Document ID: EPA-HQ-OPP-2004-0382-0017
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2005-10-06T04:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
August
31,
2005
MEMORANDUM
SUBJECT:
Thidiazuron:
Revised
HED
Chapter
of
the
Reregistration
Eligibility
Decision
Document
(
RED),
Phase
3­
Public
Comments.
PC
Code:
120301,
Case
#:
4092,
DP
Barcode:
D319302.

Regulatory
Action:
Reregistration
Risk
Assessment,
Phase
3
­
HED
Response
to
Public
Comments
Risk
Assessment
Type:
Single
Chemical,
Aggregate
FROM:
Toiya
Goodlow,
Chemist
and
Risk
Assessor
Byong­
Han
Chin,
Ph.
D.,
Toxicologist
Jeff
Dawson,
Chemist
Reregistration
Branch
1
Health
Effects
Division
(
7509C)

THROUGH:
Whang
Phang,
Ph.
D.,
Branch
Senior
Scientist
Reregistration
Branch
1
Health
Effects
Division
(
7509C)

TO:
John
Pates
Jr.,
Chemical
Review
Manager
Special
Review
and
Reregistration
Division
(
7508C)

This
document
is
a
revision
of
the
Human
Health
Risk
Assessment
for
the
Thidiazuron
Reregistration
Eligibility
Decision
Document
(
RED)
dated
May
2,
2005
(
T.
Jimerson,
W.
Phang).
The
HED
chapter
includes
the
Toxicology
and
Hazard
Assessment
from
Byong­
Han
(
Paul)
Chin,
Reregistration
Branch
I,
Residue
Chemistry
Assessments
and
Dietary
Exposure
Analysis
from
Toiya
Goodlow,
Reregistration
Branch
1,
and
the
Occupational
and
Residential
Exposure
Assessments
from
Jeff
Dawson,
Reregistration
Branch
1.
Information
was
also
drawn
from
the
Environmental
Fate
and
Effects
Division
(
EFED)
Drinking
Water
Assessment
(
A.
Clem,
8/
24/
04)
and
the
Review
of
Thidiazuron
Incident
Reports
from
Jerry
Blondell,
HED,
Chemistry
and
Exposure
Branch.
ii
This
risk
assessment
was
revised
in
response
to
public
comments.
The
corrections
were
reviewed
by
RRB1/
HED
and
revised
to
comply
with
Agency
policies.
See
DP
Barcode:
D320616,
dated
August
31,
2005
for
the
complete
HED
Response
to
Public
Comments.
iii
Table
of
Contents
1.0
Executive
Summary
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1
2.0
Ingredient
Profile
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4
2.1
Summary
of
Registered/
Proposed
Uses
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4
2.2
Structure
and
Nomenclature
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5
2.3
Physical
and
Chemical
Properties
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7
3.0
Metabolism
Assessment
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8
3.1
Comparative
Metabolic
Profile
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8
3.2
Nature
of
the
Residue
in
Foods
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8
3.2.1.
Description
of
Primary
Crop
Metabolism
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8
3.2.2
Description
of
Livestock
Metabolism
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9
3.2.3
Description
of
Rotational
Crop
Metabolism,
including
identification
of
major
metabolites
and
specific
routes
of
biotransformation
.
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11
3.3
Environmental
Degradation
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12
3.4
Tabular
Summary
of
Metabolites
and
Degradates
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13
3.5
Toxicity
Profile
of
Major
Metabolites
and
Degradates
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14
3.6
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
.
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14
3.6.1
Tabular
Summary
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14
3.6.2
Rationale
for
Inclusion
of
Metabolites
and
Degradates
.
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14
4.0
Hazard
Characterization/
Assessment
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15
4.1.
Hazard
and
Dose­
Response
Characterization
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15
4.1.1.
Database
Summary
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15
4.1.1.1.
Studies
available
and
considered
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15
4.1.1.2.
Mode
of
action,
metabolism,
toxicokinetic
data
.
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15
4.1.1.3.
Sufficiency
of
studies/
data
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16
4.1.2.
Toxicological
Effects
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16
4.1.3.
Dose­
response
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17
4.2
FQPA
Hazard
Considerations
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22
4.2.1
Adequacy
of
the
Toxicity
Data
Base
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22
4.2.2
Evidence
of
Neurotoxicity
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22
4.2.3
Developmental
Toxicity
Studies
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22
4.2.4
Reproductive
Toxicity
Study
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24
4.2.5
Additional
Information
from
Literature
Sources
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26
4.2.6
Pre­
and/
or
Postnatal
Toxicity
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26
4.2.6.1
Determination
of
Susceptibility
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26
4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
iv
Pre
and/
or
Post­
natal
Susceptibility
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26
4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
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26
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
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26
4.3.2
Evidence
that
supports
not
requiring
for
a
Developmental
Neurotoxicity
study
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26
4.3.2.1
Rationale
for
the
UF
DB
(
when
a
DNT
is
recommended)
.
26
4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
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26
4.4.1
Acute
Reference
Dose
(
aRfD)
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26
4.4.2
Chronic
Reference
Dose
(
cRfD)
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26
4.4.3
Incidental
Oral
Exposure
(
Short
and
Intermediate
Term)
.
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28
4.4.4
Dermal
Absorption
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29
4.4.5
Dermal
Exposure
(
Short,
Intermediate
and
Long
Term)
.
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29
4.4.6
Inhalation
Exposure
(
Short,
Intermediate
and
Long
Term)
.
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29
4.4.7
Margins
of
Exposure
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30
4.4.8
Recommendation
for
Aggregate
Exposure
Risk
Assessments
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30
4.4.9
Classification
of
Carcinogenic
Potential
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31
4.5
Special
FQPA
Safety
Factor
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35
4.6
Endocrine
disruption
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35
5.0
Public
Health
Data
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36
5.1
Incident
Reports
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36
6.0
Exposure
Characterization/
Assessment
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36
6.1
Dietary
Exposure/
Risk
Pathway
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36
6.1.1
Residue
Profile
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36
6.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk
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38
6.2
Water
Exposure/
Risk
Pathway
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39
6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
.
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40
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
.
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40
7.1
Acute
Aggregate
Risk
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.
41
7.2
Short­
Term
Aggregate
Risk
.
.
.
.
.
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.
41
7.3
Intermediate­
Term
Aggregate
Risk
.
.
.
.
.
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.
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.
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.
41
7.4
Long­
Term
Aggregate
Risk
.
.
.
.
.
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.
41
7.5
Cancer
Risk
.
.
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41
8.0
Cumulative
Risk
Characterization/
Assessment
.
.
.
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.
42
9.0
Occupational
Exposure/
Risk
Pathway
.
.
.
.
.
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.
42
9.1
Short/
Intermediate/
Long­
Term
Handler
Risk
.
.
.
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.
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.
43
9.2
Short/
Intermediate/
Long­
Term
Postapplication
Risk
.
.
.
.
.
.
.
.
.
.
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.
47
9.3
Occupational
Risk
Characterization
.
.
.
.
.
.
.
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.
47
10.0
Data
Needs
and
Label
Requirements
.
.
.
.
.
.
.
.
.
.
.
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.
48
10.1
Toxicology
.
.
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.
48
v
10.2
Residue
Chemistry
.
.
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.
48
10.3
Occupational
and
Residential
Exposure
.
.
.
.
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48
References:
.
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48
Appendices
.
.
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.
50
1.0
TOLERANCE
REASSESSMENT
RECOMMENDATIONS
.
.
.
.
.
.
.
.
.
.
.
.
.
.
50
2.0
TOXICOLOGY
DATA
REQUIREMENTS
.
.
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.
51
3.0
NON­
CRITICAL
TOXICOLOGY
STUDIES
.
.
.
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.
52
3.1
Non­
Critical
Studies
Using
Active
Ingredient
.
.
.
.
.
.
.
.
.
.
.
.
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.
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.
.
55
3.2
Non­
Critical
Mode
of
Action
or
Metabolite
Studies
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
57
4.0
THIDIAZURON
OCCUPATIONAL
HANDLER
RISK
ASSESSMENT
.
.
.
.
.
58
1
1.0
Executive
Summary
This
risk
assessment
was
performed
to
support
the
reregistration
eligibility
decision
for
thidiazuron
[
1­
phenyl­
3­(
1,2,3­
thidiazol­
5­
yl)
urea].
Thidiazuron
is
a
phenylurea
herbicide
used
for
the
defoliation
of
cotton.
It
removes
green
leaves
and
immature
fruiting
structures
which
contribute
to
cotton
staining.
Thidiazuron
registered
formulations
include
wettable
powders
(
WP),
soluble
concentrates
(
SC),
emulsifiable
concentrates
(
EC),
and
liquids.
These
formulations
can
be
applied
by
ground
or
air.
Thidiazuron
is
primarily
used
in
the
major
cotton
producing
areas
which
consist
of
the
Mid­
South,
Southeast,
and
Western
United
States.

The
submitted
studies
provide
adequate
information
to
determine
whether
thidiazuron
poses
a
human
health
hazard.
The
Agency
is
confident
that
the
risk
estimates
presented
in
this
document
represent
conservative
approximations
of
human
health
risks
associated
with
the
use
of
thidiazuron.

The
available
toxicity
data
indicate
the
acute
oral,
dermal,
inhalation,
and
primary
eye
and
dermal
irritation
toxicity
of
thidiazuron
to
be
in
toxicity
categories
III
and
IV.
Thidiazuron
is
not
a
dermal
sensitizer
or
a
skin
irritant.

Both
subchronic
and
chronic
toxicity
studies
in
rats
show
that
thidiazuron
causes
decreased
body
weights,
body
weight
gains,
and
food
consumption.
In
addition,
chronic
toxicity
studies
showed
bilateral
vesicle
atrophy
in
rats,
and
dilated
tubules
of
epididymis
in
mice.
In
the
subchronic
toxicity
study,
small
vesicles
and
prostate
were
also
reported.
The
data
from
the
developmental
toxicity
studies
in
rats
and
rabbits
and
of
the
2­
generation
reproduction
study
indicated
no
increase
in
susceptibility
of
fetuses
and
pups
to
the
in
utero
and/
or
postnatal
exposure
to
thidiazuron.

No
neurotoxicity
was
reported
in
any
of
the
studies.
Carcinogenicity
studies
in
both
rats
and
mice
produced
no
treatment­
related
increase
in
tumor
incidence.
The
standard
battery
of
genotoxicity
tests
was
negative.

HED
has
selected
a
chronic
reference
dose
(
RfD)
for
the
dietary
risk
assessment,
and
calculated
the
Population
Adjusted
Dose
(
PAD),
which
is
the
RfD
divided
by
the
FQPA
safety
factor.
Based
on
the
hazard
data,
HED
recommends
the
special
FQPA
SF
be
reduced
to
1X
because
there
are
no/
low
concerns
and
no
residual
uncertainties
with
regard
to
pre­
and/
or
postnatal
toxicity.
Therefore,
the
PAD
is
equal
to
the
RfD.
The
developmental
rabbit
study
and
the
oneyear
dog
study
were
the
primary
studies
used
for
the
dose­
response
assessment.
The
one­
year
dog
study
was
chosen
for
the
chronic
RfD.
The
PAD
for
chronic
effects
(
general
population)
is
equal
to
the
chronic
reference
dose
of
0.0393
mg/
kg/
day.
An
acute
dietary
endpoint
was
not
selected
because
appropriate
toxicity
attributed
to
a
single
exposure
was
not
identified.
At
the
limit
dose
(
1000
mg/
kg),
no
systemic
toxicity
or
dermal
irritation
was
noted
in
the
28­
day
dermal
toxicity
study
in
the
rat;
therefore,
no
dose
was
selected
for
short­
and
intermediate
term
dermal
risk
assessments.
The
developmental
rabbit
study
was
selected
for
both
the
short­
and
intermediate­
term
inhalation
and
incidental
oral
exposure
scenarios.

Currently,
the
combined
residues
of
thidiazuron
and
its
aniline
containing
metabolites
are
2
regulated
(
40
CFR180.403)
in
plants
and
livestock.
Tolerances
are
established
in/
on
cottonseed
(
0.4
ppm),
eggs
(
0.1
ppm),
and
milk
(
0.05
ppm).
Additional
tolerances
are
set
at
0.2
ppm
for
the
fat,
meat
and
meat
by­
products
of
cattle,
goats,
hogs,
horses,
poultry
and
sheep.
An
0.8
ppm
tolerance
for
cottonseed
hulls
has
been
revoked
by
the
Agency.
The
HED
Metabolism
Assessment
Review
Committee
(
9/
29/
95,
F.
Fort)
has
determined
that
the
residue
of
concern
in
plant
commodities
consists
of
the
parent
thidiazuron
only,
and
that
the
residues
of
concern
in
livestock
commodities
consist
of
the
parent
thidiazuron,
4­
hydroxythidiazuron,
and
phenyl
urea.
HED
recommends
that
the
tolerances
for
thidiazuron
reflect
the
residues
of
concern
as
determined
by
the
MARC,
instead
of
thidiazuron
and
its
aniline
containing
metabolites
collectively.

A
Tier
I
dietary
exposure
assessment
for
food
only
was
performed
using
DEEM­
FCID
 
and
Lifeline
 
.
The
assumptions
of
these
dietary
exposure
assessments
were
tolerance
level
residues
and
100%
crop
treated,
with
the
exception
of
meat,
meat
byproducts,
and
fat
tolerances.
The
dietary
exposure
analyses
in
this
assessment
for
thidiazuron
result
in
dietary
risk
estimates
for
food
that
are
below
the
Agency's
level
of
concern
for
chronic
dietary
exposure.
Estimates
from
both
models
show
that
the
chronic
exposure
is
<
8%
of
the
cPAD.

Potential
drinking
water
concentrations
for
the
acute
and
chronic
assessments
were
estimated
using
two
EFED
Tier
1
screening­
level
models:
FIRST,
Version
1.0
and
SCI­
GROW,
Version
2.3.
Since
the
HED
Metabolism
Assessment
Review
Committee
(
MARC)
did
not
determine
the
residues
of
concern
for
water,
EFED
provided
three
estimates
for
possible
drinking
water
concentrations.
The
most
conservative
numbers
were
used
in
this
risk
assessment,
which
included
thidiazuron
and
both
photoproducts,
photo­
thidiazuron
and
1­
cyano­
3­
phenylurea
in
its
estimate.

There
are
no
residential
uses
for
thidiazuron.
It
is
only
registered
for
agricultural
use
as
a
cotton
defoliant
late
in
the
growing
season.
Therefore,
residential
exposures
and
risks
are
not
expected.

Since
there
are
no
residential
uses,
the
aggregate
exposure
assessment
for
thidiazuron
considered
exposures
from
food
and
drinking
water
only.
A
Tier
I
chronic
dietary
risk
assessment
was
conducted
using
the
Dietary
Exposure
Evaluation
Model
(
DEEM­
FCID
 
)
,
Version
2.0,
and
Lifeline
 
Model
Version
2.0.
The
assumptions
of
these
dietary
exposure
assessments
were
tolerance
level
residues
and
100%
crop
treated,
with
the
exception
of
meat,
meat
byproducts
and
fat.
The
most
conservative
water
concentration
estimate
was
used
for
the
chronic
dietary
assessment,
as
provided
from
the
EFED
Drinking
Water
Assessment
memo.
The
dietary
exposure
analyses
in
this
assessment
for
thidiazuron
resulted
in
dietary
risk
estimates
for
food
and
water
that
are
below
the
Agency's
level
of
concern
for
chronic
dietary
exposure.
Estimates
from
both
models
show
that
the
chronic
exposure
is
<
8%
of
the
cPAD
for
thidiazuron.

There
is
a
potential
for
occupational
exposure
to
thidiazuron
when
making
applications
by
aerial
or
ground
equipment
to
late
season
cotton.
Tasks
associated
with
occupational
thidiazuron
use
include
mixing,
loading
and
applying
the
chemical
or
guiding
aerial
applications
(
flaggers).
All
these
activities
are
collectively
referred
to
as
handler
tasks.
A
total
of
5
scenarios
were
considered
representative
of
the
range
of
handler
activities,
available
formulations,
and
equipment
used
for
applications
to
cotton.
Risks
from
dermal
exposures
were
not
calculated
because
no
hazard
concern
was
identified
for
exposures
to
the
skin.
Risks
for
inhalation
exposures
were
calculated
for
varying
levels
of
personal
protection,
including
engineering
controls
such
as
water
Page
3
of
59
soluble
bags
in
which
thidiazuron
is
currently
marketed.
For
uses
of
this
type,
the
Agency
generally
considers
both
short­
and
intermediate­
term
exposures.
In
this
case,
both
the
short­
and
intermediate­
term
risk
assessment
for
thidiazuron
were
based
on
a
developmental
toxicity
study
in
rabbits
where
increased
abortions
were
noted
and
the
NOAEL
was
determined
to
be
25
mg/
kg/
day.
The
total
uncertainty
factor
applied
in
this
assessment
was
100
to
account
for
interand
intra­
species
differences.

Inhalation
risks
were
calculated
assuming
one
of
four
possible
levels
of
personal
protection
ranging
from
a
baseline
of
no
respiratory
protection
to
engineering
controls,
such
as
water
soluble
bags.
Current
thidiazuron
labels
typically
require
that
handlers
wear
long
pants,
long­
sleeved
shirts,
and
gloves
but
do
not
require
respirators.
The
wettable
powder
formulations
of
thidiazuron
marketed
by
Bayer
Crop
Sciences
are
sold
in
water
soluble
bags
and
account
for
the
vast
majority
of
wettable
powders
sold
on
an
annual
basis.
For
all
scenarios
considered,
even
for
high
acreages
without
the
use
of
a
respirator
or
engineering
controls,
inhalation
risks
were
not
of
concern
for
thidiazuron
handlers
(
i.
e.,
most
MOEs
>
10,000).

The
Agency
recognizes
that
most
activities
associated
with
the
cultivation
and
harvest
of
cotton
are
predominantly
accomplished
in
an
intensively
mechanized
fashion
that
essentially
eliminates
exposures
for
most
of
the
workers
involved.
However,
some
workers
can
be
exposed
to
thidiazuron
residues
when
entering
previously
treated
areas
to
perform
certain
activities
such
as
scouting
or
those
associated
with
harvesting
(
i.
e.,
rakers,
trampers,
module
builders).
Current
label
requirements
specify
24
hour
restricted
entry
intervals
(
REIs),
while
pre­
harvest
intervals
(
PHIs)
are
currently
5
days.
The
Agency
believes
that
dermal
exposures
may
occur
for
postapplication
workers,
but
they
are
not
of
concern
because
the
available
data
for
these
activities
show
exposures
to
be
low
and
the
Agency
has
not
identified
any
hazard
concerns
associated
with
dermal
exposures.
The
Agency
also
does
not
routinely
complete
postapplication
worker
inhalation
risk
assessments
because
available
exposure
data
show
they
do
not
occur
at
appreciable
levels.

In
conclusion,
human
health
risks
are
considered
to
be
minimal
due
to
thidiazuron's
low
acute
toxicity
(
toxicity
categories
III
and
IV)
and
its
low
dietary
risk.
Carcinogenicity
studies
reported
no
treatment­
related
increase
in
tumor
incidence
for
thidiazuron.
There
are
no
residential
uses
for
thidiazuron.
Occupational
use
data
show
dermal
exposures
to
be
low
and
inhalation
risks
were
not
of
concern
for
thidiazuron
handlers
(
i.
e.,
most
MOEs
>
10,000).

Data
gaps
include:

Toxicology
There
are
no
toxicological
data
gaps.

Residue
Chemistry
Guideline
860.1340
Residue
Analytical
Method­
Livestock
Guideline
860.1380
Storage
Stability
Data­
Plant
and
Livestock
Page
4
of
59
Occupational/
Residential
Exposure
There
are
no
occupational/
residential
exposure
data
gaps.

2.0
Ingredient
Profile
Thidiazuron
is
a
herbicide
which
defoliates
green
leaves
and
immature
fruiting
structures
that
contribute
to
cotton
staining.
For
formulations
containing
thidiazuron
as
a
single
active
ingredient,
a
maximum
of
two,
0.05­
0.2
lbs.
a.
i./
acre
applications
may
be
applied
to
mature
cotton
plants,
not
exceeding
a
total
rate
of
0.3
lb
a.
i./
A/
season
(
0.337
kg
a.
i./
ha/
season).
For
formulations
containing
a
mixture
of
thidiazuron
and
diuron,
a
maximum
of
two,
0.05­
0.125
lb
thidiazuron
a.
i./
acre
applications
may
be
applied,
not
exceeding
a
total
rate
of
0.125
lb
thidiazuron
a.
i./
A/
season
(
0.568
kg
a.
i./
ha/
season).
The
minimum
PHI
is
5
days,
and
the
REI
is
24
hours.
Thidiazuron
registered
formulations
include
wettable
powders
(
WP),
soluble
concentrates
(
SC),
emulsifiable
concentrates
(
EC),
and
liquids.
The
percentage
of
thidiazuron
used
in
each
formulation
type
ranges
from
8.4­
50%
active
ingredient
per
pound
formulated.
These
formulations
can
be
applied
by
aerial
or
ground
equipment.

2.1
Summary
of
Registered/
Proposed
Uses
Table
2.1
provides
a
summary
of
registered
uses
for
thidiazuron.

Table
2.1.
Summary
of
Directions
for
Use
of
Thidiazuron
on
Cotton.

Applic.
Timing
Applic.
Type
Applic.
Equip.
Formulation
[
EPA
Reg.
No.]
Applic.
Rate
(
lb
ai/
A)
Max.
No.
Applic.
per
Season
Max.
Seasonal
Applic.
Rate
(
lb
ai/
A)
PHI
(
days)
REI
(
hours)

Preharvest
Low
Volume
Spray
(
concentrate)
Aircraft
000264­
00622
0.2;
0.1
2
0.3
5
24
Preharvest
Broadcast
Ground
000264­
00622
0.2;
0.1
2
0.3
5
24
Preharvest
Direct
Spray
Ground
000264­
00622
0.05
2
0.3
5
24
Preharvest
Broadcast
Aircraft
051036­
00401
0.2;
0.1
2
0.3
5
24
Preharvest
Broadcast
Ground
051036­
00401
0.2;
0.1
2
0.3
5
24
Preharvest
Direct
Spray
Ground
051036­
00401
0.05
2
0.3
5
24
Preharvest
Broadcast
Aircraft
000264­
00634
0.05­
0.125
2
0.125
5
24
Preharvest
Broadcast
Low
Pressure
Ground
Sprayer
000264­
00634
0.05­
0.125
2
0.3
5
24
Preharvest
Low
Volume
Spray
(
concentrate)
Aircraft
000264­
00661
0.05­
0.125
2
0.125
5
24
Preharvest
Spray
Ground
000264­
00661
0.05­
0.125
2
0.125
5
24
Table
2.1.
Summary
of
Directions
for
Use
of
Thidiazuron
on
Cotton.

Applic.
Timing
Applic.
Type
Applic.
Equip.
Formulation
[
EPA
Reg.
No.]
Applic.
Rate
(
lb
ai/
A)
Max.
No.
Applic.
per
Season
Max.
Seasonal
Applic.
Rate
(
lb
ai/
A)
PHI
(
days)
REI
(
hours)

Page
5
of
59
N
N
S
N
H
N
H
O
Foliar
Low
Volume
Spray
(
concentrate)
Aircraft
000400­
00505
0.075
2
0.3
5
48
Foliar
Broadcast
Ground
000400­
00505
0.075
2
0.3
5
48
Preharvest
Spray
Ground
000264­
00700
0.2;
0.1
2
0.3
5
24
Preharvest
Spray
Aircraft
000264­
00700
0.2;
0.1
2
0.3
5
24
Preharvest
Spray
Ground
000264­
00821
0.05­
0.125
2
0.125
5
24
Preharvest
Spray
Aircraft
000264­
00821
0.05­
0.125
2
0.125
5
24
Preharvest
Spray
Ground
72167­
30
0.05­
0.2
2
0.3
5
24
Preharvest
Spray
Aircraft
72167­
30
0.05­
0.2
2
0.3
5
24
Preharvest
Spray
Ground
51036­
429
0.05­
0.125
2
0.125
5
24
Preharvest
Spray
Aircraft
51036­
429
0.05­
0.125
2
0.125
5
24
Preharvest
Spray
Ground
51036­
430
0.05­
0.2
2
0.3
5
24
Preharvest
Spray
Aircraft
51036­
430
0.05­
0.2
2
0.3
5
24
2.2
Structure
and
Nomenclature
Tables
2.2a­
2.2e
provide
structures
and
nomenclature
for
thidiazuron
and
its
metabolites.

TABLE
2.2a
Thidiazuron­
Test
Compound
Nomenclature
Chemical
Structure
Empirical
Formula
C9H8N4OS
Common
name
Thidiazuron
IUPAC
name
1­
phenyl­
3­(
1,2,3­
thidiazol­
5­
yl)
urea
CAS
name
N­
phenyl­
N'­
1,2,3­
thiadiazol­
5­
ylurea
CAS
Registry
Number
51707­
55­
2
End­
use
product/
EP
DROPP
®
50WP;
FreeFall;
DROPP
®
SC;
Ginstar
®
EC;
Thidiazuron
50
WSB;
Leafless
Chemical
Class
Herbicide
,
defoliant
Page
6
of
59
TABLE
2.2b
4­
Hydroxy
Thidiazuron­
Test
Compound
Nomenclature
Compound
Chemical
Structure
Common
name
4­
Hydroxy
Thidiazuron
IUPAC
name
1­(
4­
hydrophenyl)­
3­(
1,2,3­
thidiazol­
5­
yl)
urea
CAS
name
N­(
4­
hydroxyphenyl­
N'­
1,2,3­
thidiazol­
5­
yl)
urea
CAS
#
NA
TABLE
2.2c
Phenyl
Urea­
Test
Compound
Nomenclature
Compound
Chemical
Structure
Common
name
Phenylurea
IUPAC
name
1­
phenylurea
CAS
name
N­
phenylurea
CAS
#
64­
10­
8
TABLE
2.2d
Photo­
Thidiazuron­
Test
Compound
Nomenclature
Compound
Chemical
Structure
Common
name
Photo­
Thidiazuron
IUPAC
name
1­
phenyl­
3­(
1,2,5­
thidiazole­
3­
yl)
urea
CAS
name
N­
phenyl­
N'­
1,2,5­
thiadiazol­
5­
ylurea
CAS
#
71769­
74­
9
Page
7
of
59
NH
C
O
NH
C
N
TABLE
2.2e
1­
Cyano­
3­
Phenylurea­
Test
Compound
Nomenclature
Compound
Chemical
Structure
IUPAC
name
1­
cyano­
3­
phenylurea
2.3
Physical
and
Chemical
Properties
Technical
thidiazuron
is
a
yellowish­
brown,
amorphous
solid
with
a
melting
point
of
217
°
C.
Thidiazuron
is
miscible
with
dimethylsulfoxide,
dimethylformanide,
acetone,
cyclohexanone,
and
isophrone,
and
slightly
soluble
in
other
organic
solvents.
It
has
a
vapor
pressure
of
3.5
x
10­
9
mPa
at
20

C,
and
a
water
solubility
of
31.0
mg/
L
at
25

C.
Thidiazuron
is
a
member
of
the
phenylurea
group
of
herbicides,
that
includes
diuron
and
linuron.
Additional
physicochemical
properties
can
be
found
in
Table
2.3.

TABLE
2.3.
Physicochemical
Properties
Parameter
Value1
Reference
Molecular
Weight
220.25
g
Merck
12,9447
Melting
point/
range
217

C
Merck
12,9447
pH
(
20

C)
5.21
D295368,
Shyam
Mathur,
3/
1/
04.

Density
(
20

C)
0.324
gm/
cc
D295368,
Shyam
Mathur,
3/
1/
04.

Water
solubility
(
25

C,
pH
7.0)
31.0
mg/
L
D295368,
Shyam
Mathur,
3/
1/
04.

Solvent
solubility
(
temperature
not
specified)
Very
soluble
in
dimethylsulfoxide,
dimethylformanide,
acetone,
cyclohexanone,
and
isophrone.
Slightly
soluble
in
aliphatic
and
aromatic
hydrocarbons
and
water.
Merck
12,9447
Vapor
pressure
(
20

C)
3.5
x
10­
9
mPa
D295368,
Shyam
Mathur,
3/
1/
04.

Dissociation
constant,
pKa
(
25

C)
8.86
D295368,
Shyam
Mathur,
3/
1/
04.

Octanol/
water
partition
coefficient,
Ko/
w
(
25

C,
pH
7.3)
50.0
D295368,
Shyam
Mathur,
3/
1/
04.

UV/
visible
absorption
spectrum
 
max
=
238
nm;
 
=
985
M­
1
cm­
1
D295368,
Shyam
Mathur,
3/
1/
04.

1
NA=
Not
Available
Page
8
of
59
3.0
Metabolism
Assessment
3.1
Comparative
Metabolic
Profile
In
cotton,
thidiazuron
defoliates
green
leaves
and
immature
fruiting
structures.
In
plants,
thidiazuron
is
the
major
metabolite.

An
oral
metabolism
study
in
rats
indicates
that
thidiazuron
is
rapidly
absorbed
and
eliminated
primarily
in
the
urine
with
most
of
the
administered
dose
excreted
by
5
days
postdosing.
The
major
route
of
elimination
was
shown
to
be
via
urine.
Identification
of
urinary
metabolites
indicated
the
presence
of
oxidative
metabolite
(
4­
hydroxy
thidiazuron)
in
urine
and
the
presence
of
sulfate
and
glucuronide
conjugates
of
4­
hydroxy
thidiazuron.
In
feces,
the
major
metabolites
identified
were
4­
hydroxy
thidiazuron
at
the
low
dose
and
unmetabolized
thidiazuron
at
the
high
dose.
Livestock
metabolite
phenylurea
and
water
metabolites
photo­
thidiazuron
and
1­
cyano­
3­
phenylurea
were
not
found
in
the
oral
rat
metabolism
study.

3.2
Nature
of
the
Residue
in
Foods
3.2.1.
Description
of
Primary
Crop
Metabolism
The
metabolism
of
thidiazuron
in
plants
has
been
adequately
defined
for
the
current
uses
through
the
study
of
thidiazuron
14C­
radiolabeled
in
the
phenyl
and
thiazoyl
rings
and
applied
to
cotton
plants.
Several
studies
have
been
conducted,
the
results
of
which
are
shown
in
Tables
3.2.1a­
3.2.1c
below.
Based
on
these
results,
it
was
concluded
by
the
HED
Metabolism
Committee
(
9/
8/
95,
F.
Fort)
that
the
residue
of
concern
for
cotton
consists
of
the
parent
only,
thidiazuron.

Table
3.2.1a
Metabolites
in
Cotton
from
the
Application
of
14C­
Thidiazuron
labeled
in
the
phenyl
ring1
Residue
Identified
Leaves
(
21.88
ppm)
Seeds
(
0.04
ppm)

%
TRR
PPM
%
TRR
PPM
thidiazuron
29
6.31
60
0.02
photoproduct
13
2.76
7
<
0.008
bound
residue
38
8.27
<
12
<
0.008
origin
13
2.77
15
<
0.008
unknown
I
6
1.36
6
<
0.008
unknown
II
2
0.41
ND
<
0.008
1.
14C­
thidiazuron
was
applied
at
a
rate
of
0.2
lb
ai/
A
(
1x).
Identification
was
accomplished
by
one
method,
thin
layer
chromatography,
and
two
solvent
systems.
Page
9
of
59
Table
3.2.1b
Metabolites
in
Cotton
for
the
Application
of
Thidiazuron
labeled
in
the
thidiazolyl
and
phenyl
rings.
1
Metabolite
Thiadiazolyl­
labeled
(
2.96
ppm)
Phenyl­
labeled
(
3.92
ppm)

TRR
(
ppm)
Percent
TRR
TRR
(
ppm)
Percent
TRR
Thidiazuron
2.23
75.2
3.07
78.4
Photoproduct
0.04
1.5
0.02
0.4
Not
Identified
0.69
23.3
0.83
21.2
1.
14C­
thidiazuron
was
applied
at
a
rate
of
0.2
lb
ai/
A
(
1x).
Identification
was
accomplished
by
one
method,
thin
layer
chromatography,
and
two
solvent
systems.

Table
3.2.1c
Metabolites
Found
in
Cotton
Foliage
after
Application
of
14C­
Thidiazuron
labeled
in
the
phenyl
ring
Residues
%
TRR
Thidiazuron
79.2
Photoproduct
0.2
Origin
2.1
Other
products
0.6
Not
Extracted
0.3
Unaccounted
17.6
Total
100
1.
Ten
mls
of
14C­
thidiazuron
was
brushed
on
the
leaves.
Identification
was
accomplished
by
one
method,
thin
layer
chromatography,
and
two
solvent
systems.

3.2.2
Description
of
Livestock
Metabolism
The
nature
of
the
residue
in
animals
is
adequately
understood.

Ruminant
metabolism:
[
14C­
aniline]
thidiazuron
was
fed
at
a
dose
exaggeration
of
1.9x
to
a
lactating
cow
at
a
rate
of
10
ppm
for
seven
days.
The
animal
was
sacrificed
within
24
hours
of
administration
of
the
final
dose.
Parent
equivalent
radioactivity
found
was
0.05
ppm,
0.1
ppm,
1.5
ppm,
and
1.0
ppm
in
fat,
muscle,
kidney
and
liver,
respectively.
Radioactivity
reached
a
plateau
in
milk
on
the
second
day
(
0.2
ppm).
Analysis
was
performed
using
HPLC
and
TLC.

Poultry
metabolism.
[
14C­
aniline]
thidiazuron
was
fed
once
daily
at
a
dose
exaggeration
of
100x
to
six
hens
for
fourteen
days
at
a
rate
of
8
ppm.
Radioactivity
did
not
plateau
in
eggs
during
this
Page
10
of
59
period.
All
tissues
were
first
treated
with
protease
and
 ­
glucuronidase
prior
to
extraction.
Parent
equivalent
radioactivity
found
was
0.02
ppm,
0.27
ppm,
1.11
ppm,
0.66
ppm,
0.10
ppm,
0.10
ppm
and
0.34
ppm
in
fat,
gastrointestinal
tract,
gastro­
intestinal
tract
contents,
liver,
muscle,
skin
and
blood,
respectively.

Identification
and
characterization
of
residues
in
livestock
are
shown
in
Tables
3.2.2a
and
3.2.2b.
Based
on
these
results,
it
was
concluded
by
the
HED
Metabolism
Committee
(
9/
8/
95,
F.
Fort)
that
the
residues
of
concern
for
livestock
commodities
are
thidiazuron,
4­
hydroxy
thidiazuron,
and
phenylurea.

Table
3.2.2a
Metabolites
in
Ruminant
Tissues
and
Milk
from
A
Lactating
Cow
Dosed
with
14Cthidiazuron
labeled
in
the
phenyl
ring­
1.9x.

Metabolite
Liver
(
1.0
ppm)
Kidney
(
1.5
ppm)
Muscle
(
0.1
ppm)
Fat
(
0.05
ppm)
Milk
(
0.2
ppm)

%
TRR
ppm
%
TRR
ppm
%
TRR
ppm
%
TRR
ppm
%
TRR
ppm
Thidiazuron
2
0.02
3
0.04
58
0.058
­­­
­­­
31
0.062
Phenylurea
13
0.13
15
0.23
2
0.002
10
0.00
5
3
0.006
4­
hydroxythidiazuron
4
0.04
6
0.09
1
0.001
2
0.00
1
49
0.098
phenylurea
conjugate
15
0.15
18
0.27
­­­
­­­
7
0.00
4
<
3
<
0.006
4­
hydroxythidiazuron
conjugate
36
0.36
11
0.16
13
0.013
46
0.02
3
<
3
<
0.006
Polar
Fraction
22
0.22
23
0.35
­­­
­­­
11
0.00
5
11
0.022
Total
92
0.92
76
1.14
74
0.073
76
0.03
8
<
100
<
0.2
Table
3.2.2b
Metabolites
in
Poultry
and
Eggs
from
a
Laying
Hen
with
14C­
thidiazuron
labeled
in
the
phenyl
ring­
100x.

Liver
(
0.66
ppm)
Muscle
(
0.10
ppm)
Fat
(
0.02
ppm)
Eggs
(
0.15
ppm)

%
TRR
ppm
%
TRR
ppm
%
TRR
ppm
%
TRR
ppm
Thidiazuron
­­­
­­­
2
0.002
2
0.0004
20
0.03
Phenylurea
9
0.059
8
0.008
9
0.0018
16
0.024
4­
hydroxy
thidiazuron
5
0.033
3
0.003
4
0.0008
­­­
­­­

Component
G
(
phenylurea
conjugate)
14
0.092
18
0.018
11
0.0022
­­­
­­­
Page
11
of
59
Component
H
(
4­
hydroxythidiazuron
conjugate)
64
0.422
22
0.022
56
0.0112
22
0.033
Polar
Fraction
3
0.020
17
0.017
11
0.0022
13
0.02
Total
95
0.626
70
0.07
93
0.0186
71
0.107
3.2.3
Description
of
Rotational
Crop
Metabolism,
including
identification
of
major
metabolites
and
specific
routes
of
biotransformation
Confined
and
field
accumulation
rotational
crop
studies
(
MRID
No.
44415501,
10/
26/
04,
T.
Jimerson
and
MRID
No.
46298401,
11/
8/
04,
T.
Jimerson)
were
submitted
and
are
now
acceptable
for
thidiazuron.

In
the
confined
accumulation
study,
an
unidentified
component
designated
Metabolite
A
was
detected
in
both
the
organic
and
hydrolyzed
aqueous
fractions
of
14
days
after
treatment
(
DAT)
wheat
straw,
totaling
0.046
ppm
and
26.4%
TRR.
In
60­
DAT
straw
(
hydrolyzed
aqueous)
and
120­
DAT
straw
(
organic
fraction),
respectively,
Metabolite
A
accounted
for
4.1
and
8.8%
TRR
(
0.007
and
0.010
ppm).
Metabolite
A
was
chromatographically
compared
to
available
metabolite
standards
as
well
as
reasonable
candidate
compounds
available
from
synthesis
without
demonstrating
a
match.
However,
the
metabolite
was
found
to
be
more
polar
(
from
TLC
behavior)
than
any
of
the
compounds
tested.
Furthermore,
some
of
Metabolite
A
arose
from
hydrolysis
of
the
aqueous
extractable
residues,
demonstrating
that
it
is
capable
of
forming
watersoluble
conjugates
in
the
plant.

An
additional
metabolite
identified
as
1,2,3­
thiadiazol­
5­
yl
urea,
was
also
detected
at
0.023
ppm
(
13.0%
TRR)
in
14­
DAT
wheat
straw
and
0.014
ppm
(
48.6%
TRR)
in
60­
DAT
cabbage;
the
metabolite
accounted
for
0.005­
0.011
ppm
(
3.1­
9.2%
TRR)
in
60­,
120­,
and
365­
DAT
wheat
straw.
A
summary
of
metabolite
identification
in
rotated
crops
is
presented
in
Table
3.2.3.

Table
3.2.3
Summary
of
radioactive
residues
identified
in
rotated
crops
following
application
of
[
14C]
thidiazuron
at
the
5­
thiadiazol
position
to
cotton
at
~
1x.

Crop
matrix
DAT
Fraction
1,2,3­
thiadiazol­
5­
yl
urea
Metabolite
A
ppm
%
TRR
ppm
%
TRR
Wheat
straw
14
Organic
0.023
13
0.032
18.4
Aqueous
(
hydrolyzed)
ND
ND
0.014
8
Total
0.023
13
0.046
26.4
60
Aqueous
(
hydrolyzed)
0.006
3.1
0.007
4.1
120
Organic
0.011
9.2
0.01
8.8
365
Organic
0.005
9.2
ND
ND
Table
3.2.3
Summary
of
radioactive
residues
identified
in
rotated
crops
following
application
of
[
14C]
thidiazuron
at
the
5­
thiadiazol
position
to
cotton
at
~
1x.

Page
12
of
59
Cabbage
60
Organic
0.014
48.6
ND
ND
In
the
field
accumulation
study,
no
thidiazuron
residues
greater
than
LOQ
(>
0.05
ppm)
were
detected
in
any
of
the
treated
rotational
crops,
which
included
leafy
vegetable,
root,
and
small
grain
crops.
Therefore,
samples
were
not
analyzed
after
the
shortest
plant
back
interval
(
PBI)
which
was
14
days
for
wheat
and
1
month
for
root,
leafy
vegetable,
and
other
small
grain
crops.
It
was
expected
that
the
recovered
residues
would
be
even
lower
in
later
PBIs.
Thus,
no
tolerances
are
needed
for
rotational
crops
at
the
designated
plant
back
intervals
of
2
weeks
for
wheat
and
1
month
for
root,
leafy
vegetable,
and
other
small
grain
crops.

3.3
Environmental
Degradation
In
soil,
thidiazuron
is
persistent,
as
evidenced
by
laboratory
and
field
half­
lives
in
the
order
of
one
year.
It
has
moderate
soil
sorption
coefficients.
Such
persistence
and
intermediate
mobility
would
allow
some
year­
to­
year
accumulation
as
well
as
time
and,
therefore,
opportunity
for
favorable
conditions
for
runoff
from
application
sites
to
occur.
With
the
hypothetical
assumption
that
there
is
no
significant
physical
movement
of
thidiazuron
from
a
site
of
application
for
several
years,
then,
with
a
one
year
half­
life
and
uniform
annual
applications,
the
asymptotic
limit
of
build­
up
would
result
in
soil
concentrations
that
would
approach
twice
that
of
the
yearly
application
amount.
Runoff
concentrations
would
be
affected
similarly.

When
thidiazuron
reaches
surface
water,
photolysis
is
expected
to
be
the
major
route
of
transformation;
other
degradative
processes
are
essentially
negligible
by
comparison.
Aqueous
photolysis
is
rapid,
and
occurs
by
branching
in
quantitative
yield
into
two
photoproducts:
photothidiazuron
and
1­
cyano­
3­
phenylurea.
One
of
the
photodegradates,
photo­
thidiazuron,
is
a
structural
isomer
of
parent,
while
the
other,
1­
cyano­
3­
phenylurea,
has
a
substantially
altered
chemical
structure.
These
degradates
are
identified
in
Tables
2.2d
and
2.2e
of
the
Ingredient
Profile
section
by
chemical
name
and
structural
formula.
Ground
water
is
not
impacted
by
these
degradates
because
all
field
studies
show
that
parent
is
long­
lived
in
soil
(
half­
lives
of
the
order
of
one
year)
with
only
minimal
evidence
of
photolysis.

Photo­
thidiazuron
has
a
maximum
experimental
limit
of
production
of
77%
of
parent
equivalents
at
pH
5,
28%
at
pH
7,
and
17%
at
pH
9.
This
photoproduct
was
stable
to
further
photolysis
under
experimental
study
conditions.
The
second
photodegradate,
1­
cyano­
3­
phenylurea,
is
substantially
different
from
the
parent
thidiazuron.
It
has
a
complementary
asymptotic
limit
of
production
to
photo­
thidiazuron
of
23%
of
parent
at
pH
5,
72%
at
pH
7,
and
83%
at
pH
9.
This
product
was
also
stable
to
further
photolysis
under
study
conditions.
Thus,
at
different
environmental
pHs,
the
parent,
thidiazuron,
is
always
quantitatively
converted
in
complementary
proportions
into
the
two
photodegradates.
Page
13
of
59
3.4
Tabular
Summary
of
Metabolites
and
Degradates
Page
14
of
59
N
N
S
N
H
N
H
O
Table
3.4.
Tabular
Summary
of
Metabolites
and
Degradates
Chemical
Name
(
other
names
in
parenthesis)
Commodity
Percent
TRR
(
PPM)
Structure
Thiadiazolyl
Label
Phenyl
Label
Thidiazuron
Cottonseed
75.2%
78.4%

Rotational
Crops
­­
ND
in
wheat
straw
ND
in
cabbage
Ruminant
­­
2%
in
liver
­­
3%
in
kidney
­­
58%
in
muscle
31%
in
milk
Poultry
­­
2%
in
muscle
­­
2%
in
fat
­­
20%
in
eggs
Rat
0.1­
0.3%
­­

Water
­­
­­

Phenylurea
Cottonseed
­­
­­

Rotational
Crops
­­
­­

Ruminant
­­
13%
in
liver
­­
15%
in
kidney
­­
2%
in
muscle
­­
10%
in
fat
­­
3%
in
milk
Poultry
­­
9%
in
liver
­­
8%
in
muscle
­­
9%
in
fat
­­
16%
in
eggs
Rat
1%
1
­­

Water
­­
­­

4­
hydroxythidiazuron
Cottonseed
­­
­­

Rotational
Crops
­­
­­

Ruminant
­­
4%
in
liver
­­
6%
in
kidney
­­
1%
in
muscle
­­
2%
in
fat
 
49%
in
milk
Poultry
­­
5%
in
liver
­­
3%
in
muscle
­­
4%
in
fat
Rat
47%
2
­­

Water
­­
­­

Cottonseed,
Ruminant,
Poultry;
Thidiazuron
Metabolism,
F.
Fort,
9/
8/
95;
0.2
lb
ai/
A;
1x
rate
Rat
Metabolism;
MRID
No.
42529001;
single
oral
gavage
dose
10
mg/
kg
1
Tentative
identification
2
Includes
conjugates
of
4­
hydroxythidiazuron
3.5
Toxicity
Profile
of
Major
Metabolites
and
Degradates
Page
15
of
59
Livestock
metabolite
4­
hyroxythidiazuron
and
water
metabolite
photo­
thidiazuron
are
structurally
similar
to
the
parent
compound.
There
is
no
specific
toxicity
data
available
for
either
metabolite,
therefore
it
is
assumed
that
the
metabolites
and
the
parent
compound
share
similar
toxicity.

Additionally,
the
registrant
has
not
submitted
specific
toxicity
data
for
the
livestock
metabolite
phenylurea.
Phenylurea
is
structurally
similar
to
the
phenylurea
herbicides
monuron
and
diuron,
which
have
been
shown
to
produce
hemolytic
anemia
and
other
adverse
hematologic
effects.
Therefore,
in
absence
of
evidence
to
the
contrary,
phenylurea
is
assumed
to
have
similar
effects
to
the
parent
compound.
This
justification
is
also
applicable
to
the
water
metabolite
1­
cyano­
3­
phenylurea.

3.6
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
3.6.1
Tabular
Summary
Table
3.6.
Summary
of
Metabolites
and
Degradates
to
be
included
in
the
Risk
Assessment
and
Tolerance
Expression
Matrix
Residues
included
in
Risk
Assessment
Residues
included
in
Tolerance
Expression
Plants
Primary
Crop
Parent
Parent
Rotational
Crop
Parent
Parent
Livestock
Ruminant
Parent,
4­
hydroxythidiazuron,
Phenylurea
Parent,
4­
hydroxythidiazuron,
Phenylurea
Poultry
Parent,
4­
hydroxythidiazuron,
Phenylurea
Parent,
4­
hydroxythidiazuron,
Phenylurea
Drinking
Water
Parent,
Photo­
thidiazuron,
1­
cyano­
3­
phenylurea
Not
Applicable
3.6.2
Rationale
for
Inclusion
of
Metabolites
and
Degradates
Metabolites
and
degradates
included
in
this
risk
assessment
are
based
on
recommendations
from
the
HED
Metabolism
Assessment
Review
Committee
and
the
Thidiazuron
Drinking
Water
Assessment
memo
provided
by
EFED.

The
MARC
(
9/
29/
95)
has
determined
that
the
residue
of
concern
in
plant
commodities
consists
of
the
parent
only,
and
that
the
residues
of
concern
in
animal
commodities
consist
of
the
parent
thidiazuron,
4­
hydroxythidiazuron,
and
phenylurea.
The
MARC
did
not
determine
the
residues
of
concern
for
water.
EFED
provided
three
surface
water
exposure
scenarios
and
one
ground
water
concentration
estimate
for
thidiazuron
using
two
EFED
Tier
1
screening­
level
models:
FIRST,
Version
1.0
and
SCI­
GROW,
Version
2.3.
The
most
conservative
numbers
were
used
in
this
risk
assessment,
which
included
thidiazuron
and
both
photoproducts,
photo­
thidiazuron
and
1­
cyano­
3­
phenylurea
in
its
estimate.
Page
16
of
59
Residues
of
the
livestock
metabolite
phenylurea
were
found
in
ruminant
liver,
kidney,
muscle,
fat
and
milk
and
poultry
liver,
muscle,
fat
and
eggs.
Phenylurea
is
structurally
similar
to
the
phenylurea
herbicides
monuron
and
diuron,
which
have
been
shown
to
produce
hemolytic
anemia
and
other
adverse
hematologic
effects.
Therefore,
in
absence
of
evidence
to
the
contrary,
phenylurea
is
assumed
to
have
similar
effects
to
the
parent
compound.
This
justification
is
also
applicable
to
water
metabolite
1­
cyano­
3­
phenylurea.

4­
hydroxythidiazuron
(
livestock
metabolite)
residues
were
found
in
ruminant
liver,
kidney,
muscle,
fat
and
milk
and
poultry
liver,
muscle
and
fat.
4­
hyroxythidiazuron
is
structurally
similar
to
the
parent
compound.
There
is
no
specific
toxicity
data
available
that
suggests
exclusion
of
this
metabolite
is
appropriate,
therefore
it
is
assumed
that
the
metabolite
and
the
parent
compound
share
similar
toxicity.
This
rationale
is
also
applicable
to
water
metabolite
photo­
thidiazuron.

4.0
Hazard
Characterization/
Assessment
4.1.
Hazard
and
Dose­
Response
Characterization
4.1.1.
Database
Summary
4.1.1.1.
Studies
available
and
considered
Available
toxicity
studies
include
a
complete
acute
battery
of
tests
(
acute
oral
toxicity,
acute
dermal
toxicity,
acute
inhalation
toxicity,
acute
eye
irritation,
acute
dermal
irritation
and
dermal
sensitization),
subchronic
(
90­
day)
feeding
studies
in
the
rat
and
mouse,
a
subchronic
dermal
toxicity
study
in
the
rat,
chronic
studies
(
including
a
combined
chronic
feeding/
carcinogenicity
study
in
the
rat,
a
carcinogenicity
study
(
feeding)
in
the
mouse
and
a
chronic
oral
study
(
feeding)
in
the
dog),
developmental
toxicity
studies
in
both
the
rat
and
rabbit
and
a
two­
generation
reproduction
study
in
the
rat,
and
a
complete
mutagenicity
battery
(
in
vitro
bacterial
reverse
gene
mutation,
in
vitro
chromosomal
aberration
assay,
gene
mutation
assays
in
Chinese
hamster
lung
(
V79)
cells
and
a
mouse
in
vivo
mammalian
cytogenetics
­
micronucleus
assay).
A
brief
summary
of
the
studies
is
presented
in
Tables
4.1.1.1a
and
4.1.1.1b.
There
are
no
data
available
from
the
general
literature,
including
human
clinical
or
exposure
data
at
this
time.

4.1.1.2.
Mode
of
action,
metabolism,
toxicokinetic
data
In
cotton,
thidiazuron
defoliates
green
leaves
and
immature
fruiting
structures
.
In
test
animal,
the
toxic
mode
of
action
is
not
clear.

An
oral
metabolism
study
in
rats
indicates
that
thidiazuron
is
rapidly
absorbed
and
eliminated
primarily
in
the
urine
with
most
of
the
administered
dose
excreted
within
5
days
postdosing.
The
major
route
of
elimination
was
shown
to
be
via
urine.
Identification
of
urinary
metabolites
indicated
the
presence
of
oxidative
metabolite
(
4­
hydroxy
thidiazuron)
in
urine
and
the
presence
of
sulfate
and
glucuronide
conjugates
of
4­
hydroxy
thidiazuron.
In
feces,
the
major
metabolites
identified
were
4­
hydroxy
thidiazuron
at
the
low
dose
and
unmetabolized
thidiazuron
at
the
high
dose.
Page
17
of
59
4.1.1.3.
Sufficiency
of
studies/
data
The
submitted
studies
provide
adequate
information
to
determine
whether
thidiazuron
poses
a
human
health
hazard.

4.1.2.
Toxicological
Effects
The
available
toxicity
data
indicate
the
acute
oral,
dermal,
inhalation,
and
primary
eye
and
dermal
irritation
toxicity
of
thidiazuron
to
be
in
toxicity
categories
III
and
IV.
Thidiazuron
is
not
a
dermal
sensitizer
or
a
skin
irritant.

Both
subchronic
and
chronic
toxicity
studies
in
rats
showed
that
thidiazuron
caused
toxicity
as
demonstrated
by
decreased
body
weights,
body
weight
gains,
and
food
consumption.
Decreased
epididymides
and
prostate
gland
weights,
small
prostate
and
small
seminal
vesicles
were
seen
in
subchronic
studies
in
the
rats.
In
addition,
microscopic
findings
were
observed
in
the
prostate
gland,
seminal
vesicle,
mammary
gland,
thymus,
the
bone
and
marrow
of
the
sternum
and
ovary,
adrenal
gland,
kidney,
liver,
and
spleen.
Increased
bilateral
seminal
vesicle
atrophy
and
nephrotoxicity
was
seen
in
the
chronic
rat
study.
Nephrotoxicity
and
epididymis
toxicity
was
seen
in
the
chronic
mouse
study.
The
results
of
the
subchronic
feeding
study
in
mice
showed
that
thidiazuron
produced
increased
incidences
of
centrilobular
hepatocellular
hypertrophy
in
the
males
and
diffuse
acinar
hypertrophy
in
the
salivary
glands
in
the
females.

In
developmental
toxicity
studies,
maternal
toxicity
such
as
increased
incidence
of
abortions
and
decreases
in
the
body
weight
and
food
consumption
were
seen
in
rabbits
at
125
mg/
kg/
day.
At
the
same
dose,
developmental
toxicity
observed
was
abortions,
decreased
fetal
weight,
increased
number
of
runts,
and
delayed
skeletal
ossification.

In
the
rats,
maternal
toxicity
such
as
decreased
body
weight
gains
was
seen
at
300
mg/
kg/
day.
At
the
same
dose,
developmental
toxicity
observed
was
decreased
fetal
weight.

In
a
2­
generation
reproduction
study
in
rats,
maternal
toxicity
such
as
decreased
body
weight
gain
was
seen
at
108
mg/
kg/
day.
The
test
chemical
did
not
significantly
affect
any
of
the
reproductive
parameters.
For
the
offsprings,
there
was
a
decrease
in
pup
body
weight
gain
at
108
mg/
kg/
day.

No
neurotoxicity
was
reported
in
any
of
the
studies.

Carcinogenicity
studies
in
both
rats
and
mice
produced
no
treatment­
related
increase
in
tumor
incidence.

The
standard
battery
of
genotoxicity
tests
was
negative.

4.1.3.
Dose­
response
The
developmental
rabbit
study
and
the
one­
year
dog
study
were
the
primary
studies
used
for
the
dose­
response
assessment.
The
dog
is
the
most
sensitive
species
noted
from
testing
with
thidiazuron
with
the
effects
occurring
at
considerably
lower
doses
than
those
noted
for
the
rat
or
Page
18
of
59
mouse.
The
one­
year
dog
study
was
chosen
for
the
chronic
RfD.
Based
on
the
available
toxicity
data,
no
acute
toxicity
endpoint
could
be
identified.
At
the
limit
dose
(
1000
mg/
kg),
no
systemic
toxicity
or
dermal
irritation
was
noted
in
the
28­
day
dermal
toxicity
study
in
the
rat;
therefore
no
endpoint
was
selected
for
short­
and
intermediate
term
dermal
risk
assessments.
The
developmental
rabbit
study
was
selected
for
both
the
short­
and
intermediate­
term
inhalation
and
incidental
oral
exposure
scenarios.

Table
4.1.1.1a
Acute
Toxicity
Profile
Thidiazuron
Technical
Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
870.1100
Acute
Oral
­
Rat
46121501
LD50
>
2
g/
kg
III
870.1200
Acute
Dermal
­
Rat
46121502
LD50
>
5
g/
kg
IV
870.1300
Acute
Inhalation
­
Rat
46121503
LC50
>
3.48
mg/
L
IV
870.2400
Primary
Eye
Irritation
­
Rabbit
42099601
Irritation
clearing
in
48
hours
IV
870.2500
Primary
Skin
Irritation
­
Rabbit
42099602
No
dermal
effects
IV
870.2600
Dermal
Sensitization
­
Guinea
pig
46121504
Not
a
skin
sensitizer
N/
A
Table
4.1.1.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Page
19
of
59
Guideline
No./
STUDY
TYPE
 
MRID
No.
(
year)/
Classification
/
Doses
NOAEL
m/
k/
d
LOAEL
m/
k/
d
EFFECTS
SEEN
at
LOAEL
870.4300
2­
year
combined
chronic/
carcinog
enicity
 
RAT
46345201
(
2004)
acceptable
0,
200,
900,
or
1800
ppm
(
equivalent
to
0/
0,
8.0/
11.3,
36.4/
51.4,
and
75.6/
105
mg/
kg/
day)
8
36.4

body
weight
and
body
wt
gain
in
(
males),


bilateral
seminal
vesicle
atrophy,
and
nephrotoxicity
(
both
sexes)

Treatment
related
increase
in
tumor
incidence
was
not
found
870.4300
2­
year
combined
chronic/
carcinog
enicity
 
RAT
00159346
(
1986)
chronic
studyacceptable
carcinogenicity
portionunacceptable
0,
70,
200,
or
600
ppm(
0,
3.7,
10.6,
or
31.7
mg/
kg/
day
for
males
and
0,
4.6,
13,
or
40.1
mg/
kg/
day
for
females).
>
31.7
(
HDT)
not
established

sporadic
&
minimal
body
wt
and
food
consumption
observed
at
600
ppm
(
31.7
mg/
kg/
day)

870.4200b
18
month
carcinogenicity
 
Mouse
46346001
(
2004)
acceptable
0,
200,
650,
or
2000
ppm
(
0/
0,
26.5/
33.4,
86.7/
107.8,
and
279.9/
329.7
mg/
kg/
day
in
males/
females)
86.7
279.9

body
weight,
body
weight
gain,
and
food
consumption;


nephrotoxicity
(
both
sexes);


epididymis
toxicity
(
males):


(
i)
dilated
tubules;
(
ii)
interstitial
mononuclear
cell
infiltrate;
(
iii)
unilateral
and
bilateral
oligospermia;
and
(
iv)
spermatic
granuloma.


clinical
signs
of
toxicity
(
females).

Treatment
related
increase
in
tumor
incidence
was
not
found.
Guideline
No./
STUDY
TYPE
 
MRID
No.
(
year)/
Classification
/
Doses
NOAEL
m/
k/
d
LOAEL
m/
k/
d
EFFECTS
SEEN
at
LOAEL
Page
20
of
59
870.4100b
1­
year
chronic
study
in
dog
00159344
(
1985)
acceptable
0,
100,
300,
or
1000
ppm
(
0,
3.93,
11.8,
or
38.3
mg/
kg/
day
for
males
and
0,
4.01,
11.1,
or
36
mg/
kg/
day
for
females)
3.93
11.1

incidence
of
anemia,
changes
in
hematological
parameters
and
marked
hemosiderosis
in
liver
and
spleen
870.3700a
Developmental
toxicity
 
rats
00077127
(
1981)
acceptable
0,
25,
50,
100
or
300
mg/
kg/
day
Maternal
100
Developmental
100
Maternal
300
Developmental
300
decreased
body
wt.
gain
decreased
fetal
body
wt
870.3700b
Developmental
toxicity
 
rabbits
46121507
(
2003)
acceptable
0,
5,
25,
or
125
mg/
kg
MRID
46252001
 
historical
control
data
MRID
46241001­
range­
finding
developmental
toxicity
study
Maternal
25
Developmental
25
Maternal
125
Developmental
125
Maternal
abortions

body
weight
gains
(

70%
during
GD
6­
29)

food
consumption
(

19%
during
GD
6­
8;
44%
during
GD
14­
18).

Abortions

fetal
body
weights
(
12­
13%)


number
of
runts,
and
delayed
skeletal
ossification
870.3800
2­
generation
reproduction
study
 
rat
46209601
(
2003)
acceptable
0,
100,
400,
or
1200
ppm
(
equivalent
to
0/
0,
8.8/
9.9,
35.4/
39.8,
and
108.5/
121.1
mg/
kg/
day
[
M/
F]
Parental/
Systemic
35.4
Reproductive
108.5
(
HDT)

Offspring
35.4
Parental/
Systemic
108.5
Reproductive
­
­
not
determined
Offspring
108.5

body
wt
gains
(
both
sexes)

No
treatment­
related
effects
were
noted
on
sperm
parameters
(
enumeration,
motility,
or
morphology)
in
the
P
or
F1
males.

body
wt
gains
(
both
sexes)
Vaginal
opening
was
significantly
(
p

0.01)
delayed
in
the
108.5
mg/
kg/
day
females
(
37.3
days
vs
34.3
days
for
controls.
Guideline
No./
STUDY
TYPE
 
MRID
No.
(
year)/
Classification
/
Doses
NOAEL
m/
k/
d
LOAEL
m/
k/
d
EFFECTS
SEEN
at
LOAEL
Page
21
of
59
870.7485
Metabolism
study
 
RAT
42529001
(
1992)
single
oral
gavage
dose
(
10
or
1000
mg/
kg)
or
14­
day
repeated
oral
doses
at
10
mg/
kg
Acceptable
Metabolites
A/
B,
D,
and
F
=
sulfate
&
glucuronide
conjugates
of
Metabolite
J
Total
radioactivity
recovered
within
5
days
after
dosing
in
urine
(
U)
&
feces
(
F)
=
91­
104%
of
dose.
low
dose:
60­
66%
(
U)
and
29­
31%
(
F)
repeated
dose:
73­
75%
(
U)
and
26­
28%
(
F)
high
dose:
41­
47%
(
U)
and
56­
60%
(
F)
Highest
conc.
of
thidiazuron
derived
radioactivity
were
found
in
liver,
kidneys,
thyroid,
whole
blood
and
adrenals.

Urinary
metabolites
found
in
low
dose
group
Metabolite
J
(
11­
19%
of
dose;
4­
hydroxy
thidiazuron),
Metabolite
F
(
14­
38%),
Metabolite
A/
B
(
3­
6%),
metabolite
D
(
5­
9%)

870.3200
28­
Day
Dermal
Toxicity
­
Rat
46261501
(
2004)
acceptable
of
0,
100,
300,
or
1000
mg/
kg/
day
Systemic/
dermal
toxicity
1000
(
HDT)
Systemic/
dermal
toxicity
=
not
determined
870.3100
28­
day
oral
toxicity­
rat
46121509
(
2001)
SEE
under
MRID
46121506
(
90­
day
oral
toxicity)
acceptable
0,
900,
1800,
or
3600
ppm
(
equivalent
to
0,
67,
135,
and
254
mg/
kg/
day)
67
135

serum
glucose
and
urinary
pH,
small
seminal
vesicles
and
prostate
gland,
prominent
liver
lobulation,
and
focal/
multifocal
basophilic
tubules
in
the
kidneys.
Guideline
No./
STUDY
TYPE
 
MRID
No.
(
year)/
Classification
/
Doses
NOAEL
m/
k/
d
LOAEL
m/
k/
d
EFFECTS
SEEN
at
LOAEL
Page
22
of
59
870.3100
90­
day
oral
toxicity­
rat
46121506
(
2001)
acceptable
0,
200,
600,
1800,
5400,
or
16,200
ppm
(
equivalent
to
0/
0,
11.2/
14.0,
34.5/
42.1,
102/
123,
294/
325,
and
[
highest
dose
not
calculated]
mg/
kg/
day)
34.5
102

body
wts,
body
wts
gains,
and
food
consumption;
epididymides
and
prostate
gland
wt

ALP;
urea
microscopic
findings
in
adrenal
gland,
kidney,
liver,
and
spleen
(
both
sexes);
prostate
gland,
seminal
vesicle,
mammary
gland,
and
thymus
(
males);
bone
and
marrow
of
the
sternum
and
ovary
(
females)

small
prostate
and
small
seminal
vesicles
870.3100
90­
day
oral
toxicity­
mice
46121505
(
2001)
acceptable
of
0,
500,
1000,
2000,
or
4000
ppm
(
equivalent
to
0/
0,
85.2/
99.8,
170.9/
202.6,
or
351.4/
383.9
mg/
kg/
day
[
M/
F])
85.2
170.9

cholesterol
(
males)


incidences
of
centrilobular
hepatocellular
hypertrophy
(
males)
and
diffuse
acinar
hypertrophy
in
salivary
glands
(
females).

870.7600
dermal
absorptionrat
46261502
(
2004)
acceptable
5.0,
0.04
and
0.004
mg/
cm2.
Dermal
absorption
based
on
the
amount
in
systemic
compartment
(
excreta
&
tissues)
corresponding
to
the
total
amount
of
test
chemical
directly
absorbed
was
similar
after
a
24­
hour
exposure
or
a
8­
hour
exposure
and
termination
at
120
hours
post­
application
(
0.20%
and
0.22%
for
high
dose,
0.75%
and
1.25%
for
middle
dose,
1.18%
and
1.17%
for
low
dose)

870.5265
Reverse
gene
mutation
assay
46121508
(
2001)
acceptable
0,
1.5,
5,
15,
50,
150,
500,
or
1500
µ
g/
plate
(
±
S9,
Trial
2)
Not
mutagenic
There
was
no
evidence
of
induced
mutant
colonies
over
background
under
the
conditions
of
these
tests.
Guideline
No./
STUDY
TYPE
 
MRID
No.
(
year)/
Classification
/
Doses
NOAEL
m/
k/
d
LOAEL
m/
k/
d
EFFECTS
SEEN
at
LOAEL
Page
23
of
59
870.5375
In
Vitro
Chromosomal
Aberration
Assay
46121510
(
2001)
acceptable
0,
9.4,
18.75,
37.5,
75,
150,
200,
or
250
µ
g/
mL
(
±
S9)
Not
mutagenic
There
was
no
evidence
of
chromosome
aberration
induced
over
background
in
the
presence
or
absence
of
S9­
activation
at
either
time
point.

870.5550
Unscheduled
DNA
synthesis
assay
in
primary
rat
hepatocytes
41761103
(
1990)
acceptable
0.25,
0.75,
2.5,
7.5,
25
ug/
mL
not
mutagenic
There
were
no
indications
of
UDS
activity.

870.5300
Gene
mutation
assay
in
Chinese
hamster
V79
cells
41761102
(
1990)
acceptable
15,
30,
100,
250
ug/
mL
(
±
S9)
Not
mutagenic
Test
chemical
did
not
cause
mutations
at
the
HGPRT
locus
in
V79
cells
870.5385
Micronucleus
assay
070129
(
1981)
acceptable
2.4,
24,
120
mg/
mL
Not
mutagenic
No
increase
in
micronucleated
cells
was
observed.

4.2
FQPA
Hazard
Considerations
4.2.1
Adequacy
of
the
Toxicity
Database
The
database
for
evaluating
in
utero
or
postnatal
susceptibility
is
adequate
and
includes
developmental
toxicity
studies
in
both
rats
and
rabbits
and
a
two­
generation
reproduction
study
in
the
rat.

4.2.2
Evidence
of
Neurotoxicity
The
available
database
indicated
that
this
chemical
does
not
induce
neurotoxicity.

4.2.3
Developmental
Toxicity
Studies
Prenatal
Developmental
Toxicity
Study
­
Rat;
OPPTS
870.3700a
[
§
83­
3a];
OECD
414.

EXECUTIVE
SUMMARY:

In
a
developmental
toxicity
study
(
MRID
No.
00077127),
25
presumed
pregnant
Wistar
Han
78
strain
rats
per
group
were
administered
thidiazuron
(
purity:
99.4%;
batch/
lot
No.:
271006B)
by
oral
gavage
in
Myrj
53
solution
at
doses
of
0,
25,
50,
100
or
300
mg/
kg/
day
on
gestation
days
(
GD)
6­
15,
inclusive.
Page
24
of
59
On
GD
19,
dams
were
sacrificed
and
examined
grossly.
The
ovaries
and
uteri
were
excised
and
the
number
of
corpora
lutea,
live
young,
resorptions,
fetal
weights
and
the
incidence
of
external
fetal
abnormalities
were
recorded.
Approximately
2/
3
of
the
litters
were
examined
for
skeletal
abnormalities
and
the
1/
3
were
examined
for
visceral
abnormalities.
Uteri
were
examined
for
evidence
of
implantation.
Dams
were
observed
daily
and
weighed
on
days
0,
6,
15
and
19
of
pregnancy.

Maternal
Toxicity
No
dams
died
during
the
course
of
the
study.
No
clinical
observations
of
toxicity
were
noted.
A
slight
decreased
mean
body
weight
gain
(
87%
of
controls)
was
observed
in
the
females
of
the
300
mg/
kg/
day
group.
The
absolute
maternal
weight
decrease
was
marginal
(
6%)
but
the
weight
loss
persisted
even
after
termination
of
treatment
(
day
15)
(
Table
1).
Although
maternal
toxicity
was
only
marginal
at
300
mg/
kg/
day,
the
previous
study
(
MRID
No.
00077126)
also
showed
significant
decreased
mean
body
weight
gain
(
90%
of
controls)
at
250
mg/
kg/
day
and
a
frank
maternal
toxicity
(
mortality
and
reduced
body
weights)
at
900
mg/
kg/
day.
Therefore,
the
two
studies
taken
together,
the
maternal
LOAEL
in
this
study
was
considered
to
be
300
mg/
kg/
day
based
on
slightly
reduced
body
weight
gains.

The
maternal
LOAEL
was
300
mg/
kg/
day
based
on
reduced
body
weight
gains.
The
maternal
NOAEL
was
100
mg/
kg/
day.

Developmental
Toxicity
There
were
no
differences
between
the
control
group
and
the
all
treated
groups
for
number
of
litter
size,
rate
of
implantation,
and
pre­
and
post­
implantation
losses.
Mean
fetal
weights
and
mean
litter
body
weights
were
significantly
decreased
in
the
300
mg/
kg/
day
group
(
Table
1).
There
were
no
treatmentrelated
external,
visceral,
or
skeletal
malformations.

The
developmental
LOAEL
was
300
mg/
kg/
day
based
on
decreased
fetal
body
weights.
The
developmental
NOAEL
was
100
mg/
kg/
day.

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

Prenatal
Developmental
Toxicity
Study
­
Rabbit
[
OPPTS
870.3700b
(
§
83­
3b)
OECD
414].

EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
(
MRID
46121507),
Thidiazuron
(
99.5%
a.
i.;
Lot/
Batch
#
107623­
03)
in
0.5%
(
w/
v)
aqueous
methylcellulose
was
administered
daily
by
oral
gavage
at
a
dose
volume
of
4
mL/
kg
body
weight
to
25
female
New
Zealand
White
[
KBL
(
NZW)
lOPS/
SPF]
rabbits/
group
at
dose
levels
of
0,
5,
25,
or
125
mg/
kg
on
gestation
days
(
GD)
6
through
28.
All
does
were
sacrificed
on
GD
29;
their
fetuses
were
removed
by
cesarean
and
examined.

Maternal
toxicity:

At
125
mg/
kg/
day,
five
pregnant
females
aborted
between
GD
27
and
29.
These
abortions
were
considered
to
be
due
to
the
test
substance,
either
directly
or
indirectly
(
as
a
result
of
the
marked
decreases
in
food
consumption
and
body
weight).
Red
traces
(
8/
25
treated
vs
1/
25
controls),
placental
tissue
(
4/
25
treated
vs
0/
25
controls),
and/
or
feto­
placental
tissue
(
5/
25
treated
vs
0/
25
controls)
found
on
the
cage
Page
25
of
59
trays
corresponded
to
the
abortions.
Other
clinical
signs
of
toxicity
at
this
dose
included
increased
incidence
of
soft/
mucoid
feces
(
1­
3/
25
treated
vs
0/
25
controls),
few
feces
(
14/
25
treated
vs
3/
25
controls),
and
localized
soiled
fur
(
4/
25
treated
vs
0/
25
controls).

Additionally
at
125
mg/
kg/
day,
cumulative
body
weight
gains
from
GD
6
were
decreased
(
p<=
0.05)
throughout
treatment,
resulting
in
decreased
(
p<=
0.01)
body
weight
gains
for
the
overall
(
GD
6­
29)
treatment
period,
both
uncorrected
(
decr.
70%)
and
corrected
(
decr.
171%)
for
gravid
uterine
weights.
Gravid
uterine
weights
of
the
treated
groups
were
comparable
to
controls.
Food
consumption
was
decreased
by
19­
44%
(
p<=
0.01)
at
this
dose
throughout
treatment,
except
for
during
GD
26­
29
which
was
decreased
by
9%
(
not
significant)
compared
to
controls.

The
only
findings
at
25
mg/
kg/
day
were
a
single
abortion
thought
to
be
due
to
maternal
stress
from
gavage
error
(
i.
e.,
inflammation
and
red
liquid
in
trachea)
and
clinical
signs
associated
with
abortion
(
i.
e,
red
traces
and
feto­
placental
tissue
on
tray).

The
maternal
LOAEL
is
125
mg/
kg/
day,
based
on
abortions
and
decreased
body
weight
gains
and
food
consumption.
The
maternal
NOAEL
is
25
mg/
kg/
day.

Developmental
toxicity
No
effects
of
treatment
were
noted
on
numbers
of
litters,
fetuses
(
live
or
dead),
resorptions
(
early,
late,
or
complete
litter),
sex
ratio,
or
post­
implantation
loss.

At
125
mg/
kg/
day,
fetal
body
weights
were
decreased
(
p<=
0.01)
by
12­
13%,
and
the
number
of
runts
was
increased
compared
to
concurrent
and
historical
controls.
Fetal
and/
or
litter
incidences
of
the
following
variations,
indicative
of
skeletal
retardation,
were
increased
at
125
mg/
kg/
day
over
concurrent
and
historical
controls:
(
i)
unilateral
or
bilateral
holes
in
the
frontal
or
parietal
bones;
(
ii)
unossification
of
the
atlas
centrum;
(
iii)
unossification
of
the
insertion
point(
s)
on
the
pelvic
girdle;
and
(
iv)
incomplete
ossification
or
unossification
of
the
pubis.

Aside
from
the
above­
mentioned
skeletal
retardations,
there
were
no
developmental
variations
that
could
definitely
be
attributed
to
treatment.

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

The
developmental
LOAEL
is
125
mg/
kg/
day,
based
on
decreased
fetal
body
weights,
increased
number
of
runts,
and
delayed
skeletal
ossification.
The
developmental
NOAEL
is
25
mg/
kg/
day.
This
study
is
classified
acceptable/
guideline
(
OPPTS
870.3700b)
and
satisfies
the
requirements
for
a
developmental
study
in
the
rabbit.

4.2.4
Reproductive
Toxicity
Study
Reproduction
and
Fertility
Effects
Study
 
Rat
[
OPPTS
870.3800
(
§
83­
4)
OECD
416].

EXECUTIVE
SUMMARY:
In
a
two­
generation
reproduction
toxicity
study
(
MRID
46209601),
Thidiazuron
(
99.5%
a.
i.;
Batch
107623­
03)
was
administered
continuously
in
the
diet
to
Han
Wistar
(
HsdBrl
Han:
Wist)
rats
(
28
animals/
sex/
dose)
at
dose
levels
of
0,
100,
400,
or
1200
ppm
(
equivalent
to
Page
26
of
59
0/
0,
8.8/
9.9,
35.4/
39.8,
and
108.5/
121.1
mg/
kg/
day
[
M/
F]).
The
P
and
F
1
parents
were
dosed
for
10
weeks
before
they
were
mated
to
produce
the
F
1
and
F
2
litters.
The
F
1
pups
were
weaned
on
postnatal
day
(
PND)
21,
and
24
pups/
sex/
group
(
1
pup/
sex/
litter
as
nearly
as
possible)
were
randomly
selected
as
parents
of
the
F
2
generation.

In
the
parental
animals,
no
treatment­
related
effects
were
observed
on
survival,
clinical
signs,
or
food
consumption
or
efficiency.

At
1200
ppm,
body
weight
gains
were
decreased
in
the
P
males
(
statistics
not
performed)
during
premating
(
Weeks
0­
10)
by
10%,
and
overall
(
Weeks
0­
17)
by
10%
(
p

0.05).
In
the
P
females
at
this
dose,
body
weight
gains
were
decreased
(
p

0.01)
during
pre­
mating
by
16%.
Body
weight
gains
continued
to
be
decreased
(
p

0.05)
by
10%
throughout
gestation
(
GD
0­
20).
In
the
F
1
females
at
this
dose,
an
increased
(
p

0.01)
incidence
of
five
day
irregular
estrous
cycles
or
acyclicity
was
observed.
However,
since
no
effects
were
noted
on
fertility
or
reproductive
performance,
this
finding
was
considered
equivocal.

No
treatment­
related
findings
were
noted
at
100
or
400
ppm.

The
LOAEL
for
parental
toxicity
is
1200
ppm
(
equivalent
to
108.5/
121.1
mg/
kg/
day
[
M/
F]),
based
on
decreased
body
weight
gains
in
both
sexes.
The
NOAEL
is
400
ppm
(
equivalent
to
35.4/
39.8
mg/
kg/
day
[
M/
F]).

In
the
offspring,
no
treatment­
related
effects
were
observed
on
post­
implantation
survival,
live
birth,
viability,
or
lactation
indices,
on
the
sex
ratio,
clinical
signs,
sexual
maturation,
organ
weights,
or
gross
pathology.

At
1200
ppm,
body
weight
gains
were
decreased
(

7­
10%;
p

0.05)
in
the
F
1
pups
during
PND
1­
21
and
during
PND
1­
28,
and
in
the
F
2
pups
during
PND
1­
28
in
the
males,
and
during
PND
1­
21
and
PND
1­
28
in
the
females.

No
effects
of
treatment
were
observed
at
100
or
400
ppm.

The
LOAEL
for
offspring
toxicity
is
1200
ppm
(
equivalent
to
108.5/
121.1
mg/
kg/
day
[
M/
F]),
based
on
decreased
body
weight
gains
in
both
sexes.
The
NOAEL
is
400
ppm
(
equivalent
to
35.4/
39.8
mg/
kg/
day
[
M/
F]).

In
the
parental
animals,
no
treatment­
related
effects
were
observed
on
sperm
measures,
ovarian
follicles,
corpora
lutea,
pre­
coital
interval,
duration
of
gestation,
or
on
mating,
fertility,
gestation,
or
parturition
indices.

The
LOAEL
for
reproductive
performance
was
not
observed.
The
NOAEL
for
reproductive
performance
is
1200
ppm
(
equivalent
to
108.5/
121.1
mg/
kg/
day
[
M/
F]).

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

4.2.5
Additional
Information
from
Literature
Sources
Page
27
of
59
There
were
no
data
available
from
the
general
literature,
including
human
clinical
or
exposure
data
at
this
time.

4.2.6
Pre­
and/
or
Postnatal
Toxicity
4.2.6.1
Determination
of
Susceptibility
There
is
no
evidence
of
increased
susceptibility
following
in
utero
or
post­
natal
exposure
to
thidiazuron
either
in
the
rat
or
rabbit
developmental
toxicity
study
as
well
as
a
two­
generation
reproduction
toxicity
study
in
rats.

4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre­
and/
or
Postnatal
Susceptibility
There
are
no
concerns
or
residual
uncertainties
for
pre­
and/
or
post­
natal
toxicity
following
exposure
to
thidiazuron.

4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
Abortions
and
other
minimal
developmental
effects
would
warrant
a
recommendation
for
conducting
a
developmental
neurotoxicity
study.

4.3.2
Evidence
that
supports
not
requiring
a
Developmental
Neurotoxicity
study
The
available
toxicity
data
showed
no
neurotoxicity
or
offspring
toxicity
in
a
reproduction
study
which
would
warrant
a
recommendation
for
conducting
a
developmental
neurotoxicity
study.

4.3.2.1
Rationale
for
the
UFDB
(
when
a
DNT
is
recommended)

A
rationale
for
an
UF
DB
is
not
required
at
this
time
because
a
DNT
study
is
not
recommended,
and
the
toxicity
database
is
otherwise
complete.

4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
Summary
of
toxicology
endpoint
selected
for
thidiazuron
are
presented
in
Table
4.4.

4.4.1
Acute
Reference
Dose
(
aRfD)

Based
upon
the
available
toxicological
data,
no
acute
toxicity
endpoint
could
be
identified.

4.4.2
Chronic
Reference
Dose
(
cRfD)

Study
selected:
chronic
toxicity
study
­
dog
OPPTS
870.4100b
MRID
No.:
00159344
Page
28
of
59
EXECUTIVE
SUMMARY:

In
a
chronic
toxicity
study
(
MRID
No.
00159344),
thidiazuron
(
purity:
98.8%
a.
i.;
Batch
No:
7/
9.82)
was
administered
to
5
beagle
dogs/
sex/
dose
in
the
diet
at
levels
of
0,
100,
300,
or
1000
ppm
for
1
year.
Corresponding
daily
intakes
of
test
material
for
the
one­
year
study
were
0,
3.93,
11.8,
or
38.3
mg/
kg/
day
for
males
and
0,
4.01,
11.1,
or
36
mg/
kg/
day
for
females.

No
spontaneous
deaths
occurred
during
the
study.
One
high­
dose
male
(
No.
4744)
and
female
(
No.
4731)
exhibited
compound
related
signs
of
toxicity
(
apathy,
high
heart
frequency,
severe
anemia,
and
inspiratory
dyspnea).
The
male
dog
was
sacrificed
moribund
in
study
week
7.
The
female
dog
was
fed
control
diet
for
a
reversibility
study
after
week
38.

Thidiazuron
caused
no
significant
change
in
group
mean
body
weights
and
food
consumption
except
for
the
two
high­
dose
animals
(
Nos.
4744
and
4731)
described
above.

In
the
low­
dose
group,
no
compound­
related
clinical
signs
of
toxicity
were
observed.

In
the
mid­
dose
group,
one
male
dog
showed
symptoms
of
anemia.
Also,
in
two
males
(
Nos.
4702
and
4728),
decreased
hematocrit
(
64­
66%
of
controls
at
week
27),
decreased
hemoglobin
(
56%
of
controls
at
week
27),
decreased
red
cell
count
(
43­
57%
of
controls
at
weeks
27
and
39),
and
increased
reticulocyte
count
(
280­
1480%
of
controls
at
weeks
27
and
39)
were
observed.

Significant
(
p<
0.05
or
0.01)
compound­
related
changes
in
clinical
chemistry
parameters
(
alkaline
phosphatase
and
albumin/
globulin
ratio)
were
observed
in
the
mid­
dose
animals,
however,
the
observed
changes
were
not
considered
biologically
significant
because
there
were
no
clear
dose­
related
trends.

The
changes
in
organ
weights
were
statistically
insignificant
because
of
the
small
number
of
animals
used
in
the
test.
In
mid­
dose
males,
increases
in
absolute
and
relative
weights
for
liver
(
19%
and
24%
of
controls,
respectively),
spleen
(
22%
and
27%
of
controls,
respectively),
and
lymph
nodes
(
48%
and
49%
of
controls,
respectively)
were
observed.
In
females,
absolute
and
relative
spleen
weights
(
21%
and
22%
of
controls,
respectively)
were
increased
.
Histologically,
there
was
an
increased
incidence
of
marked
hemosiderosis
in
Kupffer
cells
in
liver
(
2/
5)
and
spleen
(
1/
5)
and
an
increase
in
Kupffer
cells
in
liver
(
3/
5)
of
males.

In
the
high­
dose
group,
four
animals
(
two
of
each
sex)
showed
symptoms
of
anemia.
Also,
in
the
females,
decreased
hematocrit
(
at
weeks
12
and
29),
decreased
hemoglobin
(
week
12)
and
increased
reticulocyte
count
(
week
12)
were
observed.
Significant
(
p<
0.05
or
0.01)
compound­
related
changes
in
clinical
chemistry
parameters
(
alkaline
phosphatase,
total
serum
protein
and
albumin/
globulin
ratio)
were
observed
in
the
high­
dose
animals,
however,
the
observed
changes
were
not
considered
biologically
significant
because
there
were
no
clear
dose­
related
trends.

The
changes
in
organ
weights
were
statistically
insignificant
because
of
the
small
number
of
animals
used
in
the
test.
In
high­
dose
males,
absolute
and
relative
weights
for
liver
(
14
%
and
19%
of
controls,
respectively),
spleen
(
123
and
107%
of
controls,
respectively),
and
lymph
nodes
(
116%
and117%
of
controls,
respectively)
were
increased
.
In
females,
absolute
and
relative
weights
for
liver
(
29%
and
12%
of
controls,
respectively),
spleen
(
167%
and
132%
of
controls,
respectively)
and
lymph
node
(
54%
and
31%
of
controls,
respectively)
were
increased
compared
to
controls.
Page
29
of
59
Histologically,
there
was
an
increased
incidence
of
pigment
deposition
in
liver,
kidney,
and
spleen
and
an
increase
in
Kupffer
cells
in
liver
of
high­
dose
males
and
females.
The
two
high­
dose
females
with
severe
anemia
had
increased
Kupffer
cells,
hemosiderin
in
the
spleen,
increased
splenic
hematopoiesis,
and
ironnegative
pigment
in
the
tubular
epithelium
of
the
kidney.
Localized
infiltration
of
lymphocytes
in
the
mucosa
of
the
gallbladder
was
found
in
all
high­
dose
animals
(
2/
5
control
males;
1/
5
control
females).
In
addition,
the
following
lesions
were
found
in
females:
early
or
progressive
involution
in
the
thymus
(
highdose
4/
5;
control,
1/
5),
interfollicular
cell
increase
in
the
thyroid
(
high­
dose;
3/
5
;
control,
0/
5),
and
follicular
hyperplasia
in
the
lymph
nodes
(
high­
dose,
2/
5;
control,
1/
5).

The
LOAEL
is
300
ppm
(
11.1
mg/
kg/
day)
based
on
increased
incidence
of
anemia,
changes
in
hematological
parameters
and
marked
hemosiderosis
in
liver
and
spleen.
The
NOAEL
is
100
ppm
(
3.93
mg/
kg/
day).

This
chronic
study
in
the
dog
is
classified
as
acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
chronic
oral
study
in
the
dog
[
OPPTS
870.4100b].

Dose
and
Endpoint
for
Establishing
cRfD:
The
NOAEL
is
100
ppm
(
3.93
mg/
kg/
day)
based
on
increased
incidence
of
anemia,
changes
in
hematological
parameters
and
marked
hemosiderosis
in
liver
and
spleen
at
the
LOAEL
of
300
ppm
(
11.1
mg/
kg/
day).

Uncertainty
Factor(
s):
100X
[
10
interspecies;
10X
intraspecies]

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
The
route
and
duration
of
exposure
are
appropriate
for
selection
of
the
chronic
dietary
endpoint.

Chronic
RfD
=
3.93
mg/
kg/
day
=
0.0393
mg/
kg/
day
100
4.4.3
Incidental
Oral
Exposure
(
Short­
and
Intermediate­
Term)

Incidental
Oral
Exposure:
Short­
Term
(
1­
30
days)
and
Incidental
Oral
Exposure:
Intermediate­
Term
(
1
­
6
Months)

Study
Selected:
developmental
toxicity
­
rabbit
OPPTS
870.3700b;
§
83­
3
(
b)

MRID
No.:
46121507
Executive
Summary:
Developmental
toxicity
study
in
rabbit
(
MRID
46121507).
In
this
study,
maternal
toxicity
such
as
increased
incidence
of
abortions
and
decreases
in
the
body
weight
and
food
consumption
were
seen
in
rabbits
at
125
mg/
kg/
day.
At
the
same
dose,
developmental
toxicity
observed
were
abortions,
decreased
fetal
weight,
increased
number
of
runts,
and
delayed
skeletal
ossification.
See
section
4.2.3
for
complete
executive
summary,
maternal
toxicity
and
developmental
toxicity.

Dose
and
Endpoint
for
Risk
Assessment:
Maternal
toxicity
NOAEL
=
25
mg/
kg/
day,
based
on
abortions
Page
30
of
59
and
decreased
body
weight
gains
and
food
consumption
at
the
LOAEL
of
125
mg/
kg/
day.

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
The
route
and
duration
of
exposure
are
appropriate
for
selection
of
the
short­
and
intermediate
term
incidental
oral
endpoint.

4.4.4
Dermal
Absorption
Based
on
the
amount
in
systemic
compartment
(
excreta
&
tissues)
corresponding
to
the
total
amount
of
test
chemical
directly
absorbed,
the
dermal
absorption
was
similar
after
a
24­
hour
exposure
or
a
8­
hour
exposure
and
termination
at
120
hours
post­
application
(
0.20%
and
0.22%
for
high
dose,
0.75%
and
1.25%
for
middle
dose,
1.1
8%
and
1.17%
for
low
dose)
(
MRID
No.
46261502).

4.4.5
Dermal
Exposure
(
Short­,
Intermediate­
and
Long­
Term)

Dermal
Exposure:
Short­
Term
(
1­
30
days)
Exposure
and
Dermal
Exposure:
Intermediate­
Term
(
1
­
6
Months)

Study
Selected:
none
MRID
No.:
none
Executive
Summary:
none
Dose
and
Endpoint
for
Risk
Assessment:
N/
A
Comments
about
Study/
Endpoint:
There
is
no
systemic
or
localized
hazard
noted
in
a
28­
day
dermal
toxicity
study
in
the
rat
tested
at
limit
dose
(
1000
mg/
kg).
In
rabbits,
no
toxic
effects
were
expected
at
equivalent
dermal
dose
of
2500
mg/
kg/
day
(
greater
than
the
limit
dose).
The
equivalent
dermal
dose
of
2500
mg/
kg/
day
was
estimated
by
adjusting
the
rabbit
developmental
toxicity
NOAEL
of
25
mg/
kg/
day
for
1%
dermal
absorption
from
the
rat
dermal
absorption
study.
The
dermal
absorption
of
thidiazuron
in
rats
was
low
(
1%
of
the
administered
dose)
(
MRID
No.
46261502)
and
no
dermal
or
systemic
toxicity
was
expected
from
both
rat
and
rabbit,
therefore,
quantitation
of
short­
and
intermediate­
term
dermal
exposure
to
thidiazuron
is
not
necessary.

Dermal
Exposure
Long­
Term
(>
6
Months)

The
endpoint
is
not
applicable
because
use
pattern
does
not
indicate
long­
term
exposure.

4.4.6
Inhalation
Exposure
(
Short­,
Intermediate­
and
Long­
Term)

Inhalation
Exposure:
Short­
Term
(
1­
30
days)
and
Inhalation
Exposure:
Intermediate
t­
Term
(
1­
30
days)

Study
Selected:
Developmental
toxicity
study
in
rabbit
(
MRID
46121507).
In
this
study,
maternal
toxicity
such
as
increased
incidence
of
abortions
and
decreases
in
the
body
weight
and
food
consumption
were
seen
in
rabbits
at
125
mg/
kg/
day.
At
the
same
dose,
developmental
toxicity
observed
were
abortions,
decreased
fetal
weight,
increased
number
of
runts,
and
delayed
skeletal
ossification.
See
section
Page
31
of
59
4.2.3
for
complete
executive
summary,
maternal
toxicity
and
developmental
toxicity.

Dose
and
Endpoint
for
Risk
Assessment:
Maternal
toxicity
NOAEL
=
25
mg/
kg/
day,
based
on
abortions
and
decreased
body
weight
gains
and
food
consumption
at
the
LOAEL
of
125
mg/
kg/
day.

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
The
route
and
duration
of
exposure
are
appropriate
for
selection
of
the
short­
and
intermediate
term
incidental
inhalation
endpoint.
HED
assumes
100%
absorption
following
inhalation
exposure.

Inhalation
Exposure:
Long­
Term
(>
6
Months)

The
endpoint
is
not
applicable
because
use
pattern
does
not
indicate
long­
term
exposure.

4.4.7
Margins
of
Exposure
Summary
of
target
Margins
of
Exposure
(
MOEs)
for
risk
assessment.

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

Occupational
(
Worker)
Exposure
Dermal
N/
A
N/
A
N/
A
Inhalation
100
100
N/
A
Residential
(
Non­
Dietary)
Exposure
Oral
100
100
N/
A
Dermal
N/
A
N/
A
N/
A
Inhalation
100
100
N/
A
For
Occupational
exposure:
This
is
based
on
the
conventional
uncertainty
factor
of
100X
(
10X
for
intraspecies
variation
and
10X
for
interspecies
extrapolation).

For
Residential
exposure:
This
is
based
on
the
conventional
uncertainty
factor
of
100X
(
10X
for
intraspecies
variation
and
10X
for
interspecies
extrapolation).

4.4.8
Recommendation
for
Aggregate
Exposure
Risk
Assessments
Currently
there
are
no
residential
uses
for
thidiazuron.
Therefore,
residential
exposures
are
not
expected
and
associated
risks
were
not
calculated.
However,
when
there
are
potential
residential
exposures
to
the
pesticide,
aggregate
risk
assessment
must
consider
exposures
from
three
major
sources:
oral,
dermal
and
inhalation
exposures.
The
toxicity
endpoints
selected
for
these
routes
of
exposure
may
be
aggregated
as
follows:
For
short­
and
intermediate­
term
aggregate
exposure
risk
assessments,
the
oral
and
inhalation
routes
can
be
combined
because
toxicity
endpoints
(
reduced
body
weight
gain
and
reduced
food
Page
32
of
59
consumption)
via
these
routes
were
selected
from
the
same
study.

4.4.9
Classification
of
Carcinogenic
Potential
Both
rat
and
mouse
carcinogenicity
studies
did
not
show
treatment
related
increase
in
tumor
incidences.

Studies
Supporting
Carcinogenic
Classification:

Combined
chronic
toxicity/
carcinogenicity
(
diet)
­
rat
OPPTS
870.4300/
§
83­
5/
OECD
453
EXECUTIVE
SUMMARY:

In
this
combined
chronic
toxicity/
carcinogenicity
study
(
MRID
46345201),
Thidiazuron
(
99.5%
a.
i.;
Batch
No.:
107623­
03)
was
administered
in
the
diet
for
2
years
to
70
WI­
IOPS
AF
Wistar
rats/
sex/
dose
at
doses
of
0,
200,
900,
or
1800
ppm
(
equivalent
to
0/
0,
8.0/
11.3,
36.4/
51.4,
and
75.6/
105
mg/
kg/
day).
After
12
months,
10
rats/
sex/
dose
were
sacrificed.
Additionally,
15
rats/
sex/
dose
were
treated
at
0
or
1800
ppm
for
12
months,
fed
control
diet
for
3
months,
and
then
sacrificed.

No
treatment­
related
effects
were
observed
during
the
ophthalmoscopic
examinations
or
hematology.

In
the
200
ppm
group,
there
were
some
minor
changes
seen
after
24
months
but
these
observations
were
equivocal
and
not
considered
adverse.

At
>=
900
ppm,
the
following
findings
were
observed:
(
i)
increased
incidence
of
a
wasted
appearance
in
the
males
during
the
second
year;
(
ii)
decreased
body
weights
in
males,
either
sporadically
(
900
ppm)
or
generally
throughout
the
study
(
1800
ppm);
(
iii)
decreased
overall
(
Days
1­
708)
body
weight
gains
in
males;
(
iii)
decreased
food
consumption
in
females,
frequently
throughout
the
study;
and
(
iv)
increased
serum
urea
in
males
at
Months
6
and
12
(
900
ppm)
or
throughout
the
study
(
1800
ppm).
The
following
microscopic
lesions
were
observed
at
12
months:
renal
glomerular
mineralization
in
both
sexes;
golden
brown
pigment
in
the
tuboepithelial
cells
in
the
kidney
in
the
males;
and
renal
papillary
mineralization
in
the
females.
The
following
lesions
were
observed
at
24
months:
(
i)
renal
collecting
duct
hyperplasia
in
both
sexes;
(
ii)
suburothelial
congestion
in
the
females;
(
iii)
glomerular
mineralization
in
both
sexes;
(
iv)
bilateral
pelvic
dilatation
in
the
males;
(
v)
chronic
progressive
nephropathy
in
the
females;
(
vi)
urothelial
mineralization
in
the
females;
and
(
vii)
bilateral
seminal
vesicle
atrophy.

At
1800
ppm,
several
additional
findings
were
observed:
(
i)
reduced
motor
activity,
general
pallor,
and
soiling
around
the
anogenital
region
in
the
males
during
the
second
year;
(
ii)
increased
mortality
in
the
males;
(
iii)
decreased
body
weights
and
overall
(
Days
1­
708)
body
weight
gain
in
males;
(
iv)
decreased
food
consumption
in
males;
(
v)
increased
cholesterol,
triglycerides,
and
phosphorus
in
the
males;
(
vi)
increased
urea
and
cholesterol
in
the
females;
(
vii)
decreased
albumin/
globulin
and
glucose
in
males;
and
(
viii)
increased
incidence
of
urinary
protein
concentration
>=
3
g/
L
in
both
sexes.
Grossly,
an
increased
incidence
of
irregular
kidney
surface
was
observed
in
males
at
15
months
(
recovery).
After
24
months,
an
increase
of
small
seminal
vesicles
in
males;
and
irregular
kidney
surface
and
pale
kidney
in
both
sexes
were
observed.
Increased
relative­
to­
body
kidney
weights
were
observed
after
24
months.
Increased
incidence
of
the
following
microscopic
lesions
were
also
observed:
(
i)
chronic
progressive
nephropathy
in
both
sexes
at
12,
15,
and
24
months;
(
ii)
bilateral
renal
pelvic
dilatation
in
the
females
at
12
months;
(
iii)
diffuse
germinal
cell
atrophy
in
the
testes,
unilateral
at
12
months
and
bilateral
at
24
months;
(
iv)
unilateral
Page
33
of
59
luminal
dilation
in
the
testes
at
12
months;
(
v)
oligospermia
in
the
epididymis,
unilateral
at
12
months
and
bilateral
at
24
months;
(
vi)
renal
glomerular
mineralization
in
both
sexes
at
15
months;
(
vii)
golden
brown
pigment
in
the
renal
tuboepithelial
cells
in
males
at
15
and
24
months;
and
(
viii)
renal
suburothelial
congestion
in
the
females
at
15
months.
Additionally,
increased
incidence
of
the
following
microscopic
lesions
were
observed
in
males
at
24
months:
(
i)
renal
transitional
cell
hyperplasia;
(
ii)
renal
glomerular
hyaline
deposit,
(
iii)
arteritis
in
kidneys,
testes,
and
epididymis;
(
iv)
epithelial
degenerative
changes
in
the
epididymis;
(
v)
mixed
cell
infiltrate
in
the
seminal
vesicles;
(
vi)
diffuse
parathyroid
hyperplasia;
(
vii)
focal/
multifocal
parathyroid
hyperplasia;
(
viii)
fibrous
osteodystrophy
in
the
sternum
and
articular
surface;
and
(
ix)
hyperosteoidosis
in
the
articular
surface.

Only
13%
of
the
1800
ppm
males
survived
24
months.
The
cause
of
death
of
26/
49
of
these
males
was
considered
to
be
chronic
progressive
nephropathy,
and
at
least
95%
of
the
animals
at
this
dose
had
chronic
progressive
nephropathy
and
renal
glomerular
mineralization.
Therefore,
findings
in
these
animals
may
have
been
confounded
by
severe
renal
dysfunction.
In
particular,
parathyroid
hyperplasia,
osteodystrophy,
and
hyperosteoidosis
may
have
been
related
to
renal
dysfunction.

The
LOAEL
is
900
ppm
(
equivalent
to
36.4/
51.4
mg/
kg/
day
in
males/
females),
based
on
decreased
body
weight
and
body
weight
gain
in
the
males,
increased
bilateral
seminal
vesicle
atrophy,
and
nephrotoxicity
in
both
sexes.
The
NOAEL
is
200
ppm
(
equivalent
to
8.0/
11.3
mg/
kg/
day).

At
the
doses
tested,
there
was
not
a
treatment­
related
increase
in
tumor
incidence
when
compared
to
controls.
Dosing
was
considered
adequate
based
on
decreased
survival,
body
weights,
body
weight
gains,
and
food
consumption,
increased
clinical
signs,
differences
in
clinical
chemistry
parameters,
nephrotoxicity,
and
male
reproductive
system
toxicity.

This
study
is
classified
as
acceptable/
guideline
and
satisfies
the
guideline
requirements
(
OPPTS
870.4300;
OECD
453)
for
a
combined
chronic
toxicity/
carcinogenicity
study
in
rats.

Carcinogenicity
feeding
­
mouse
[
OPPTS
870.4200b
(
§
83­
2(
b))];
OECD
451.

EXECUTIVE
SUMMARY:

In
a
carcinogenicity
study
(
MRID
46346001),
Thidiazuron
(
99.5%
a.
i.;
Batch
#
107623­
03)
was
administered
in
the
diet
to
C57BL/
6
mice
(
60/
sex/
dose)
at
doses
of
0,
200,
650,
or
2000
ppm
(
0/
0,
26.5/
33.4,
86.7/
107.8,
and
279.9/
329.7
mg/
kg/
day
in
males/
females)
for
up
to
18
months.
Ten
mice/
sex/
dose
were
sacrificed
at
52
weeks.

No
treatment­
related
effect
was
observed
on
mortality
or
hematology.

At
2000
ppm,
tremors
were
observed
in
both
sexes.
In
the
females,
increased
incidences
of
wasted
appearance,
prolapsed
rectum,
and
soiled
anogenital
region
were
observed.
Body
weights
were
decreased
in
both
sexes
throughout
the
study.
Body
weight
gain
was
decreased
at
2000
ppm
in
both
sexes
at
Days
1­
92,
92­
540,
and
1­
540.
In
both
sexes,
food
consumption
generally
was
decreased
throughout
treatment,
and
overall
(
Weeks
1­
80)
group
mean
food
consumption
was
also
decreased.

At
2000
ppm
at
the
interim
sacrifice
(
n=
10),
increased
incidence
of
slight
renal
cortical
basophilic
tubules
was
observed
in
the
females.
Page
34
of
59
At
2000
ppm
at
the
terminal
sacrifice,
the
epididymis
and
kidney
were
identified
as
target
organs.
The
incidence
of
grossly
enlarged
epididymis
was
increased.
The
incidences
of
the
following
microscopic
lesions
in
the
epididymis
were
increased:
(
i)
dilated
tubules;
(
ii)
interstitial
mononuclear
cell
infiltrate;
(
iii)
unilateral
and
bilateral
oligospermia;
and
(
iv)
spermatic
granuloma.
Relative­
to­
body
kidney
weight
was
increased
in
the
females,
as
was
the
incidence
of
gross
renal
pelvic
dilatation.
The
incidences
of
the
following
microscopic
renal
lesions
were
increased:
(
i)
cortical
basophilic
tubules
in
the
females;
(
ii)
proteinaceous
casts
in
the
males;
(
iii)
interstitial
mononuclear
cell
infiltrate
in
the
males;
and
(
iv)
bilateral
pelvic
dilatation
in
the
males
and
females.
Additionally,
there
was
a
decrease
in
renal
corticoepithelial
vacuolation
in
the
males.

At
650
ppm,
marginal
effects
were
observed.
At
the
terminal
sacrifice,
the
incidences
of
the
following
lesions
in
the
epididymis
were
slightly
increased:
(
i)
dilated
tubules;
(
ii)
interstitial
mononuclear
cell
infiltrate;
and
(
iii)
bilateral
oligospermia.
Additionally,
there
was
a
decrease
in
renal
corticoepithelial
vacuolation
in
the
males.
In
females,
minor
decreases
in
body
weight
gain
at
Days
92­
540
and
at
Days
1­
540
and.
overall
group
mean
food
consumption
was
observed.
The
incidence
of
renal
cortical
basophilic
tubules
was
increased
in
the
females.
The
above
effects
found
in
650
ppm
animals
became
more
severe
and
numerous
at
2000
ppm
indicating
that
the
syndrome
of
toxicity
may
have
begun
at
650
ppm.

Hepatotoxicity
was
equivocally
indicated
as
follows.
At
the
interim
sacrifice
(
n=
10),
slight
to
minimal
centrilobular
hypertrophy
was
observed
in
the
2000
ppm
males.
Relative­
to­
body
liver
weights
were
increased
in
the
2000
ppm
males
and
the
>=
650
ppm
females
at
the
interim
sacrifice.
The
incidences
(
and
usually
severity)
of
the
following
hepatic
lesions
were
increased
at
the
terminal
sacrifice:
oval
cell
proliferation
in
the
>=
650
ppm
males
and
2000
ppm
females;
centrilobular
hepatocellular
hypertrophy
and
focus(
i)
of
altered
hepatocytes
(
basophilic
cells)
in
the
2000
ppm
males.
There
was
no
indication
that
hepatic
function
was
impaired
nor
that
carcinogenesis
resulted
from
these
observed
effects.

The
LOAEL
is
650
ppm
(
equivalent
to
86.7/
107.8
mg/
kg/
day
in
males/
females)
based
on
decreased
body
weight
gain,
and
food
consumption;
and
increased
nephrotoxicity
in
females;
and
increased
epididymis
toxicity
in
males.
The
NOAEL
is
200
ppm
(
equivalent
to
26.5/
33.4
mg/
kg/
day
in
males/
females).

At
the
doses
tested,
there
was
not
a
treatment­
related
increase
in
tumor
incidence
when
compared
to
controls.
Dosing
was
considered
adequate
based
on
systemic
toxicity
and
toxicity
in
the
kidney
and
epididymis.

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

Table
4.4,
below,
summarizes
the
toxicological
doses
and
endpoints
for
thidiazuron
for
use
in
human
risk
assessments.
Page
35
of
59
Table
4.4.
Summary
of
Toxicological
Doses
and
Endpoints
for
Thidiazuron
for
Use
in
Human
Risk
Assessments
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Dietary
Risk
Assessments
Acute
Dietary
(
All
populations)
NOT
APPLICABLE.
A
dose
and
endpoint
were
not
selected
for
this
population
group
because
there
were
no
effects
observed
in
the
available
toxicology
studies
could
be
attributable
to
a
single
exposure
(
dose).

Chronic
Dietary
(
All
populations)
NOAEL=
3.93
mg/
kg/
day
UF
=
100
Chronic
RfD
=
0.0393
mg/
kg/
day
FQPA
SF
=
1X
cPAD
=
chronic
RfD
FQPA
SF
=
0.0393
mg/
kg/
day
Dog
chronic
toxicity
study
LOAEL
=
11.1
mg/
kg/
day
based
on
increased
incidence
of
anemia,
changes
in
hematological
parameters
and
marked
hemosiderosis
in
liver
and
spleen.

Non­
Dietary
Risk
Assessments
Incidental
Oral
Short­
term
Residential
Only
NOAEL=
25
mg/
kg/
day
FQPA
SF
=
1X
Developmental
Toxicity
­
Rabbit
LOAEL
=
125
mg/
kg/
day
based
on
decreased
body
weight
gains
(
decreased.
70%
during
GD
6­
29)
and
food
consumption
(
decreased
19
during
GD
6­
8;
44%
during
GD
14­
18).

Incidental
Oral
Intermediate­
Term
Residential
Only
NOAEL=
25
mg/
kg/
day
UF
=
100
FQPA
SF
=
1X
Developmental
Toxicity
­
Rabbit
LOAEL
=
125
mg/
kg/
day
(
see
as
above)

dermal
all
durations
Quantitation
of
dermal
exposure
to
thidiazuron
is
not
necessary.

Inhalation
Short­
term
a
NOAEL=
25
mg/
kg/
day
FQPA
SF
=
1X
Developmental
Toxicity
­
Rabbit
LOAEL
=
125
mg/
kg/
day
(
see
as
above)

Inhalation
Intermediate­
Term
b
NOAEL=
25
mg/
kg/
day
FQPA
SF
=
1X
Developmental
Toxicity
­
Rabbit
LOAEL
=
125
mg/
kg/
day
(
see
as
above)

Inhalation
Long­
Term
(>
6
months)
The
endpoint
is
not
applicable
because
use
pattern
does
not
indicate
long
term
exposure.

Cancer
Both
rat
and
mouse
carcinogenicity
studies
did
not
show
treatment
related
increase
in
tumor
incidences.

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
Page
36
of
59
a
Since
an
oral
NOAEL
was
selected,
an
inhalation
absorption
factor
of
100%
(
default
value)
should
be
used
in
route­
to­
route
extrapolation.

4.5
Special
FQPA
Safety
Factor
Based
on
the
hazard
data,
HED
recommended
the
special
FQPA
SF
be
reduced
to
1X
because
there
were
no/
low
concerns
and
no
residual
uncertainties
with
regard
to
pre­
and/
or
postnatal
toxicity.
The
thidiazuron
risk
assessment
team
evaluated
the
quality
of
the
exposure
data;
and,
based
on
these
data,
recommended
that
the
special
FQPA
SF
be
reduced
to
1X.
The
recommendation
is
based
on
the
following:

°
The
toxicity
data
showed
no
increase
in
susceptibility
in
fetuses
and
pups
with
in
utero
and
postnatal
exposure.

°
The
dietary
food
exposure
assessment
utilizes
proposed
tolerance
level
residues
or
high
end
estimates
and
100%
CT
information
for
all
commodities.
By
using
these
screening­
level
assessments,
chronic
exposures/
risks
will
not
be
underestimated.

°
The
dietary
drinking
water
assessment
(
Tier
1
estimates)
utilizes
values
generated
by
model
and
associated
modeling
parameters
which
are
designed
to
provide
conservative,
health
protective,
high­
end
estimates
of
water
concentrations.

°
There
are
no
residential
uses
for
thidiazuron.
Therefore,
residential
exposures
are
not
expected
and
associated
risks
were
not
calculated.

4.6
Endocrine
disruption
EPA
is
required
under
the
FFDCA,
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
pesticide
active
and
other
ingredients)
"
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
the
recommendations
of
its
Endocrine
Disruptor
Screening
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
scientific
bases
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC's
recommendation
that
the
Program
include
evaluations
of
potential
effects
in
wildlife.
For
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).

The
results
of
the
subchronic
dietary
feeding
studies
in
rats
showed
that
thidiazuron
produced
decreased
epididymides
and
prostate
gland
weights,
small
prostate
and
small
seminal
vesicles.
In
addition,
microscopic
findings
observed
were
slight
to
mild
diminished
secretion
of
the
prostate
gland
and
slight
to
marked
diminished
secretion
of
the
seminal
vesicle.
In
carcinogenicity
study
in
mice,
epididymis
toxicity
was
observed.
For
example,
there
were
increased
incidence
of
grossly
enlarged
epididymis
at
the
highest
dose
treated
in
mice.
In
addition,
the
incidences
of
the
following
microscopic
lesions
in
the
epididymis
were
increased:
(
i)
dilated
tubules;
(
ii)
interstitial
mononuclear
cell
infiltrate;
(
iii)
unilateral
and
bilateral
Page
37
of
59
oligospermia;
and
(
iv)
spermatic
granuloma.
However,
these
findings
were
not
verified
in
the
reproduction
study
in
rats,
and
were
found
at
doses
that
were
substantially
higher
than
the
NOAEL
which
was
used
for
this
risk
assessment.

When
the
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
thidiazuron
may
be
subjected
to
additional
screening
and/
or
testing
to
better
characterize
effects
related
to
possible
endocrine
disruption.

5.0
Public
Health
Data
5.1
Incident
Reports
The
following
databases
have
been
consulted
for
the
poisoning
incident
data
on
the
active
ingredient
thidiazuron:
OPP
Incident
Data
System
(
IDS),
Poison
Control
Centers,
California
Department
of
Pesticide
Regulation,
and
the
National
Institute
of
Occupational
Safety
and
Health's
Sentinel
Event
Notification
System
for
Occupational
Risks
(
NIOSH
SENSOR).
Since
1992,
OPP
IDS
has
only
reported
5
incidents
as
a
result
of
thidiazuron
exposure,
which
all
show
similar
symptoms.
The
Poison
Control
Center
database
reported
no
incidents
from
1993­
1998;
from
1999­
2001,
there
was
one
report
of
a
child
exposed.
However,
there
were
no
symptoms
reported
and
the
child
was
not
seen
at
a
health
care
facility.
NIOSH
SENSOR
data
from
1998­
2002
reported
a
single
thidiazuron
exposure
incident
due
to
drift
from
an
aerial
application
in
1998.
There
were
no
poisoning
reports
due
to
thidiazuron
in
California
from
1982­
2002,
according
to
the
California
Department
of
Pesticide
Regulation.
Additionally,
there
were
no
incidents
of
poisoning
or
other
human
health
effects
related
to
thidiazuron
found
in
scientific
literature.
Relatively
few
incidents
of
illness
have
been
reported
due
to
thidiazuron;
as
a
result,
no
recommendations
are
warranted.

6.0
Exposure
Characterization/
Assessment
6.1
Dietary
Exposure/
Risk
Pathway
6.1.1
Residue
Profile
The
combined
residues
of
thidiazuron
and
its
aniline
containing
metabolites
are
currently
regulated
(
40
CFR180.403).
Tolerances
are
established
in/
on
cottonseed
(
0.4
ppm),
cottonseed
hulls
(
0.8
ppm),
eggs
(
0.1
ppm),
and
milk
(
0.05
ppm).
Additional
tolerances
are
set
at
0.2
ppm
for
the
fat,
meat
and
meat
byproducts
of
cattle,
goats,
hogs,
horses,
poultry
and
sheep.
HED
recommends
that
the
tolerances
for
thidiazuron
reflect
the
residues
of
thidiazuron
only
for
plants
and
residues
of
the
parent,
4­
hydroxy
thidiazruon,
and
phenylurea
for
livestock
commodities
as
determined
by
the
MARC,
instead
of
thidiazuron
and
its
aniline
containing
metabolites
collectively.

No
Codex
MRLs
are
established
or
proposed
for
residues
of
thidiazuron.
Therefore,
there
are
no
issues
regarding
the
compatibility
of
the
U.
S.
tolerances
with
Codex
MRLs.

The
qualitative
nature
of
the
residue
in
cotton
is
adequately
understood.
The
parent
compound
thidiazuron
is
the
residue
of
concern.
The
nature
of
the
residue
in
animals
is
sufficiently
understood.
The
parent
compound,
thidiazuron,
and
metabolites
4­
hydroxythidiazuron
and
phenyl
urea
are
the
residues
of
concern
Page
38
of
59
for
livestock
commodities.
Most
of
the
radioactivity
was
extractable
(>
80%).
Attempts
were
made
to
release
unextractable
residues
in
cow
liver,
cow
kidney
and
hen
liver;
however,
release
of
unextractable
residues
in
hen
muscle,
which
accounted
for
13%
(
0.01
ppm)
of
the
tissue
radioactivity,
was
not
attempted.
The
registrant's
attempt
to
identify/
characterize
low
level
polar
fractions
was
unsuccessful;
however,
these
fractions
were
negligible
(<
0.02ppm)
with
the
exception
of
cow
kidney
(
0.35
ppm).
Previously
unidentified
metabolites
G
and
H
were
sufficiently
characterized
as
conjugates
of
4­
hydroxythidiazuron
and
phenylurea,
respectively.

Analytical
methods
available
for
enforcing
tolerances
in
plant
commodities
are
listed
in
PAM,
Volume
II
(
Sec.
180.403)
as
Methods
I
and
A.
Method
I
is
a
GLC
method
with
electron
capture
detection
which
involves
the
hydrolysis
of
thidiazuron
to
an
aniline
which
is
subsequently
steam
distilled,
partitioned
into
hydrochloric
acid,
brominated,
and
determined
as
2,4,6­
tribromoaniline.
Method
A
is
a
reverse­
phase
HPLC
with
UV
detection
which
determines
thidiazuron
per
se.
Additionally,
`
Determination
of
Thidiazuron
and
Photo­
thidiazuron
in
Cottonseed
and
Gin
Trash
by
HPLC'
is
a
pending
enforcement
method
for
thidiazuron
that
also
analyzes
thidiazuron
per
se.
This
method
has
been
sent
to
EPA's
Analytical
Chemistry
Laboratory
(
Beltsville,
MD)
for
petition
method
validation
(
D246804,
1/
22/
99,
S.
Mason).
Since
tolerances
will
no
longer
be
established
for
thidiazuron
and
it
analine
metabolites
collectively,
it
is
recommended
that
the
common
moiety
method
I,
be
removed
from
PAM
II.

Currently,
there
are
no
adequate
enforcement
methods
for
thidiazuron
in
animal
commodities.
Submitted
analytical
methods
have
been
unsuccessful
in
simultaneously
quantifying
all
three
residues
of
concern
in
livestock
commodities:
thidiazuron,
4­
hydroxy
thidiazuron,
and
phenylurea.

Thidiazuron
was
subjected
to
the
Multiresidue
Method
of
Analysis
in
PAM
I,
Protocol
C.
Thidiazuron
is
not
a
N­
methyl
carbamate
nor
an
acid
or
phenol,
and
cottonseed
(
only
registered
use)
is
an
oily
crop;
therefore,
Protocols
A,
B,
and
D
were
not
required.
Testing
through
Protocol
C
was
unsuccessful
and
further
testing
was
suspended.

The
available
residue
data
from
crop
field
trials
provide
sufficient
information
to
reduce
the
0.4
ppm
tolerances
for
residues
of
thidiazuron
in/
on
cottonseed
and
its
processed
commodities
to
0.3
ppm.
For
cottonseed,
thidiazuron
residues
above
LOQ
(
0.05
ppm)
were
found
in
8/
10
trials.
The
residue
range
was
0.05­
0.21
ppm.
For
cotton
gin
byproducts,
thidiazuron
residues
above
the
LOQ
(
0.5
ppm)
were
found
in
all
10
trials.
The
residue
range
was
1.62­
22.12
ppm.
The
data
suggests
that
a
tolerance
of
24
ppm
be
established
for
cotton
gin
byproducts.

A
processing
study
performed
at
the
5x
application
rate
demonstrated
sufficient
evidence
of
thidiazuron
residue
dissipation.
Residues
in/
on
cottonseed,
the
raw
agricultural
commodity,
averaged
0.10
ppm.
Thidiazuron
residues
in/
on
refined
oil
and
meal
were
<
LOQ
(<
0.05)
and
did
not
concentrate,
indicating
that
separate
tolerances
for
cottonseed
meal
and
refined
oil
are
not
necessary.
Thidiazuron
residues
in/
on
cottonseed
hulls
did
concentrate
slightly
with
a
concentration
factor
of
1.4x.
However,
based
on
this
concentration
factor
and
the
highest
field
trial
residue,
cottonseed
hull
residues
are
not
expected
to
exceed
the
recommended
0.3
ppm
cottonseed
tolerance.
It
is
recommended
that
the
current
0.8
ppm
tolerance
(
40
CFR
§
180.403)
for
cottonseed
hulls
be
removed.

A
Magnitude
of
the
Residue
study
for
meat/
milk/
poultry/
eggs
was
requested
during
the
thidiazuron
Phase
IV
review.
The
ruminant
study
was
submitted
and
reviewed
(
D220968,
2/
15/
96,
S.
Funk).
Dose
levels
were
based
on
a
maximum
theoretical
dietary
burden
(
MTDB)
on
cottonseed
and
cottonseed
hulls
(
now
Page
39
of
59
revoked)
tolerances.
The
MTDB
was
initially
calculated
using
the
current
cotton
gin
byproduct
20%
diet
contribution
value
listed
in
OPPTS
860.100
Table
1,
which
resulted
in
an
actual
dose
(
1.48
ppm)
that
was
only
0.3x
of
the
MTDB.
However,
the
HED
Chemistry
Scientific
Advisory
Council
decided
the
contribution
of
cotton
gin
byproducts
to
the
dietary
burden
for
ruminants
could
be
reduced
to
5%
of
the
diet
for
beef
cattle,
as
proposed
by
the
registrant
since
HED
is
in
the
process
of
revising
the
current
20%
value
for
cotton
gin
byproducts
to
reflect
diet
contributions
of
5%
for
finishing
beef.
Dairy
cattle
were
not
considered,
since
cotton
gin
byproducts
are
no
longer
used
as
a
feed
item
for
dairy
cattle.
It
has
also
been
concluded
that
until
Table
1
revisions
are
complete,
reductions
to
the
diet
contribution
percentages
for
cotton
gin
byproducts
will
be
decided
on
a
case
by
case
basis.
Using
the
5%
value,
the
actual
dose
tested
is
0.9x
of
the
MTDB.
Consequently,
the
submitted
ruminant
feeding
study
is
now
upgradable.
In
order
for
this
study
to
be
acceptable
the
registrant
must
submit:
storage
stability
data,
raw
data
to
support
findings
in
the
study,
and
an
analytical
enforcement
method
that
simultaneously
quantifies
residues
of
thidiazuron
and
its
two
livestock
metabolites.
A
new
feeding
study
for
ruminants
is
no
longer
required;
however,
tolerances
for
ruminants
livestock
commodities
will
not
be
determined
until
the
additional
data
has
been
submitted.
Table
6.1.1
illustrates
the
MTDB
based
on
the
proposed
cotton
gin
byproduct
tolerance.

Table
6.1.1.
Tentative
Calculation
of
Maximum
Theoretical
Dietary
Burden
of
Thidiazuron
to
Beef
Cattle.

Feedstuff
%
Dry
Matter
1
Expected
tolerance
(
ppm)
Maximum
%
in
diet
2
Dietary
burden
(
ppm)
3
Cotton
gin
byproducts
90
24
5
1.3
Total
5
Max
Dietary
Burden
1.3
1
As
per
Table
1
(
OPPTS
860.1000).
2
Additional
untreated
feedstuffs
will
be
fed
up
to
95%
to
complete
a
reasonably
balanced
diet
at
100%
total.
3
Burden
=
[
tolerance
÷
%
DM
X
%
diet].

A
poultry
feeding
study
was
not
submitted
in
response
to
the
thidiazuron
Phase
IV
review.
However,
HED
concluded
that
the
processing
study
performed
at
the
5x
application
rate
demonstrated
sufficient
evidence
of
thidiazuron
residue
dissipation
and
this
requirement
has
been
waived.
Therefore,
tolerances
are
no
longer
required
for
residues
of
thidiazuron
in/
on
poultry;
the
presently
registered
uses
of
thidiazuron
are
classified
as
Category
3
of
40
CFR
§
180.6(
a)
with
respect
to
the
need
for
tolerances
in
poultry
and
eggs
i.
e.,
there
is
no
reasonable
expectation
of
finite
residues.

6.1.2
Chronic
Dietary
Exposure
and
Risk
A
chronic
dietary
risk
assessment
was
conducted
for
food
only,
using
the
Dietary
Exposure
Evaluation
Model
(
DEEM­
FCID
 
)
and
Lifeline
 
Model
Version
2.0.
Both
models
use
food
consumption
data
from
the
United
States
Department
of
Agriculture's
(
USDA's)
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.

Chronic
Dietary
Exposure
Results
and
Characterization
A
Tier
I
chronic
dietary
exposure
assessment
was
performed
for
thidiazuron.
The
assumptions
of
these
dietary
exposure
assessments
were
tolerance
level
residues
and
100%
crop
treated,
with
the
exception
of
ruminant
meat,
meat
byproducts,
and
fat
tolerances.
Page
40
of
59
Adequate
magnitude
of
residue
data
are
not
available
for
livestock
commodities.
It
is
tentatively
concluded,
pending
a
storage
stability
and
raw
data
to
validate
the
feeding
study,
that
residues
of
thidiazuron
and
its
metabolites
of
concern
are
not
expected
to
exceed
0.05
ppm
for
milk
and
0.4
ppm
for
meat,
meat
byproducts,
and
fat.
HED
used
these
estimates
in
the
dietary
assessment
from
the
existing
magnitude
of
residue
study
to
obtain
reasonable
high
end
estimates
of
total
thidiazuron
residues
in
ruminant
livestock
commodities.

The
dietary
exposure
analyses
for
thidiazuron
result
in
dietary
risk
estimates
for
food
only
that
are
below
the
Agency's
level
of
concern
for
chronic
dietary
exposure.
The
highest
exposure
and
risk
estimates
were
for
children
1
to
2
years
old.
For
DEEM­
FCID
 
,
the
chronic
exposure
for
children
1
to
2
years
old
was
0.002835
mg/
kg/
day,
which
utilizes
7.2
%
of
the
chronic
Population­
Adjusted
Dose
(
cPAD)
for
thidiazuron.
For
the
Lifeline
Model,
the
chronic
exposure
for
children
1
to
2
years
was
old
0.00257
mg/
kg/
day,
which
also
utilizes
6.5%
of
the
cPAD
for
thidiazuron.
The
results
of
the
chronic
dietary
analyses
for
both
models
are
reported
in
Table
6.1.2.

Table
6.1.2
Result
of
Chronic
Dietary
Exposure
and
Risk
Estimates
for
Thidiazuron­
Food
Only.

Population
Subgroup
1
PAD,
mg/
kg/
day
DEEM­
FCID
Lifeline
Exposure,
mg/
kg/
day
%
PAD
2
Exposure,
mg/
kg/
day
%
PAD
2
Chronic
Dietary
Estimates
U.
S.
Population
0.0393
0.000878
2.2
0.000827
2.1
All
infants
(<
1
yr)
0.0393
0.000859
2.2
0.000831
2.1
Children
1­
2
yrs
0.0393
0.002835
7.2
0.00257
6.5
Children
3­
5
yrs
0.0393
0.002223
5.7
0.00218
5.6
Children
6­
12
yrs
0.0393
0.001462
3.7
0.00139
3.6
Youth
13­
19
yrs
0.0393
0.000854
2.2
0.000816
2.1
Adults
20­
49
yrs
0.0393
0.000660
1.7
0.000714
1.8
Adults
50+
yrs
0.0393
0.000547
1.4
0.000694
1.8
Females
13­
49
yrs
0.0393
0.000576
1.5
0.000822
2.1
Cancer
Dietary
Estimate
U.
S.
Population
Toxicological
studies
did
not
indicate
any
cancer
risks
for
thidiazuron,
thus
a
cancer
assessment
was
not
performed.

1
The
values
for
the
population
with
the
highest
risk
for
each
type
of
risk
assessment
are
bolded.
2
Reported
to
2
significant
figures.

6.2
Water
Exposure/
Risk
Pathway
The
water
residues
of
concern
were
calculated
in
the
Thidiazuron
Drinking
Water
Assessment
provided
by
EFED
(
D244574,
9/
24/
04,
A.
Clem).
Since
the
HED
Metabolism
Assessment
Review
Committee
(
MARC)
did
not
determine
the
residues
of
concern
for
water,
EFED
provided
three
surface
water
exposure
scenarios
and
one
ground
water
concentration
estimate
for
thidiazuron
using
two
EFED
Tier
1
screeninglevel
models:
FIRST,
Version
1.0
and
SCI­
GROW,
Version
2.3.
A
summary
of
all
four
exposure
scenarios
can
be
found
in
Tables
6.2.
a
and
6.2.
b.
The
most
conservative
number
was
used
for
the
chronic
Page
41
of
59
assessment,
which
included
thidiazuron
and
both
photoproducts,
photo­
thidiazuron
and
1­
cyano­
3­
phenylurea
in
its
estimate.
The
water
concentration
value
used
was
0.001
ppm
(
1.0
ppb)
for
the
chronic
assessment.

Table
6.2.
a
Surface
Water
Concentrations
(
derived
from
FIRST
model,
Ver.
1.0)

THREE
ALTERNATIVE
DEGREES
OF
PROTECTION
1
PEAK
DAY
(
ACUTE)
CONCENTRATION
(
ppb
or
µ
g/
L)
ANNUAL
AVERAGE
(
CHRONIC)
CONCENTRATION
(
ppb
or
µ
g/
L)

Parent
+
photo­
thidiazuron
and
1­
cyano­
3­
phenylurea
3.5
1.0
Parent
+
photo­
thidiazuron
3.5
0.82
Parent
Only
3.4
0.068
1
The
value
used
in
the
risk
assessment
is
bolded.

Table
6.2.
b
Groundwater
Concentration
(
derived
from
SCI­
GROW
regression
model,
Ver.
2.3
)

Acute
and
Chronic
Concentration:
0.066
ppb
(
µ
g/
L)

6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
There
are
no
residential
uses
for
thidiazuron.
It
is
only
registered
for
agricultural
use
as
a
cotton
defoliant
late
in
the
growing
season.
Therefore,
residential
exposures
are
not
expected
and
associated
risks
were
not
calculated.

However,
spray
drift
is
always
a
potential
source
of
exposure
to
residents
nearby
to
spraying
operations.
This
is
particularly
the
case
with
aerial
application,
but,
to
a
lesser
extent,
could
also
be
a
potential
source
of
exposure
from
the
ground
application
method
employed
for
thidiazuron.
The
Agency
has
been
working
with
the
Spray
Drift
Task
Force,
EPA
Regional
Offices
and
State
Lead
Agencies
for
pesticide
regulation
and
other
parties
to
develop
the
best
spray
drift
management
practices.
On
a
chemical
by
chemical
basis,
the
Agency
is
now
requiring
interim
mitigation
measures
for
aerial
applications
that
must
be
placed
on
product
labels/
labeling.
The
Agency
has
completed
its
evaluation
of
the
new
data
base
submitted
by
the
Spray
Drift
Task
Force,
a
membership
of
U.
S.
pesticide
registrants,
and
is
developing
a
policy
on
how
to
appropriately
apply
the
data
and
the
AgDRIFT
computer
model
to
its
risk
assessments
for
pesticides
applied
by
air,
orchard
airblast
and
ground
hydraulic
methods.
After
the
policy
is
in
place,
the
Agency
may
impose
further
refinements
in
spray
drift
management
practices
to
reduce
off­
target
drift
with
specific
products
with
significant
risks
associated
with
drift.

7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
In
accordance
with
the
FQPA,
HED
must
consider
and
aggregate
pesticide
exposures
and
risks
from
three
major
sources:
food,
drinking
water,
and
residential
exposures.
Since
there
are
no
residential
uses,
an
aggregate
exposure
assessment
for
thidiazuron
includes
consideration
of
exposures
from
food
and
drinking
water.
In
an
aggregate
assessment,
exposures
from
relevant
sources
are
added
together
and
compared
to
Page
42
of
59
quantitative
estimates
of
hazard
(
e.
g.,
a
NOAEL
or
PAD),
or
the
risks
themselves
can
be
aggregated.
When
aggregating
exposures
and
risks
from
various
sources,
HED
considers
both
the
route
and
duration
of
exposure.
A
chronic
dietary
risk
assessment
(
D311281,
12/
8/
04,
T.
Jimerson)
was
conducted
using
the
Dietary
Exposure
Evaluation
Model
(
DEEM­
FCID
 
)
,
Version
2.0,
and
Lifeline
 
Model
Version
2.0.
Both
models
use
food
consumption
data
from
the
United
States
Department
of
Agriculture's
(
USDA's)
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.

7.1
Acute
Aggregate
Risk
There
are
no
acute
aggregate
risks
for
thidiazuron.

7.2
Short­
Term
Aggregate
Risk
There
are
no
short­
term
aggregate
risks
for
thidazuron.

7.3
Intermediate­
Term
Aggregate
Risk
There
are
no
intermediate­
term
aggregate
risks
for
thidazuron.

7.4
Long­
Term
Aggregate
Risk
A
Tier
I
chronic
dietary
exposure
assessment
was
performed
for
thidiazuron.
The
assumptions
of
these
dietary
exposure
assessments
were
tolerance
level
residues
and
100%
crop
treated,
with
the
exception
of
meat,
meat
byproducts,
and
fat
tolerances.
Existing
meat,
meat
byproduct,
and
fat
tolerance
levels
were
not
used
in
the
aggregate
assessment
because
the
magnitude
of
the
residue
study
for
ruminant
commodities
suggests
higher
residue
values
than
the
current
tolerance
level.
Therefore,
HED
extrapolated
from
the
existing
magnitude
of
residue
study
to
obtain
reasonable
high
end
estimates
of
total
thidiazuron
residues
in
livestock
commodities.

The
dietary
exposure
analyses
in
this
assessment
for
thidiazuron
result
in
dietary
risk
estimates
for
food
and
water
that
are
below
the
Agency's
level
of
concern
for
chronic
dietary
exposure.
For
the
chronic
analyses,
the
highest
exposure
and
risk
estimates
were
for
children
1
to
2
years
old.
For
DEEM­
FCID
 
,
the
chronic
exposure
for
children
1
to
2
years
old
was
0.002867
mg/
kg/
day,
which
utilizes
7.3%
of
the
chronic
Population­
Adjusted
Dose
(
cPAD)
for
thidiazuron.
For
the
Lifeline
Model,
the
chronic
exposure
for
children
1
to
2
years
was
old
0.00254
mg/
kg/
day,
which
also
utilizes
6.5%
of
the
cPAD
for
thidiazuron.
The
results
of
the
chronic
dietary
analyses
for
both
models
are
reported
in
Summary
Table
7.1.

7.5
Cancer
Risk
Both
rat
and
mouse
carcinogenicity
studies
did
not
show
treatment
related
increase
in
tumor
incidences.
Thus,
a
cancer
dietary
exposure
assessment
was
not
performed.
Page
43
of
59
Table
7.1.
Result
of
Chronic
Dietary
Exposure
and
Risk
Estimates
for
Thidiazuron­
Food
and
Water
Population
Subgroup
1
PAD,
mg/
kg/
day
DEEM­
FCID
Lifeline
Water
Concentration
Estimates
(
ppb)
Exposure,
mg/
kg/
day
%
PAD
2
Exposure,
mg/
kg/
day
%
PAD
2
Chronic
Dietary
Estimates
U.
S.
Population
0.0393
0.000899
2.3
0.000832
2.1
1.0
All
infants
(<
1
yr)
0.0393
0.000928
2.4
0.000809
2.1
1.0
Children
1­
2
yrs
0.0393
0.002867
7.3
0.00254
6.5
1.0
Children
3­
5
yrs
0.0393
0.002252
5.7
0.00219
5.6
1.0
Children
6­
12
yrs
0.0393
0.001482
3.8
0.00139
3.5
1.0
Youth
13­
19
yrs
0.0393
0.000869
2.2
0.000814
2.1
1.0
Adults
20­
49
yrs
0.0393
0.000680
1.7
0.000725
1.9
1.0
Adults
50+
yrs
0.0393
0.000567
1.4
0.000701
1.8
1.0
Females
13­
49
yrs
0.0393
0.000595
1.5
0.000830
2.1
1.0
Cancer
Dietary
Estimate
U.
S.
Population
Toxicological
studies
did
not
indicate
any
cancer
risks
for
thidiazuron,
thus
a
cancer
assessment
was
not
performed.

1
The
values
for
the
population
with
the
highest
risk
for
each
type
of
risk
assessment
are
bolded.
2
Reported
to
1
significant
figure.

8.0
Cumulative
Risk
Characterization/
Assessment
Unlike
other
pesticides
for
which
EPA
has
followed
a
cumulative
risk
approach
based
on
a
common
mechanism
of
toxicity,
EPA
has
not
formally
made
a
common
mechanism
of
toxicity
finding
as
to
thidiazuron
and
any
other
substances
and
thidiazuron
does
not
appear
to
produce
a
toxic
metabolite
produced
by
other
substances.
For
the
purposes
of
this
tolerance
action,
therefore,
EPA
has
not
assumed
that
thidiazuron
has
a
common
mechanism
of
toxicity
with
other
substances.
However,
it
is
noted
that
thidiazuron
is
a
member
of
the
phenylurea
group
of
herbicides,
that
includes
diuron
and
linuron.
For
information
regarding
EPA's
efforts
to
determine
which
chemicals
have
a
common
mechanism
of
toxicity
and
to
evaluate
the
cumulative
effects
of
such
chemicals,
see
the
policy
statements
released
by
EPA's
Office
of
Pesticide
Programs
concerning
common
mechanism
determinations
and
procedures
for
cumulating
effects
from
substances
found
to
have
a
common
mechanism
on
EPA's
website
at
http://
www.
epa.
gov/
pesticides/
cumulative/.

9.0
Occupational
Exposure/
Risk
Pathway
This
section
of
the
risk
assessment
addresses
exposures
to
individuals
who
are
exposed
as
part
of
their
employment.
These
exposures
can
occur
because
people
have
contact
with
thidiazuron
residues
while
using
commercial
products
containing
thidiazuron
(
i.
e.,
handlers)
or
by
being
in
areas
that
have
been
previously
treated
(
postapplication
workers).
Page
44
of
59
Section
9.1:
Short/
Intermediate/
Long­
Term
Handler
Risk
describes
the
data,
methods,
and
risk
results
associated
with
the
use
of
commercial
products
which
contain
thidiazuron.
Section
9.2:
Short/
Intermediate/
Long­
Term
Postapplication
Risk
provides
a
qualitative
description
of
the
exposures
which
may
occur
for
those
who
work
in
areas
that
have
been
previously
treated
with
thidiazuron.
Section
9.3:
Occupational
Risk
Characterization
provides
information
pertaining
to
the
quality
of
the
assessment
including
data
used,
uncertainties
with
the
methods,
and
any
other
information
that
might
be
used
to
describe
the
quality
of
the
results.

9.1
Short/
Intermediate/
Long­
Term
Handler
Risk
The
Agency
completes
occupational
handler
risk
assessments
based
on
scenarios
described
in
the
U.
S.
EPA
Guidelines
For
Exposure
Assessment.
For
commercial
pesticide
products,
the
Agency
categorizes
handler
exposures
based
on
the
kinds
of
formulations
(
e.
g.,
liquids
or
various
solids),
the
kinds
of
equipment
used
to
make
applications
(
e.
g.,
groundboom
or
aerial),
the
nature
of
the
task
(
e.
g.,
mixing/
loading
or
applying),
and
the
level
of
personal
protection
used.
Identifying
the
duration
of
exposure
is
also
a
critical
element
in
the
development
of
a
risk
assessment
to
ensure
that
the
proper
hazard
component
is
used.

For
thidiazuron
uses,
the
Agency
identified
5
major
occupational
exposure
scenarios
based
on
the
types
of
equipment
and
techniques
that
potentially
can
be
used
for
thidiazuron
applications.
Most
of
the
scenarios
were
classified
as
having
short­
term
and
intermediate­
term
exposures
(
up
to
30
days
and
30
days
to
several
months,
respectively).

The
quantitative
exposure/
risk
assessment
developed
for
occupational
handlers
was
based
on
the
following
scenarios.

Mixing/
Loading
(
1a)
Liquids
for
Aerial;
(
1b)
Liquids
for
Groundboom/
Commercial
Applications;
(
1c)
Liquids
for
Groundboom/
Grower
Applications;
(
2a)
Wettable
Powders
for
Aerial;
(
2b)
Wettable
Powders
for
Groundboom/
Commercial
Applications;
(
2c)
Wettable
Powders
for
Groundboom/
Grower
Applications;

Applicator:
(
3)
Aerial/
Liquid
Application;
(
4a)
Groundboom
Application/
Commercial;
(
4b)
Groundboom
Application/
Grower;
and
Flaggers:
(
5)
Flagging
For
Liquid
Sprays.

No
hazard
concerns
were
identified
for
dermal
exposures
as
described
above.
As
such,
For
each
of
these
scenarios,
risk
calculations
were
completed
based
on
four
levels
of
inhalation
personal
protection
that
were
defined
based
on
the
following:

1)
Baseline
Protection
(
no
respiratory
protection);
Page
45
of
59
2)
Minimum
Personal
Protective
Equipment
(
a
dust/
mist
respirator
with
a
protection
factor
of
5);

3)
Maximum
Personal
Protective
Equipment
(
an
air
purifying
respirator
with
a
protection
factor
of
10);

4)
Engineering
Controls
(
use
of
an
appropriate
engineering
control
such
as
a
water
soluble
bag).

Current
labels
require
single
layer
clothing,
chemical­
resistant
gloves,
and
no
respirator.

Data
and
Assumptions:
A
series
of
assumptions
and
exposure
factors
served
as
the
basis
for
completing
the
occupational
handler
risk
assessments.
The
inputs
are
consistent
with
current
Agency
policy
for
completing
occupational
exposure
assessments
(
e.
g.,
Pesticide
Handlers
Exposure
Database
­
PHED,
Surrogate
Exposure
Guide
and
Exposac
Policy
9:
Standard
Values
For
Daily
Acres
Treated
In
Agriculture).
[
Note:
PHED
is
a
database
that
contains
monitored
field
data
used
for
assessments.]
No
chemical­
specific
exposure
monitoring
data
were
available
for
thidiazuron
so
PHED
served
as
the
basis
for
all
assessments.

$
Average
body
weight
of
an
adult
handler
considered
in
this
assessment
is
60
kg
as
the
hazard
concern
was
a
developmental
effect
identified
in
a
rabbit
developmental
toxicity
study
(
i.
e.,
increased
abortions).

$
The
generic
protection
factor
values
used
for
respiratory
protection
(
i.
e.,
PF
5
or
PF
10)
are
based
on
the
NIOSH
Respirator
Decision
Logic.
The
data
used
to
represent
engineering
controls
(
e.
g.,
water
soluble
bags
or
closed
cockpits
for
pilots)
were
from
monitoring
studies
­
no
generic
factor
was
required
to
complete
these
calculations.

$
Flagging
during
aerial
applications
has
been
addressed
even
though
it
may
be
limited
in
nature
(
10
to
15%
of
aerial
application
operations).
Engineering
controls
(
e.
g.,
Global
Positioning
Satellite
technology)
are
now
predominantly
used
by
pilots
as
indicated
by
the
1998
National
Agricultural
Aviation
Association
(
NAAA)
survey
of
their
membership.

$
The
maximum
application
rate
allowed
by
labels
(
0.2
lb
ai/
acre)
served
as
the
basis
for
this
risk
assessment.
Additional
information,
such
as
lower
maximum
rates
for
differing
agricultural
situations
were
also
considered
to
provide
for
a
more
informed
risk
management
decision
(
i.
e.,
0.05
and
0.10
lb
ai/
acre).

$
The
average
occupational
workday
is
assumed
to
be
8
hours.
The
daily
areas
to
be
treated
were
defined
for
each
handler
scenario
by
determining
the
amount
that
can
be
reasonably
treated
in
a
single
day
(
e.
g.
acres).
The
factors
used
for
the
thidiazuron
assessment
are
the
same
as
those
detailed
in
the
HED
Science
Advisory
Committee
on
Exposure
Policy
9:
Standard
Values
for
Daily
Acres
Treated
in
Agriculture.
Bayer
Crop
Sciences
also
provided
information
pertaining
to
the
number
of
acres
treated
per
day
by
commercial
applicators
and
growers
which
has
been
incorporated
into
this
assessment
(
i.
e.,
values
provided
in
briefing
materials
from
6/
12/
03
SMART
meeting).
The
daily
acres
treated,
excerpted
from
policy
9
include:

$
Aerial
applications:
1200
acres
for
large
cotton
fields,
350
acres
for
other
fields;
and
Page
46
of
59
$
Groundboom:
200
acres
for
large
field,
80
acres
for
other
fields.

The
values
provided
by
Bayer
Crop
Sciences,
used
in
conjunction
with
the
Agency
values,
include:

$
Aerial
applications:
1000
to
1200
acres
per
day
­
1200
was
used
which
reflects
current
Agency
policy;
and
$
Groundboom:
commercial
applicators
from
500
to
600
acres
per
day
­
600
used
for
assessment,
and
grower
applicators
from
300
to
400
acres
per
day
­
400
used
for
the
assessment.

Noncancer
risks
were
calculated
using
the
Margin
of
Exposure
(
MOE)
approach,
which
is
a
ratio
of
the
body
burden
to
the
toxicological
concern.
MOEs
were
not
calculated
for
dermal
exposures
since
no
hazard
concern
was
identified
for
that
route
of
exposure.
Inhalation
MOEs
for
short­/
intermediate­
term
exposures
were
calculated
using
a
NOAEL
of
25
mg/
kg/
day
from
the
oral
developmental
neurotoxicity
study
in
rabbits.
Body
burden
values
were
determined
by
first
calculating
daily
exposures
using
application
parameters
(
i.
e.,
rate
and
area
treated)
along
with
unit
exposure
levels
from
PHED.
Exposures
were
then
normalized
by
body
weight
and
adjusted
for
absorption
factors
(
100
percent
for
inhalation)
as
appropriate
to
calculate
average
daily
dose
levels
(
i.
e.,
body
burdens)
as
illustrated
in
equation
below.

Daily
Exposure
(
mg
ai/
day)
=

Unit
Exposure
(
mg
ai/
lb
ai)
x
Application
Rate
(
lb
ai/
A)
x
Daily
Acres
Treated
(
A/
day)

Where:

Daily
Exposure
=
Amount
that
is
inhaled,
also
referred
to
as
potential
dose
(
mg
ai/
day);
Unit
Exposure
=
Normalized
exposure
value
derived
from
August
1998
PHED
Surrogate
Exposure
Table
and
various
referenced
exposure
studies
noted
above
(
mg
ai/
lb
ai);
Application
Rate
=
Normalized
application
rate
based
on
a
logical
unit
treatment
such
as
acres
(
lb
ai/
A);
and
Daily
Acres
Treated
=
Normalized
application
area
based
on
a
logical
unit
treatment
such
as
acres
(
A/
day).

No
specific
inhalation
absorption
factor
is
available
for
thidiazuron.
Therefore,
a
factor
of
100
percent
was
used
for
route­
to­
route
calculations
as
is
done
with
all
pesticides.
The
Daily
Exposure
values
calculated
above
were
also
adjusted
to
a
body
weight
basis
to
calculate
Average
Daily
Dose
values
(
mg
ai/
kg/
day).
MOEs
were
then
calculated
using
the
following
formula.

MOE
=
NOAEL
(
mg
ai/
kg/
day)
Average
Daily
Dose
(
mg
ai/
kg/
day)

Where:

MOE
=
Margin
of
exposure,
value
used
to
represent
risk
or
how
close
a
chemical
exposure
is
to
being
a
concern
(
unitless);
Average
Daily
Dose
=
The
amount
as
absorbed
dose
received
from
exposure
to
a
pesticide
in
a
given
scenario
(
mg
pesticide
active
ingredient/
kg
body
weight/
day);
and
NOAEL
=
No
observed
adverse
effect
level
or
dose
level
in
a
toxicity
study
where
no
observed
adverse
effects
occurred
in
the
study
(
mg
pesticide
active
ingredient/
kg
body
weight/
day).
Page
47
of
59
Short­/
Intermediate­
term
Risks:
Current
thidiazuron
labels
typically
require
that
handlers
wear
long
pants,
long­
sleeved
shirts,
and
gloves
but
do
not
require
respirators.
In
all
scenarios,
MOEs
meet
or
exceed
the
required
uncertainty
factor
of
100
without
any
respiratory
protection
which
represents
the
current
label
requirements.
In
many
cases
even
for
high
acreage
situations,
MOEs
were
well
above
the
uncertainty
factor
of
100
(
e.
g.,
10,000
or
greater).
To
allow
for
a
comprehensive
characterization
of
the
risks
and
to
evaluate
the
manner
in
which
thidiazuron
is
currently
marketed
and
used,
inhalation
risks
were,
however,
calculated
assuming
one
of
four
possible
levels
of
personal
protection
ranging
from
a
baseline
of
no
respiratory
protection
to
engineering
controls,
such
as
water
soluble
bags.
The
wettable
powder
formulations
of
thidiazuron
marketed
by
Bayer
Crop
Sciences
are
sold
exclusively
in
water
soluble
bags
and
account
for
the
vast
majority
of
wettable
powders
sold
on
an
annual
basis.
The
vast
majority
of
pilots
would
also
be
flying
in
closed
cockpit
aircraft.
Table
9.1
summarizes
the
results
for
short­
term
and
intermediate­
term
occupational
handlers,
complete
results
can
be
found
in
Appendix
3.0.
[
Note:
Scenarios
are
still
of
concern
if
the
MOE
<
100.]

Table
9.1.
Summary
of
Short­/
Intermediate­
Term
Occupational
Handler
Noncancer
Risks
For
Thidiazuron
Scenario
Rate
(
lb
ai/
acre)

[
unless
noted]
Area
Treated
(
acres/
day)

[
unless
noted]
Risk
Summary
MOEs
Min.
Req.
PPE
Mixer/
Loaders
1a
Liquid:
Aerial
(
Commercial
Applicators)
0.05­
0.20
350
­
1200
5200
­
71000
NR
1b
Liquid:
Ground
(
Commercial
Applicators)
0.05­
0.20
200
­
600
10000
­
130000
NR
1c
Liquid:
Ground
(
GrowerApplicators)
0.05­
0.20
80
­
400
16000
­
310000
NR
2a
Wettable
Powder:
Aerial
(
Commercial
Applicators)
0.05­
0.20
350
­
1200
150
­
2000
NR
2b
Wettable
Powder:
Ground
(
Commercial
Applicators)
0.05­
0.20
200
­
600
300
­
3500
NR
2c
Wettable
Powder:
Ground
(
GrowerApplicators)
0.05­
0.20
80
­
400
400
­
8700
NR
Applicators
3
Aerial
Liquid
Application
0.05­
0.20
350
­
1200
92000
­
1300000
NR
(
closed
cockpit
aircraft)

4a
Groundboom:
Commercial
Applicator
0.05­
0.20
200
­
600
17000
­
200000
NR
4
b
Groundboom:
Grower
Applicator
0.05­
0.20
80
­
400
25000
­
510000
NR
Flaggers
5
Flagger:
Aerail
Liquid
Spray
Applications
0.05­
0.20
350
­
1200
18000
­
240000
NR
Table
9.1.
Summary
of
Short­/
Intermediate­
Term
Occupational
Handler
Noncancer
Risks
For
Thidiazuron
Scenario
Rate
(
lb
ai/
acre)

[
unless
noted]
Area
Treated
(
acres/
day)

[
unless
noted]
Risk
Summary
MOEs
Min.
Req.
PPE
Page
48
of
59
NR
=
No
respiratory
protection
PF5
=
Protection
factor
5
respirator
PF10
=
Protection
factor
10
respirator
Current
label
does
not
require
a
respirator
Min.
Req.
PPE
=
level
of
PPE
where
MOEs
>
100,
where
current
label
is
exceeded
or
no
adequate
PPE
is
found,
results
are
bold.

9.2
Short/
Intermediate/
Long­
Term
Postapplication
Risk
The
Agency
recognizes
that
most
activities
associated
with
the
cultivation
and
harvest
of
cotton
are
predominantly
accomplished
in
an
intensively
mechanized
fashion
that
essentially
eliminates
exposures
for
most
of
those
involved.
However,
workers
can
be
exposed
to
thidiazuron
residues
when
entering
previously
treated
areas
to
perform
certain
activities
such
as
scouting
or
those
associated
with
harvesting
(
i.
e.,
rakers,
trampers,
module
builders).
Current
label
requirements
specify
24
hour
restricted
entry
intervals
while
pre­
harvest
intervals
are
currently
5
days.
The
Agency
believes
that
dermal
exposures
may
occur
for
postapplication
workers,
but
they
are
not
of
concern
because
available
data
for
these
activities
show
exposures
to
be
low
and
the
Agency
has
not
identified
any
hazard
concerns
associated
with
dermal
exposures.
The
Agency
also
does
not
routinely
complete
postapplication
worker
inhalation
risk
assessments
because
available
exposure
data
show
they
do
not
occur
at
appreciable
levels.

9.3
Occupational
Risk
Characterization
In
all
cases,
the
Pesticide
Handlers
Exposure
Database
(
PHED)
was
used
to
develop
the
unit
exposure
values.
The
quality
of
the
data
included
in
PHED
vary
widely
from
scenarios
that
meet
guideline
requirements
for
studies
to
others
where
a
limited
number
of
poor
quality
datapoints
are
available.
The
results
for
each
scenario
should
be
reviewed
in
the
context
of
the
quality
of
these
data.

The
application
rates
that
were
selected
for
use
in
the
risk
assessment
were
defined
based
on
labels
and
information
provided
by
the
Bayer
Crop
Sciences
at
the
June
12,
2003
SMART
Meeting
for
thidiazuron.
The
other
key
input
for
completing
handler
risk
assessments
used
for
defining
how
much
chemical
can
be
used
in
a
day
is
how
much
can
be
treated
in
a
day
which
is
generally
expressed
as
the
number
of
acres
treated
per
day.
The
values
that
were
used
for
this
parameter
represent
the
latest
Agency
thinking
on
this
issue.
In
fact,
the
Science
Advisory
Council
For
Exposure
recently
updated
the
policy
for
these
inputs
(
July
2000
Exposure
SAC
Policy
9:
Standard
Values
for
Daily
Acres
Treated
in
Agriculture).
These
most
recent
values
have
been
used
for
the
calculations.
Additionally,
Bayer
Crop
Sciences
provided
estimates
of
the
acres
treated
per
day
for
commercial
applicators
and
growers
who
make
their
own
applications.
These
estimates
were
also
incorporated
into
the
assessment.
The
PHED
exposure
data,
upon
which
the
risks
are
based,
were
from
studies
where
much
lower
acreage
were
treated
compared
to
those
reported
by
Bayer
Crop
Sciences.
As
such,
it
is
likely
there
is
uncertainty
associated
with
the
coupling
of
these
values
with
high
daily
acreage
treated
estimates.
Analysis
of
this
phenomena
in
PHED
indicates
it
results
in
a
likely
overestimation
of
risks.
Page
49
of
59
In
addition
to
the
key
sources
of
information
considered
above,
there
are
many
underlying
factors
that
may
impact
the
overall
results
of
a
risk
assessment.
For
example,
the
protection
factors
used
for
adding
additional
levels
of
respiratory
protection
may
impact
the
overall
risk
picture.
The
factors
used
in
this
assessment
by
the
Agency
for
respiratory
protection
are
the
ones
that
have
been
used
for
several
years
and
are
commonly
used
for
occupational
health
purposes.

In
summary,
the
Agency
believes
that
the
risk
values
presented
in
this
occupational
assessment
represent
the
highest
quality
results
that
could
be
produced
given
the
exposure,
use,
and
toxicology
data
that
are
available.
Certainly
risk
managers
and
other
interested
parties
should
consider
the
quality
of
individual
inputs
when
interpreting
the
results
and
make
decisions
accordingly.
It
is
difficult
to
ascertain
where
on
a
distribution
the
values
which
have
been
calculated
fall
because
the
distributional
data
for
exposure,
application
rates,
acres
treated
and
many
other
parameters
are
unrefined.
The
Agency
does
believe,
however,
that
the
risks
represent
conservative
estimates
of
exposure
because
maximum
application
rates
are
coupled
with
large
acreage
estimates
to
define
risk
estimates
that
likely
fall
in
the
upper
percentiles
of
the
actual
exposure
distributions.
Additionally,
risk
estimates
are
thought
to
be
conservative
even
when
measures
of
central
tendency
are
combined
because
values
that
would
be
considered
to
be
in
the
lower
percentile
aspect
of
any
input
parameter
have
not
been
used
in
the
calculations.

10.0
Data
Needs
and
Label
Requirements
10.1
Toxicology
There
are
no
toxicological
data
gaps.

10.2
Residue
Chemistry
Guideline
860.1340
Residue
Analytical
Method­
Livestock
Guideline
860.1380
Storage
Stability
Data­
Plant
and
Livestock
Guideline
860.1480
Meat,
Milk,
Poultry,
and
Eggs­
Additional
data
for
the
ruminant
feeding
study
are
required.

10.3
Occupational
and
Residential
Exposure
There
are
no
occupational
and
residential
exposure
data
gaps.

References:

Felecia
A.
Fort.
September
29,
1995.
HED
Metabolism
Committee
Decision
following
the
9/
18/
95
meeting.

DP
Barcode
D295368.
Shyam
B.
Mathur.
March
1,
2004.
Product
Chemistry
Review
of
Thidiazuron
Technical.

Felecia
A.
Fort.
September
8,
1995.
Thidiazuron
Metabolism.
Page
50
of
59
MRID
No.
44415501.
DP
Barcode
D241202.
Toiya
Jimerson.
October
26,
2004.
Thidiazuron:
Registrant's
Response
to
Residue
Chemistry
Data
Requirements.

MRID
No.
46298401.
DP
Barcode
D294543.
Toiya
Jimerson.
November
8,
2004.
Magnitude
of
Residue
in
Rotational
Crops
Following
Cotton
Treated
with
DROPP
®
SC.

MRID
No.
42529001.
DP
Barcode
D294560.
Byong­
Han
Chin.
Rat
Metabolism.

MRID
No.
44558701.
DP
Barcode
D246804.
Sherrie
L.
Mason.
January
21,
1999.
Independent
Laboratory
Validation
of
Analytical
Method
AW/
02/
96
for
the
Analysis
of
Thidiazuron
and
Photothidiazuron
in/
on
Cottonseed
Commodities.

MRID
43781901.
DP
Barcode
D220968.
Stephen
Funk.
February
15,
1996.
Thidiazuron:
Response
to
the
Phase
4
Review
Magnitude
of
the
Residue
in
Ruminants.

DP
Barcode
D244574.
Alex
Clem.
September
24,
2004.
Drinking
Water
Assessment
DP
Barcode
D316043.
Toiya
Jimerson.
May
2,
2005.
Thidiazuron:
Chronic
Dietary
Exposure
Assessment
for
the
Reregistration
Eligibility
Decision­
Revised.

DP
Barcode
D311489.
Jerry
Blondell.
December
21,
2004.
Review
of
Thidiazuron
Incident
Reports.
Page
51
of
59
Appendices
1.0
TOLERANCE
REASSESSMENT
RECOMMENDATIONS
The
residue
data
set
for
reassessing
the
tolerances
for
thidiazuron
is
incomplete.
Until
additional
data
for
Guideline
860.1480
Meat,
Milk,
Poultry
and
Eggs
study
has
been
submitted,
tolerances
for
ruminant
livestock
commodities
cannot
be
reassessed.
A
summary
of
thidiazuron
tolerances
are
presented
in
Table
1.

Table
1.
Summary
of
Thidiazuron
Tolerance
Reassessments
Commodity
Current
Tolerance
(
ppm)
Tolerance
Reassessment1
(
ppm)

Cattle:
fat
0.2
TBD
Cattle:
meat
and
meat
byproducts
0.2
TBD
Cotton,
undelinted
seed
0.4
0.3
Cotton,
gin
byproduct
Not
established
24
Cotton,
hulls
0.8
Revoked
Egg
0.1
Revoked
Goat:
fat
0.2
TBD
Goat:
meat
and
meat
byproduct
0.2
TBD
Hog:
fat
0.2
TBD
Hog:
meat
and
meat
byproduct
0.2
TBD
Horse:
fat
0.2
TBD
Horse:
meat
and
meat
byproduct
0.2
TBD
Milk
0.05
TBD
Poultry:
fat,
meat,
and
meat
byproduct
0.2
Revoked
Sheep:
fat
0.2
TBD
Sheep:
meat
and
meat
byproduct
0.2
TBD
1
TBD
=
To
Be
Determined
Page
52
of
59
2.0
TOXICOLOGY
DATA
REQUIREMENTS
The
requirements
(
40
CFR
158.340)
for
food
use
for
thidiazuron
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.

Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1200
Acute
Dermal
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1300
Acute
Inhalation
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2400
Primary
Eye
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2500
Primary
Dermal
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2600
Dermal
Sensitization
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100
Oral
Subchronic
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3150
Oral
Subchronic
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3200
21­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3250
90­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3465
90­
Day
Inhalation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
no
no
yes
yes
(
a)
yes
­
­

870.3700a
Developmental
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3700b
Developmental
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
870.3800
Reproduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
870.4100a
Chronic
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4100b
Chronic
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200a
Oncogenicity
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200b
Oncogenicity
(
mouse)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4300
Chronic/
Oncogenicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.5100
Mutagenicity
 
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
870.5300
Mutagenicity
 
Gene
Mutation
­
mammalian
.
.
.
.
.
.
870.5xxx
Mutagenicity
 
Structural
Chromosomal
Aberrations
870.5xxx
Mutagenicity
 
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
870.6100a
Acute
Delayed
Neurotox.
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6100b
90­
Day
Neurotoxicity
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
.
.
870.6300
Develop.
Neuro
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
no
no
­
­
­
­
­

870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Subchronic
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Six­
month
Oral
(
dog)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
­
­
­

(
a)
No
subchronic
oral
study
is
required
at
this
time
because
the
toxicological
data
requirements
for
90­
day
feeding
study
in
non­
rodents
(
dog)
are
satisfied
by
the
1­
year
feeding
study
in
dogs.
Page
53
of
59
3.0
NON­
CRITICAL
TOXICOLOGY
STUDIES
3.1
Non­
Critical
Studies
Using
Active
Ingredient
Metabolism
­
Rat
In
a
metabolism
study
(
MRID
42529001),
groups
of
male
and
female
Sprague­
Dawley
CD
rats
were
dosed
with
14C­
thidiazuron
[(
14C­
aniline)
thidiazuron
or
(
14C­
thiadizaole)
thidiazuron
(
purity:
>
97%
a.
i.;
batch
No:
1695­
3
and
1695­
4)]
at
a
single
oral
gavage
dose
(
10
or
1000
mg/
kg)
or
14­
day
repeated
oral
doses
of
thidiazuron
at
10
mg/
kg
followed
by
a
single
oral
dose
of
14C­
thidiazuron
at
10
mg/
kg.
An
intravenous
dose
group
was
not
included
in
this
study.

The
results
of
the
pilot
study
showed
that
less
than
0.2%
of
administered
radioactivity
was
eliminated
as
14CO
2
from
administration
of
either
(
14C­
aniline)
thidiazuron
or
(
14C­
thiadizaole)
thidiazuron.
In
addition,
the
study
showed
no
significant
differences
in
the
percentages
eliminated
through
urine
or
feces
from
administration
of
the
two
radiolabeled
forms.

Absorption
of
thidiazuron
was
rapid
but
incomplete
at
both
doses,
and
appeared
decreased
at
the
high
dose
relative
to
the
low
dose.
Elimination
of
thidiazuron
was
relatively
rapid
at
the
single
low
oral
dose
level.
The
major
route
of
elimination
was
shown
to
be
via
urine.
The
single
low,
single
high,
and
multiple
low
oral
dose
studies
indicate
that
the
total
radioactivity
recovered
within
5
days
after
dosing
in
the
urine
and
feces
were
91­
104%
of
administered
dose.
At
the
low
dose,
the
radioactivity
recovered
in
the
urine
and
feces
was
60­
66%
and
29­
31%
of
the
dose
over
a
5­
day
period,
respectively.
At
the
repeated
low
oral
dose,
the
radioactivity
recovered
in
the
urine
and
feces
was
73­
75%
and
26­
28%
of
the
dose
over
a
5­
day
period,
respectively.
At
the
high
dose,
the
radioactivity
recovered
in
the
urine
and
feces
was
41­
47%
and
56­
60%
of
the
dose
over
a
5­
day
period,
respectively.
Administration
of
a
single
high
dose
resulted
in
a
decreased
percentage
of
thidiazuron
derived
radioactivity
eliminated
in
urine
(
approximately
20%),
with
concomitant
rise
in
fecal
elimination.
This
alteration
is
likely
due
to
reduced
absorption
of
test
material
at
the
high
dose.

Terminal
tissue
distribution
data
showed
that
highest
concentrations
of
thidiazuron
derived
radioactivity
at
sacrifice
were
found
in
the
liver,
kidneys,
thyroid,
whole
blood
and
adrenals
at
both
low
and
high
doses.
Repeated
oral
dosing
did
not
significantly
affect
distribution
of
thidiazuron
derived
radioactivity.

Identification
of
urinary
and
fecal
metabolites
by
TLC
and
HPLC
indicated
the
presence
of
one
oxidative
metabolite
in
urine
(
4­
hydroxy
thidiazuron,
metabolite
J)
and
the
presence
of
sulfate
and
glucuronide
conjugates
of
4­
hydroxy
thidiazuron
(
metabolites
A/
B,
D,
and
F).
However,
insufficient
evidence
was
presented
to
justify
the
presence
of
more
than
one
sulfate
and
one
glucuronide
conjugate
of
4­
hydroxy
thidiazuron
in
urine.
This
deficiency
does
not
render
the
study
inadequate,
as
the
other
possible
oxidative
metabolite(
s)
as
candidates
for
conjugation
represent
a
minor
percentage
of
metabolized
thidiazuron.

In
urine,
the
significant
metabolites
found
at
low
dose
were
metabolite
F
(
males,
36­
38%
of
dose;
females,
14­
21%),
metabolite
J
(
males,
11%;
females,
18­
19%),
metabolite
A/
B
(
males,
4%;
females,
3­
6%),
and
metabolite
D
(
males,
5­
8%;
females,
7­
9%).
Significant
urinary
metabolites
in
rats
from
the
repeated
low
dose
group
were
metabolites
F
(
24­
41%),
metabolite
J
(
12­
25%),
metabolite
A/
B
(
3­
4%),
and
metabolite
D
(
7­
9%).
Percentages
of
each
of
metabolites
F
and
J
rose
slightly
in
both
sexes
of
rats
from
repeated
low
dose
administration,
indicating
a
possible
mild
induction
of
metabolism.
At
high
dose,
the
percentage
of
Page
54
of
59
metabolite
F
in
males
and
females
(
2%
of
dose)
was
smaller
than
that
of
metabolite
J
(
7­
11%).

In
feces,
the
major
metabolites
identified
were
4­
hydroxy
thidiazuron
(
14­
16%)
at
the
low
and
repeated
low
dose,
and
unmetabolized
thidiazuron
(
37­
44%)
at
the
high
dose.

This
study
is
classified
as
Acceptable/
Guideline
and
satisfied
the
guideline
data
requirement
for
a
metabolism
study
(
85­
1)
in
rats.

90­
Day
Oral
Toxicity
Study
in
Mice
EXECUTIVE
SUMMARY
­
In
a
subchronic
oral
toxicity
study
(
MRID
46121505),
Thidiazuron
(
99.5%
a.
i.,
Batch/
Lot
#:
107623­
03)
was
administered
to
10
C57BL/
6JICO
mice/
sex/
dose
in
the
diet
at
doses
of
0,
500,
1000,
2000,
or
4000
ppm
(
equivalent
to
0/
0,
85.2/
99.8,
170.9/
202.6,
or
351.4/
383.9
mg/
kg/
day
[
M/
F])
for
up
to
90
days.

Urinalysis,
hematology,
neurological
evaluations,
and
ophthalmoscopic
examinations
were
not
performed.
There
were
no
treatment­
related
macroscopic
findings.

All
mice
in
the
4000
ppm
group
died
or
were
sacrificed
moribund
on
Days
6­
9.
In
this
group,
animals
exhibited
the
following
clinical
signs
of
toxicity
prior
to
their
death
or
sacrifice:
(
i)
reduced
motor
activity,
prostration,
piloerection,
dyspnea,
cold
to
touch,
thin
appearance,
and
hunched
posture
in
both
sexes;
(
ii)
staggering
step
in
males;
and
(
iii)
no
feces
in
females.
Body
weights
were
decreased
by
28­
29%
(
p<=
0.001)
in
the
two
males
and
three
females
still
alive
on
Day
8.
Food
consumption
was
decreased
by
53­
62%
(
p<=
0.001)
in
both
sexes
for
Days
1­
8.

At
2000
ppm,
hunched
posture
was
observed
in
two
males
and
one
female
on
Day
15,
and
reduced
motor
activity
was
noted
in
one
female
on
Days
28­
29.
Body
weights
were
decreased
by
4­
7%
(
p<=
0.05)
throughout
treatment
in
the
males,
except
Days
57
and
90,
and
throughout
treatment
by
6­
17%
in
the
females.
Overall
(
Days
1­
90)
body
weight
gains
at
this
dose
were
decreased
in
the
males
(
decr.
19%;
not
significant)
and
females
(
decr.
40%;
p<=
0.001).
Weekly
food
consumption
was
decreased
throughout
treatment
in
the
females
(
decr.
7­
23%),
resulting
in
decreased
average
food
consumption
for
the
overall
(
Days
1­
90)
study
(
decr.
12%;
p<=
0.01).
Additionally
in
the
2000
ppm
males,
alkaline
phosphatase
was
increased
by
14%
(
p<=
0.05),
and
albumin
was
decreased
by
9%
(
p<=
0.05).
At
2000
ppm
in
both
sexes,
terminal
body
weights
were
decreased
by
5­
9%
(
p<=
0.05),
and
relative
(
to
body)
liver
weights
were
increased
by
10­
16%
(
p<=
0.01).
Slight
centrilobular
hepatocellular
hypertrophy
was
observed
in
the
2000
ppm
females
(
2/
10
treated
vs
0/
10
controls).

At
>=
1000
ppm
in
the
males,
cholesterol
was
dose­
dependently
decreased
by
16­
34%
(
p<=
0.05)
and
absolute,
relative
(
to
body),
and
relative
(
to
brain)
kidney
weights
were
decreased
by
9­
15%
(
p<=
0.01).
The
organ
weight
changes
in
the
kidney
were
considered
equivocal
because
there
were
no
macroscopic
or
microscopic
findings
in
the
kidney.
Additionally,
slight
centrilobular
hepatocellular
hypertrophy
was
observed
in
the
>=
1000
ppm
males
(
1­
9/
10
treated
vs
0/
10
controls).
Increased
incidences
of
slight
diffuse
acinar
hypertrophy
were
observed
in
the
submaxillary
salivary
glands
of
the
>=
1000
ppm
females
(
4­
8/
10
treated
vs
1/
10
controls).

At
500
ppm,
no
treatment­
related
effects
were
found.
Page
55
of
59
The
LOAEL
is
1000
ppm
(
equivalent
to
170.9/
202.6
mg/
kg/
day
in
M/
F)
based
on
decreased
cholesterol
in
the
males
and
on
increased
incidences
of
centrilobular
hepatocellular
hypertrophy
in
the
males
and
diffuse
acinar
hypertrophy
in
the
salivary
glands
in
the
females.
The
NOAEL
is
500
ppm
(
equivalent
to
85.2/
99.8
mg/
kg/
day
in
M/
F).

This
study
is
classified
acceptable/
guideline
and
satisfies
the
guideline
requirement
(
OPPTS
870.3100;
OECD
408)
for
a
90­
day
oral
toxicity
study
in
the
mouse.

Subchronic
Oral
Toxicity
Study
in
Rats
EXECUTIVE
SUMMARY:
In
a
subchronic
oral
toxicity
study
(
MRID
46121506),
thidiazuron
(
99.5%
a.
i.,
Batch
#
107623­
03)
was
administered
to
10
Wistar
(
RJ:
WI[
IOPS
HAN])
rats/
sex/
dose
in
the
diet
at
dose
levels
of
0,
200,
600,
1800,
5400,
or
16,200
ppm
(
equivalent
to
0/
0,
11.2/
14.0,
34.5/
42.1,
102/
123,
294/
325,
and
[
highest
dose
not
calculated]
mg/
kg/
day)
for
90
days.

No
treatment­
related
effects
were
observed
at
200
or
600
ppm,
or
on
ophthalmology
or
hematology
at
any
dose.

At
>=
1800
ppm
in
the
males,
decreased
body
weights,
overall
(
Days
1­
90)
body
weight
gains,
and
food
consumption
were
observed.
Increased
serum
alkaline
phosphatase
was
noted.
Decreases
were
noted
in
absolute
epididymides
weight
and
absolute
and
relative
(
to
body)
prostate
gland
weight,
and
small
prostate
gland
and
small
seminal
vesicles
were
observed.
The
following
alterations
in
microscopic
pathology
were
noted:
(
i)
slight
to
mild
diminished
secretion
of
the
prostate
gland;
(
ii)
slight
to
mild
diffuse
hypertrophy
of
the
zona
glomerulosa
of
the
adrenal
gland;
(
iii)
slight
to
mild
vacuolation/
mineralization
glomerulopathy
of
the
kidney;
(
iv)
slight
to
mild
bilateral
hyperplasia
of
the
pelvic
epithelium
of
the
kidney;
(
v)
slight
to
mild
mineralized
concretions
of
the
renal
pelvis;
(
vi)
slight
focal
mononuclear
cell
inflammation
of
the
kidney;
(
vii)
slight
to
mild
centrilobular
hepatocellular
hypertrophy;
(
viii)
slight
to
mild
hyperplasia
of
germinal
centers
in
the
spleen;
(
ix)
slight
to
marked
diminished
secretion
of
the
seminal
vesicle;
(
x)
slight
to
moderate
diffuse
atrophy
of
the
mammary
gland;
and
(
xi)
slight
to
mild
germinal
centers
in
the
medulla
of
the
thymus.

At
>=
1800
ppm
in
the
females,
the
following
alterations
in
microscopic
pathology
were
noted:
(
i)
slight
to
mild
diffuse
hypertrophy
of
the
zona
glomerulosa
of
the
adrenal
gland;
(
ii)
slight
to
mild
vacuolation/
mineralization
glomerulopathy
of
the
kidney;
(
iii)
slight
centrilobular
hepatocellular
hypertrophy;
(
iv)
slight
to
moderate
adipose
infiltration
of
the
bone
and
marrow
of
the
sternum;
(
v)
slight
to
mild
hypertrophy
of
the
interstitial
gland
of
the
ovary;
and
(
vi)
slight
to
moderate
hyperplasia
of
germinal
centers
in
the
spleen.

At
>=
1800
ppm,
increased
urea
was
observed
in
both
sexes.

At
5400
ppm
in
the
males,
the
following
increases
in
relative
organ
weights
were
observed:
(
i)
adrenal
gland;
(
ii)
kidney;
(
iii)
liver;
and
(
iv)
spleen.
Relative
testes
weight
was
decreased.
Additionally,
the
following
alterations
in
microscopic
pathology
were
observed:
(
i)
slight
focal
mononuclear
cell
inflammation
of
the
epididymis;
(
ii)
slight
focal
mineralization
of
the
inner
medulla
of
the
kidney;
(
iii)
slight
to
mild
adipose
infiltration
of
the
bone
and
marrow
of
the
sternum;
(
iv)
slight
focal
foamy
alveolar
macrophages;
(
v)
slight
focal
hemorrhage
of
the
lung;
(
vi)
slight
to
mild
germinal
centers
of
the
mesenteric
Page
56
of
59
and
inguinal
lymph
nodes;
and
(
vii)
slight
unilateral
atrophy
of
the
seminiferous
epithelium
of
the
testes.

At
5400
ppm
in
the
females,
decreased
body
weights,
overall
(
Days
1­
90)
body
weight
gains,
and
food
consumption
were
observed.
Increased
serum
alkaline
phosphatase
and
phosphorus
were
noted.
Decreases
were
noted
in
absolute
and
relative
adrenal
gland
and
uterus
weights.
Increases
in
relative
kidney
and
liver
weights
were
observed,
and
decreased
absolute
mesenteric
lymph
node
weight
was
noted.
Small
uterus
was
observed.
The
following
alterations
in
microscopic
pathology
were
observed:
(
i)
slight
to
mild
atrophy
of
the
zona
reticularis
of
the
adrenal
gland;
(
ii)
slight
brown
pigment
in
the
zona
reticularis
of
the
adrenal
gland;
(
iii)
no
cyclical
activity
of
the
uterus;
(
iv)
slight
to
marked
diffuse
atrophy
of
the
uterus;
(
v)
slight
to
marked
diffuse
atrophy
of
the
vagina;
(
vi)
reduced
numbers
of
recent
corpora
lutea
in
the
ovary;
(
vii)
slight
to
mild
diffuse
atrophy
of
the
mammary
gland;
(
viii)
slight
germinal
centers
of
the
mesenteric
and
inguinal
lymph
nodes;
and
(
ix)
slight
to
mild
atrophy
of
the
trabecular
bone.

At
5400
ppm
in
both
sexes,
rats
exhibited
piloerection,
appeared
thin,
and
excreted
few
feces.
Increased
cholesterol
and
potassium
were
observed,
and
urine
volume
was
increased.
At
16,200
ppm,
males
were
observed
to
have
hunched
posture,
and
all
animals
demonstrated
deficits
in
righting,
grasping,
corneal,
pupillary,
head
shaking,
and
auditory
startle
reflexes.
All
animals
in
this
dose
group
were
either
found
dead
or
were
sacrificed
moribund
by
Day
10.

The
LOAEL
is
1800
ppm
(
equivalent
to
102/
123
mg/
kg/
day
[
M/
F]),
based
on
decreased
body
weights,
overall
(
Days
1­
90)
body
weight
gains,
and
food
consumption,
increased
serum
alkaline
phosphatase,
decreased
absolute
epididymides
and
absolute
and
relative
(
to
body)
prostate
gland
weight,
small
prostate
and
small
seminal
vesicles,
and
microscopic
findings
in
the
prostate
gland,
seminal
vesicle,
mammary
gland,
and
thymus
of
the
males,
microscopic
findings
in
the
bone
and
marrow
of
the
sternum
and
ovary
of
the
females,
and
increased
urea
and
microscopic
findings
in
the
adrenal
gland,
kidney,
liver,
and
spleen
of
both
sexes.
The
NOAEL
is
600
ppm
(
equivalent
to
34.5/
42.1
mg/
kg/
day
[
M/
F]).

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

Bacterial
Reverse
Gene
Mutation
Assay
EXECUTIVE
SUMMARY
­
In
two
independent
reverse
gene
mutation
assays
in
bacteria
(
MRID
46121508),
Salmonella
typhimurium
strains
TA98,
TA100,
TA1535,
and
TA1537
and
Escherichia
coli
strain
WP2
uvrA/
pKM101
(
CM891)
were
exposed
to
Thidiazuron
(
98.7%
purity,
Batch/
Lot
#:
CH
107623­
02)
in
dimethylsulfoxide
(
DMSO)
at
concentrations
of
0,
5,
15,
50,
150,
500,
1500,
or
5000
µ
g/
plate
(
±
S9,
Trial
1),
and
0,
1.5,
5,
15,
50,
150,
500,
or
1500
µ
g/
plate
(
±
S9,
Trial
2).
The
standard
plate
incorporation
method
was
performed
in
Trial
1
and
a
pre­
incubation
step
was
added
in
Trial
2.
Standard
strain­
specific
mutagens
served
as
positive
controls.

Thidiazuron
was
tested
at
up
to
the
limit
dose
(
5000

g/
plate)
in
Trial
1,
and
up
to
cytotoxic
concentrations
(
1500
µ
g/
plate)
in
Trial
2.
Cytotoxicity
(
indicated
by
an
incomplete
background
lawn)
was
observed
in
all
strains
at
>=
1500
µ
g/
plate
in
Trial
1
(
plate
incorporation
test),
and
in
all
strains
at
>=
500
µ
g/
plate
in
Trial
2
(
pre­
incubation
test).
No
treatment­
related
increases
in
the
number
of
revertants/
plate
were
observed
in
any
bacterial
strain
at
any
dose
level
of
Thidiazuron
in
the
presence
or
absence
of
S9­
Page
57
of
59
activation,
compared
to
solvent
controls.
The
positive
controls
induced
the
appropriate
responses.
There
was
no
evidence
of
induced
mutant
colonies
over
background
under
the
conditions
of
these
tests.

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

In
Vitro
Chromosomal
Aberration
Assay
in
Human
Peripheral
Blood
Lymphocytes
EXECUTIVE
SUMMARY
­
In
independently
performed
mammalian
cell
cytogenetic
(
chromosome
aberration)
assays
(
MRID
46121510),
lymphocyte
cultures
prepared
from
human
peripheral
blood
were
exposed
to
Thidiazuron
(
98.7%
a.
i.,
Batch/
Lot
#:
CH107623­
02)
in
dimethyl
sulfoxide
for
4
hours
at
concentrations
of
0,
9.4,
18.75,
37.5,
75,
150,
200,
or
250
µ
g/
mL
both
in
the
presence
and
absence
of
S9­
activation,
and
for
20
hours
at
concentrations
of
0,
4.7,
9.4,
18.75,
37.5,
75,
150,
or
200
µ
g/
mL
in
the
absence
of
S9­
activation.
Cells
were
harvested
at
20
hours
after
initiation
of
treatment.

Thidiazuron
was
tested
up
to
cytotoxic
concentrations
(
mitotic
suppression;
53­
60%
at
150
µ
g/
mL
[
±
S9]
at
4
hours
of
exposure
and
51%
at
37.5
µ
g/
mL
[­
S9]
at
20
hours
of
exposure).
No
significant
increases
in
aberration
frequency
were
observed
at
up
to
150
µ
g/
mL
(
±
S9)
after
4
hours
of
exposure
or
at
up
to
37.5
µ
g/
mL
(­
S9)
after
20
hours
of
exposure.
The
positive
controls
induced
the
appropriate
response.
There
was
no
evidence
of
chromosome
aberration
induced
over
background
in
the
presence
or
absence
of
S9­
activation
at
either
time
point.

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

28­
Day
Dermal
Toxicity
in
Rats
EXECUTIVE
SUMMARY
­
In
a
28­
day
dermal
toxicity
study
(
MRID
46261501),
Thidiazuron
(>
99.9%
a.
i.,
Batch
#:
107623­
03)
was
moistened
with
tap
water
and
applied
by
semi­
occlusive
dressing
to
the
shaved
intact
skin
of
10
HsdCpb:
WU
rats/
sex/
dose
at
dose
levels
of
0,
100,
300,
or
1000
mg/
kg
bw/
day
(
limit
dose),
6
hours/
day
for
5
days/
week
(
males
and
females
received
20
and
21
applications,
respectively)
during
a
29­
day
period.

No
compound­
related
effects
were
observed
in
mortality,
clinical
signs,
dermal
effects,
body
weight,
body
weight
gain,
food
or
water
consumption,
hematology,
clinical
chemistry,
ophthalmology,
absolute
or
relative
organ
weights,
gross
or
histologic
pathology.

The
LOAEL
was
not
observed.
The
NOAEL
was
1000
mg/
kg/
day
(
HDT)
(
limit
dose).

This
study
is
classified
as
acceptable/
guideline
and
satisfies
the
Guideline
requirement
(
OPPTS
870.3200;
OECD
410)
for
a
28­
day
dermal
toxicity
study
in
rats.
A
LOAEL
was
not
observed;
however,
the
compound
was
tested
at
the
limit
dose.
Page
58
of
59
Rat
In
Vivo
Dermal
Absorption
EXECUTIVE
SUMMARY:

In
a
dermal
penetration
study
(
MRID
46261502)
Thidiazuron
(
99.9
%
a.
i.,
batch
#
OR
1844
(
SEL/
1098),
[
phenyl­
U­
14C]­
thidiazuron)
was
administered
to
5
male
Sprague
Dawley
CD
rats/
dose
to
a
12
cm2
area
of
the
back
in
a
formulation
and
water
dilution
thereof
at
dose
levels
of
5.0,
0.04
and
0.004
mg/
cm2.
Exposure
durations
and
percent
of
dose
absorbed
are
presented
in
the
table
below.

Dose
Level
Mean
Percentage
of
Dose
Absorbed
1
hour
4
hours
8
hours
24
hours
24
hours*
72
hours*
120
hours*
5.0
mg/
cm2
0.04
mg/
cm2
0.004
mg/
cm2
0.114
0.214
0.455
0.147
0.406
0.534
0.141
0.388
0.721
0.204
0.754
1.179
0.137
0.634
0.635
0.178
0.660
0.910
0.220
1.252
1.170
*
washed
at
8
hours
The
mean
total
recoveries
were
in
the
range
88%
and
99.54%
dose
for
all
groups.
The
amount
in
the
stratum
corneum
was
0.73%,
10.68%
and
8.14%
at
24
hours
for
the
high,
middle
and
low
dose
groups
respectively
after
a
24­
hours
exposure
and
0.41%,
3.24%
and
5.37%
at
120
hours
following
8­
hours
exposure
for
the
high,
middle
and
low
dose
groups
respectively.
However,
the
results
showed
that
the
majority
of
the
radioactive
material
in
the
stratum
corneum
was
lost
by
desquamation
and
upward
renewal
of
the
stratum
corneum
with
time.

This
study
in
the
rat
is
acceptable
and
satisfies
the
guideline
requirement
for
a
dermal
penetration
study
(
870.7600)
in
rats.

3.2
Non­
Critical
Mode
of
Action
or
Metabolite
Studies
Not
found.
Page
59
of
59
4.0
THIDIAZURON
OCCUPATIONAL
HANDLER
RISK
ASSESSMENT