolute
and
relative
(
to
body)
liver
weights
in
males
and
females
were
observed.
In
a
6­
month
oral
(
capsule)
study
in
the
dog,
increased
absolute
and
relative
(
to
body)
liver
weights,
liver
enlargement,
discolored
kidneys,
decreased
red
cell
indices,
increased
platelets
in
males;
and
increased
alkaline
phosphatase.
In
dermal
toxicity
studies
with
technical
trifluralin
and
a
formulation,
no
systemic
toxicity
was
observed
at
the
limit
dose;
dermal
effects
included
sub­
epidermal
inflamation
and
ulcerations.
In
a
30­
day
inhalation
study
in
rats,
increased
methemoglobin
and
bilirubin,
as
well
as
dyspnea
and
ruffled
fur
were
observed.

4.2.1
Subchronic
Oral
Toxicity
4.2.1.1
870.3100
90­
Day
Oral
Toxicity
­
Rat
Executive
Summary:
In
a
3­
month
oral
toxicity
study
(
MRID
00151906),
HOE
38474
(
trifluralin;
purity
not
reported,
Lot/
Batch
#
AT204)
was
administered
to
20
HOE:
Wistar
(
SPF
71)
rats/
sex/
group
in
the
diet
at
dose
levels
of
0,
800,
2000,
or
5000
ppm
(
0/
0,
59/
69,
154/
168,
and
392/
421
mg/
kg/
day
in
males/
females)
for
three
months.
Ten
rats/
sex/
dose
were
sacrificed
at
the
end
of
the
3­
month
treatment
period,
and
the
remaining
10
rats/
sex/
dose
were
sacrificed
after
a
15­
day
recovery
period
in
which
they
were
given
control
diets.
In
the
main
study,
there
were
no
effects
of
treatment
on
mortality,
clinical
observations,
ophthalmology,
gross
pathology,
or
histopathology.
There
were
no
adverse
effects
on
urinalysis.
In
the
recovery
group,
urine
color
returned
to
normal;
otherwise,
findings
(
when
reported)
were
similar
to
the
main
study.

Absolute
and
relative
(
to
body)
liver
weights
were
dose­
dependently
increased
in
females
dosed
at
800
ppm
and
higher
(
11­
48%)
and
in
males
dosed
at
2000
ppm
and
higher
(
28­
48%).
On
day
93,
blood
serum
phosphate
was
dose­
dependently
increased
in
all
female
dose
groups
(
21­
29%)
and
in
the
2000
and
5000
ppm
males
(
35­
41%).

Additionally
at
5000
ppm,
overall
body
weight
gains
were
decreased
9%
each
in
males
and
females
compared
to
controls.
Food
consumption
was
decreased
16­
18%
on
day
8
in
males
and
females
and
remained
decreased
10%
on
day
92
in
females.
Similarly,
relative
(
to
body)
food
consumption
was
decreased
on
day
8
in
males
and
females
(
10.38­
10.48%
treated
vs
11.64­
12.08%
controls)
and
remained
decreased
on
day
92
in
females
(
6.79%
treated
vs
7.10%
controls).
Additionally
in
the
males
in
this
group,
hemoglobin
was
decreased
6
to
9%
at
weeks
7
and
13;
alanine
aminotransferase,
on
days
1,
44,
and
93
(
20­
26%);
and
alkaline
phosphatase,
26
to
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
7
30%
on
days
44
and
93.

The
LOAEL
for
this
study
is
5000
ppm
(
392/
421
mg/
kg/
day
[
M/
F])
based
on
minor
decreases
in
overall
body
weight
gains
and
food
consumption
in
males
and
females,
decreased
hemoglobin
and
alkaline
phosphatase
in
the
males,
and
increased
absolute
and
relative
(
to
body)
liver
weights
in
males
and
females.
The
NOAEL
is
2000
ppm
(
154/
168
mg/
kg/
day
[
M/
F]).

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

4.2.1.2
870.3100
90­
Day
Oral
Toxicity
­
Mouse
Executive
Summary:
In
a
13­
week
oral
toxicity
study
(
MRID
00151905),
trifluralin
(>
99%
a.
i.,
Batch
#
AZ01751)
was
administered
to
10
NMRI
KFM­
Han
mice/
sex/
dose
in
diet
at
dose
levels
of
0,
400,
1000,
or
2500
ppm
(
approximately
equivalent
to
0,
60,
150,
and
375
mg/
kg/
day
as
calculated
by
the
reviewers).

Mortality,
clinical
signs,
neurological
status,
body
weights,
food
consumption
and
efficiency,
ophthalmology,
hearing,
organ
weights,
and
gross
and
histological
pathology
for
both
sexes
at
all
doses
were
unaffected
by
treatment.
There
were
no
unequivocal
adverse
effects
observed
in
either
sex
at
any
dose.

The
following
changes
were
equivocally
treatment­
related
and
may
have
been
toxicologically
adverse
(
historical
control
values
were
not
reported).
Platelets
were
increased
by
23%
each
in
the
2500
ppm
males
and
females.
Creatinine
was
increased
by
33­
64%
in
the
1000
ppm
females
and
the
2500
ppm
males
and
females.
Urea
was
increased
by
42%
in
the
2500
ppm
males,
but
not
in
females.
Total
bilirubin
and
cholesterol
were
increased
by
90
and
52%,
respectively,
in
the
2500
ppm
females,
but
not
in
the
males.
Although
statistically
significant
increases
were
observed
for
methemoglobin
concentrations
at
1000
(
0.8%
females)
and
2500
ppm
(
1.9%
males,
1.2%
females),
this
findings
was
not
considered
to
be
an
adverse
effect;
control
value
was
0.5%
for
both
sexes.
Since
the
changes
in
clinical
pathology
do
not
fit
a
pattern
consistent
with
a
treatment­
related
effect
and
the
negative
histopathological
results,
these
effects
were
not
considered
to
be
treatment
related.

The
LOAEL
was
not
observed.
The
NOAEL
is
2500
ppm
(
375
mg/
kg/
day),
the
highest
dose
tested.

This
study
is
unacceptable/
not
upgradable
guideline
and
does
not
satisfy
the
requirements
of
a
90­
day
oral
toxicity
study
(
OPPTS
870.3100;
OECD
408)
in
mice.
The
animals
could
have
tolerated
a
higher
dose.

4.2.1.3
870.3150
90­
Day
Oral
Toxicity
­
Dog
Executive
Summary:
In
a
6­
month
oral
toxicity
study
(
MRID
00151907),
HOE
38474
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
8
(
trifluralin;
96.1%
a.
i.,
Lot/
Batch
#
8900)
was
administered
to
6
Hoe:
BEAK
strain
(
Hoechst
breed)
beagle
dogs/
sex/
group
in
the
diet
at
dose
levels
of
0,
400,
1000,
or
2500
ppm
(
equivalent
to
0,
10,
25,
and
63
mg/
kg/
day;
based
on
1
ppm
=
0.025
mg/
kg)
for
six
months.
Four
dogs/
sex/
dose
were
sacrificed
at
the
end
of
the
6­
month
treatment
period,
and
the
remaining
2
dogs/
sex/
dose
were
sacrificed
after
a
1­
month
recovery
period
in
which
they
were
given
control
diets.

There
were
no
treatment­
related
effects
on
urinalyses
or
histopathology.

At
2500
ppm,
one
female
and
one
male
were
sacrificed
in
extremis
on
days
39
and
85,
respectively,
due
to
marked
reduction
in
food
consumption,
cachexia
(
general
ill
health
due
to
rejection
of
food),
and/
or
mild
neurologic
impairment.
Overall
body
weight
gains
were
decreased
in
males
and
females
by
0.5
kg
compared
to
increases
of
1.0
kg
in
female
and
1.6
kg
in
male
controls.
Food
consumption
was
decreased
4­
35%
for
individual
males
and
females
compared
to
controls.

Corneal
vascularization
was
dose­
dependently
increased
at
the
end
of
the
main
study,
occurring
in
3/
12,
5/
12,
and
7/
12
dogs
in
the
400,
1000,
and
2500
ppm
groups,
respectively,
vs
0/
12
controls.
Corneal
necrosis
and
ulceration
were
observed
in
control
(
7/
12
dogs),
400
ppm
(
7/
12
dogs),
1000
ppm
(
8/
12
dogs)
and
2500
ppm
(
9/
10
dogs)
groups.
These
lesions
were
still
present
at
the
end
of
the
recovery
period.
In
the
early
part
of
the
study,
these
lesions
were
thought
to
be
due
to
introduction
of
sand
from
the
dog
run
area
into
the
animals
eyes.
However,
the
doserelationship
indicates
an
effect
of
treatment,
either
direct
or
indirect
(
e.
g.
behavioral
alterations
increased
the
likelihood
of
getting
sand
in
their
eyes).
In
another
chronic
dog
study
(
MRID
00151908),
no
treatment­
related
effects
on
ophthalmology
were
observed
at
doses
up
to
750
ppm.

Dose­
dependent
decreases
(
7­
29%)
were
observed
in
hemoglobin,
erythrocytes,
and
hematocrit
in
the
400
ppm
males
and
1000
and
2500
ppm
animals
at
week
8
and
in
the
2500
ppm
animals
(
12­
26%)
at
6
months.
At
6
months,
leukocytes
were
increased
31­
41%
in
the
1000
and
2500
ppm
females.
Platelets
were
increased
at
400
ppm
and
higher
in
males
(
42­
51%)
and
2500
ppm
females
at
week
8
(
62%)
and
in
the
2500
ppm
animals
at
6
months
(
82­
98%).
Alkaline
phosphatase
was
increased
in
females
at
400
ppm
at
3
months
(
99%),
at
1000
ppm
at
2,
5,
and
6
months
(
84­
146%),
and
at
2500
ppm
throughout
the
study
(
121­
241%).

Absolute
and
relative
to
body
liver
weights
were
dose­
dependently
increased
22­
81%
in
males
and
females
dosed
at
400
ppm
and
higher.
At
the
schedule
6
month
sacrifice,
the
following
macroscopic
findings
were
noted
(
vs
0
controls):
(
i)
liver
enlargement
in
all
treated
animals;
(
ii)
discolored
kidneys
in
all
treated
animals
(
except
for
one
2500
ppm
male);
(
iii)
small
testes
and
prostate
at
1000
(
2/
4)
and
2500
(
2/
3)
ppm;
(
iv)
black
gravelly
contents
in
the
gall
bladder
in
the
2500
ppm
males
(
2/
3)
and
females
(
1/
3);
and
(
v)
discolored
(
yellowish)
fatty
tissues
in
the
1000
(
1/
4)
and
2500
(
3/
3)
ppm
females;
this
discoloration
is
characteristic
of
dinitroaniline
treatment
and
not
considered
to
be
treatment
related.

The
LOAEL
for
this
study
is
400
ppm
(
10
mg/
kg/
day)
based
on
increased
absolute
and
relative
(
to
body)
liver
weights,
liver
enlargement,
discolored
kidneys,
and
corneal
necrosis
and
ulceration
in
males
and
females;
decreased
red
cell
indices
and
increased
platelets
in
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
9
males;
and
increased
alkaline
phosphatase
in
females.
The
NOAEL
was
not
observed.

The
submitted
study
is
classified
as
unacceptable/
not
upgradable
and
does
not
satisfy
the
guideline
requirements
for
a
subchronic
oral
toxicity
study
in
the
dog
(
OPPTS
870.3150;
OECD
409)
because
a
NOAEL
was
not
observed,
and
dietary
analyses
(
homogeneity,
stability,
and
concentration)
were
not
provided
in
the
report.

4.2.2
Subchronic
Dermal
Toxicity
4.2.2.1
31­
day
Dermal
Toxicity
Study
­
Rat
Executive
Summary:
In
a
31­
day
dermal
toxicity
study
(
MRID
00153171),
HOE
38474
(
trifluralin;
>
99%
a.
i.;
Lot/
Batch
#:
OH
AT
210)
in
2%
(
w/
v)
carboxymethlycellulose
was
applied
to
the
shaved
intact
skin
of
10
Wistar
rats/
sex/
dose
at
dose
levels
of
0,
40,
200,
or
1000
mg/
kg/
day
(
limit
dose),
6
hours/
day,
5
days/
week
for
a
total
of
23
applications.
Additional
recovery
groups
consisting
of
5
rats/
sex/
dose
were
similarly
treated
and
then
observed
for
13
days
after
the
final
dermal
application.
Dermal
irritation
was
evaluated
daily
using
the
Draize
method.

No
compound­
related
effects
on
mortality,
clinical
signs,
body
weight,
body
weight
gain,
food
consumption,
food
conversion,
ophthalmoscopy,
hematology,
clinical
chemistry,
or
gross
pathology
parameters
were
observed.

At
>=
200
mg/
kg,
the
following
histopathological
effects
(#
affected/
10)
were
noted
in
the
treated
skin
of
the
main
study
animals:
(
i)
minimal
to
slight
sub­
epidermal
inflamation
(
7­
8
males
and
4
females
each
vs
0
controls);
(
ii)
minimal
to
slight
ulcerations
(
1
treated
male
vs
0
controls
and
1
treated
female
each
vs
1
control);
(
iii)
minimal
to
moderate
acanthosis
(
8­
9
treated
males
vs
6
minimal
controls
and
7­
9
treated
females
vs
5
minimal
to
slight
controls);
and
(
iv)
minimal
to
slight
sebaceous
gland
hyperplasia
(
5­
10
treated
males
vs
7
slight
controls
and
4­
6
treated
females
vs
3
slight
controls).
In
the
recovery
groups,
minimal
acanthosis
was
still
observed
in
2
treated
females
each
(
vs
0
controls).

The
only
findings
at
40
mg/
kg
were
minimal
to
slight
sub­
epidermal
inflammation
(
4
males
and
1
female
vs
0
controls);
minimal
to
slight
acanthosis
(
3
treated
males
vs
6
minimal
controls
and
2
treated
females
vs
5
minimal
to
slight
controls);
and
slight
sebaceous
gland
hyperplasia
(
2
treated
males
vs
7
minimal
controls).
Additionally,
minimal
acanthosis
was
noted
in
one
40
mg/
kg
recovery
group
female
(
vs
0
controls).

The
systemic
LOAEL
was
not
observed.
The
systemic
NOAEL
is
1000
mg/
kg/
day.

The
dermal
LOAEL
is
200
mg/
kg/
day
based
on
sub­
epidermal
inflammation
and
ulcerations
in
males
and
females.
The
dermal
NOAEL
is
40
mg/
kg/
day.

This
study
is
classified
as
acceptable/
guideline
and
satisfies
the
guideline
requirement
(
OPPTS
870.3200;
OECD
410)
for
a
dermal
toxicity
study
in
rats.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
10
4.2.2.2
870.3200
21­
Day
Dermal
Toxicity
B
Rabbit
Executive
Summary:
In
a
21­
day
dermal
toxicity
study
(
MRID
00152888),
trifluralin
(
96.45%
a.
i.;
Lot/
Batch
#:
00554AP2)
was
applied
undiluted
to
the
shaved
intact
skin
of
5
New
Zealand
White
rabbits/
sex/
dose
at
dose
levels
of
0
or
1000
mg/
kg/
day
(
limit
dose),
6
hours/
day
for
21
consecutive
days.
Dermal
irritation
was
evaluated
daily
using
the
Draize
method.

No
compound­
related
effects
on
mortality,
clinical
signs,
body
weight,
body
weight
gain,
food
consumption,
ophthalmoscopic
examinations,
hematology,
clinical
chemistry,
organ
weights,
or
gross
or
histopathological
parameters
were
observed
in
either
sex.
At
1000
mg/
kg,
all
animals
showed
signs
of
dermal
irritation,
characterized
by
moderate
to
severe
erythema
and
slight
to
moderate
edema
accompanied
by
coriaceous,
cracked,
and
bleeding
skin
beginning
at
6­
12
days
after
initiation
of
treatment
and
persisting
until
the
end
of
the
study
with
desquamination
being
observed
within
11­
20
days
after
initiation
of
treatment.

At
1000
mg/
kg,
increased
incidences
of
the
following
gross
and
histopathological
lesions
of
the
treated
skin
were
observed:
(
i)
thickened
treatment
area;
(
ii)
minimal
to
slight
acanthosis;
(
iii)
slight
hyperkeratosis;
and
(
iv)
minimal
to
slight
inflamation
of
the
dermis.
Additionally,
minimal
to
slight
hyperplasia
of
the
bone
marrow
was
noted
(
2
males
and
4
females
vs
0
controls).
These
findings
were
considered
secondary
to
the
dermal
irritation
observed,
rather
than
primary
compound
related
effects.

The
systemic
LOAEL
was
not
observed.
The
systemic
NOAEL
is
1000
mg/
kg/
day.

The
dermal
LOAEL
was
1000
mg/
kg/
day
(
limit
dose)
based
on
erythema,
edema,
and
desquamination
of
the
treated
skin.
The
dermal
NOAEL
was
not
established.

This
study
is
classified
as
acceptable/
guideline
and
satisfies
the
guideline
requirement
(
OPPTS
870.3200;
OECD
410)
for
a
21­
day
dermal
toxicity
study
in
rabbits.

4.2.2.3
870.3200
21­
Day
Dermal
Toxicity
­
Rabbit
Executive
Summary:
In
a
21­
day
dermal
toxicity
study
(
MRID
41993810),
XRM­
5313
(
a
formulation
containing
35.8%
trifluralin
and
2.6%
XRD­
498;
Lot/
Batch
#:
AGR
291670)
was
applied
undiluted
to
the
shaved
intact
skin
of
5
New
Zealand
White
rabbits/
sex/
dose
at
dose
levels
of
0,
100,
500,
or
1000
mg/
kg/
day,
6
hours/
day
for
5
days/
week
over
a
21
day
period
for
a
total
of
15
applications.

No
compound­
related
effects
on
mortality,
clinical
signs,
body
weight,
body
weight
gain,
hematology,
clinical
chemistry,
organ
weight,
or
gross
or
histopathology
parameters
were
observed
at
any
dose
level
in
either
sex.
There
were
signs
of
dermal
irritation
(
slight
to
moderate
erythema,
edema,
and/
or
scaling
and
fissuring)
at
all
doses.
The
dermal
signs
in
the
100
mg/
kg
group
reversed
by
study
termination.

The
systemic
LOAEL
was
not
observed.
The
systemic
NOAEL
is
1000
mg/
kg/
day
(
limit
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
11
dose).

The
dermal
LOAEL
was
100
mg/
kg/
day
based
on
erythema,
edema,
and/
or
scaling
and
fissuring.
The
dermal
NOAEL
was
not
established.

This
study
is
classified
as
acceptable/
guideline
and
satisfies
the
guideline
requirement
(
OPPTS
870.3200;
OECD
410)
for
a
21­
day
dermal
toxicity
study
in
rabbits.

4.2.3
870.3465
30­
Day
Inhalation
B
Rat
Executive
Summary:
In
a
30­
day
inhalation
toxicity
study
(
MRID
40392312,
00151904),
HOE
38474
(
trifluralin;
>
99%
a.
i.;
Lot/
batch
#
AZ
01751)
was
dissolved
in
70%
acetone
and
administered
via
nose­
only
inhalation
to
Wistar
KFM­
Han
(
outbred,
SPF­
quality)
rats
(
15/
sex/
dose)
for
6
hours/
day,
5
days/
week
for
up
to
30
days
at
nominal
dose
levels
of
0
(
air
control),
0
(
acetone
control),
100,
300,
or
1000
mg/
m3
(
equivalent
to
0,
27,
81
and
270
mg/
kg/
day).
Ten
rats/
sex/
dose
were
sacrificed
after
30
days,
and
the
remaining
5
rats/
sex/
dose
were
sacrificed
after
a
14­
day
recovery
period.

There
were
no
adverse
effects
of
treatment
on
mortality,
body
weights,
body
weight
gains,
food
consumption,
food
conversion
ratio,
water
consumption,
ophthalmology,
or
gross
pathology.

At
1000
mg/
m3,
all
rats
showed
slight
dyspnea
and
ruffled
fur;
these
symptoms
were
seen
daily
just
after
exposure
starting
with
day
1
and
were
not
observed
on
non­
exposure
days
(
i.
e.
weekends)
or
during
the
recovery
period.
In
the
females
at
this
dose,
increases
in
methemoglobin
(
1.59%
treated
vs
0.79%
acetone
control)
and
total
bilirubin
(
62%)
were
observed
at
the
end
of
the
main
study
but
were
comparable
to
controls
at
the
end
of
the
recovery
period.
Direct
bilirubin
was
increased
in
females;
however,
data
were
not
provided.

Treatment­
related
effects
on
the
liver
were
observed;
however,
these
changes
were
limited
to
increased
liver
weights
and
centrilobular
hypertrophy
and
were
considered
adaptive.
At
the
end
of
the
main
study,
absolute
and
relative
(
to
body)
liver
weights
were
dose­
dependently
increased
9­
32%
in
the
300
and
1000
mg/
m3
animals.
Relative
(
to
brain)
liver
weights
were
dose­
dependently
increased
10­
14%
in
the
100
and
300
mg/
m3
females
and
21­
28%
in
the
1000
mg/
m3
animals.
Incidence
of
minimal
to
slight
centrilobular
hypertrophy,
characterized
by
increased
homogeneity
and
reduced
basophilia
of
the
cytoplasm
in
enlarged
hepatocytes,
was
dose­
dependently
increased
in
the
>=
100
mg/
m3
males
(
4­
10/
10
treated
vs
0/
10
each
control
group)
and
in
the
1000
mg/
m3
females
(
7/
10
treated
vs
0/
10
each
control
group).
At
the
end
of
the
recovery
period,
liver
weights
(
absolute,
relative
to
body,
and
relative
to
brain)
remained
dose­
dependently
increased
(
19­
26%;
)
in
males
at
>=
100
mg/
m3.

The
LOAEL
for
this
study
is
1000
mg/
m3
(
270
mg/
kg/
day)
based
on
increased
methemoglobin
and
bilirubin
in
females
and
incidences
of
dyspnea
and
ruffled
fur
in
males
and
females.
The
NOAEL
is
300
mg/
m3
(
81
mg/
kg/
day).

This
30­
day
inhalation
toxicity
study
in
the
rat
is
classified
as
acceptable/
non­
guideline
and
is
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
12
satisfactory
as
a
range­
finding
study.
Due
to
its
duration
(
30
days),
this
study
does
not
meet
the
guideline
requirements
for
a
90­
day
inhalation
toxicity
study
(
OPPTS
870.3465
[
§
82­
4];
OECD
413)

4.3
Prenatal
Developmental
Toxicity
Adequacy
of
Data
Base
for
Prenatal
Developmental
Toxicity:
The
data
base
for
developmental
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
In
the
rat,
resorptions,
decreased
fetal
body
weight,
reduced
ossification
of
vertebrae
and
ribs,
and
thickened,
wavy,
or
bent
ribs
were
observed
at
the
same
dose
levels
where
maternal
toxicity
was
observed
[
mortality,
clinical
signs,
decreased
body­
weight
gains
and
food
consumption,
increased
incidence
of
resorptions,
increased
liver
and
spleen
weights].
In
the
rabbit,
abortions
were
observed
at
the
same
dose
levels
where
maternal
toxicity
was
observed
[
abortions,
macroscopic
changes
in
the
liver
and
lungs,
and
decreased
food
consumption].
More
severe
developmental
toxicity
[
increased
resorptions,
decreased
fetal
body
weights,
decreased
number
of
live
fetuses,
increased
number
of
runts,
incomplete
ossification
of
vertebrae,
and
skeletal
abnormalities]
was
observed
in
the
rabbit
at
the
next
higher
dose,
at
which
more
severe
maternal
toxicity
also
occurred
[
mortalities,
decreased
body
weight
and
body­
weight
gain].

4.3.1
870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
Executive
Summary:
In
a
prenatal
developmental
toxicity
study
(
MRIDs
00151899,
00159620
and
40392310),
HOE
38474
(
trifluralin;
99.0%
a.
i.,
Lot/
Batch
#
AT210)
in
sesame
oil
was
administered
to
pregnant
Wistar
(
Hoe:
WISKf
strain,
SPF
71)
rats
(
24/
dose)
via
gavage
at
concentrations
of
0,
20,
100,
or
500
mg/
kg/
day
on
gestation
days
(
GD)
7
through
16.
All
dams
were
sacrificed
on
GD
21
and
their
uterine
contents
examined.
Additionally,
a
replicate
study
with
animals
dosed
only
at
500
mg/
kg/
day
(
with
no
concurrent
control
group)
was
conducted
in
order
to
clarify
results
from
the
main
study
(
no
explanation
given).

At
500
mg/
kg,
one
dam
from
the
replicate
group
died
after
eight
treatments;
no
clinical
signs
of
toxicity
were
noted
on
the
previous
day,
and
advanced
autolysis
precluded
a
necropsy.
Yellow
or
orange­
yellow
discolored
urine
was
observed
in
all
dams,
and
increased
urination
was
noted
in
16
dams
of
both
groups.
Yellow
discoloration
of
fatty
tissues
was
noted
in
most
dams
at
this
dose.
This
discoloration
was
not
considered
to
be
treatment
related
and
is
characteristic
of
dinitroaniline
treatment.
One
dam
in
the
main
study
group
was
markedly
drowsy
and
had
a
blood­
encrusted
nose
on
GD
8­
9.
Piloerection
was
noted
in
one
dam
in
the
main
study
and
2
dams
in
the
replicate
group
during
the
second
half
of
the
treatment
period.
Maternal
body
weight
gains
were
decreased
26%
in
the
main
study
group
and
52%
in
the
replicate
group
during
the
treatment
period.
Food
consumption
was
decreased
5­
8%
during
GD
14­
17
and
increased
9­
22%
post­
treatment
in
both
groups.
Increases
in
liver
weights
of
14­
17%
and
in
spleen
weights
of
27­
36%
were
observed
in
both
groups.
The
number
of
resorptions/
dam
was
increased
in
the
main
study
and
replicate
group
(
1.08­
2.31
treated
vs
0.25
controls),
resulting
in
a
decreased
number
of
live
fetuses/
dam
(
10.8
each
treated
vs
11.8
controls).
Distension
of
the
renal
pelves
was
observed
in
two
dams
in
the
main
study
group
and
two
dams
in
the
replicate
group.
The
following
other
macroscopic
renal
findings
were
observed
(
1
each
treated):
(
i)
clear
fluid
in
the
renal
pelvis;
(
ii)
grey
hollows
on
the
kidney
surface;
and
(
iii)
enlarged
kidney
with
yellow
calculi
in
the
pelvis.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
13
The
only
findings
at
100
mg/
kg/
day
included
complete
litter
resorption
in
one
dam
of
20
and
distension
of
the
renal
pelves
in
one
dam.
Yellow
discoloration
of
fatty
tissues
was
noted
in
most
dams
at
this
dose.
Again,
this
discoloration
was
not
considered
to
be
treatment
related
and
is
characteristic
of
dinitroaniline
treatment
The
only
finding
at
20
mg/
kg/
day
was
distension
of
the
renal
pelves
in
one
dam.

The
maternal
LOAEL
is
500
mg/
kg/
day
based
on
mortality,
clinical
signs,
decreased
body
weight
gains,
decreased
food
consumption,
increased
liver
and
spleen
weights.
The
maternal
NOAEL
is
100
mg/
kg/
day.

At
500
mg/
kg/
day,
statistically
significant
increases
were
observed
in
the
incidence
[
fetal
%
(
litter
%)]
of
reduced
ossification
of
the
vertebrae
[
7.6
(
25);
control
0
(
0)]
and
ribs
[
10.9
(
31.3),
control
0
(
0)],
as
well
as
thickened,
wavy,
or
bent
ribs
[
34.8
(
81.3),
control
3.3
(
15);
historical
control
5
(
21)].

The
developmental
LOAEL
was
established
at
500
mg/
kg/
day,
based
on
reduced
ossification
of
the
vertebrae
and
ribs,
thickened,
wavy
or
bent
ribs
and
increased
incidences
of
resorptions.
The
developmental
NOAEL
was
established
at
100
mg/
kg/
day.

This
developmental
toxicity
study
is
classified
acceptable/
guideline
(
OPPTS
870.3700;
§
83­
3a)
and
satisfies
the
requirement
for
a
developmental
toxicity
study
in
the
rat.

4.3.2
870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
Executive
Summary:
In
a
prenatal
developmental
toxicity
study
(
MRID
00152419),
trifluralin
(
96.7%
a.
i.,
Lot
#
00554AP2)
was
administered
(
via
gavage
in
10%
aqueous
acacia)
to
pregnant
Charles
River
Crl:
COBS,
CD
(
SD)
BR
rats
(
25/
dose)
at
concentrations
of
0,
100,
225,
470,
or
1000
mg/
kg/
day
on
gestation
days
(
GD)
7
through
17.
All
dams
were
sacrificed
on
GD
21
and
their
uterine
contents
examined.

All
animals
survived
to
terminal
sacrifice
without
the
appearance
of
any
treatment­
related
clinical
signs.
Yellow
or
orange­
yellow
discoloration
of
the
urine
and
fatty
tissue
was
observed
at
all
dose
levels;
this
discoloration
was
not
considered
to
be
treatment
related
and
is
characteristic
of
dinitroaniline
treatment.

Maternal
body
weights
were
significantly
decreased
5
to
7%
on
GD
12
to
21
at
475
(
5
to
7%)
and
1000
(
5
to
8%)
mg/
kg/
day.
Significant
decreases
in
food
consumption
was
observed
at
all
dose
levels
of
GD
7
­
12
and
persisted
from
GD
12
­
17
in
the
two
highest
dose
levels.

The
maternal
LOAEL
was
established
at
1000
mg/
kg/
day
based
decreased
body
weights
and
decreased
food
consumption.
The
maternal
NOAEL
was
established
at
475
mg/
kg/
day.

At
1000
mg/
kg/
day,
fetal
body
weights
were
significantly
decreased
by
7%
in
males
and
6%
in
females.
External,
visceral
and
skeletal
examinations
of
the
fetuses
did
not
reveal
any
treatment­
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
14
related
effects.

The
offspring
LOAEL
was
established
at
1000
mg/
kg/
day
based
on
decreased
fetal
body
weights.
The
offspring
NOAEL
was
established
at
475
mg/
kg/
day.

The
developmental
LOAEL
was
not
established.
The
developmental
NOAEL
was
established
at
1000
mg/
kg/
day.

This
developmental
toxicity
study
is
classified
acceptable/
guideline
(
OPPTS
870.3700;
§
83­
3[
a])
and
satisfies
the
requirement
for
a
developmental
toxicity
study
in
the
rat.

4.3.3
870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
Executive
Summary:
In
a
developmental
toxicity
study
(
MRID
00152421),
trifluralin
(
Lot/
batch
#
0554AP2;
96.7%
a.
i.)
was
administered
at
dose
levels
of
0,
100,
225,
or
500
mg/
kg/
day
in
10%
(
w/
v)
aqueous
acacia
(
10
mL/
kg)
by
gavage
to
25
artificially
inseminated
female
Dutch
Belted
rabbits/
group
on
gestation
days
(
GDs)
6
through
18.
All
surviving
does
were
sacrificed
on
GD
28
and
their
fetuses
removed
by
cesarean
section
and
examined.

Abortions
occurred
between
GD
17
and
28
at
225
(
4/
18)
and
500
(
5/
17)
mg/
kg/
day
vs
0/
16
controls.
Following
a
protracted
period
of
anorexia
and
cachexia,
two
500
mg/
kg/
day
does
died
on
GD
13
and
15.
The
maternal
mortalities
and
abortions
resulted
in
a
decreased
number
of
litters
at
225
(
14
treated
vs
16
controls)
and
500
(
10
treated)
mg/
kg.
Orange­
colored
urine
was
observed
at
225
and
500
mg/
kg/
day,
and
orange­
colored
pelage
was
noted
at
500
mg/
kg,
this
was
due
to
trifluralin
and/
or
its
metabolites
and
not
considered
to
be
treatment
related.

In
the
500
mg/
kg/
day
does,
body
weights
were
decreased
6­
16%
(
not
significant)
beginning
on
GD
19,
and
body
weight
gains
were
decreased
during
the
treatment
and
post­
treatment
intervals,
resulting
in
decreased
absolute
and
corrected
(
for
gravid
uterine
weight)
body
weight
gains
for
the
overall
study.
Food
consumption
was
dose­
dependently
decreased
at
225
(
28­
40%)
and
500
(
43­
67%)
mg/
kg/
day
during
the
treatment
interval
and
remained
decreased
(
53%;
)
at
500
mg/
kg/
day
during
the
post­
treatment
interval.

At
necropsy,
dose­
dependent
increases
(
vs
0/
25
controls)
of
hair
in
the
stomach
and
empty
intestines
were
noted
in
the
100
(
1/
25
treated),
225
(
5/
25
treated),
and
500
(
12/
25
treated)
mg/
kg/
day
does.
Liver
that
was
pale,
mottled,
fatty,
and/
or
had
reticulated
reddening
was
noted
at
225
and
500
mg/
kg/
day
(
4/
25
each
treated
vs
0/
25
controls).
Dark
red
lungs
were
observed
at
225
(
1/
25
treated
vs
0/
25
controls)
and
500
(
3/
25
treated)
mg/
kg.
Additionally
at
500
mg/
kg,
yellow
adipose
tissue
was
observed
in
7/
25
does
(
vs
0/
25
controls).
This
discoloration
was
not
considered
to
be
treatment
related
and
is
characteristic
of
dinitroaniline
treatment.

The
maternal
LOAEL
is
225
mg/
kg/
day
based
on
abortions,
macroscopic
changes
in
the
liver
and
lungs,
and
decreased
food
consumption.
The
maternal
NOAEL
is
100
mg/
kg/
day.
At
the
highest
dose
tested
(
500
mg/
kg/
day),
abortions,
mortalities,
decreased
body
weight
and
body
weight
gains,
and
decreased
food
consumption
were
observed.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
15
At
500
mg/
kg,
the
numbers
of
early,
late,
and
complete
resorptions
were
increased,
resulting
in
an
increased
post­
implantation
loss
(
64.8%
treated
vs
15.5%
controls)
and
a
decreased
number
of
live
fetuses/
doe
(
2.1
treated
vs
5.3
controls).
At
500
mg/
kg,
fetal
weights
were
decreased
13­
18%,
and
the
percent
of
fetal
runts
was
significantly
increased
in
the
males
(
37.5%
vs
0.0%,
control)
and
increased
(
not
significant)
in
the
females
(
40
%
vs
3.3%,
controls).
Edema
and
hemorrhagic
area(
s)
were
noted
at
225
mg/
kg/
day
(
1.4%
fetuses;
8.3%
litters)
and
500
mg/
kg/
day
(
4.8­
9.5%
fetuses;
20.0%
litters)
compared
to
0%
in
the
concurrent
controls.
Additionally
at
500
mg/
kg,
hypoplastic
thymus,
cardiomegaly,
and
hypoplastic
lungs
were
observed
among
the
fetal
runts
from
one
litter
(
9.5%
fetuses
and
20.0%
litters,
each
finding)
compared
to
0%
in
the
concurrent
controls.
Increased
incidences
of
spade
ribs
(
9.5%
fetuses;
20.0%
litters),
fused
vertebrae
(
4.8%
fetuses;
20.0%
litters),
and
incomplete
ossification
of
the
vertebrae
(
14.3%
fetuses;
40.0%
litters)
were
observed
at
500
mg/
kg/
day
compared
to
0%
in
concurrent
controls.

The
developmental
toxicity
LOAEL
is
225
mg/
kg/
day
based
on
abortions.
The
developmental
toxicity
NOAEL
is
100
mg/
kg/
day.
At
the
highest
dose
tested
(
500
mg/
kg/
day),
increased
resorptions,
decreased
fetal
body
weights,
decreased
number
of
live
fetuses,
increased
number
of
runts,
incomplete
ossification
of
vertebrae,
and
skeletal
abnormalities
were
observed.

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

4.3.4
870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
Executive
Summary:
In
a
prenatal
developmental
toxicity
study
(
MRID
00151900),
HOE
38474
(
trifluralin;
98.4%
a.
i.,
Lot/
Batch
#
AT210)
in
sesame
oil
was
administered
to
pregnant
hybrid
chinchilla
rabbits
(
16/
dose)
via
gavage
in
a
dosing
volume
of
2
mL/
kg
at
concentrations
of
0,
4,
16,
or
60
mg/
kg/
day
on
gestation
days
(
GD)
6
through
18.
All
does
were
sacrificed
on
GD
28
and
their
uterine
contents
examined.

All
maternal
animals
survived
until
termination.
There
were
no
effects
of
treatment
on
clinical
observations,
body
weight
gains
(
absolute
and
corrected
for
gravid
uterine
weight),
food
consumption,
gross
pathology,
the
number
of
resorptions,
post­
implantation
losses,
the
numbers
of
fetuses
(
live
and
dead),
fetal
weights,
and
sex
ratios.

The
maternal
LOAEL
was
not
observed.
The
maternal
NOAEL
is
60
mg/
kg/
day
(
the
highest
dose
tested).

There
were
no
treatment­
related
external,
visceral,
or
skeletal
findings
in
the
fetuses.

The
developmental
LOAEL
was
not
observed.
The
developmental
NOAEL
is
60
mg/
kg/
day
(
the
highest
dose
tested).

This
developmental
toxicity
study
is
classified
unacceptable/
not
upgradable
and
does
not
satisfy
the
guideline
requirements
(
OPPTS
870.3700;
§
83­
3[
b])
for
a
developmental
toxicity
study
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
16
in
the
rabbit
because
a
LOAEL
was
not
established
for
maternal
or
developmental
effects,
and
animals
were
not
dosed
to
the
limit
dose
(
1000
mg/
kg/
day).

4.4
Reproduction
and
Fertility
Effects
Adequacy
of
data
base
for
Prenatal
Developmental
Toxicity:
The
data
base
for
reproductive
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
Reproductive
toxicity
was
observed
in
the
rat,
as
evidenced
by
a
decrease
in
lactation
index
in
the
F1a
pups
and
decreased
number
of
implantation
sites,
newborn
pups,
litter
size,
and
pup
weights
in
both
generations.

4.4.1
870.3800
Reproduction
and
Fertility
Effects
­
Rat
Executive
Summary:
In
a
multi­
generation
reproduction
toxicity
study
(
MRIDs
00151901,
00151902,
00151903,
and
00159619),
trifluralin
(>
99%
a.
i.;
Lot/
batch
#
AT
210)
was
administered
continuously
in
the
diet
to
outbred
Wistar
KFM­
Man
SPF
quality
rats
at
nominal
dose
levels
of
0,
200,
650,
or
2000
ppm
(
equivalent
to
approximately
0,
10,
32.5
and
100
mg/
kg/
day;
1
ppm
=
0.05
mg/
kg).
The
P
animals
(
30/
sex/
dose)
were
given
test
article
diet
formulations
for
80
days
prior
to
mating
to
produce
the
F1a
litters.
Ten
days
after
weaning
of
the
F1a
litters,
a
second
mating
of
the
P
generation
(
using
different
pairs)
was
conducted
to
produce
the
F1b
litters.
When
possible,
animals
that
were
not
fertile
after
the
first
breeding
were
subsequently
paired
with
fertile
animals.
After
weaning,
26
rats/
sex/
dose
from
the
F1b
litters
were
selected
to
be
F1
parents
and
were
given
the
same
diet
concentration
as
their
dam
for
at
least
100
days
prior
to
mating.
F1
parents
were
bred
(
siblings
not
paired)
to
produce
F2a
and
F2b
litters
using
the
same
procedures
described
for
their
parents.

Parental
mortalities
included
one
650
ppm
P
generation
male
and
one
F1
generation
female
each
from
the
control,
650
ppm,
and
2000
ppm
groups.
The
death
in
650
ppm
female
was
attributed
to
acute
renal
failure;
no
cause
of
death
was
stated
for
the
other
mortalities.
Yellow
discoloration
of
the
urine
was
reportedly
dose
dependently
increased;
however,
neither
summary
nor
individual
data
were
provided.
Yellow
discoloration
of
the
adipose
tissue
was
noted
in
the
650
ppm
females
and
2000
ppm
males
and
females
of
both
generations.
This
discoloration
was
not
considered
to
be
treatment
related
and
is
characteristic
of
dinitroaniline
treatment.
Relative
(
to
body)
liver
weights
were
increased
at
650
ppm
in
the
P
males
and
F1
males
and
females
(
6­
10%)
and
at
2000
ppm
in
the
P
and
F1
males
and
females
(
16­
27%).
In
the
parental
males,
relative
kidney
weights
were
increased
8­
14%
at
650
and
2000
ppm
in
the
both
generations.
Relative
testes
weights
were
increased
8­
13%
at
650
ppm
in
the
F1
generation
and
at
2000
ppm
in
both
generations.
In
the
650
and
2000
ppm
F1
females,
incidences
of
lesions
of
the
renal
proximal
tubules
were
increased,
and
corticomedullary
mineralization
was
decreased.
Hyaline
droplets
in
the
tubular
epithelium
occurred
in
females
of
all
dosed
groups.

Additionally
at
2000
ppm,
body
weights
were
decreased
in
the
F1
females
during
pre­
mating
(
6­
15%),
gestation
(
7­
9%),
and
lactation
(
4­
9%)
for
both
litters.
In
the
males,
food
consumption
was
decreased
in
the
P
generation
during
week
1
of
pre­
mating
(
9%).
Food
consumption
was
decreased
in
the
P
females
during
pre­
mating
(
12%
each
during
weeks
1
and
3)
and
lactation
(
7­
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
17
10%
after
LD
4).
Food
consumption
was
decreased
in
the
F1b
females
during
gestation
(
7­
10%
during
weeks
1
and
3)
and
throughout
lactation
(
10­
13%).
Relative
thymus
weights
were
decreased
15­
16%
in
the
F1
males
and
females.

The
only
finding
at
200
ppm
was
an
increase
of
6%
in
relative
kidney
weight
in
the
P
generation
males.

The
LOAEL
for
parental
toxicity
is
650
ppm
(
32.5
mg/
kg/
day)
based
increased
lesions
of
the
renal
proximal
tubules
in
the
F1
females,
increased
relative
(
to
body)
weights
of
the
liver,
kidney
(
males),
and
testes
in
both
generations.
The
NOAEL
is
200
ppm
(
10
mg/
kg/
day).

There
was
no
adverse
effect
of
treatment
on
pup
mortality.
Pup
weights
were
decreased
in
the
following
litters:
(
i)
both
F1
litters
at
650
and
2000
ppm
on
post­
natal
days
(
PND)
7
and
21
(
5­
12%);
(
ii)
F2a
litter
at
2000
ppm
on
PND
1,
7,
and
21
(
3­
8%);
and
(
iii)
F2b
litters
at
650
and
2000
ppm
on
PND
21
(
2­
7%).
Litter
size
(
the
number
of
live
pups)
was
decreased
13­
16%
at
2000
ppm
in
the
F2a
litter
on
PND
0
and
in
the
F2b
litter
on
PND
0
and
21.
Relative
liver
weights
were
increased
at
650
ppm
in
the
F2b
females
and
at
2000
ppm
in
the
F2a
males
and
females
and
F2b
females
(
6­
13%).
Additionally
at
2000
ppm,
relative
kidney
weights
were
increased
5%
in
the
F2b
females,
and
relative
testes
weights
were
increased
8%
(
each)
in
both
F1
litters.

There
were
no
effects
of
treatment
at
200
ppm.

The
LOAEL
for
offspring
toxicity
is
650
ppm
(
32.5
mg/
kg/
day)
based
on
decreased
pup
weights
in
both
generations
and
increased
relative
to
body
liver
weights
in
the
F2b
females.
The
NOAEL
is
200
ppm
(
10
mg/
kg/
day).

There
were
no
effects
of
treatment
on
precoital
interval,
gestation
length,
behavior
of
dams
during
parturition
and
lactation,
pup
mortality,
or
the
proportion
of
parents
that
mated,
became
pregnant,
delivered,
or
reared
litters
to
weaning.

The
LOAEL
for
reproductive
toxicity
was
not
observed.
The
NOAEL
for
reproductive
toxicity
is
2000
ppm
(
100
mg/
kg/
day).

This
study
is
acceptable/
guideline
and
satisfies
the
guideline
requirements
for
a
twogeneration
reproductive
study
in
the
rat
(
OPPTS
870.3800;
OECD
416).

4.4.2
870.3800
Reproduction
and
Fertility
Effects
­
Rat
Executive
Summary:
In
a
multi­
generation
reproduction
toxicity
study
(
MRID
40405007),
trifluralin
(
97.3%
a.
i.;
Lot/
batch
#
5320)
was
administered
continuously
in
the
diet
to
CD(
CRL)
rats
(
25/
sex/
dose)
at
nominal
dose
levels
of
0,
50,
450,
or
4000
ppm
(
0,
3.9/
4.7,
35/
42,
295/
337
mg/
kg/
day,
M/
F).
The
P
animals
were
given
test
article
diet
formulations
for
10
weeks
prior
to
mating
to
produce
the
F1a
litters;
and
a
second
mating
was
conducted
with
treated
males
and
untreated
females
of
the
P
generation
to
produce
the
F1b
litters.
After
weaning,
25
rats/
sex/
dose
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
18
from
the
F1a
litters
were
randomly­
selected
(
one/
sex/
litter,
when
possible)
to
become
the
parents
of
the
F2
generation
and
were
given
the
same
concentration
test
formulation
as
their
dam
for
at
least
10
weeks
prior
to
mating.
There
were
no
effects
of
treatment
on
parental
survival,
clinical
signs,
or
pup
sex
ratio.

At
4000
ppm,
body
weights
were
decreased
during
pre­
mating
in
the
P
generation
males
and
females
(
6­
15%)
and
F1
males
and
females
(
15­
25%)
and
during
gestation
and
lactation
in
the
P
(
7­
19%)
and
F1
(
18­
24%)
dams.
Body
weight
gains
were
decreased
consistently
during
premating
in
the
P
males,
during
week
1
in
the
P
females
and
F1
males,
and
during
weeks
1,
5,
10
in
the
F1
females.
Food
consumption
was
decreased
in
the
P
generation
males
and
females
(
8­
20%)
and
F1
males
and
females
during
pre­
mating
(
13­
30%)
and
during
gestation
and
lactation
in
the
P
(
13­
28%)
and
F1
(
21­
32%)
dams.
Food
efficiency
during
pre­
mating
was
decreased
consistently
in
the
P
males,
during
week
1
in
the
P
females,
and
during
weeks
1
and
10
in
the
F1
females.
Hematocrit,
hemoglobin,
and
erythrocytes
were
reduced
approximately
5­
10%
in
the
P
and
F1
males
and
females;
increases
in
mean
corpuscular
volume,
platelets
(
10%),
and
reticulocytes
(
130­
180%)
were
also
noted
in
these
animals.
Absolute
(
20%
each)
and
relative
to
body
(
10­
11%)
ovary
weights
were
decreased
in
both
generations.
Yellow
discolored
adipose
tissue
was
observed
in
the
P
and
F1
males
and
females
(
23/
25
to
24/
25
treated
vs
0/
25
controls).
This
discoloration
was
not
considered
to
be
treatment
related
and
is
characteristic
of
dinitroaniline
treatment.
Colon
distension
was
observed
in
the
F1
males
(
4/
25
treated
vs
0/
25
controls).
Denser
stroma
of
the
endometrium
were
observed
in
the
P
and
F1
females
(
14­
15/
25
treated
vs
0/
25
controls),
indicating
uterine
atrophy.

The
only
findings
at
450
ppm
were
minor
and/
or
transient
decreases
in
body
weight
and
food
consumption
and
colon
distension
in
the
F1
males
(
1/
25
treated
vs
0/
25
controls).
Yellow
discolored
adipose
tissue
in
the
P
females
(
2/
25
treated
vs
0/
25
controls),
but
was
not
considered
to
be
treatment
related
and
is
characteristic
of
dinitroaniline
treatment.

There
were
no
effects
of
treatment
at
50
ppm.

The
LOAEL
for
parental
systemic
toxicity
is
4000
ppm
(
295/
337
mg/
kg/
day,
M/
F)
based
on
decreased
body
weights,
body
weight
gains,
food
consumption,
and
food
efficiency
in
males
and
females
of
both
generations;
decreased
ovary
weights
in
both
generations;
colon
distension
in
the
F1
males;
and
uterine
atrophy
in
the
females
of
both
generations.
The
NOAEL
is
450
ppm
(
35/
42
mg/
kg/
day,
M/
F).

At
4000
ppm,
decreases
were
observed
in
the
P
generation
(
F1a
litters)
in
fetal
viability
(
86%
treated
vs
94%
controls),
neonatal
viability
index
(
85%
treated
vs
97%
controls),
and
litter
viability
(
80%
treated
vs
100%
controls).
Lactation
index
was
decreased
(
not
significant)
in
these
animals
(
62%
treated
vs
75%
controls).
The
number
of
implantation
sites
was
decreased
in
the
F1a
(
9%)
and
F2
(
18%)
litters,
resulting
in
a
decreased
number
of
newborn
pups
(
17­
22%)
and
significantly
reduced
litter
size
on
post­
natal
days
(
PND)
1
and
4
(
17­
25%).
Litter
size
remained
decreased
(
3­
14%)
throughout
the
remainder
of
lactation
in
both
generations.
Pre­
implantation
loss
was
increased
(
15.5%
treated
vs
9.8%
controls;
)
in
the
F1b
litters
(
mating
of
treated
males
with
untreated
females),
resulting
in
a
decreased
(
11%;
)
number
of
live
fetuses.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
19
At
4000
ppm
pup
weights
were
decreased
throughout
lactation
in
the
F1a
litters
(
average
15%)
and
on
PND
14
and
21
in
the
F1a
litters
(
74­
81%).

There
were
no
offspring
effects
at
50
or
450
ppm.

The
LOAEL
for
reproductive
toxicity
is
4000
ppm
(
equivalent
to
295/
337
mg/
kg/
day,
M/
F)
based
on
decreased
ovarian
weights
in
both
generations;
decreased
lactation
index
in
the
F1a
pups;
and
decreased
number
of
implantation
sites,
newborn
pups,
litter
size,
and
pup
weights
in
both
generations.
The
NOAEL
is
450
ppm
(
equivalent
to
35/
42
mg/
kg/
day,
M/
F).

The
LOAEL
for
offspring
toxicity
is
4000
ppm
(
295/
337
mg/
kg/
day
M/
F),
based
on
decreased
fetal,
neonatal,
and
litter
viability;
decreased
pup
weights
in
F1a
litters;
and
decreased
number
of
newborn
pups,
litter
size,
and
pup
weights
in
both
generations.
The
NOAEL
for
offspring
toxicity
is
450
ppm
(
35/
42
mg/
kg/
day,
M/
F).

This
study
is
acceptable/
guideline
and
satisfies
the
guideline
requirements
for
a
twogeneration
reproductive
study
in
the
rat
(
OPPTS
870.3800
OPP
§
83­
4).

4.4.3
870.3800
Reproduction
and
Fertility
Effects
­
Rat
Executive
Summary:
In
a
multi­
generation
reproduction
toxicity
study
(
MRIDs
00162543
and
44135107),
trifluralin
(
96.4%
a.
i.;
Lot/
batch
#
554AP2)
was
administered
continuously
in
the
diet
to
Crl:
CD(
SD)
rats
(
25/
sex/
dose)
at
nominal
dose
levels
of
0,
200,
630,
or
2000
ppm
(
equivalent
to
approximately
0,
15,
47,
and
148
mg/
kg/
day).
The
P
animals
were
given
test
article
diet
formulations
for
70
days
prior
to
mating
to
produce
the
F1a
litters.
After
weaning,
25
rats/
sex/
dose
from
the
F1a
litters
were
given
the
same
concentration
test
formulation
as
their
dam
for
69
days
prior
to
mating
to
produce
the
F2a
litters.
A
gross
necropsy
was
performed
on
one
pup/
sex/
litter
from
the
weanlings
not
selected
as
parents.
At
25
weeks
of
age,
a
second
mating
of
the
P
animals
was
conducted
to
produce
the
F1b
litters,
and
a
second
mating
of
the
F1a
animals
was
conducted
to
produce
the
F2b
litters.
After
weaning,
F1b
and
F2b
animals
were
sacrificed
and
given
a
gross
necropsy.
Parental
animals
were
sacrificed
at
36
weeks
and
given
a
gross
necropsy.

There
were
no
effects
of
treatment
on
parental
mortality,
mating/
fertility
indices,
number
of
females
with
live­
born
progeny,
gestation
length,
gestation
survival,
live­
born
litter
size,
sex
ratio,
or
pup
survival.

At
630
ppm,
body
weights
and
food
consumption
were
decreased
in
the
F1
parental
males
at
the
end
of
pre­
mating
(
6%
each).
Body
weights
were
decreased
in
the
P
females
during
gestation
from
the
F1b
mating
(
7­
9%).

At
2000
ppm,
body
weights
and
food
consumption
were
decreased
6­
13%
during
(
14­
20%,
males;
7­
20%,
females)
and
at
the
end
(
14%,
males;
11%,
females)
of
pre­
mating
in
the
P
and
F1
parents.
Body
weights
were
also
decreased
10%
in
the
F1
females
at
the
beginning
of
pre­
mating.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
20
Body
weight
gains
for
the
overall
pre­
mating
period
were
decreased
9­
23%
in
both
generations.
Food
efficiency
was
decreased
14%
during
pre­
mating
in
the
P
generation
females.
During
the
reproduction
period,
body
weights
were
decreased
6­
10%
in
the
males
in
both
generations.
During
gestation,
body
weights
of
the
parental
females
were
decreased
8­
18%
for
both
matings
in
both
generations.
During
lactation,
food
consumption
was
comparable
to
controls,
and
body
weight
gains
were
dose­
dependently
increased
in
the
P
generation
(
both
litters)
and
F1
generation
(
F2a
litter).
These
increases
attained
significance
at
2000
ppm
(­
5.6
to
5.9
g
treated
vs
­
25.6
to
­
11
g
controls).
Pale
yellow
adipose
tissue
was
observed
at
necropsy
in
this
group.
This
discoloration
was
not
considered
to
be
treatment
related
and
is
characteristic
of
dinitroaniline
treatment.
Microscopic
examination
revealed
normal
tissue.

The
LOAEL
for
parental
toxicity
is
630
ppm
(
47
mg/
kg/
day)
based
on
decreased
body
weights
and
food
consumption.
The
NOAEL
is
200
ppm
(
15
mg/
kg/
day).

The
LOAEL
for
reproductive
toxicity
was
not
observed.
The
NOAEL
is
2000
ppm
(
148
mg/
kg/
day).

Pup
weights
were
decreased
6­
12%
in
both
generations
at
2000
ppm
starting
at
post­
natal
day
4.
In
the
combined
F1a,
F1b,
F2a,
and
F2b
litters,
small
pups
(
approximately
half
the
size
of
litter
mates)
were
noted
in
the
630
(
3
litters),
and
2000
(
4
litters)
ppm
groups
compared
to
concurrent
controls
(
0
litters).
Additionally,
a
slight
increase
in
microphthalmia
was
observed
at
2000
ppm
(
4
pups
treated
vs
1
control);
however,
three
of
these
pups
were
from
the
same
litter.
Yellow
adipose
tissue
was
observed
in
the
2000
ppm
pups.
Again,
this
discoloration
was
not
considered
to
be
treatment
related
and
is
characteristic
of
dinitroaniline
treatment
The
only
finding
at
200
ppm
was
small
pups
in
one
litter
out
of
all
combined
F1a,
F1b,
F2a,
and
F2b
litters.

The
LOAEL
for
offspring
toxicity
is
630
ppm
(
47
mg/
kg/
day)
based
on
small
pup
size
in
3
litters.
The
NOAEL
is
200
ppm
(
15
mg/
kg/
day).

This
study
is
acceptable/
guideline
and
satisfies
the
guideline
requirements
for
a
twogeneration
reproductive
study
in
the
rat
(
OPPTS
870.3800;
OPP
§
83­
4).

4.5
Chronic
Toxicity
Adequacy
of
data
base
for
chronic
toxicity:
The
data
base
for
chronic
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
Chronic
toxicity
to
trifluralin
was
evaluated
in
the
rat,
mouse,
and
dog.
Systemic
toxicity
in
rats
included
decreases
in
body
weight
and
body
weight
gains;
no
systemic
toxicity
was
observed
at
the
highest
dose
tested
in
a
2­
year
oncogenicity
study
in
the
mouse.
Two
12­
month
oral
(
capsule)
toxicity
studies
were
performed
in
the
dog.
In
one
study,
increased
frequency
of
abnormal
stool,
decreased
body
weights
and
body
weight
gains,
decreased
erythrocytes
and
hemoglobin,
and
increased
thrombocytes
in
males
were
observed,
while
increased
absolute
liver
weights
were
observed
in
the
other.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
21
4.5.1
870.4300
Chronic
Toxicity/
Carcinogenicity
B
Rat
Executive
Summary:
In
a
chronic
toxicity/
carcinogenicity
study
(
MRID
00162457,
00162458),
trifluralin
(>
99%
a.
i.,
Lot
No.
10653
OP.
112/
80)
was
administered
daily
in
the
diet
to
36
Hoe:
WISKf
(
SPF71)
rats/
sex/
dose
for
up
to
25
months
at
nominal
doses
of
0,
200,
800,
or
3200
ppm
(
achieved
intake:
0/
0,
10/
13,
40/
53,
and
169/
219
mg/
kg/
day
in
males/
females).
In
the
chronic
toxicity
test,
20
rats/
sex/
dose
were
sacrificed
at
24
months.
For
trifluralin
residue
analysis
in
the
tissues
of
10
rats/
sex/
dose,
2
rats/
sex/
dose
were
sacrificed
at
months
6,
12,
and
18,
and
the
remaining
animals
were
sacrificed
at
month
24.
The
bromosulfophthalein
hepatic
function
test
and
phenolsulfonaphthalein
kidney
function
test
were
performed
in
the
survivors
of
a
group
of
6
rats/
sex/
dose
at
months
6,
12,
18,
and
24.
In
a
carcinogenicity
study
(
MRID
00162458),
an
additional
60
rats/
sex
were
treated
at
the
same
dosages
for
28
months.

Mortality,
clinical
signs,
food
consumption,
ophthalmoscopic
findings,
hematology,
clinical
chemistry,
urinalysis,
hepatic
and
renal
function
tests,
organ
weights,
and
gross
pathology
for
both
sexes
at
all
doses
were
unaffected
by
treatment.
No
treatment­
related
adverse
differences
in
any
parameter
were
observed
in
the
200
and
800
ppm
groups.

At
3200
ppm,
the
terminal
body
weights
were
decreased
by
16­
23%.
During
the
studies,
decreased
body
weights
were
frequently
observed
(
4­
28%).
Overall
body
weight
gains
(
calculated
by
the
reviewers)
were
decreased
by
24­
39%.
Relative
water
consumption
(
as
%
body
weight)
was
increased
(
11­
54%;
or
NS)
throughout
the
study;
however,
the
biological
significance
was
unclear.

During
months
6,
12,
18,
and
24,
trifluralin
residues
were
found
concentrated
in
tissues
of
the
3200
ppm
group,
including
the
fatty
tissue,
kidney,
and
skeletal
muscle
(
females
only),
and
in
the
fatty
tissue
of
the
800
ppm
females.
A
generally
time­
dependent
accumulation
of
trifluralin
residue
was
observed
in
the
remaining
carcass
of
the
3200
ppm
group,
but
was
not
observed
in
any
other
tissue.
Tissue
residues
were
generally
higher
in
females
than
in
males.

The
LOAEL
is
3200
ppm
(
169/
219
mg/
kg/
day
in
males/
females)
based
on
decreases
in
body
weight
and
body
weight
gains.
The
NOAEL
is
800
ppm
(
40/
53
mg/
kg/
day
in
males/
females).

At
the
doses
tested,
the
carcinogenic
potential
of
trifluralin
was
negative.
Dosing
was
considered
adequate
based
on
differences
in
body
weight
and
body
weight
gains.

This
study
is
acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
chronic/
carcinogenicity
study
(
OPPTS
870.4100a,
OECD
453)
in
rats.

4.5.2
870.4100b
Chronic
Toxicity
­
Dog
Executive
Summary:
In
a
chronic
oral
toxicity
study
(
MRID
42447001),
trifluralin
(
99.86%
a.
i.,
Lot/
batch
#
326EF8)
was
administered
in
gelatin
capsules
to
4
beagle
dogs/
sex/
group
at
dose
levels
of
0,
0.75,
2.4,
or
40
mg/
kg/
day
for
one
year.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
22
There
were
no
adverse
effects
of
treatment
on
mortality,
food
consumption,
ophthalmology,
urinalysis,
or
gross
pathology.

At
40
mg/
kg,
the
frequency
of
abnormal
stool
(
mucoid,
soft,
runny,
and/
or
containing
white
flakes),
calculated
by
the
reviewers,
was
increased
over
controls
in
males
and
females.
Relative
to
controls,
body
weights
were
decreased
(
7­
18%)
in
females
during
the
last
six
months
of
the
study.
Cumulative
body
weight
change
for
the
overall
study
was
lower
than
controls
(
87.5%
treated
vs
103.4%
controls).
Absolute
liver
weights
were
increased
in
males
(
40%;
)
and
females
(
41%).
Increases
were
also
noted
in
relative
(
to
body)
liver
weights
(
45­
62%;
)
and
relative
(
to
brain)
liver
weights
(
28­
33%)
in
these
animals.
Minimal
to
slight
multifocal
pigment
deposition
was
observed
in
the
liver
in
males
(
1/
4
treated
vs
0
controls)
and
females
(
2/
4
treated
vs
0/
4
controls).
Minimal
focal
inflammation
of
the
liver
was
observed
in
females
(
1/
4
treated
vs
0/
4
controls).
Treatmentrelated
hematological
and
clinical
chemistry
differences
included
the
following:
(
i)
decreased
erythrocytes
in
males
on
days
92
and
363
(
9­
12%);
(
ii)
decreased
hemoglobin
in
males
on
days
33,
92,
and
363
(
7­
11%);
(
iii)
increased
thrombocytes
in
males
on
days
92,
180,
and
363
(
42­
53%);
(
iv)
decreased
ALT
in
males
on
day
363
(
44%);
(
v)
decreased
AST
in
males
on
day
363
(
31%);
(
vi)
increased
cholesterol
in
males
on
days
180
and
363
(
51­
65%);
(
vii)
increased
methemoglobin
in
females
on
days
180
(
1.225%
treated
vs
0.250%
controls)
and
363
(
1.23%
treated
vs
0.18%
controls)
however,
these
differences
were
deemed
not
treatment­
related
or
toxicologically
important
because
they
were
minor,
transient
and/
or
not
dose­
related.;
(
viii)
decreased
GGT
in
females
on
day
363
(
47%);
and
(
ix)
decreased
ALT
in
females
on
days
180
and
363
(
40­
56%).
The
toxicological
significance
of
decreases
in
ALT,
AST,
and
GGT
are
not
known.
Slight
yellow
adipose
tissue
was
observed
in
males
and
females
(
1/
4
each
treated).
This
discoloration
was
not
considered
to
be
treatment
related;
this
discoloration
is
characteristic
of
dinitroaniline
treatment
Microscopic
examination
revealed
normal
tissues.
Minimal
to
slight
multifocal
cortical
tubular
cytoplasmic
pigment
deposition
was
noted
in
the
kidneys
in
males
and
females
(
1/
4
each
treated
vs
0/
4
controls).

The
only
findings
at
2.4
mg/
kg/
day
were
decreased
(
41­
44%)
ALT
and
GGT
in
females
on
day
363
and
minimal
multifocal
cortical
tubular
pigment
deposition
in
the
kidneys
in
males
and
females
(
1/
4
each
treated
vs
0/
4
controls).

The
only
finding
at
0.75
mg/
kg/
day
was
decreased
GGT
(
31%,
)
in
females
on
day
363.

The
LOAEL
for
this
study
is
40
mg/
kg/
day
based
on
increased
frequency
of
abnormal
stool
and
pigment
deposition
in
the
kidney
and
liver
in
males
and
females,
decreased
body
weights
and
body
weight
gains,
and
on
decreased
erythrocytes
and
hemoglobin
and
increased
thrombocytes
in
males.
The
NOAEL
is
2.4
mg/
kg/
day.

The
submitted
study
is
classified
as
acceptable/
guideline
and
satisfies
the
guideline
requirements
for
a
chronic
oral
toxicity
study
in
the
dog
(
OPPTS
870.4100b;
OECD
452).

4.5.3
870.4100b
Chronic
Toxicity
­
Dog
Executive
Summary:
In
a
12­
month
oral
toxicity
study
(
MRID
00151908,
00159618),
HOE
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
23
38474
(
trifluralin;
>
99%
a.
i.,
Lot/
Batch
#
AT210)
was
administered
to
6
purebred
beagle
dogs/
sex/
group
in
the
diet
at
dose
levels
of
0,
30,
150,
or
750
ppm
(
0.0,
0.8,
3.8,
18.8
mg/
kg/
day;
based
on
1
ppm
=
0.025
mg/
kg/
day)
for
12
months.
There
were
no
effects
of
treatment
on
mortality,
food
consumption,
ophthalmology,
auditory
tests,
urinalyses,
or
histopathology.

At
150
ppm,
absolute
liver
weights
were
increased
by
9%
in
the
males.
Methemoglobin
levels
were
increased
in
males
at
months
6
and
9
(
1.2­
1.5%
treated
vs
0.8­
1.0%
controls)
and
in
females
at
month
12
(
1.8%
treated
vs
0.7­
1.1%
controls).

At
750
ppm,
one
male
sacrificed
in
a
moribund
condition
on
day
142
exhibited
myocardial
necrosis
with
fatty
changes,
pericarditis/
epicarditis,
arteritis
in
the
urinary
bladder
and
epididymis,
and
myeloid
hyperplasia
and
erythroid
hypoplasia
in
the
bone
marrow.
However,
it
was
stated
that
this
death
was
considered
unrelated
to
treatment.
Occurrences
of
diarrhea
were
more
frequent
than
controls
in
the
males
during
weeks
1­
41
and
in
the
females
throughout
the
study.
Body
weight
gains
were
lower
than
controls
in
males
from
week
18
onward
and
in
females
during
weeks
17­
44.
Overall
body
weight
gains
were
decreased
by
24­
28%
in
males
and
females
after
one
month.
Methemoglobin
was
increased
in
males
and
females
throughout
the
study
(
1.1­
2.4%
treated
vs
0.7­
1.1%
controls);
these
effects
were
considered
minor
and
not
toxicologically
significant.
Erythrocytes
and
hemoglobin
were
intermittently
decreased
in
males
and
females.
Increases
in
total
lipids
(
31­
55%),
total
cholesterol
(
22­
57%),
and
triglycerides
(
12­
58%)
were
observed
in
males
and
females.
With
the
exception
of
methemoglobin,
all
differences
in
hematology
and
clinical
chemistry
fell
within
the
95%
confidence
interval
of
the
historical
controls.
Absolute,
relative
to
body,
and
relative
to
brain
liver
weights
were
increased
by
28­
52%
in
males
and
females.
Absolute
and
relative
to
body
spleen
weights
were
increased
by
31­
41%
in
females,
and
relative
to
body
spleen
weights
were
increased
by
61%
in
males
after
1
month.
Hepatomegaly,
splenomegaly,
and
yellow
discoloration
of
the
body
fat
were
observed
in
one
male.
This
discoloration
was
not
considered
to
be
treatment
related
and
is
characteristic
of
dinitroaniline
treatment.

The
LOAEL
for
this
study
is
150
ppm
(
3.8
mg/
kg/
day)
based
on
increased
absolute
liver
weights
in
males.
The
NOAEL
is
30
ppm
(
0.8
mg/
kg/
day).

The
submitted
study
is
classified
as
acceptable/
guideline
and
satisfies
the
guideline
requirements
for
a
chronic
oral
toxicity
study
in
the
dog
(
OPPTS
870.4100b;
OECD
452).

4.6
Carcinogenicity
Adequacy
of
data
base
for
Carcinogenicity:
The
data
base
for
carcinogenicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
The
oncogenic
potential
of
trifluralin
was
addressed
by
the
Agency
(
PD1/
2/
3
and
PD
4),
CPRC
(
TXR
0005578,
0007362)
in
1986,
as
well
as
an
IARC
Monograph
in
1991.
Oncogenicity
studies
with
purified
trifluralin
revealed
malignant
neoplasms
of
the
renal
pelvis
and
benign
urinary
bladder
neoplasms
in
the
rat.
After
review
of
the
cancer
data
by
the
CPRC,
new
rat
and
mouse
oncogenicity
studies
were
submitted
to
the
Agency.
However,
the
CPRC
concluded
that
the
results
of
these
studies
were
insufficient
to
warrant
reevaluation.
The
CPRC
concluded
that
trifluralin
is
a
"
Group
C"
(
limited
evidence
of
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
24
carcinogenicity)
carcinogen,
based
on
the
results
of
a
chronic
feeding/
oncogenicity
study
in
the
rat
(
MRID
00044337,
TXR
0005535,
0005578)
which
showed
renal
pelvis
carcinomas,
follicular
cell
adenomas,
papillary
adenomas,
and
cystadenomas.

Trifluralin
has
a
Q1*
of
0.00579
(
mg/
kg/
day)­
1
based
on
male
rat
follicular
cell
adenomas,
papillary
adenoma,
cystadenoma,
and
carcinoma
combined
tumor
rates.
The
Q1*
was
calculated
using
an
interspecies
scaling
factor
of
3/
4.

4.6.1
870.4200a
Carcinogenicity
Study
­
Rat
Executive
Summary:
See
section
4.5.1
4.6.2
870.4200a
Carcinogenicity
Study
­
Rat
Executive
Summary:
In
a
2­
year
rat
study
(
MRID
00044337)
doses
were
0,
813,
3250,
or
6500
ppm
(
equivalent
to
41,
163
and
325
mg/
kg/
day).
The
NOEL
level
for
non­
oncogenic
effects
was
813
ppm
(
41
mg/
kg/
day),
marked
body
weight
depression,
and
elevated
BUN
occurring
at
the
higher
doses.
With
respect
to
neoplastic
changes,
there
was
a
significant
increase
in
malignant
neoplasms
in
the
kidneys
of
all
treated
male
rats,
which
was
dose
related.
There
was
also
a
significant
and
dose
related
increase
in
benign
bladder
neoplasms
in
female
rats.
There
also
is
a
trend
toward
oncogenicity
for
thyroid
follicular
epithelial
tumors
in
males
when
the
Cochrane­
Armitage
Test
is
applied,
but
not
with
the
Fisher's
Exact
Test
with
a
Bonferroni
correction.

4.6.3
870.4200b
Carcinogenicity
Study
­
Mouse
Executive
Summary:
In
a
carcinogenicity
study
(
MRIDs
00158935
and
40392313),
trifluralin
(>
99%
a.
i.,
Batch
No.
HOE
38474
O
H
AT210)
was
administered
daily
in
the
diet
to
60
NMRI,
KFM­
Han,
outbred
(
SPF)
mice/
sex/
dose
for
up
to
104
weeks
at
nominal
doses
of
0,
50,
200,
or
800
ppm
(
0/
0,
7.5/
10.5,
29/
41,
and
118/
165
mg/
kg/
day
in
males/
females).
Ten
mice/
sex/
dose
were
sacrificed
at
52
weeks,
and
the
remaining
survivors
were
sacrificed
at
104
weeks.

Mortality,
clinical
signs,
food
consumption,
body
weights,
body
weight
gains,
ophthalmology,
audiology,
teeth
and
mucous
membrane,
clinical
chemistry,
organ
weights,
gross
pathology,
and
histology
for
both
sexes
at
all
doses
were
unaffected
by
treatment.

The
LOAEL
was
not
observed.
The
NOAEL
for
this
study
is
800
ppm
(
118/
165
mg/
kg/
day
in
males/
females),
the
highest
dose
tested.

At
the
doses
tested,
the
carcinogenic
potential
of
trifluralin
was
negative.
Dosing
was
considered
inadequate
as
a
toxic
effect
was
not
observed,
and
the
limit
dose
was
not
tested.

This
study
is
unacceptable/
guideline
and
does
not
satisfy
the
guideline
requirement
for
a
carcinogenicity
study
[
OPPTS
870.4200b;
OECD
451]
in
mice.
The
LOAEL
was
not
observed,
the
limit
dose
was
not
tested,
and
the
range­
finding
study
indicated
that
dosing
was
inadequate.
The
NOAEL
for
the
range
finder
was
2500
ppm
(
375
mg/
kg/
day),
the
highest
dose
tested.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
25
4.6.4
870.4200a/
b
Carcinogenicity
Study
­
Rat
and
Mouse
A
NCI
cancer
study
(
MRID
00124928,
TXR
0051428)
in
both
rat
and
mouse
is
unacceptable
and
not
suitable
for
regulatory
purposes.
Although
this
carcinogenicity
study
(
MRID
00124928)
was
reviewed
in
1978
and
found
to
be
acceptable/
guideline,
the
trifluralin
used
in
the
study
was
subsequently
found
to
be
contaminated
with
dipropylnitrosamine
at
concentrations
of
84
to
88
ppm
The
liver
tumors
observed
in
both
the
rat
and
mouse
were
a
result
of
this
impurity.
More
recent
studies
in
both
the
rat
and
mouse
were
found
to
be
negative
for
hepatic
carcinogenicity.

This
study
is
unacceptable/
guideline,
not
upgradable,
and
does
not
satisfy
the
guideline
requirement
for
a
carcinogenicity
studies
in
either
rats
[
OPPTS
870.4200a;
OECD
451]
or
mice
[
OPPTS
870.4200b;
OECD
451].

4.7
Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
The
data
base
for
mutagenicity
is
considered
adequate
based
on
pre­
1991
guidelines.
No
mutagenic
potential
was
seen
in
adequately
conducted
pre­
1991
guideline
mutagenicity
studies
with
trifluralin.
The
mutagenicity
tests
requested
in
PD
4
were
submitted
to
the
Agency
and
found
to
be
acceptable.
There
is
no
mutagenic
concern.

4.7.1
Gene
Mutation
870.5100
Bacterial
reverse
gene
mutation
assay
MRID
00148345
(
1984)
TXR
0051428
Acceptable/
Guideline
Trifluralin
was
tested
up
to
the
limit
of
solubility
(
400

g/
plate
­
S9;
800

g/
plate
+
S9).
No
cytotoxicity
was
observed
in
any
strain
at
up
to
800
(+
S9)
or
400
(­
S9)

g/
plate.
No
treatment­
related
increases
in
revertant
colonies
were
observed
at
any
dose
in
any
strain
(
±
S9).
The
positive
controls
induced
the
appropriate
responses.
There
was
no
evidence
of
induced
mutant
colonies
over
background
870.5100
Bacterial
reverse
gene
mutation
assay
MRID
40334707
(
1987)
TXR
0051428
Acceptable/
Guideline
In
a
reverse
gene
mutation
assay
in
bacteria
(
MRID
40334707),
Salmonella
typhimurium
strains
TA98,
TA100,
TA1535,
TA1537,
and
TA1538
were
exposed
to
trifluralin
(
96.8%
a.
i.,
Lot/
Batch
#:
335/
336)
in
dimethylsulfoxide
(
DMSO)
at
concentrations
of
30,
100,
300,
1000,
3000,
or
10,000

g/
plate
in
the
presence
and
absence
of
mammalian
metabolic
activation
(
S9).
The
standard
plate
incorporation
method
was
used.
Standard
strain­
specific
mutagens
served
as
positive
controls.

Trifluralin
was
tested
up
to
the
limit
of
solubility
(
3000

g/
plate,
+/­
S9).
No
cytotoxicity
was
observed
in
any
strain
at
up
to
3000

g/
plate
(+/­
S9).
No
treatment­
related
increases
in
revertant
colonies
were
observed
at
any
dose
in
any
strain
(+/­
S9).
The
positive
controls
induced
the
appropriate
responses.
There
was
no
evidence
of
induced
mutant
colonies
over
background.

870.5100
Bacterial
reverse
gene
mutation
assay
MRID
00153173
(
1979)
TXR
005898
Acceptable/
Guideline
In
a
reverse
gene
mutation
assay
in
bacteria
(
MRID
00153173),
Salmonella
typhimurium
strains
TA98,
TA100,
TA1535,
TA1537,
and
TA1538
were
exposed
to
HOE
38474
(
trifluralin;
purity
not
reported;
Lot/
Batch
#:
OH
AT204)
in
DMSO
at
concentrations
of
0,
4,
20,
100,
500,
2500,
or
10,000

g/
plate
(+/­
S9).
Standard
strain­
specific
positive
controls
were
used.

HOE
38474
was
tested
up
to
the
limit
dose
(
10,000

g/
plate,
+/­
S9).
No
treatment­
related
increases
in
revertant
colonies
were
observed
at
any
dose
in
any
strain
(
±
S9).
The
positive
controls
induced
the
appropriate
responses.
There
was
no
evidence
of
induced
mutant
colonies
over
background.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
26
870.5250
Gene
Mutation
Assay
­
Yeast
MRID
00151898
((
1982)

Acceptable/
Guideline
The
test
material
was
tested
up
to
the
limit
of
solubility
(
1000
mg/
L);
however,
no
solubility
data
were
provided.
No
treatment­
related
increases
in
mutation
frequency
were
observed
at
any
dose
with
or
without
S9­
activation.
The
positive
controls
induced
the
appropriate
response.
There
was
no
concentration­
related
positive
response
of
induced
mutant
colonies
over
background.

870.5300
In
vitro
mammalian
cell
gene
mutation
assay
MRID
0040392306
126661
Acceptable/
Guideline
In
a
mammalian
cell
gene
mutation
assay
at
the
thymidine
kinase
(
TK)
locus,
mouse
lymphoma
L5178Y
cells
cultured
in
vitro
were
exposed
to
trifluralin
(
95.0%
a.
i.;
Lot/
Batch
#:
00554AP2)
in
DMSO
for
4
hours
at
8
concentrations
ranging
from
0.5
to
20

g/
mL
(
individual
doses
not
reported)
both
in
the
presence
and
absence
of
S9­
activation.

Trifluralin
was
tested
up
to
cytotoxic
concentrations
(
20

g/
mL,
+/­
S9).
No
treatment­
related
increases
in
mutation
frequency
were
observed
at
any
dose
compared
to
controls.
The
positive
controls
induced
the
appropriate
response.
There
was
no
concentration­
related
positive
response
of
induced
mutant
colonies
over
background.

870.5300
Forward
Gene
Mutation
Assay
MRID
00148318
(
1984)
TXR
0051428
Acceptable/
Guideline
In
a
mammalian
cell
gene
mutation
assay
at
the
HGPRT
locus
(
MRID
00148318),
Chinese
hamster
ovary
(
CHO)
cells
cultured
in
vitro
were
exposed
to
triflurex
technical
(
trifluralin;
purity
not
reported;
Lot/
Batch
#:
not
reported)
in
ethanol
for
4
hours
at
concentrations
of
10,
50,
100,
200,
300,
400,
or
500

g/
mL
(­
S9)
and
50,
100,
200,
300,
400,
500,
or
600

g/
mL
(+
S9).

Triflurex
technical
was
tested
up
to
cytotoxic
concentrations
(>=
200

g/
mL,
­
S9
and
>=
300

g/
mL,
+
S9)
and
the
limit
of
solubility
(>=
100

g/
mL,
+/­
S9).
No
treatment­
related
increases
in
mutant
frequency
were
observed
in
either
trial
in
the
presence
or
absence
of
S9.
The
positive
controls
induced
the
appropriate
response.
There
was
no
evidence
of
induced
mutant
colonies
over
background
in
the
presence
or
absence
of
S9­
activation.

870.5300
Forward
Gene
Mutation
Assay
MRID
40765601
(
1988)
TXR
0051428
Acceptable/
Guideline
In
a
mammalian
cell
gene
mutation
assay
at
the
HGPRT
locus
(
MRID
40765601),
Chinese
hamster
ovary
(
CHO)
cells
cultured
in
vitro
were
exposed
to
trifluralin
(
97.6%
a.
i.;
Lot/
Batch
#:
39)
in
dimethyl
sulfoxide
for
4
hours
at
concentrations
of
50,
100,
150,
200,
300,
400,
or
500

g/
mL
(
Trial
1,
­
S9);
50,
100,
200,
300,
500,
600,
or
700

g/
mL
(
Trial
2,
­
S9);
50,
100,
200,
250,
300,
400,
or
500

g/
mL
(
Trial
1,
+
S9);
and
50,
100,
200,
300,
400,
500,
or
600

g/
mL
(
Trial
2,
+
S9).

Trifluralin
was
tested
up
to
cytotoxic
concentrations
(>=
200

g/
mL,
+/­
S9)
and
the
limit
of
solubility
(>=
100

g/
mL,
+/­
S9).
No
treatment­
related
increases
in
mutant
frequency
were
observed
in
either
trial
in
the
presence
or
absence
of
S9.
The
positive
controls
induced
the
appropriate
response.
There
was
no
evidence
of
induced
mutant
colonies
over
background
in
the
presence
or
absence
of
S9­
activation.

4.7.2
Cytogenetics
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
27
870.5385
In
Vivo
Mammalian
Cytogenetics
[
Bone
Marrow/
Spermatogonial
Aberration
Test]

MRID
40765603
(
1988)
TXR
0051428
Acceptable/
Guideline
In
a
bone
marrow/
spermatogonial
chromosome
aberration
assay
(
MRID
40765603),
ICR
mice
(
10
males/
dose,
spermatogonial
tissue;
and
5/
sex/
dose,
bone
marrow)
were
dosed
once
daily
via
gavage
(
10
mL/
kg)
with
trifluralin
(
97.6%
a.
i.,
Lot/
BatchNo
39)
in
corn
oil
at
doses
of
0,
62.5,
208,
or
625
mg/
kg
for
5
consecutive
days.
Bone
marrow
and
spermatogonial
cells
were
harvested
at
4.5
hours
after
the
last
treatment.

Mortalities
were
observed
in
the
625
mg/
kg
females
(
2/
5
treated
vs
1/
5
controls),
and
at
62.5
mg/
kg
in
the
males
(
2/
10
treated
vs
1/
10
controls)
and
females
(
2/
5
treated
vs
1/
5
controls).
Clinical
signs
of
toxicity
(
lethargy,
swollen
neck,
and
yellow
stains
around
the
mouth
and
perianal
area)
were
also
observed
at
>=
62.5
mg/
kg.
No
statistically
significant
increases
in
the
percent
of
aberrant
cells
were
observed
at
any
dose
in
either
sex
in
the
bone
marrow
assay
or
in
the
males
in
the
spermatogonial
assay.
Trifluralin
was
tested
at
an
adequate
dose
based
on
mortalities
observed
at
>=
62.5
mg/
kg.
The
positive
control
induced
the
appropriate
response.
There
was
no
evidence
of
chromosome
aberration
induced
over
background
870.5385
In
Vivo
Mammalian
Cytogenetics
[
Bone
Marrow
Chromosome
Aberration
Test]

MRID
00148320
TXR
0051428
Acceptable/
Guideline
In
a
bone
marrow
chromosome
aberration
assay
(
MRID
00148320),
5
Sprague­
Dawley
(
HSD:([
SD]
BR)
rats/
sex/
dose/
sacrifice
time
were
treated
once
via
oral
gavage
with
Triflurex
technical
(
trifluralin;
97.3%
a.
i.;
Batch
#:
5320),
in
corn
oil
at
doses
of
0,
500,
1650,
or
5000
mg/
kg.
Bone
marrow
cells
were
harvested
at
6,
24,
or
48
hours
after
treatment.

Mortality
was
observed
at
1650
(
3/
15
males
and
5/
15
females)
and
5000
(
2/
15
males
and
1/
15
females)
mg/
kg
upon
initial
dosing;
however,
these
animals
were
replaced
and
only
one
replacement
1650
mg/
kg
female
in
the
48
hour
group
died
after
dosing.
Triflurex
technical
induced
minimal
bone
marrow
toxicity
(
as
indicated
by
decreased
mitotic
index)
at

500
mg/
kg
in
males
and

1650
mg/
kg
in
females.
Dosing
was
considered
adequate
based
on
bone
marrow
toxicity
and
that
the
animals
were
dosed
above
the
limit
dose
(
2000
mg/
kg).
No
statistically
significant
increases
in
the
percent
of
aberrant
cells
were
observed
at
any
dose
or
sampling
time
compared
to
concurrent
controls.
The
positive
control
induced
the
appropriate
response.
There
was
no
evidence
of
chromosome
aberration
induced
over
background.

870.5395
In
vivo
Mouse
Erythrocyte
Micronucleus
assay
MRID
00151895
(
1981)
TXR
Acceptable/
Guideline
In
a
bone
marrow
micronucleus
assay,
5
NMRI
mice/
sex/
dose
were
treated
via
oral
gavage
with
HOE
38474
(
Trifluralin;
98.3%
a.
i.,
Lot/
Batch
#:
OH
AT208),
in
sesame
oil
at
doses
of
0,
25,
250,
or
2500
mg/
kg
on
two
consecutive
days
(
24
hours
apart).
Bone
marrow
cells
were
harvested
at
6
hours
after
the
last
treatment.

No
unscheduled
deaths
occurred
during
the
study.
No
clinical
signs
of
toxicity
were
observed.
No
statistically
significant
differences
in
the
number
of
micronucleated
polychromatic
erythrocytes
(
MPCE)
or
normocytes
and
no
decrease
in
polychromatic
erythrocyte
to
normocyte
(
PCE:
NCE)
ratios
were
noted
in
the
treated
animals
compared
to
controls;
however,
only
individual
data
were
provided.
Additionally,
although
no
evidence
of
cytotoxicity
(
decreased
PCE:
NCE)
was
noted
in
the
bone
marrow,
the
animals
were
sufficiently
dosed
(
the
limit
dose
was
given
twice).
The
test
material
was
absorbed
as
indicated
by
the
presence
of
orange
urine
in
the
2500
mg/
kg
animals.
The
positive
control
induced
the
appropriate
response.
There
was
no
significant
increase
in
the
frequency
of
micronucleated
polychromatic
erythrocytes
in
bone
marrow
compared
to
controls.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
28
870.5450
Dominant
Lethal
­
Mouse
MRID
00151896
(
1984)

Acceptable/
Guideline
In
a
dominant
lethal
assay
(
MRID
00151896),
30
male
NMRI
mice
were
dosed
once
daily
for
5
consecutive
days
via
oral
gavage
(
5
mL/
kg)
with
HOE
38474
(
trifluralin;
98.3%
a.
i.;
Lot/
Batch
#:
OHZD99002),
in
sesame
oil
at
concentrations
of
0,
10,
100,
or
1000
mg/
kg.
After
the
final
treatment,
each
male
was
mated
with
13
untreated
females
during
separate
4­
day
intervals
over
a
52
day
period.

No
treatment­
related
mortalities
were
noted
during
the
study.
No
treatmentrelated
effects
on
clinical
signs,
body
weight,
fertilization
rate,
and
pre­
or
postimplantation
loss
were
observed;
however,
no
data
were
provided.
The
positive
control
(
cyclophosphamide)
increased
the
number
of
post­
implantation
fetal
losses.
There
was
no
time­
related
positive
response
of
increased
pre­
or
post­
implantation
loss
compared
to
controls.

870.5450
Dominant
Lethal
­
Rat
MRID
00148319
(
1984)
TXR
0051428
Acceptable/
Guideline
In
a
dominant
lethal
assay
(
MRID
00148319),
groups
of
20
male
Sprague­
Dawley
(
CD)
rats/
dose
were
treated
once
daily
via
gavage
(
1.0
mL/
dose)
with
Triflurex
technical
(
trifluralin;
97.3%
a.
i.;
Batch
#:
5320),
in
corn
oil
for
5
consecutive
days
at
doses
of
0,
100,
333,
or
1000
mg/
kg/
day
(
total
doses
of
0,
500,
1665,
or
5000
mg/
kg).
Beginning
two
days
after
the
last
exposure,
each
male
was
mated
sequentially
to
two
untreated
female
rats
per
week
for
seven
weeks.
At
14
days
after
the
midpoint
of
each
mating
week,
the
females
were
killed,
determined
to
be
pregnant
or
not
pregnant,
and
the
number
of
corpora
lutea,
living,
dead,
and
total
implantations
was
determined.
On
the
fifth
day
of
dosing,
the
positive
control
males
were
given
a
single
dose
of
triethylenemelamine
(
TEM;
0.3
mg/
kg,
i.
p.
in
0.9%
saline).

One
1000
mg/
kg
male
(#
8476)
was
found
dead
72
hours
after
the
last
treatment.
Triflurex
technical
was
tested
at
the
limit
dose
(
5000
mg/
kg
=
1000
mg/
kg/
day
X
5
days).
There
were
no
treatment­
related
effects
on
fertility,
number
of
implants,
pre­
implantation
losses,
number
of
dead
implants,
number
of
females
with

1
or

2
dead
implants,
or
ratio
of
dead
implants
to
total
implants
at
any
dose
in
the
study.
The
positive
control
induced
the
appropriate
response.
There
was
no
time­
related
positive
response
of
increased
pre­
or
postimplantation
loss
compared
to
controls.

4.7.3
Other
Genotoxicity
870.5550
Unscheduled
DNA
synthesis
in
mammalian
cell
culture
MRID
40765602
(
1988)
TXR
0051428
Acceptable/
Guideline
In
an
unscheduled
DNA
synthesis
assay
(
MRID),
primary
rat
hepatocyte
cultures
were
exposed
to
trifluralin
(
97.6%
a.
i.;
Lot/
Batch
#:
39)
in
DMSO
for
18­
19
hours
at
concentrations
of
0,
0.032,
0.214,
0.404,
0.917,
2.22,
4.36,
8.52,
21.3,
42.9,
88.0,
448,
or
898

g/
mL.
Fifteen
doses
ranging
from
0.032­
898

g/
mL
were
used
in
each
assay;
however,
the
three
doses
between
0.032
and
0.214

g/
mL
were
not
reported.

Trifluralin
was
tested
up
to
cytotoxic
levels
(
determined
by
trypan
blue
exclusion),
88.0

g/
mL
in
rat
#
1
and
42.9

g/
mL
in
rat
#
2.
There
were
no
marked
increases
observed
in
the
mean
NNG
or
percent
cells
in
repair
at
any
dose
in
either
trial.
The
positive
controls
induced
marked
increases
in
mean
NNG
and
the
percent
of
cells
in
repair.
There
was
no
evidence
that
unscheduled
DNA
synthesis,
as
determined
by
radioactive
tracer
procedures
(
nuclear
silver
grain
counts),
was
induced.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
29
870.5550
Unscheduled
DNA
synthesis
in
mammalian
cell
culture
MRID
00151894
TXR
0051428
Acceptable/
Guideline
In
an
unscheduled
DNA
synthesis
assay
(
MRID
00151894),
HeLa
cell
cultures
were
exposed
to
HOE
38474
(
trifluralin,
98.3%
a.
i.;
Lot/
Batch
#:
OH
AT
208)
in
DMSO
for
1
hour
at
concentrations
of
0,
50,
100
or
500

g/
mL
both
in
the
presence
and
absence
of
S9­
activation.

HOE
38474
was
tested
up
to
cytotoxic
concentrations
(>=
50

g/
mL,
+/­
S9).
No
statistically
significant
increases
in
mean
counts
per
minute
of
the
test
material
with
hydroxyurea
were
noted
compared
to
concurrent
solvent
controls
at
any
dose
level,
either
in
the
presence
or
absence
of
S9­
activation.
The
positive
controls
induced
the
appropriate
response.
There
was
no
evidence
that
unscheduled
DNA
synthesis,
as
determined
by
liquid
scintillation
counting
procedures,
was
induced.

870.5900
In
vivo
Sister
Chromatid
Exchange
Assay
MRID
00133426
(
1983)
TXR
005535,
051428
Acceptable/
Guideline
In
a
mammalian
cell
cytogenetics
assay
[
SCE]
using
the
BrdU
tablet
method
,
groups
of
3
female
Chinese
hamsters/
dose
were
exposed
once
via
gavage
(
10
mL/
kg)
to
trifluralin
(
95.0%
a.
i.,
Lot/
batch
No
00554AP2)
in
DMSO
and
10%
acacia
at
concentrations
of
200,
300,
400,
or
500
mg/
kg
at
5
hours
following
BrdU
tablet
implantation.
Bone
marrow
was
collected
at
21
hours
after
treatment.

Trifluralin
was
tested
up
to
cytotoxic
concentrations
(>=
400
mg/
kg).
Cytotoxicity
(
as
indicated
by
an
increase
in
the
number
of
first
division
metaphase
figures)
was
observed
in
all
animals
at
>=
400
mg/
kg.
No
statistically
significant
increases
in
SCE
frequency
were
observed
at
any
dose
compared
to
controls.
The
positive
control
induced
the
appropriate
response.
There
was
no
evidence
of
SCE
induced
over
background
4.8
Neurotoxicity
Adequacy
of
data
base
for
Neurotoxicity:
The
HIARC
concluded
that
there
were
no
signs
of
neurotoxicity
in
the
trifluralin
data
base.
None
of
the
guideline
neurotoxicity
studies
are
required.

4.8.1
870.6100
Delayed
Neurotoxicity
Study
­
Hen
Executive
Summary:
In
an
acute
delayed
neurotoxicity
study
(
MRID
00159616),
White
Leghorn
hens
were
gavaged
with
trifluralin
(
98.4%,
Batch
No.
038474)
at
0
(
10
mL/
kg
sesame
oil)
or
5000
mg/
kg;
positive
control
hens
received
500
mg/
kg
triorthocresyl
phosphate
(
TOCP)
trifluralin
via
capsule
at
doses
of
800,
2000
or
5000
mg/
kg..
The
acute
oral
LD50
for
trifluralin
was
greater
than
5000
mg/
kg.

Trifluralin­
treated
hens
showed
marginal
disturbances
in
muscle
coordination
from
days
9
to
11;
from
day
12
on,
no
further
disturbances
were
noted.
Histopathological
evaluation
of
the
brain,
spinal
cord
and
sciatic
nerve
did
not
show
any
evidence
of
neurotoxic
effects.

Under
the
conditions
of
this
study,
trifluralin
at
5000
mg/
kg
did
not
produce
acute
delayed
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
30
neurotoxicity.

This
study
is
acceptable/
guideline
(
OPPTS
870.6100)
and
satisfied
requirements
for
an
acute
delayed
neurotoxicity
study
in
the
hen.

4.8.2
870.6200
Acute
Neurotoxicity
Screening
Battery
Not
required
4.8.3
870.6200
Subchronic
Neurotoxicity
Screening
Battery
Not
required
4.8.4
870.6300
Developmental
Neurotoxicity
Study
Not
required
4.9
Metabolism
4.9.1
Adequacy
of
data
base
for
metabolism:

Adequacy
of
data
base
for
metabolism:
The
data
base
for
metabolism
is
considered
to
be
complete.
No
additional
studies
are
required
at
this
time.
In
a
rat
metabolism
study,
14C­
trifluralin
appears
to
be
extensively
metabolized,
as
evidenced
by
many
non­
conjugated
(
20­
30)
and
conjugated
(
10­
20)
metabolites
observed.
Although
the
percent
of
the
administered
dose
excreted
in
the
urine
is
not
known,
the
majority
of
the
metabolites
were
present
at
1
to
2%
of
the
total
urinary
radioactivity.
Based
on
the
metabolic
profile,
four
metabolic
pathways
were
identified
(
1)
oxidative
N­
dealkylation
of
one
or
both
propyl
groups
and
metabolites
which
were
hydroxylated
on
the
propyl
side
chain,
(
2)
reduction
of
one
or
both
nitro
groups
to
the
corresponding
amine,
(
3)
cyclization
reactions
to
give
a
variety
of
substituted
and
unsubstituted
benzimidazole
metabolites,
and
(
4)
conjugation
reactions,
including
acetylation
of
the
reduced
nitro
groups,
sulfate,
and
glucuronic
acid
conjugates.

4.9.2
870.7485
Metabolism
­
Rat
Executive
Summary:
In
a
rat
metabolism
study
(
MRID
41218901),
14C­
trifluralin
(
Lot
no.
553­
VE9­
116,
>
98%
radiochemical
purity)
in
corn
oil
was
administered
by
gavage
at
300
mg/
kg/
day
to
5
Fischer
344
rats/
sex
on
three
consecutive
days.
Metabolite
characterization
of
the
24­
48
hour
urinary
samples
(
pooled
by
sex)
and
quantitation
of
urinary
samples
collected
at
0­
24,
24­
48,
and
48­
54
hours
and
pooled
by
sex
were
performed
using
liquid
scintillation
counting,
silica
gel
column
chromatography,
TLC,
HPLC,
NMR,
and
mass
spectroscopy.
The
objective
of
this
study
was
to
identify
the
urinary
metabolites
of
trifluralin.

There
was
no
sex­
dependent
effect
on
metabolic
profiles.
A
minimum
of
20­
30
nonconjugated
metabolites
and
an
additional
10­
20
conjugated
metabolites
were
present
in
the
urine,
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
31
but
no
parent
compound
was
detected.
Information
on
the
percentage
of
the
administered
dose
excreted
in
the
urine
was
not
provided.
However,
no
single
metabolite
accounted
for
more
than
8­
10%
of
the
total
urinary
radioactivity,
and
the
majority
of
the
metabolites
were
present
at
1­
2%
of
the
total
urinary
radioactivity.
Thus,
almost
all
of
the
metabolites
were
minor
(<
5%
of
the
total
radioactive
dose).
Metabolite
F1B
was
found
at
8.2­
8.9%
of
the
total
urinary
radioactivity
in
both
sexes,
and
Metabolite
F2,
N­{[
3­(
acetylamino)­
2­
amino­
5­(
trifluoromethyl)]
phenyl}
acetamide,
was
found
at
4.0­
5.2%.
Metabolite
F1B
was
partially
characterized
as
retaining
the
trifluoromethyl
groups,
the
two
equivalent
aromatic
protons,
and
the
two
nitro
groups,
but
the
propyl
groups
were
lost.
Ten
other
metabolites
were
identified
(<
0.1­
3.7%
of
total
urinary
radioactivity,
each
compound
in
each
sex).
Two
additional
metabolites
were
partially
characterized
(
0.1­
2.6%
of
total
urinary
radioactivity,
each
compound
in
each
sex).

Four
metabolic
pathways
were
identified
as
follows:
(
i)
oxidative
N­
dealkylation
of
one
or
both
propyl
groups
and
metabolites
which
were
hydroxylated
on
the
propyl
side
chain;
(
ii)
reduction
of
one
or
both
nitro
groups
to
the
corresponding
amine;
(
iii)
cyclization
reactions
to
give
a
variety
of
substituted
and
unsubstituted
benzimidazole
metabolites;
and
(
iv)
conjugation
reactions,
including
acetylation
of
the
reduced
nitro
groups,
sulfate,
and
glucuronic
acid
conjugates.

This
study
is
classified
as
acceptable/
non­
guideline
and
satisfies
the
purpose
for
which
it
was
intended.

4.9.3
870.7600
Dermal
Absorption
­
Rat
Although
there
is
a
dermal
absorption
study
with
trifluralin
(
MRID
40673701),
it
was
found
to
be
unacceptable.
However,
there
is
an
acceptable
dermal
absorption
study
with
ethalfluralin
in
monkeys.
Trifluralin
and
ethalfluralin
have
similar
structures
(
differing
only
in
the
dialkyl
groups)
and
physical
constants
(
melting
points,
solubilities,
and
the
log
Kows).
Using
the
dermal
absorption
percentage
for
ethalfluralin
(
3%)
is
a
more
accurate
estimation
for
trifluralin
than
assuming
a
value
of
100%
for
conversion
of
an
oral
study
to
a
dermal
endpoint
for
intermediate
and
long­
term
occupational
exposure.
Further,
the
dermal
absorption
value
of
3%
is
similar
to
the
approximation
from
the
ratio
of
the
dermal
and
oral
NOAELs
(
1000/
154
=
6%).

Executive
Summary
(
Ethalfluralin):
Four
monkeys
(
2
males
and
2
females)
were
administered
2
mg/
kg
radio­
labeled
ethalfluralin
in
ethanol
intravenously
or
topically
to
the
forearm
and
the
plasma
level
determined
for
120
hours
to
determine
an
area
under
the
curve
for
both
types
of
applications
(
MRID:
00132820,
92062028).
Two
compartments
were
noted
with
one­
half
lives
of
1.71
hours
for
the
plasma
distributive
phase
and
79.1
hours
for
the
terminal
plasma
disappearance
phase.
After
120
hours
label
was
not
detectable
in
2
(
1
male
and
1
female)
of
the
4
animals
studied.
Since
the
2
animals
with
undetectable
plasma
levels
at
120
hour
yielded
the
most
consistent
data,
data
from
these
animals
were
used
to
calculate
the
AUCs.
The
dermal
absorption
was
determined
by
ratio
of
the
area
under
the
plasma
curve
AUC;
[(
AUC­
dermal/(
AUC­
i.
v.)]
x
100
=
2.84%.

Percentage
(%)
Dermal
Absorption:
3%
for
ethalfluralin
as
a
surrogate
for
trifluralin.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
32
4.10
Other
Studies
Special
studies
were
submitted
to
determine
the
NOAEL/
LOAEL
for
nephrotoxicity
in
male
rats.
The
findings
included
the
presence
of
tubular
cytoplasmic
hyaline
droplets,
increased
urinary
volume,
and
increased
total
protein,
AST,
and
LDH
in
the
urine.
Electrophoresis
revealed
albumin,

1­
globulin
and

2­
globulin
in
the
urine.

4.10.1
Urinary
Tract
Effects
(
Range
Finding)
­
Rat
Executive
Summary:
In
a
2­
week
oral
toxicity
study
(
MRID
00157154),
trifluralin
(
96.4%
a.
i.,
Batch
#
554AP2)
was
administered
to
10
male
Fischer
344
rats
at
6500
ppm
(
approximately
346.47
mg/
kg/
day)
or
5
rats
at
0
ppm.
The
objective
of
this
study
was
to
determine
the
effects
of
trifluralin
on
the
urinary
tract
of
male
rats.

All
animals
survived
until
the
scheduled
sacrifice.
Food
consumption
was
reduced
by
27%,
and
may
have
been
indicative
of
a
lack
in
palatability.
Additionally,
decreases
(
not
statistically
significant)
in
body
weight
gain
(
5.4
g
treated
vs
15.6
g
control)
and
food
utilization
(
2.6
treated
vs
6.3
controls)
were
observed.

The
treated
animals
urinated
orange­
yellow
fluid,
indicative
of
the
test
compound
and/
or
metabolites,
resulting
in
soiled
genital
areas.
During
urinalysis,
the
following
observations
were
made:
(
i)
urine
clarity
was
reduced
in
the
treated
animals
on
days
6
and
13;
(
ii)
triple
phosphate
crystals
were
observed
in
all
treated
animals
and
were
particularly
abundant
on
days
6
and
13
(
vs
3/
5
control
rats);
(
iii)
amorphous
material
was
found
in
the
urine
of
treated
animals;
(
iv)
LDH
and
AST
were
increased
at
days
6
and
13;
on
day
13
the
increase
was
84%
for
LDH
and
205%
for
AST;
(
v)
mildly
increased
protein
concentrations
were
observed
on
days
6
and
13.
Cytoplasmic
hyaline
droplet
formation
in
many
renal
cortical
tubules
of
each
treated
animal
indicated
epithelial
degeneration
(
vs
0/
5
controls).

This
study
is
classified
as
acceptable/
non­
guideline
and
satisfies
the
purpose
for
which
it
was
intended.

4.10.2
Urinary
Tract
Effects
in
Male
Rats
Executive
Summary:
The
purpose
of
this
special
study
(
MRID
00157156,
40138301,
41086101)
was
to
provide
additional
information
to
establish
a
NOAEL
for
nephrotoxicity,
which
was
observed
in
a
chronic
feeding
study
in
rats
at
the
lowest
dose
tested.
Trifluralin
(
96­
97%
a.
i.;
Lot/
Batch
#
00554AP2)
was
administered
continuously
via
the
diet
to
Fischer
344
male
rats
at
nominal
doses
of
0,
50,
200,
800,
3200,
and
6400
ppm
(
time­
weighted
daily
averages
through
month
4:
0,
2.5,
10.1,
40.1,
164,
and
330
mg/
kg/
day)
for
up
to
4
months.
The
rats
(
n=
10,
except
n=
15
in
controls
and
0.05%
group)
were
sacrificed
at
30,
60,
and
90
days.
At
0
and
50
ppm,
45
rats
were
treated,
and
30
rats
were
treated
in
each
of
the
other
doses.
The
rats
(
n=
10­
15)
were
sacrificed
at
30,
60,
and
90
days.
Additionally,
a
satellite
group
of
15
rats
at
0
and
50
ppm
and
10
rats
in
each
of
the
other
doses
was
treated
for
4
months,
followed
by
6
weeks
of
maintenance
on
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
33
the
control
diet.
All
satellite
study
animals
were
sacrificed
on
day
171.
Body
weight,
body
weight
gain,
food
consumption,
food
efficiency,
gross
pathology,
and
histopathology
of
the
kidney
and
urinary
bladder
were
evaluated.
Measurements
of
numerous
parameters
were
made
during
urine
chemistry
and
protein
electrophoresis
of
the
urine.

No
treatment­
related
adverse
effects
were
observed
on
mortality,
clinical
signs,
body
weight,
or
body
weight
gain
through
month
3;
after
4
months
of
treatment,
there
was
a
significant
decrease
in
body
weight,
body
weight
gain
and
food
utilization
at
>=
3200
ppm.
Urine
was
discolored
by
the
dinitroaniline
compound
at
3200
and
6400
ppm.
No
effect
was
observed
in
the
50
ppm
group.
Recovery
was
evident
following
6
weeks
of
maintenance
on
the
control
diet
in
all
groups,
but
was
incomplete
in
the
6400
ppm
group.

There
was
a
dose
related
increase
(>=
200
ppm)
in
the
incidence
of
intra­
cytoplasmic
hyaline
droplet
formation
in
the
renal
cortical
tubular
epithelial
cells
(
minimal
to
moderate
severity)
and
an
increase
in
urine
 1­
globulin
and
 2­
globulin
(
all
biochemical
indicators
of
kidney
toxicity).

In
the
>=
800
ppm
groups,
significant
increases
of
73­
489%
in
urinary
total
protein,
AST,
and
LDH
and
in
the
urinary
volume
(
38­
89%)
were
observed.

In
the
6400
ppm
group,
increases
of
27­
169%
in
urinary
calcium
and
sodium
were
observed.

The
LOAEL
for
nephrotoxicity
is
800
ppm
(
40.1
mg/
kg/
day),
based
on
the
presence
of
tubular
cytoplasmic
hyaline
droplets;
increased
total
protein,
AST,
and
LDH
in
the
urine;
albumin
 1­
globulin
and
 2­
globulin
observed
by
urine
electrophoresis;
and
increased
urinary
volume.
The
NOAEL
is
200
ppm
(
10.1mg/
kg/
day).

This
study
is
classified
as
acceptable/
non­
guideline
and
satisfies
the
purpose
for
which
it
was
intended
5
TOXICITY
ENDPOINT
SELECTION
5.1
Endpoint
Selection
See
Section
9.2
for
Endpoint
Selection
Table.

5.2
Acute
Reference
Dose
(
aRfD)

5.2.1
General
Population
There
was
no
appropriate
single
dose
endpoint
for
this
population
sub­
group.

5.2.2
Females
13­
50
Study
Selected:
Developmental
Toxicity
Study
­
Rat
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
34
100
mg/
kg/
day
(
NOAEL)
Acute
RfD
=
=
1.0
mg/
kg
100
(
UF)

2.4
mg/
kg/
day
(
NOAEL)
Chronic
RfD
=
=
0.024
mg/
kg/
day
100
(
UF)
MRID
No.:
00151899,
00159620
and
40392310
Executive
Summary:
See
section
4.3.1
Dose
and
Endpoint
for
Establishing
aRfD:
Developmental
NOAEL
=
100
mg/
kg/
day,
based
on
increased
incidences
of
resorptions
at
the
developmental
LOAEL
of
500
mg/
kg/
day.

Uncertainty
Factors:
100X
(
10x
for
interspecies
extrapolation
and
10x
for
intraspecies
variation).

Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
This
study
and
endpoint
are
appropriate
for
the
acute
RfD.
Increased
early
resorptions
observed
at
500
mg/
kg/
day
could
be
due
to
a
single
dose.

5.3
Chronic
Reference
Dose
(
cRfD)

Study
Selected:
Chronic
toxicity
oral
(
capsule)
­
dog
MRID
No.:
42447001
Executive
Summary:
See
section
4.5.2
Dose
and
Endpoint
for
Establishing
cRfD:
NOAEL
=
2.4
mg/
kg/
day,
based
on
increased
frequency
of
abnormal
stool,
decreased
body
weights
and
body
weight
gains,
and
on
decreased
erythrocytes
and
hemoglobin
and
increased
thrombocytes
in
males
at
the
LOAEL
of
40
mg/
kg/
day.

Uncertainty
Factors:
100X
(
10x
for
interspecies
extrapolation
and
10x
for
intraspecies
variation).

Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
The
HIARC
reaffirmed
the
previously
established
chronic
RfD.
This
study
is
of
the
appropriate
duration
of
exposure
for
this
risk
assessment.
The
lower
NOAEL
of
0.75
mg/
kg/
day
established
in
the
other
dog
study
(
MRID
00151908)
was
not
selected
since
the
endpoint
(
increase
in
liver
weights)
was
not
accompanied
by
any
other
corroborative
changes
such
as
alterations
in
clinical
chemistry
parameters
or
histopathological
changes
in
the
liver.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
35
5.4
Occupational/
Residential
Exposure
5.4.1
Incidental
Oral
Exposure
5.4.1.1
Short­
Term
(
1
­
30
days)
Incidental
Oral
Exposure
Selected
Study:
Two­
Generation
Reproduction
Study
­
Rat
§
870.3800
MRID
No.:
00151901,
00151902,
00151903,
and
00159619
Executive
Summary:
See
section
4.4.1
Dose
and
Endpoint
for
Risk
Assessment:
Offspring
NOAEL
=
10
mg/
kg/
day,
based
on
decreased
pup
body
weight
in
the
F1a
and
F1b
generations
on
post­
natal
days
7
and
21
at
the
LOAEL
of
32.5
mg/
kg/
day.

Comments
about
Study/
Endpoint/
Margin
of
Exposure:
This
study
and
endpoint
are
appropriate
for
the
population
(
infants
and
children)
and
duration
(
1
to
30
days).
On
post­
natal
day
1,
pups
in
the
32.5
mg/
kg/
day
group
had
mean
body
weights
comparable
to
the
control
group
indicating
that
there
was
no
in
utero
effect
on
pup
body
weight.
On
post­
natal
days
7
and
21,
however,
there
were
significant
decreases
in
pup
weights.

5.4.1.2
Incidental
Oral
Exposure:
Intermediate­
Term
(
1
­
6
Months)

Selected
Study:
Special
Urinalysis
Study
[
feeding]
­
rat
§
Non­
guideline
MRID
No.:
00157156,
40138301,
41086101
Executive
Summary:
See
section
4.10.2
Dose
and
Endpoint
for
Risk
Assessment:
NOAEL:
10.1
mg/
kg/
day,
based
on
cortical
tubular
cytoplasmic
hyaline
droplets;
increased
total
protein,
AST,
and
LDH
in
the
urine;
and
albumin
 1­
globulin
and
 2­
globulin
observed
by
urine
electrophoresis;
and
increased
urinary
volume
observed
at
the
LOAEL
of
40.1
mg/
kg/
day.

Comments
about
Study/
Endpoint/
Margin
of
Exposure:
The
dose,
endpoint
and
study,
as
well
as
the
population
of
concern
(
infants
and
children)
are
appropriate
for
this
exposure
scenario.

5.4.2
Dermal
Exposure
5.4.2.1
Dermal
Exposure:
Short
Term
(
1
­
30
Days)
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
36
Quantification
of
dermal
risk
for
this
exposure
period
is
not
required
since
no
systemic
toxicity
was
observed
at
1000
mg/
kg/
day
(
limit
dose)
in
the
21­
day
dermal
toxicity
studies.
Also
no
nephrotoxicity
was
seen
in
the
dermal
studies.

The
technical
grade
trifluralin
caused
typical
delayed
hypersensitivity
in
guinea
pigs.
Repeated
dermal
applications
to
rats
resulted
in
skin
lesions
that
progressed
in
severity
and
therefore
may
have
the
potential
for
adverse
effects.
Because
risk
can
not
be
quantified,
the
HIARC
also
recommends
that
the
products
containing
trifluralin
should
be
labeled
as
SENSITIZER
and
should
avoid
human
contact.
A
Local
Lymph
Node
Assay
in
rats
may
be
used
to
define
the
NOAEL
for
dermal
sensitization
and
allow
quantification.

5.4.2.2
Dermal
Exposure:
Intermediate­
Term
(
1
­
6
Months)

Selected
Study:
Special
Urinalysis
Study
[
feeding]
­
rat
§
Non­
guideline
MRID
No.:
00157156,
40138301,
41086101
Executive
Summary:
See
section
4.10.2
Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
=
10.1
mg/
kg/
day
corrected
for
3%
absorption
by
the
dermal
route
relative
to
oral
absorption,
based
on
cortical
tubular
cytoplasmic
hyaline
droplets;
increased
total
protein,
AST,
and
LDH
in
the
urine;
albumin
 1­
globulin
and
 2­
globulin
observed
by
urine
electrophoresis;
and
increased
urinary
volume
observed
at
the
LOAEL
of
40.1
mg/
kg/
day.

Comments
about
Study/
Endpoint/
Margin
of
Exposure:
The
HIARC
selected
this
study
to
address
the
nephrotoxic
concerns
seen
after
subchronic
exposure,
which
is
appropriate
for
this
exposure
period
of
concern.

5.4.2.3
Dermal
Exposure
Long­
Term
(>
6
Months)

Study
Selected:
Chronic
toxicity
oral
(
capsule)
­
dog
MRID
No.:
42447001
Executive
Summary:
See
section
4.5.2
Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
=
2.4
mg/
kg/
day
corrected
for
3%
absorption
by
the
dermal
route
relative
to
oral
absorption,
based
on
increased
frequency
of
abnormal
stool,
decreased
body
weights
and
body
weight
gains,
and
on
decreased
erythrocytes
and
hemoglobin
and
increased
thrombocytes
in
males
at
the
LOAEL
of
40
mg/
kg/
day.

Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
This
dose,
endpoint
and
study
were
selected
to
establish
the
chronic
RfD.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
37
5.4.3
INHALATION
EXPOSURE
5.4.3.1
Short­
term
Inhalation
Exposure
(
1
to
30
days)

Selected
Study:
30­
Day
Inhalation
Study
in
the
Rat
§
870.3465
MRID
No.:
40392312,
00151904
Executive
Summary:
See
section
4.2.3
Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
=
300
mg/
m3
(
81
mg/
kg/
day)
based
on
increased
bilirubin
in
females
and
incidences
of
dyspnea
and
ruffled
fur
in
males
and
females
at
1000
mg/
m3
(
270
mg/
kg/
day).

Comment
about
the
Study/
Endpoint/
Margin
of
Exposure:
This
is
the
appropriate
route
of
administration
and
duration
of
exposure.

5.4.3.2
Inhalation
Exposure:
Intermediate­
Term
(
1­
6Months)

Selected
Study:
Special
Urinalysis
Study
[
feeding]
­
rat
§
Non­
guideline
MRID
No.:
00157156,
40138301,
41086101
Executive
Summary:
See
section
4.10.2
Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
=
10.1
mg/
kg/
day
inhalation
absorption
assumed
to
be
equivalent
to
oral
absorption.
Based
on
cortical
tubular
cytoplasmic
hyaline
droplets;
increased
total
protein,
AST,
and
LDH
in
the
urine;
and
albumin
 1­
globulin
and
 2­
globulin
observed
by
urine
electrophoresis;
and
increased
urinary
volume
observed
at
the
LOAEL
of
40.1
mg/
kg/
day.

Comments
about
Study/
Endpoint/
Margin
of
Exposure:
The
inhalation
study
was
not
selected
since
the
NOAEL
(
81
mg/
kg/
day)
would
not
address
the
nephrotoxicity
seen
at
40.1
mg/
kg/
day
in
the
special
urinalysis
study.
Since
an
oral
dose
was
selected
absorption
via
inhalation
is
presumed
to
be
equivalent
to
oral
absorption.

5.4.3.3
Inhalation
Exposure:
Long­
Term
(>
6
Months)

Study
Selected:
Chronic
toxicity
oral
(
capsule)
­
dog
MRID
No.:
42447001
Executive
Summary:
See
section
4.5.2
Dose
and
Endpoint
for
Establishing
RfD:
NOAEL
=
2.4
mg/
kg/
day
with
inhalation
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
38
absorption
assumed
to
be
equivalent
to
oral
absorption.
Based
on
increased
frequency
of
abnormal
stool,
decreased
body
weights
and
body
weight
gains,
and
on
decreased
erythrocytes
and
hemoglobin
and
increased
thrombocytes
in
males
at
the
LOAEL
of
40
mg/
kg/
day.

Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
Since
an
oral
dose
was
selected,
absorption
via
inhalation
is
presumed
to
be
equivalent
to
oral
absorption.

5.5
Dermal
Absorption
Selected
Study:
Percutaneous
absorption
14C­
ethalfluralin
in
monkeys.
Guideline
#:
NG
MRID
No.:
00132820,
92062028
Executive
Summary:
See
section
4.9.3
Dermal
Absorption
Factor:
3%

5.6
Classification
and
Quantification
of
Carcinogenic
Potential
5.6.1
Classification
of
Carcinogenic
Potential
The
CPRC
concluded
that
trifluralin
is
a
"
Group
C"
(
limited
evidence
of
carcinogenicity)
carcinogen,
based
on
the
results
of
a
chronic
feeding/
oncogenicity
study
in
the
rat
(
MRID
00044337)
which
showed
renal
pelvis
carcinomas,
follicular
cell
adenomas,
papillary
adenomas,
and
cystadenomas.

5.6.2
Quantification
of
Carcinogenic
Potential
Q1*
=
0.00579
(
mg/
kg/
day)­
1
based
on
male
rat
follicular
cell
adenomas,
papillary
adenoma,
cystadenoma,
and
carcinoma
combined
tumor
rates.
The
Q1*
was
calculated
using
an
interspecies
scaling
factor
of
3/
4
(
TXR
0051890).

6
FQPA
CONSIDERATIONS
6.1
Special
Sensitivity
to
Infants
and
Children
6.1.1
Determination
of
Susceptibility
There
was
qualitative
evidence
of
increased
susceptibility
in
the
rat
developmental
toxicity
study,
where
fetal
developmental
effects
(
increased
resorptions
and
wavy
ribs)
occurred
in
the
presence
of
less
severe
maternal
effects
(
decreases
in
body
weight
gain,
clinical
signs,
and
changes
in
organ
weights).
Qualitatively,
there
is
an
indication
of
increased
sensitivity
in
the
2­
generation
reproduction
study
in
the
rat
in
that
offspring
effects
(
decreased
fetal,
neonatal
and
litter
viability)
were
observed
at
a
dose
level
where
there
was
less
severe
maternal
toxicity
(
decreased
body
weight,
body
weight
gain
and
food
consumption).
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
39
6.1.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
The
concern
is
low
for
the
qualitative
susceptibility
seen
in
the
developmental
rat
study
because
the
dose
response
was
well
characterized,
the
developmental
effects
sere
seen
in
the
presence
of
maternal
toxicity,
and
clear
NOAELs/
LOAELs
were
established
for
maternal
and
developmental
toxicities.
There
is
low
concern
for
the
qualitative
susceptibility
observed
in
the
rat
reproduction
study
since
the
dose­
response
was
well
characterized;
there
was
a
clear
NOAEL/
LOAEL
for
maternal
and
developmental
toxicities;
and
the
effects
were
seen
at
a
high­
dose
level
(
295/
337
mg/
kg/
day).
Offspring
viability
was
not
adversely
affected
in
the
two
other
2­
generation
studies
with
trifluralin
at
dose
levels
up
to
100
and
148
mg/
kg/
day.
There
are
no
residual
uncertainties
for
pre­
and
postnatal
toxicities
since
the
doses
selected
for
overall
risk
assessments
will
address
the
concerns
seen
in
these
studies.

6.1.3
Special
FQPA
Safety
Factor(
s):

Based
on
the
above
data,
the
HIARC
determined
that
no
Special
FQPA
Safety
Factor
is
needed
(
1X)
since
there
are
no
residual
uncertainties
for
pre­
and/
or
post­
natal
toxicity.

6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
HIARC
concluded
that
there
is
not
a
concern
for
developmental
neurotoxicity
resulting
from
exposure
to
trifluralin.

7
REFERENCES
00044337
Emmerson,
J.
L.;
Pierce,
E.
C.;
McGrath,
J.
P.;
et
al.
(
1980)
The
Chronic
Toxicity
of
Compound
36352
(
Trifluralin)
Given
as
a
Component
of
the
Diet
to
Fischer
344
Rats
for
Two
Years:
Studies
R­
87
and
R­
97.
(
Unpublished
study
received
Sep
18,
1980
under
1471­
35;
submitted
by
Elanco
Products
Co.,
Div.
of
Eli
Lilly
and
Co.,
Indianapolis,
Ind.;
CDL:
243289­
A,
243290)

00044338
Emmerson,
J.
L.;
Owen,
N.
V.;
McGrath,
J.
D.;
et
al.
(
1980)
The
Chronic
Toxicity
of
Compound
36352
(
Trifluralin)
Given
as
a
Component
of
the
Diet
to
the
B6C3F1
Mouse
for
24
Months:
Studies
M­
9067
and
M­
9077.
(
Unpublished
study
received
Sep
18,
1980
under
471­
35;
submitted
by
Elanco
Products
Co.,
Div.
of
Eli
Lilly
and
Co.,
Indianapolis,
Ind.;
CDL:
243291­
A;
243292;
243293)

00126661
Oberly,
T.;
Emerson,
J.;
Bewsey,
B.;
et
al.
(
1983)
The
Effect
of
Trifluralin
(
Compound
36352)
on
the
Induction
of
Forward
Mutation
at
the
Thymidine
Kinase
Locus
of
L5178Y
Mouse
Lymphoma
Cells:
Study
830201MLA2055.
(
Unpublished
study
received
Apr
5,
1983
under
1471­
70;
submitted
by
Elanco
Products
Co.,
Div.
of
Eli
Lilly
and
Co.,
Indianapolis,
IN;
CDL:
249846­
C)
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
40
00124928
Weisburger,
J.;
Weisburger,
E.;
Powers,
M.;
et
al.
(
1977)
Bioassay
of
Trifluralin
for
Possible
Carcinogenicity:
DHEW
Publication
No.
(
NIH)
78­
834;
Pre­
RPAR
Review
Submissions
#
4
and
#
5.
(
Unpublished
study
received
Nov
9,
1977
under
1471­
35;
prepared
by
U.
S.
National
Institutes
of
Health,
National
Cancer
Institute,
Div.
of
Cancer
Cause
and
Prevention,
Carcinogenesis
Testing
Program
and
others,
submitted
by
Elanco
Products
Co.,
Div.
of
Eli
Lilly
and
Co.,
Indianapolis,
IN;
CDL:
233235­
A;
233234)

00132820
Bridge,
T.;
van
Lier,
R.;
Adams,
E.;
et
al.
(
1982)
Percutaneous
Absorption
of
14CEthalfluralin
(
EL­
161,
Compound
94961)
in
Monkeys:
Studies
M­
6162
and
P03282.
(
Unpublished
study
received
Dec
2,
1983
under
4F3006;
submitted
by
Elanco
Products
Co.,
Div.
of
Eli
Lilly
and
Co.,
Indianapolis,
IN;
CDL:
072180­
B)

00133426
Neal,
S.;
Emmerson,
J.;
Probst,
G.;
et
al.
(
1983)
The
Effect
of
Trifluralin
(
Compound
36352)
on
the
in
vivo
Induction
of
Sister
Chromatid
Exchange
in
Bone
Marrow
of
Chinese
Hamsters:
Study
830207SCE2055.
(
Unpublished
study
received
Dec
9,
1983
under
unknown
admin.
no.;
submitted
by
Elanco
Products
Co.,
Div.
of
Eli
Lilly
and
Co.,
Indianapolis,
IN;
CDL:
251921­
K)

00148318
Young,
R.
(
1984)
Evaluation
of
Triflurex
Technical
(
Trifluralin)
in
the
CHO/
HGPRT
Forward
Mutation
Assay:
Final
Report:
LBI
Project
No.
22207.
Unpublished
study
prepared
by
Litton
Bionetics,
Inc.
27
p.

.

00148319
Moore,
M.
(
1984)
Evaluation
of
Triflurex
Technical
in
the
Rat
Dominant
Lethal
Assay:
Final
Report:
Project
No.
22203.
Unpublished
study
prepared
by
Litton
Bionetics.
69
p.

00148320
Ivett,
J.
(
1984)
Mutagenicity
Evaluation
Triflurex
Technical,
Batch
No.
5320
in
the
Bone
Marrow:
Cytogenic
Assay:
Final
Report:
LBI
Project
No.
22202.
Unpublished
study
prepared
by
Litton
Bionetics.
32
p.

00148345
Jagannath,
D.
(
1984)
Mutagenicity
Evaluation
of
Triflurex
Tech
(
Trifluralin)
Batch
5230
in
the
Ames
Salmonella/
Microsome
Plate
Test:
Final
Report:
LBI
Project
No.
20988.
Unpublished
study
prepared
by
Litton
Bionetics,
Inc.
19
p.

00151894
Mellano,
D.
(
1982)
Study
of
the
Capacity
of
the
Test
Article
HOE
38474
OH
at
208
to
Induce
"
Unscheduled
DNA
Synthesis"
in
Cultured
Hela
Cells:
Study
No.
M
372.
Unpublished
study
prepared
by
Istituto
Di
Ricerche
Biomediche
"
Antoine
Marxer"
S.
p.
A.
19
p.

00151895
Leist;
Weigand;
Kramer
(
1981)
Testing
of
Hoe
38474
­
Active
Ingredient
for
Mutagenicity
in
the
Micronucleus
Test
following
Oral
Administration
to
NMRI
Mice:
(
Code:
HOE
38474
OH
AT
208):
Report
No.
285/
81.
Unpublished
report
prepared
by
Hoechst
Aktiengesellschaft.
16
p.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
41
00151896
Horstmann
(
1984)
Dominant­
lethal
Test
for
Determination
of
Mutagenic
Effect
in
Male
NMRI­
mice
after
Oral
Administration:
Trifluralin:
Code:
Hoe
38474
OHZD99
0002:
Report
No.
84.0763.
Un­
published
report
prepared
by
Hoechst
Aktiengesellschaft.
89
p.

00151898
Fumero,
S.
(
1982)
Study
of
the
Mutagenic
Activity
"
In
Vitro"
of
the
Compound
HOE
38474
OH
AT
208
with
Schizosaccharomyces
Pombe:
Study
No.
M
374.
Unpublished
study
prepared
by
Instituto
Di
Ricerche
Biomediche
"
Antoine
Marxer"
S.
p.
A.
16
p.

00151899
Baeder,
Weigand,
Kramer
(
1983)
Testing
for
Embryotoxicity
in
Wister
Rats
following
Oral
Administration:
HOE
38474
­
Active
Ingredient:
Report
No.
83.0557:
Study
No.
G2R0383.
Unpublished
study
prepared
by
Hoechst
Aktiengesellschaft.
51
p.

00151901
Becker,
H.
(
1984)
Multiple
Generation
Study
in
the
Rat:
Trifluralin
Substance
Technical
Grade
(
Code
:
HOE
38474
OH
AT210):
Project
No.
008875.
Unpublished
study
prepared
by
Research
&
Consulting
Co.,
AG.
604
p.

00151902
Ellgehausen,
H.
(
1984)
Determination
of
Trifluralin
Substance
Technical
Grade
(
Code
:
HOE
38474
O
H
AT210)
in
Rodent
Feed:
Project
No.
008875.
Unpublished
study
prepared
by
Research
&
Consulting
Co.
26
p.

00151903
Westen,
H.
(
1984)
Multiple
Generation
Study
in
Rat:
Trifluralin
Substance
Technical
Grade
(
Code:
HOE
38474
O
H
AT210):
Pathology
Report
Part
II:
Project
No.
008875.
Unpublished
study
prepared
by
Research
&
Consulting
Co.,
AG.
704
p.

00151904
Ullmann,
L.
(
1982)
30
Day
Repeated
Dose
Inhalation
Toxicity
Study
with
HOE
38474
OH
AT
210
Active
Ingredient
(
Technical)
in
Rats:
Part
1:
Project
No.
005488.
Unpublished
study
prepared
by
Research
&
Consulting
Co.,
Ltd.
400
p.

00151905
Suter,
P.
(
1983)
13­
Week
Toxicity
Study
with
Trifluralin
(
HOE
38474
O
H
AT210)
in
Mice
following
Dietary
Administration:
Report:
Project
No.
008842.
Unpublished
study
prepared
by
Research
&
Consulting
Co.,
AG.
223
p.

00151906
Schutz;
Weigand;
Kramer
(
1980)
Repeated­
dose
(
3
Months)
Oral
Toxicity
Study
of
the
Active
Substance
HOE
38474
(
Code:
HOE
38474
O
H
AT204)
Administered
in
the
Feed
to
Rats:
Report
No.
618/
80.
Unpublished
study
prepared
by
Hoechst
Aktiengesellschaft.
422
p.

00151907
Brunk;
Weigand;
Kramer
(
1981)
Toxicology
Testing
of
Trifluralin
(
Hoe
38474
OH
AT
204)
by
Repeated
Oral
Administration
to
Beagle
Dogs
for
Six
Months:
Report
No.
636/
81.
Unpublished
report
prepared
by
Hoechst
Aktiengesellschaft.
742
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Bathe,
R.
(
1984)
12­
Month
Oral
Toxicity
(
Feeding)
Study
in
Beagle
Dogs:
Trifluralin
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
42
Substance
Technical
Grade
(
Code:
HOE
38474
O
H
AT210):
Project
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008864:
Report
Part
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Unpublished
study
prepared
by
Research
&
Consulting
Co.
439
p
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Byrd,
R.
(
1984)
A
Teratology
Study
of
Trifluralin
(
El­
152,
Compound
36352)
Administered
Orally
to
Charles
River
CD
Rats:
Study
R08484.
Unpublished
study
prepared
by
Lilly
Research
Labs.
308
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00152421
Byrd,
R.
(
1984)
A
Teratology
Study
(
II)
of
Trifluralin
(
El­
152,
Compound
36352)
Administered
Orally
to
Dutch
Belted
Rabbits:
Study
B01784.
Unpublished
study
prepared
by
Lilly
Research
Labs.
223
p.

00153171
Suter,
P.
(
1982)
31
Days
Dermal
Toxicity
Study
with
Hoe
38474
OH
AT
210
Active
Ingredient
(
Technical)
in
Rats:
Project
005490.
Unpublished
study
prepared
by
Research
&
Consulting
Co.,
Ltd.
450
p.

00152888
Negilski,
D.
(
1985)
Subchronic
(
21­
day)
Dermal
Toxicity
Study
in
New
Zealand
White
Rabbits
with
Technical
Trifluralin:
Study
B00184.
Unpublished
study
prepared
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Lilly
Research
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222
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00153173
Engelbart
(
1979)
Test
for
Mutagenicity
in
Bacteria
Strains
in
the
Absence
and
Presence
of
a
Liver
Preparation:
Hoe
38474
OH
AT204
(
Active
Ingredient)
Trifluralin:
Report
No.
74/
79.
Unpublished
study
prepared
by
Hoechst
AG.
7
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00155261
Leist,
K.
(
1981)
Four
Hour
LC50
Aerosol
Inhalation
Toxicity
Study
in
Rats
on
HOE
38474
OH
at
210
Active
Ingredient
(
Technical):
Report:
Project
005477.
Unpublished
study
prepared
by
Research
&
Consulting
Co.
Ltd.
37
p.

00157154
Jordan,
W.
(
1983)
A
Preliminary
Dietary
Study
of
the
Effects
of
Trifluralin
on
the
Urinary
Tract
of
Male
Fischer
344
Rats:
Study
No.
R15083:
Report
No.
1.
Unpublished
study
prepared
by
Lilly
Research
Labs.
89
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00157156
Usher,
R.
(
1985)
A
Special
Urinalysis
Study
in
Fischer
344
Rats
Maintained
on
Diets
Containing
Trifluralin
(
Compound
36352)
for
Three
Months:
Study
No.
R04785.
Unpublished
study
prepared
by
Lilly
Research
Labs.
711
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00157482
Vigna,
E.
(
1985)
Trifluralin
Technical:
Acute
Dermal
Toxicity
Study
in
Rats:
RBM
Exp.
No.
2159.
Unpublished
study
prepared
by
Istituto
di
Ricerche
Biomediche
"
Antoine
Marxer",
RBM
S.
p.
A.
13
p.

00157483
Vigna,
E.
(
1985)
Trifluralin
Technical:
Acute
Eye
Irritation
Study
in
Rabbits:
RBM
Exp.
No.
2160.
Unpublished
study
prepared
by
Istituto
di
Ricerche
Biomediche
"
Antoine
Marxer",
RBM
S.
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15
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00157484
Bassi,
L.
(
1985)
Trifluralin
Technical:
Dermal
Sensitization
Study
in
Guinea
Pigs:
RBM
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
43
Exp.
No.
I
892.
Unpublished
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by
Istituto
di
Ricerche
Biomediche
"
Antoine
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RBM
S.
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15
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00157485
Vigna,
E.
(
1985)
Trifluralin
Technical:
Acute
Dermal
Irritation
Study
in
Rabbit:
RBM
Exp.
No.
2161.
Unpublished
study
prepared
by
Istituto
di
Ricerche
Biomediche
"
Antoine
Marxer",
RBM
S.
p.
A.
13
p.

00157486
Vigna,
E.
(
1985)
Trifluralin
Technical:
Acute
Toxicity
Study
by
Oral
Route
in
Rats:
RBM
Exp.
No.
2162.
Unpublished
study
prepared
by
Istituto
di
Ricerche
Biomediche
"
Antoine
Marxer",
RBM
S.
p.
A.
13
p.

00158935
Suter,
P.
(
1986)
Oncogenicity
Study
with
Trifluralin
Active
Ingredient
Technical
(
HOE
38474
O
H
AT210)
in
Mice:
Project
No.
008853.
Unpublished
study
prepared
by
Research
&
Consulting
Company
AG.
6478
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00159616
Ebert,
E.
(
1985)
Trifluralin­
Active
Ingredient
Technical
Testing
for
Acute
Delayed
Neurotoxicity
in
White
Leghorn
Hens:
Report
No.
85.0742.
Unpublished
study
prepared
by
Hoechst
AG.
38
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00159618
Bathe,
R.
(
1985)
Trifluralin,
Substance
Technical
Grade:
12­
Month
Oral
Toxicity
(
Feeding)
Study
in
Beagle
Dogs:
Concentration
of
Trifluralin,
Substance
Technical
Grade
in
Dog
Feed
¿
:
Project
No.
008864:
Report
No.
A32778.
Unpublished
study
prepared
by
Research
&
Consulting
Co.
AG.
4
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00159619
Becker,
H.
(
1985)
Trifluralin,
Substance
Technical
Grade:
Multiple
Generation
Study
in
the
Rat:
Diet
Preparation,
Stability,
and
Analysis
of
the
Test
Article
¿
:
1st
Amendment
to
Report:
Project
No.
008875:
Report
No.
A32777.
Unpublished
study
prepared
by
Research
&
Consulting
Co.
AG.
4
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Baeder;
Mayer
(
1986)
Testing
for
Embryotoxicity
in
Wistar
Rats
following
Oral
Administration
of
Hoe
38474:
Incidence
of
Wavy
Ribs
in
Control
Studies
and
at
Dose
Levels
Toxic
to
Either
Dams
or
Embryos:
Supplement
to
Report
No.
83.0557:
Report
No.
86.0166.
Unpublished
study
prepared
by
Hoechst
AG.
15
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00162458
Donaubauer
(
1986)
Carcinogenicity
Study
in
Rats
(
28­
month
Feeding
Study):
Trifluralin:
Study
No.
680:
Report
No.
85.0087.
Unpublished
study
prepared
by
Hoechst
Aktiengesellschaft,
Pharma
Forschung
Toxikologie.
3126
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00162543
Hoyt,
J.
(
1986)
A
One­
year
Two­
generation
Reproduction
Study
in
CD
Rats
Maintained
on
Diets
Containing
Trifluralin
(
EL­
152,
Com­
pound
36352):
Studies
R06384
and
R13984.
Unpublished
study
prepared
by
Lilly
Research
Laboratories.
778
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00162457
Donaubauer
(
1986)
Chronic
Feeding
Study
(
24
Months)
in
Rats:
Trifluralin:
Study
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
44
No.
680:
Report
No.
85.0302.
Unpublished
study
prepared
by
Hoechst
Aktiengellschaft,
Pharma
Forschung
Toxikologie.
1837
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40138301
Usher,
R.
(
1986)
A
Supplementary
Report
of
a
Special
Urinalysis
Study
in
Fischer
344
Rats
Maintained
on
Diets
Containing
Trifluralin
(
Compound
36352)
for
Three
Months:
Study
R04785.
Unpublished
study
prepared
by
Lilly
Research
Laboratories.
263
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40334707
Loveday,
K.
(
1987)
Evaluation
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Trifluralin
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the
Ames
Mutagenesis
Assay:
ADL
Reference:
88720­
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Unpublished
study
prepared
by
Arthur
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Little,
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28
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40392310
Leist,
K.;
Penseler,
D.;
Mayer
(
1987)
Trifluralin
Substance
Technical
Grade
(
Code:
HOE
38474
OH
AT210):
Testing
for
Embryotoxicity
in
Wistar
Rats
following
Oral
Administration:
Supplementary
Data
in
Support
of
Previously
Submitted
Study
Acc.
No.
258993:
Laboratory
Project
No.
87.0997,
Report
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A
36041.
Unpublished
study
prepared
by
Hoechst
Aktiengesellschaft.
19
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40392312
Ullman,
L.
(
1987)
30­
Day
Repeated
Dose
Inhalation
Toxicity
Study
with
HOE
38474
OH
at
210
in
Rats:
Amended
Version
of
Previously
Submitted
Study
Acc.
No.
258996:
Laboratory
Project
No.
005488,
Report
No.
A
22688
and
A
36084.
Unpublished
study
prepared
by
Research
&
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Ag.
711
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40392313
Suter,
P.;
Horst,
K.;
Vogel,
W.;
et
al.
(
1987)
Oncogenicity
Study
with
Trifluralin
Active
Ingredient
Technical
(
HOE
38474
OH
AT210)
in
Mice:
Supplementary
Data
in
Support
of
Previously
Submitted
Study
Acc.
No.
262516­
262520:
Laboratory
Project
No.
008853,
Report
No.
A
36197.
Unpublished
study
prepared
by
Research
&
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Co.
AG.
47
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40405007
Rubin,
Y.;
et
al.
(
1987)
Triflurex:
Two­
generation
Reproduction
Study
in
theRat:
Laboratory
Project
ID
AGN/
125/
TRI.
Unpublished
study
prepared
by
Life
Science
Research
Israel
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1664
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40673701
Adams,
E.;
Glass,
S.;
Van
Lier,
R.
(
1988)
Percutaneous
(
Dermal)
Absorption
of
Carbon
14­
Trifluralin
in
Rhesus
Monkeys:
Laboratory
Project
ID:
P07487
and
P03087.
Unpublished
study
prepared
by
Lilly
Research
Laboratories.
55
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40765601
Young,
R.
(
1988)
Mutagenicity
Test
on
Trifluralin
Technical
Grade:
Batch
Number
39
in
the
CHO/
HGPRT
Foreward
Mutation
Assay:
Project
ID.
10137­
0­
435.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
46
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40765602
Cifone,
M.
(
1988)
Mutagenicity
Test
on
Trifluralin,
Technical
Grade
in
the
Rat
Primary
Hepatocyte
Unscheduled
DNA
Synthesis
Assay:
Project
ID.
10137­
0­
447.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
39
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40765603
Ivett,
J.
(
1988)
Mutagenicity
Test
on
Trifluralin
Technical
Grade
in
the
Mouse
Bone
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
45
Marrow
and
Spermatogonial
Cell
Cytogenetics
Assay:
Project
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10137­
0­
473.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
51
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41086101
Adams,
E.;
Bendele,
R.;
Emmerson,
J.
(
1989)
Reanalysis
and
Discussion
of
Urine
Protein
Electrophoresis
Data
From
a
Special
Urinalysis
Study
in
Fischer
344
Rats
with
Trifluralin
(
Compound
36352).
Unpublished
supplemental
submission
prepared
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Lilly
Research
Laboratories
63p.

41218901
Magnussen,
J.
(
1989)
Identification
of
the
Urinary
Metabolites
of
carbon
14Trifluralin
in
Rats:
Project
ID:
Experiment
ABC­
0433.
Unpublished
study
prepared
by
Lilly
Research
Laboratories.
53
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41993810
Vedula,
U.;
Kociba,
R.;
Bond,
D.
(
1991)
XRM­
5313:
A
Formulation
Containing
Trifluralin
and
XRD­
498­­
21
Day
Dermal
Study
in
New
Zealand
White
Rabbits:
Lab
Project
Number:
M­
005313­
003A.
Unpublished
study
prepared
by
The
Dow
Chemical
Co.,
Tox.
Research
Lab.
166
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42447001
Adams,
E.;
Bernhard,
N.;
Jordon,
W.
(
1992)
A
Chronic
Toxicity
Study
of
Trifluralin
(
Compound
036352)
Administered
Orally
to
Beagle
Dogs
for
One
Year
(
Supp.):
Lab
Project
Number:
D07190.
Unpublished
study
prepared
by
Lilly
Research
Labs.
470
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42972701
Shapiro,
R.
(
1993)
EPA
Acute
Oral
Toxicity­
Defined
LD50
in
Rats:
Trilin
5,
Lot
#
227284:
Lab
Project
Number:
T­­
2527:
2527:
P320.
Unpublished
study
prepared
by
Product
Safety
Labs.
34
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42972702
Shapiro,
R.
(
1993)
EPA
Acute
Dermal
Toxicity
Limit
Test:
Rabbits:
Trilin
5,
Lot
227284:
Lab
Project
Number:
T­­
2530:
2530:
P322.
Unpublished
study
prepared
by
Product
Safety
Labs.
20
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42972703
Shapiro,
R.
(
1993)
EPA
Acute
Inhalation­­
Defined
LC50:
Rats:
Trilin
5,
Lot
#
227284:
Lab
Project
Number:
T­­
2532.
Unpublished
study
prepared
by
product
Safety
Labs.
54
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42972704
Shapiro,
R.
(
1993)
EPA
Primary
Eye
Irritation:
Rabbit:
Trilin
5,
Lot
#
227284:
Lab
Project
Number:
T­­
2528:
P324:
E30715­
1.
Unpublished
study
prepared
by
Product
Safety
Labs.
30
42972705
Shapiro,
R.
(
1993)
EPA
Primary
Dermal
Irritation
Test:
Rabbits:
trilin
5,
Lot
227284:
Lab
Project
Number:
T­­
2529:
2529:
P326.
Unpublished
study
prepared
by
Product
Safety
Labs
23
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42972706
Shapiro,
R.
(
1993)
EPA
Topical
Skin
Sensitization
Test
in
Guinea
Pigs
(
Buehler):
Trilin
5,
Lot
#
227284:
Lab
Project
Number:
T­­
2531:
2531.
Unpublished
study
prepared
by
Product
Safety
Labs.
33
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TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
46
43447301
Kuhn,
J.
(
1994)
Trific
10G:
Acute
Oral
Toxicity
Study
in
Rats:
Lab
Project
Number:
0875­
93.
Unpublished
study
prepared
by
Stillmeadow,
Inc.
11
p.

43447302
Kuhn,
J.
(
1994)
Trific
10G:
Acute
Dermal
Toxicity
Study
in
Rabbits:
Lab
Project
Number:
0876­
93.
Unpublished
study
prepared
by
Stillmeadow,
Inc.
11
p.

43447303
Holbert,
M.
(
1994)
Trific
10G:
Acute
Inhalation
Toxicity
Study
in
Rats:
Lab
Project
Number:
0877­
93.
Unpublished
study
prepared
by
Stillmeadow,
Inc.
20
p.

43447304
Kuhn,
J.
(
1994)
Trific
10G:
Primary
Eye
Irritation
in
Rabbits:
Lab
Project
Number:
0878­
93.
Unpublished
study
prepared
by
Stillmeadow,
Inc.
18
p.

43447305
Kuhn,
J.
(
1994)
Trific
10G:
Primary
Dermal
Irritation
in
Rabbits:
Lab
Project
Number:
0879­
93.
Unpublished
study
prepared
by
Stillmeadow,
Inc.
12
p.

43447306
Kuhn,
J.
(
1994)
Trific
10G:
Dermal
Sensitization
Study
in
Guinea
Pigs:
Lab
Project
Number:
0880­
93.
Unpublished
study
prepared
by
Stillmeadow,
Inc.
17
p.

44135107
Adams,
E.;
Markham,
J.
(
1996)
A
One­
Year
Two­
Generation
Reproduction
Study
in
CD
Rats
Maintained
on
Diets
Containing
Trifluralin:
Supplement
#
1
to
MRID
No.
00162543:
Lab
Project
Number:
R06384:
R13984­
S1:
R13984.
Unpublished
study
prepared
by
Lilly
Research
Labs.
16
p
92062028
Environ
Corp.
(
1990)
Dowelanco
Phase
3
Summary
of
MRID
00132820.
Percutaneous
Absorption
of
(
Carbon­
14)
­
Ethalfluralin
in
Monkeys:
M­
6162
and
P03282.
Prepared
by
LILLY
RESEARCH
LABS.
7
p
IARC
(
1991)
IARC
Monographs
on
the
Evaluation
of
Carcinogenic
Risks
to
Humans,
Trifluralin,
Vol
53,
1991
USEPA
(
1979)
Trifluralin
(
Treflan
®
)
Position
Document
1/
2/
3,
44
FR
50911,
NTIS
#
PB80­
213937,
Aug
30,
1979.

USEPA
(
1982)
Alpha,
alpha,
alpha­
trifluoro­
2,6­
dinitro­
N,
N­
dipropyl­
p­
toluidine,
Trifluralin
(
Treflan
®
)
Position
Document
4,
47
FR
33777,
NTIS#
PB82­
263252,
Aug
4,
1982.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
47
8
APPENDICES
Tables
for
Use
in
Risk
Assessment
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
48
8.1
Toxicity
Profile
Summary
Tables
8.1.1
Acute
Toxicity
Table
­
See
Section
4.1
8.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Comments
870.3100
2­
Week
R­
F
Feeding
­
Rats
(
male)
00157154
(
1983)

0,
6500
ppm
range­
finding
study
for
00157156
(
1985),
41038301
(
1986)

Acceptable/
Nonguideline
NOAEL
=
not
achieved
LOAEL
=
6500
ppm
based
on
renal
epith
damage,
urine
triple
phosphates
crystals
and
urinary
sediment
870.3100
90­
Day
Oral
toxicity
­
Rat
00151906
(
1980)

0,
800,
2000,
or
5000
ppm
M:
0,
59,
154,
and
392
mg/
kg/
day
F:
0,
69,
168,
and
421
mg/
kg/
day
Acceptable/
Guideline
NOAEL
=
2000
ppm
(
154/
168
mg/
kg/
day,
M/
F)
LOAEL
=
5000
(
392/
421
mg/
kg/
day,
M/
F)
Based
on
minor
decreases
in
overall
body
weight
gains
and
food
consumption
in
males
and
females,
decreased
hemoglobin,
alkaline
phosphatase,
and
alanine
aminotransferase
in
the
males,
and
increased
absolute
and
relative
(
to
body)
liver
weights
in
males
and
females.

870.3200
21/
28­
Day
dermal
toxicity­
rabbit
41993810
(
1991)

0,
100,
500,
or
1000
mg/
kg
/
day,
[
formulation
containing
35.8%
trifluralin
and
2.6%
XRD­
498]

Acceptable/
Guideline
Systemic
NOAEL
=
1000
mg/
kg/
day
Systemic
LOAEL
=
Not
achieved
Dermal
NOAEL
=
Not
achieved
Dermal
LOAEL
=
100
mg/
kg/
day,
edema,
and/
or
scaling
and
fissuring
100
mg/
kg/
day
based
skin
irritation
870.3200
31­
Day
dermal
toxicity­
rat
00153171
(
1982)

0,
40,
200,
or
1000
mg/
kg/
day
Acceptable/
Guideline
Systemic
NOAEL
=
1000
mg/
kg/
day
(
limit
dose)
Systemic
LOAEL
=
not
achieved
Dermal
NOAEL
=
40
mg/
kg/
day.
Dermal
LOAEL
=
200
mg/
kg/
day
based
on
subepidermal
inflamation
and
ulcerations
in
males
and
females.

870.3200
21/
28­
Day
dermal
toxicity­
rat
00152888
(
1985)

0,
1000
mg/
kg/
day
(
limit
dose)

Acceptable/
Guideline
Systemic
NOAEL
=
1000
mg/
kg/
day.
Systemic
LOAEL
=
Not
achieved
Dermal
NOAEL=
Not
achieved
Dermal
LOAEL
=
1000
mg/
kg/
day
(
limit
dose)
based
on
erythema,
edema,
and
desquamination
of
the
treated
skin.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Comments
49
870.3465
30­
Day
inhalation
toxicity
40392312
(
1987)
reformat
of
00151904
(
1982)

0,
100,
301,
1006
mg/
m3
(
6
hours/
day
5
days/
week
for
up
to
30
days)

Acceptable/
Nonguideline
NOAEL
=
301
mg/
m3
LOAEL
=
1006
mg/
m3
based
on
increased
bilirubin
in
females
and
incidences
of
dyspnea
and
ruffled
fur
in
males
and
females.

870.3700
[
83­
3(
a)]

Developmental
Toxicity
Study
­
Rat
00151899
(
1983),
159620
(
1986),
40392310
(
1987)

0,
20,
100,
500
mg/
kg/
day
Systemic
Maternal
NOAEL
=
100
mg/
kg/
day
Systemic
Maternal
LOAEL
=
500
mg/
kg/
day
based
on
mortality,
clinical
signs,
decreased
body
weight
gains,
decreased
food
consumption,
and
increased
liver
and
spleen
weights,

Developmental
NOAEL
=
100
mg/
kg/
day.
Developmental
LOAEL
=
500
mg/
kg/
day
based
on
reduced
ossification
of
the
vertebrae
and
ribs
and
thickened,
wavy
or
bent
ribs
and
increased
incidences
of
resorptions
870.3700
[
83­
3(
a)]

Developmental
Toxicity
Study
­
Rat
00152419
(
1984)
0,
100,
225,
470,
or
1000
mg/
kg/
day
Acceptable/
Guideline
Maternal
NOAEL
=
475
mg/
kg/
day
Maternal
LOAEL
=
1000
mg/
kg/
day
based
decreased
body
weights
and
decreased
food
consumption.

Offspring
NOAEL
=
475
mg/
kg/
day
Offspring
LOAEL
=
1000
mg/
kg/
day
based
on
decreased
fetal
body
weights.

Developmental
NOAEL
=
1000
mg/
kg/
day
Developmental
LOAEL
was
not
established.

870.3700
[
83­
3(
b)]

Developmental
Toxicity
­
Rabbit
00152421
(
1984)

0,
100,
225,
500
mg/
kg/
day
Acceptable/
Guideline
Maternal
NOAEL
=
100
mg/
kg/
day
Maternal
LOAEL
=
225
mg/
kg/
day
based
on
abortions,
macroscopic
changes
in
the
liver
and
lungs,
and
decreased
food
consumption.

Developmental
NOAEL
=
100
mg/
kg/
day
Developmental
LOAEL
=
225
mg/
kg
based
on
abortions.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Comments
50
870.3800
[
83­
4]
2­
Gen
Repro
­
Rat
00151901
(
1984)
00151902
(
1984)
Feed
analysis
00151903
(
1984)
Path
0,
200,
650,
2000
ppm
0,
20,
32.5,
200
mg/
kg/
day
(
1
ppm
=
0.5
mg/
kg/
day)

Acceptable/
Guideline
Parental
NOAEL
=
200
ppm
(
10
mg/
kg/
day).
Parental
LOAEL
=
650
ppm
(
32.5
mg/
kg/
day)
based
on
mortality
due
to
acute
renal
failure
and
increased
lesions
of
the
renal
proximal
tubules
in
the
F1
females;
increased
relative
(
to
body)
weights
of
the
liver,
kidney
(
males),
and
testes
in
both
generations.

Offspring
NOAEL
=
200
ppm
(
10
mg/
kg/
day)
Offspring
LOAEL
=
650
ppm
(
32.5
mg/
kg/
day)
based
on
decreased
pup
weights
in
both
generations
and
increased
relative
to
body
liver
weights
in
the
F2b
females
Repro
NOAEL
=
2000
ppm
(
100
mg/
kg/
day)
Repro
LOAEL
=
Not
established.

870.3800
[
83­
4]
2­
Gen
Repro
­
Rat
00162543
(
1986)
44135107
(
1996)

0,
200,
630,
2000
ppm
0,
15,
47,
148
mg/
kg/
day
Acceptable/
Guideline
Parental
NOAEL
=
200
ppn
(
15
mg/
kg/
day)
Parental
LOAEL
=
630
ppm
(
47
mg/
kg/
day),
based
on
decreased
BWG
and
food
consumption
Offspring
NOAEL
=
200
ppm
(
15
mg/
kg/
day)
Offspring
LOAEL
=
630
ppm
(
47
mg/
kg/
day)
based
on
small
pup
size
in
3
litters
Repro
NOAEL
=
2000
ppm
(
148
mg/
kg/
day)
Repro
LOAEL
=
Not
established
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Comments
51
870.3800
[
83­
4]
2­
Gen
Repro
­
Rat
40405007
(
1987)

0,
50,
450,
4000
ppm
M:
0,
3.9,
35,
295
mg/
kg/
day
F:
0,
4.7,
42,
337
mg/
kg/
day
Acceptable/
Guideline
Parental
NOAEL
=
450
ppm
[
35/
42
mg/
kg/
day
M/
F]
Parental
LOAEL
=
4000
ppm
[
295/
337
mg/
kg/
day
M/
F]
based
on
decreased
body
weights,
body
weight
gains,
food
consumption,
and
food
efficiency
in
males
and
females
of
both
generations;
decreased
ovary
weights
in
both
generations;
colon
distension
in
the
F1
males;
and
uterine
atrophy
in
the
females
of
both
generations.

Offspring
NOAEL
=
450
ppm
(
35/
42
mg/
kg/
day
M/
F]
Offspring
LOAEL
=
4000
ppm
[
295/
337mg/
kg/
day
,
M/
F]
based
on
decreased
pup
weight
in
F1a
litters
Repro
NOAEL
=
450
ppm
(
35/
42
mg/
kg/
day)
Repro
LOAEL
=
4000
ppm
[
295/
337
mg/
kg/
day
,
M/
F),
based
on
decreased
fetal,
neonatal,
and
litter
viability
and
decreased
lactation
index
in
the
F1a
pups;
and
decreased
number
of
implantation
sites,
newborn
pups,
litter
size,
and
pup
weights
in
both
generations.

870.4100
[
83­
1(
b)]
1­
Year
Oral
(
capsule)
Study
­
Dog
00151908(
1984),
00159618
(
1985)

0,
30,
150,
or
750
ppm
0.0,
0.8,
3.8,
18.8
mg/
kg
/
day
Acceptable/
guideline
NOAEL
=
30
ppm
(
0.8
mg/
kg/
day
LOAEL
=
150
ppm
(
3.8
mg/
kg/
day)
based
on
increased
absolute
liver
weights
in
males
870.4100
[
83­
1(
b)]
1­
Year
Oral
(
capsule)
Study
­
Dog
42447001
(
1992)

0,
0.75,
2.4,
40
mg/
kg/
day
Acceptable/
Guideline
Systemic
NOAEL
=
2.4
mg/
kg/
day
Systemic
LOAEL
=
40
mg/
kg/
day,
based
on
increased
frequency
of
abnormal
stool
and
pigment
deposition
in
the
kidney
and
liver
in
males
and
females,
decreased
body
weights
and
body
weight
gains,
and
on
decreased
erythrocytes
and
hemoglobin
and
increased
thrombocytes
in
males.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Comments
52
870.4300
[
83­
5(
a)]
24­
Month
Chronic
Toxicity/
Carcinogenicity
Study
­
Rat
00162457
(
1985),
00162458
(
1985)

0,
200,
800,
or
3200
ppm
M:
0,
10,
40,
and
169
mg/
kg/
day
F:
0,
13,
53,
and
219
mg/
kg/
day
Acceptable/
guideline
NOAEL
=
800
ppm
(
40/
53
mg/
kg/
day
M/
F).
LOAEL
=
3200
ppm
(
169/
219
mg/
kg/
day
M/
F)
based
on
decreases
in
body
weight
and
body
weight
gains.

At
the
doses
tested,
the
carcinogenic
potential
of
trifluralin
was
negative.
Dosing
was
considered
adequate
based
on
differences
in
body
weight
and
body
weight
gains
870.4300
[
83­
2(
a)]
24­
Month
Carcinogenicity
Study
­
Mouse
00158935
(
1986),
40392313
(
1987)

0,
50,
200,
or
800
ppm
M:
0,
7.5,
29,
and
118
mg/
kg/
day
F:
0,
10.5,
41,
and
165
mg/
kg/
day
Unacceptable/
guideline
Sys
NOAEL
=
800
ppm
(
118/
165
mg/
kg/
day
in
males/
females)
Sys
LOAEL
=
Not
achieved
At
the
doses
tested,
the
carcinogenic
potential
of
trifluralin
was
negative.
Dosing
was
considered
inadequate
as
a
toxic
effect
was
not
observed,
and
the
limit
dose
was
not
tested
870.5100
Bacterial
reverse
gene
mutation
assay
MRID
00148345
(
1984)
Acceptable/
Guideline
Trifluralin
was
tested
up
to
the
limit
of
solubility
(
400

g/
plate
­
S9;
800

g/
plate
+
S9).
No
cytotoxicity
was
observed
in
any
strain
at
up
to
800
(+
S9)
or
400
(­
S9)

g/
plate.
No
treatmentrelated
increases
in
revertant
colonies
were
observed
at
any
dose
in
any
strain
(
±
S9).
The
positive
controls
induced
the
appropriate
responses.
There
was
no
evidence
of
induced
mutant
colonies
over
background
870.5100
Bacterial
reverse
gene
mutation
assay
MRID
40334707
(
1987)
Acceptable/
Guideline
In
a
reverse
gene
mutation
assay
in
bacteria
(
MRID
40334707),
Salmonella
typhimurium
strains
TA98,
TA100,
TA1535,
TA1537,
and
TA1538
were
exposed
to
trifluralin
(
96.8%
a.
i.,
Lot/
Batch
#:
335/
336)
in
dimethylsulfoxide
(
DMSO)
at
concentrations
of
30,
100,
300,
1000,
3000,
or
10,000

g/
plate
in
the
presence
and
absence
of
mammalian
metabolic
activation
(
S9).
The
standard
plate
incorporation
method
was
used.
Standard
strain­
specific
mutagens
served
as
positive
controls.

Trifluralin
was
tested
up
to
the
limit
of
solubility
(
3000

g/
plate,
+/­
S9).
No
cytotoxicity
was
observed
in
any
strain
at
up
to
3000

g/
plate
(+/­
S9).
No
treatment­
related
increases
in
revertant
colonies
were
observed
at
any
dose
in
any
strain
(+/­
S9).
The
positive
controls
induced
the
appropriate
responses.
There
was
no
evidence
of
induced
mutant
colonies
over
background.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Comments
53
870.5100
Bacterial
reverse
gene
mutation
assay
MRID
00153173
(
1979)

Acceptable/
Guideline
In
a
reverse
gene
mutation
assay
in
bacteria
(
MRID
00153173),
Salmonella
typhimurium
strains
TA98,
TA100,
TA1535,
TA1537,
and
TA1538
were
exposed
to
HOE
38474
(
trifluralin;
purity
not
reported;
Lot/
Batch
#:
OH
AT204)
in
DMSO
at
concentrations
of
0,
4,
20,
100,
500,
2500,
or
10,000

g/
plate
(+/­
S9).
Standard
strain­
specific
positive
controls
were
used.

HOE
38474
was
tested
up
to
the
limit
dose
(
10,000

g/
plate,
+/­
S9).
No
treatment­
related
increases
in
revertant
colonies
were
observed
at
any
dose
in
any
strain
(
±
S9).
The
positive
controls
induced
the
appropriate
responses.
There
was
no
evidence
of
induced
mutant
colonies
over
background.

870.5250
Gene
Mutation
Assay
­
Yeast
MRID
00151898
((
1982)
Acceptable/
Guideline
The
test
material
was
tested
up
to
the
limit
of
solubility
(
1000
mg/
L);
however,
no
solubility
data
were
provided.
No
treatment­
related
increases
in
mutation
frequency
were
observed
at
any
dose
with
or
without
S9­
activation.
The
positive
controls
induced
the
appropriate
response.
There
was
no
concentration­
related
positive
response
of
induced
mutant
colonies
over
background.

870.5300
In
vitro
mammalian
cell
gene
mutation
assay
MRID
00126661
Acceptable/
Guideline
In
a
mammalian
cell
gene
mutation
assay
at
the
thymidine
kinase
(
TK)
locus,
mouse
lymphoma
L5178Y
cells
cultured
in
vitro
were
exposed
to
trifluralin
(
95.0%
a.
i.;
Lot/
Batch
#:
00554AP2)
in
DMSO
for
4
hours
at
8
concentrations
ranging
from
0.5
to
20

g/
mL
(
individual
doses
not
reported)
both
in
the
presence
and
absence
of
S9­
activation.

Trifluralin
was
tested
up
to
cytotoxic
concentrations
(
20

g/
mL,
+/­
S9).
No
treatment­
related
increases
in
mutation
frequency
were
observed
at
any
dose
compared
to
controls.
The
positive
controls
induced
the
appropriate
response.
There
was
no
concentration­
related
positive
response
of
induced
mutant
colonies
over
background.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Comments
54
870.5450
Dominant
Lethal
­
Rat
MRID
00148319
(
1984)
Acceptable/
Guideline
In
a
dominant
lethal
assay
(
MRID
00148319),
groups
of
20
male
Sprague­
Dawley
(
CD)
rats/
dose
were
treated
once
daily
via
gavage
(
1.0
mL/
dose)
with
Triflurex
technical
(
trifluralin;
97.3%
a.
i.;
Batch
#:
5320),
in
corn
oil
for
5
consecutive
days
at
doses
of
0,
100,
333,
or
1000
mg/
kg/
day
(
total
doses
of
0,
500,
1665,
or
5000
mg/
kg).
Beginning
two
days
after
the
last
exposure,
each
male
was
mated
sequentially
to
two
untreated
female
rats
per
week
for
seven
weeks.
At
14
days
after
the
midpoint
of
each
mating
week,
the
females
were
killed,
determined
to
be
pregnant
or
not
pregnant,
and
the
number
of
corpora
lutea,
living,
dead,
and
total
implantations
was
determined.
On
the
fifth
day
of
dosing,
the
positive
control
males
were
given
a
single
dose
of
triethylenemelamine
(
TEM;
0.3
mg/
kg,
i.
p.
in
0.9%
saline).

One
1000
mg/
kg
male
(#
8476)
was
found
dead
72
hours
after
the
last
treatment.
Triflurex
technical
was
tested
at
the
limit
dose
(
5000
mg/
kg
=
1000
mg/
kg/
day
X
5
days).
There
were
no
treatment­
related
effects
on
fertility,
number
of
implants,
pre­
implantation
losses,
number
of
dead
implants,
number
of
females
with

1
or

2
dead
implants,
or
ratio
of
dead
implants
to
total
implants
at
any
dose
in
the
study.
The
positive
control
induced
the
appropriate
response.
There
was
no
time­
related
positive
response
of
increased
pre­
or
post­
implantation
loss
compared
to
controls.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Comments
55
870.5300
Forward
Gene
Mutation
Assay
MRID
40765601
(
1988)
Acceptable/
Guideline
In
a
mammalian
cell
gene
mutation
assay
at
the
HGPRT
locus
(
MRID
40765601),
Chinese
hamster
ovary
(
CHO)
cells
cultured
in
vitro
were
exposed
to
trifluralin
(
97.6%
a.
i.;
Lot/
Batch
#:
39)
in
dimethyl
sulfoxide
for
4
hours
at
concentrations
of
50,
100,
150,
200,
300,
400,
or
500

g/
mL
(
Trial
1,
­
S9);
50,
100,
200,
300,
500,
600,
or
700

g/
mL
(
Trial
2,
­
S9);
50,
100,
200,
250,
300,
400,
or
500

g/
mL
(
Trial
1,
+
S9);
and
50,
100,
200,
300,
400,
500,
or
600

g/
mL
(
Trial
2,
+
S9).

Trifluralin
was
tested
up
to
cytotoxic
concentrations
(>=
200

g/
mL,
+/­
S9)
and
the
limit
of
solubility
(>=
100

g/
mL,
+/­
S9).
No
treatment­
related
increases
in
mutant
frequency
were
observed
in
either
trial
in
the
presence
or
absence
of
S9.
The
positive
controls
induced
the
appropriate
response.
There
was
no
evidence
of
induced
mutant
colonies
over
background
in
the
presence
or
absence
of
S9­
activation.

870.5300
Forward
Gene
Mutation
Assay
MRID
00148318
(
1984)
Acceptable/
Guideline
In
a
mammalian
cell
gene
mutation
assay
at
the
HGPRT
locus
(
MRID
00148318),
Chinese
hamster
ovary
(
CHO)
cells
cultured
in
vitro
were
exposed
to
triflurex
technical
(
trifluralin;
purity
not
reported;
Lot/
Batch
#:
not
reported)
in
ethanol
for
4
hours
at
concentrations
of
10,
50,
100,
200,
300,
400,
or
500

g/
mL
(­
S9)
and
50,
100,
200,
300,
400,
500,
or
600

g/
mL
(+
S9).

Triflurex
technical
was
tested
up
to
cytotoxic
concentrations
(>=
200

g/
mL,
­
S9
and
>=
300

g/
mL,
+
S9)
and
the
limit
of
solubility
(>=
100

g/
mL,
+/­
S9).
No
treatment­
related
increases
in
mutant
frequency
were
observed
in
either
trial
in
the
presence
or
absence
of
S9.
The
positive
controls
induced
the
appropriate
response.
There
was
no
evidence
of
induced
mutant
colonies
over
background
in
the
presence
or
absence
of
S9­
activation.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Comments
56
870.5385
In
Vivo
Mammalian
Cytogenetics
[
Bone
Marrow/
Spermatogonial
Aberration
Test]
MRID
40765603
(
1988)
Acceptable/
Guideline
In
a
bone
marrow/
spermatogonial
chromosome
aberration
assay
(
MRID
40765603),
ICR
mice
(
10
males/
dose,
spermatogonial
tissue;
and
5/
sex/
dose,
bone
marrow)
were
dosed
once
daily
via
gavage
(
10
mL/
kg)
with
trifluralin
(
97.6%
a.
i.,
Lot/
BatchNo
39)
in
corn
oil
at
doses
of
0,
62.5,
208,
or
625
mg/
kg
for
5
consecutive
days.
Bone
marrow
and
spermatogonial
cells
were
harvested
at
4.5
hours
after
the
last
treatment.

Mortalities
were
observed
in
the
625
mg/
kg
females
(
2/
5
treated
vs
1/
5
controls),
and
at
62.5
mg/
kg
in
the
males
(
2/
10
treated
vs
1/
10
controls)
and
females
(
2/
5
treated
vs
1/
5
controls).
Clinical
signs
of
toxicity
(
lethargy,
swollen
neck,
and
yellow
stains
around
the
mouth
and
perianal
area)
were
also
observed
at
>=
62.5
mg/
kg.
No
statistically
significant
increases
in
the
percent
of
aberrant
cells
were
observed
at
any
dose
in
either
sex
in
the
bone
marrow
assay
or
in
the
males
in
the
spermatogonial
assay.
Trifluralin
was
tested
at
an
adequate
dose
based
on
mortalities
observed
at
>=
62.5
mg/
kg.
The
positive
control
induced
the
appropriate
response.
There
was
no
evidence
of
chromosome
aberration
induced
over
background
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Comments
57
870.5385
In
Vivo
Mammalian
Cytogenetics
[
Bone
Marrow
Chromosome
Aberration
Test]
MRID
00148320
Acceptable/
Guideline
In
a
bone
marrow
chromosome
aberration
assay
(
MRID
00148320),
5
Sprague­
Dawley
(
HSD:([
SD]
BR)
rats/
sex/
dose/
sacrifice
time
were
treated
once
via
oral
gavage
with
Triflurex
technical
(
trifluralin;
97.3%
a.
i.;
Batch
#:
5320),
in
corn
oil
at
doses
of
0,
500,
1650,
or
5000
mg/
kg.
Bone
marrow
cells
were
harvested
at
6,
24,
or
48
hours
after
treatment.

Mortality
was
observed
at
1650
(
3/
15
males
and
5/
15
females)
and
5000
(
2/
15
males
and
1/
15
females)
mg/
kg
upon
initial
dosing;
however,
these
animals
were
replaced
and
only
one
replacement
1650
mg/
kg
female
in
the
48
hour
group
died
after
dosing.
Triflurex
technical
induced
minimal
bone
marrow
toxicity
(
as
indicated
by
decreased
mitotic
index)
at

500
mg/
kg
in
males
and

1650
mg/
kg
in
females.
Dosing
was
considered
adequate
based
on
bone
marrow
toxicity
and
that
the
animals
were
dosed
above
the
limit
dose
(
2000
mg/
kg).
No
statistically
significant
increases
in
the
percent
of
aberrant
cells
were
observed
at
any
dose
or
sampling
time
compared
to
concurrent
controls.
The
positive
control
induced
the
appropriate
response.
There
was
no
evidence
of
chromosome
aberration
induced
over
background.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Comments
58
870.5395
In
vivo
Mouse
Erythrocyte
Micronucleus
assay
MRID
00151895
(
1981)
Acceptable/
Guideline
In
a
bone
marrow
micronucleus
assay,
5
NMRI
mice/
sex/
dose
were
treated
via
oral
gavage
with
HOE
38474
(
Trifluralin;
98.3%
a.
i.,
Lot/
Batch
#:
OH
AT208),
in
sesame
oil
at
doses
of
0,
25,
250,
or
2500
mg/
kg
on
two
consecutive
days
(
24
hours
apart).
Bone
marrow
cells
were
harvested
at
6
hours
after
the
last
treatment.

No
unscheduled
deaths
occurred
during
the
study.
No
clinical
signs
of
toxicity
were
observed.
No
statistically
significant
differences
in
the
number
of
micronucleated
polychromatic
erythrocytes
(
MPCE)
or
normocytes
and
no
decrease
in
polychromatic
erythrocyte
to
normocyte
(
PCE:
NCE)
ratios
were
noted
in
the
treated
animals
compared
to
controls;
however,
only
individual
data
were
provided.
Additionally,
although
no
evidence
of
cytotoxicity
(
decreased
PCE:
NCE)
was
noted
in
the
bone
marrow,
the
animals
were
sufficiently
dosed
(
the
limit
dose
was
given
twice).
The
test
material
was
absorbed
as
indicated
by
the
presence
of
orange
urine
in
the
2500
mg/
kg
animals.
The
positive
control
induced
the
appropriate
response.
There
was
no
significant
increase
in
the
frequency
of
micronucleated
polychromatic
erythrocytes
in
bone
marrow
compared
to
controls.

870.5450
Dominant
Lethal
­
Mouse
MRID
00151896
(
1984)
Acceptable/
Guideline
In
a
dominant
lethal
assay
(
MRID
00151896),
30
male
NMRI
mice
were
dosed
once
daily
for
5
consecutive
days
via
oral
gavage
(
5
mL/
kg)
with
HOE
38474
(
trifluralin;
98.3%
a.
i.;
Lot/
Batch
#:
OHZD99002),
in
sesame
oil
at
concentrations
of
0,
10,
100,
or
1000
mg/
kg.
After
the
final
treatment,
each
male
was
mated
with
13
untreated
females
during
separate
4­
day
intervals
over
a
52
day
period.

No
treatment­
related
mortalities
were
noted
during
the
study.
No
treatment­
related
effects
on
clinical
signs,
body
weight,
fertilization
rate,
and
pre­
or
post­
implantation
loss
were
observed;
however,
no
data
were
provided.
The
positive
control
(
cyclophosphamide)
increased
the
number
of
post­
implantation
fetal
losses.
There
was
no
time­
related
positive
response
of
increased
pre­
or
post­
implantation
loss
compared
to
controls.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Comments
59
870.5550
Unscheduled
DNA
synthesis
in
mammalian
cell
culture
MRID
40765602
(
1988)
Acceptable/
Guideline
In
an
unscheduled
DNA
synthesis
assay
(
MRID),
primary
rat
hepatocyte
cultures
were
exposed
to
trifluralin
(
97.6%
a.
i.;
Lot/
Batch
#:
39)
in
DMSO
for
18­
19
hours
at
concentrations
of
0,
0.032,
0.214,
0.404,
0.917,
2.22,
4.36,
8.52,
21.3,
42.9,
88.0,
448,
or
898

g/
mL.
Fifteen
doses
ranging
from
0.032­
898

g/
mL
were
used
in
each
assay;
however,
the
three
doses
between
0.032
and
0.214

g/
mL
were
not
reported.

Trifluralin
was
tested
up
to
cytotoxic
levels
(
determined
by
trypan
blue
exclusion),
88.0

g/
mL
in
rat
#
1
and
42.9

g/
mL
in
rat
#
2.
There
were
no
marked
increases
observed
in
the
mean
NNG
or
percent
cells
in
repair
at
any
dose
in
either
trial.
The
positive
controls
induced
marked
increases
in
mean
NNG
and
the
percent
of
cells
in
repair.
There
was
no
evidence
that
unscheduled
DNA
synthesis,
as
determined
by
radioactive
tracer
procedures
(
nuclear
silver
grain
counts),
was
induced.

870.5550
Unscheduled
DNA
synthesis
in
mammalian
cell
culture
MRID
00151894
(
1982)
Acceptable/
Guideline
In
an
unscheduled
DNA
synthesis
assay
(
MRID
00151894),
HeLa
cell
cultures
were
exposed
to
HOE
38474
(
trifluralin,
98.3%
a.
i.;
Lot/
Batch
#:
OH
AT
208)
in
DMSO
for
1
hour
at
concentrations
of
0,
50,
100
or
500

g/
mL
both
in
the
presence
and
absence
of
S9­
activation.

HOE
38474
was
tested
up
to
cytotoxic
concentrations
(>=
50

g/
mL,
+/­
S9).
No
statistically
significant
increases
in
mean
counts
per
minute
of
the
test
material
with
hydroxyurea
were
noted
compared
to
concurrent
solvent
controls
at
any
dose
level,
either
in
the
presence
or
absence
of
S9­
activation.
The
positive
controls
induced
the
appropriate
response.
There
was
no
evidence
that
unscheduled
DNA
synthesis,
as
determined
by
liquid
scintillation
counting
procedures,
was
induced.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Comments
60
870.5900
In
vivo
Sister
Chromatid
Exchange
Assay
MRID
00133426
(
1983)
Acceptable/
Guideline
In
a
mammalian
cell
cytogenetics
assay
[
SCE]
using
the
BrdU
tablet
method
,
groups
of
3
female
Chinese
hamsters/
dose
were
exposed
once
via
gavage
(
10
mL/
kg)
to
trifluralin
(
95.0%
a.
i.,
Lot/
batch
No
00554AP2)
in
DMSO
and
10%
acacia
at
concentrations
of
200,
300,
400,
or
500
mg/
kg
at
5
hours
following
BrdU
tablet
implantation.
Bone
marrow
was
collected
at
21
hours
after
treatment.

Trifluralin
was
tested
up
to
cytotoxic
concentrations
(>=
400
mg/
kg).
Cytotoxicity
(
as
indicated
by
an
increase
in
the
number
of
first
division
metaphase
figures)
was
observed
in
all
animals
at
>=
400
mg/
kg.
No
statistically
significant
increases
in
SCE
frequency
were
observed
at
any
dose
compared
to
controls.
The
positive
control
induced
the
appropriate
response.
There
was
no
evidence
of
SCE
induced
over
background
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Comments
61
870.7845
(
85­
1)
Metabolism
­
Rat
Urinary
metabolites
41218901
(
1989)
Acceptable/
Guideline
There
was
no
sex­
dependent
effect
on
metabolic
profiles.
A
minimum
of
20­
30
non­
conjugated
metabolites
and
an
additional
10­
20
conjugated
metabolites
were
present
in
the
urine,
but
no
parent
compound
was
detected.
Information
on
the
percentage
of
the
administered
dose
excreted
in
the
urine
was
not
provided.
However,
no
single
metabolite
accounted
for
more
than
8­
10%
of
the
total
urinary
radioactivity,
and
the
majority
of
the
metabolites
were
present
at
1­
2%
of
the
total
urinary
radioactivity.
Thus,
almost
all
of
the
metabolites
were
minor
(<
5%
of
the
total
radioactive
dose).
Metabolite
F1B
was
found
at
8.2­
8.9%
of
the
total
urinary
radioactivity
in
both
sexes,
and
Metabolite
F2,
N­[(
3­(
acetylamino)­
2­
amino­
5­
(
trifluoromethyl)
phenyl]
acetamide,
was
found
at
4.0­
5.2%.
Metabolite
F1B
was
partially
characterized
as
retaining
the
trifluoromethyl
groups,
the
two
equivalent
aromatic
protons,
and
the
two
nitro
groups,
but
the
propyl
groups
were
lost.
Ten
other
metabolites
were
identified
(<
0.1­
3.7%
of
total
urinary
radioactivity,
each
compound
in
each
sex).
Two
additional
metabolites
were
partially
characterized
(
0.1­
2.6%
of
total
urinary
radioactivity,
each
compound
in
each
sex).

Four
metabolic
pathways
were
identified
as
follows:
(
i)
oxidative
N­
dealkylation
of
one
or
both
propyl
groups
and
metabolites
which
were
hydroxylated
on
the
propyl
side
chain;
(
ii)
reduction
of
one
or
both
nitro
groups
to
the
corresponding
amine;
(
iii)
cyclization
reactions
to
give
a
variety
of
substituted
and
unsubstituted
benzimidazole
metabolites;
and
(
iv)
conjugation
reactions,
including
acetylation
of
the
reduced
nitro
groups,
sulfate,
and
glucuronic
acid
conjugates.

Special
study
3­
Mo
Feeding
­
Rat
with
Urinalysis
study
00157156
(
1985),
40138301(
1986)
41086101
(
1989)

0,
50,
200,
800,
3200,
and
6400
ppm
0,
2.6,
10.7,
42.2,
170.2,
and
342.1
mg/
kg/
day
Acceptable/
Nonguideline
NOAEL
=
200
ppm
(
10.7
mg/
kg/
day)
LOAEL
for
nephrotoxicity
=
800
ppm
(
42.2
mg/
kg/
day),
based
on
the
presence
of
cortical
tubular
cytoplasmic
hyaline
droplets;
increased
total
protein,
AST,
and
LDH
in
the
urine;
and
increased
urinary
volume
upon
protein
electrophoresis
and
urinalysis.
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
62
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
63
8.2
Summary
of
Toxicological
Dose
and
Endpoints
Summary
of
Toxicological
Dose
and
Endpoints
for
Trifluralin
(
PC
Code
036101)

Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
Females
13­
50
years
of
age)
NOAEL
=
100
mg/
kg/
day
UF
=
100
Acute
RfD
=
1.0
mg/
kg/
day
FQPA
SF
=
1
aPAD
=
acute
RfD
FQPA
SF
=
1.0
mg/
kg/
day
Developmental
Toxicity
Study
­
Rat
LOAEL
=
500
mg/
kg/
day
based
on
increased
total
liter
resorptions.

Acute
Dietary
(
General
population
including
infants
and
children)
No
appropriate
single
dose
endpoint
was
found
for
this
population
sub
group
Chronic
Dietary
(
All
populations)
NOAEL=
2.4
mg/
kg/
day
UF
=
100
Chronic
RfD
=
0.024
mg/
kg/
day
FQPA
SF
=
1
cPAD
=
chronic
RfD
FQPA
SF
=
0.024
mg/
kg/
day
Chronic
Toxicity
(
capsule)
­
Dog
LOAEL
=
40
mg/
kg/
day
based
on
based
on
increased
frequency
of
abnormal
stool,
decreased
body
weights
and
body
weight
gains,
and
on
decreased
erythrocytes
and
hemoglobin
and
increased
thrombocytes
in
males
Short­
Term
Incidental
Oral
(
1­
30
days)
NOAEL=
10
mg/
kg/
day
Residential
LOC
for
MOE
=
100
Occupational
=
NA
Two­
generation
Reproduction
Study
­
Rat
LOAEL
=
32.5
mg/
kg/
day
based
on
decreased
pup
weights
in
both
generations
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
64
Intermediate­
Term
Incidental
Oral
(
1­
6
months)
NOAEL=
10
mg/
kg/
day
Residential
LOC
for
MOE
=
100
Occupational
=
NA
Special
Urinalysis
Study
­
Rat
LOAEL
=
40
mg/
kg/
day
based
on
based
on
the
presence
of
tubular
cytoplasmic
hyaline
droplets;
increased
total
protein,
AST,
and
LDH
in
the
urine;
albumin
 1­
globulin
and
 2­
globulin
observed
by
urine
electrophoresis;
and
increased
urinary
volume
Short­
Term
Dermal
(
1
to
30
days)
No
quantification
required.
since
there
was
no
systemic
toxicity
at
the
limit
dose
in
the
dermal
toxicity
study.
There
are
no
developmental
toxicity
concerns.
Also,
because
risk
can
not
be
quantified,
the
HIARC
also
recommends
that
the
products
containing
trifluralin
should
be
labeled
as
SENSITIZER
and
should
avoid
human
contact
Intermediate­
Term
Dermal
(
1
to
6
months)
Oral
study
NOAEL
=
10
mg/
kg/
day
(
dermal
absorption
rate
=
3
%
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
Special
Urinalysis
Study
­
Rat
LOAEL
=
40
mg/
kg/
day
based
on
based
on
the
presence
of
tubular
cytoplasmic
hyaline
droplets;
increased
total
protein,
AST,
and
LDH
in
the
urine;
albumin
 1­
globulin
and
 2­
globulin
observed
by
urine
electrophoresis;
and
increased
urinary
volume
Long­
Term
Dermal
(>
6
months)
Oral
study
NOAEL=
2.4
mg/
kg/
day
(
dermal
absorption
rate
=
3
%
when
appropriate)
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
Chronic
Toxicity
(
capsule)
­
Dog
LOAEL
=
40
mg/
kg/
day
based
on
based
on
increased
frequency
of
abnormal
stool,
decreased
body
weights
and
body
weight
gains,
and
on
decreased
erythrocytes
and
hemoglobin
and
increased
thrombocytes
in
males
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
65
Short­
Term
Inhalation
(
1
to
30
days)
Inhalation
study
NOAEL=
81
mg/
kg/
day
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
30­
Day
Inhalation
Study
­
Rat
LOAEL
=
270
mg/
kg/
day
based
on
increased
methemoglobin
and
bilirubin
in
females
and
incidences
of
dyspnea
and
ruffled
fur
in
males
and
females
Intermediate­
Term
Inhalation
(
1
to
6
months)
Oral
study
NOAEL
=
10
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
Special
Urinalysis
Study
­
Rat
LOAEL
=
40
mg/
kg/
day
based
on
based
on
the
presence
of
tubular
cytoplasmic
hyaline
droplets;
increased
total
protein,
AST,
and
LDH
in
the
urine;
albumin
 1­
globulin
and
 2­
globulin
observed
by
urine
electrophoresis;
and
increased
urinary
volume
Long­
Term
Inhalation
(>
6
months)
Oral
study
NOAEL=
2.4
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
Chronic
Toxicity
(
capsule)
­
Dog
LOAEL
=
40
mg/
kg/
day
based
on
based
on
increased
frequency
of
abnormal
stool,
decreased
body
weights
and
body
weight
gains,
and
on
decreased
erythrocytes
and
hemoglobin
and
increased
thrombocytes
in
males
Cancer
(
oral,
dermal,
inhalation)
Q1*
=
0.00579
(
mg/
kg/
day)­
1
"
Group
C"
(
limited
evidence
of
carcinogenicity)

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
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
NA
=
Not
Applicable
NOTE:
The
Special
FQPA
Safety
Factor
recommended
by
the
HIARC
assumes
that
the
exposure
databases
(
dietary
food,
drinking
water,
and
residential)
are
complete
and
that
the
risk
assessment
for
each
TRIFLURALIN
(
036101)
October
2003
TRED
Toxicology
Chapter
66
potential
exposure
scenario
includes
all
metabolites
and/
or
degradates
of
concern
and
does
not
underestimate
the
potential
risk
for
infants
and
children.
