Document ID: EPA-HQ-OPP-2005-0505-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-02-22T05:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
MEMORANDUM
November
7,
2005
SUBJECT:
Tridemorph
HED
Risk
Assessment
for
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
Document
PC
Code
No.
121401;
DP
Barcode
Nos.
D322126
&
D322128
FROM:
Becky
Daiss
Environmental
Health
Scientist
Reregistration
Branch
4
Health
Effects
Division
(
7509C)

THROUGH:
Susan
V.
Hummel
Branch
Senior
Scientist
Reregistration
Branch
4
Health
Effects
Division
(
7509C)

TO:
Rosanna
Louie
Chemical
Review
Manager
Reregistration
Branch
2
Special
Review
and
Registration
Division
(
7508C)

Attached
is
Health
Effects
Division's
(
HED's)
risk
assessment
of
tridemorph
for
purposes
of
issuing
a
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
Document
for
this
active
ingredient.
The
disciplinary
science
chapters
and
other
supporting
documentation
are
incorporated
into
the
risk
assessment
or
included
as
appendices
as
follows:

Hazard
Identification
Assessment;
Santhini
Ramasamy
­
Section
4
Residue
Chemistry
Assessment;
Gary
Otakie
(
D322128,
9/
1/
05)
Dietary
Exposure
Assessment;
Becky
Daiss
­
Section
5
Page
2
of
30
TABLE
OF
CONTENTS
pg.
1.0
EXECUTIVE
SUMMARY
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3
2.0
INGREDIENT
PROFILE
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5
2.1
Summary
of
Registered
and
Proposed
Uses
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5
2.2
Structure,
Nomenclature
and
Physical/
Chemical
Properties
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5
3.0
METABOLISM
ASSESSMENT
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6
4.0
HAZARD
CHARACTERIZATION
AND
DOSE
RESPONSE
ASSESSMENT
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4.1
Hazard
Characterization
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8
4.2
FQPA
Hazard
Considerations
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15
4.2.1
Adequacy
of
the
Toxicity
Data
Base
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15
4.2.2
Evidence
of
Neurotoxicity
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15
4.2.3
Developmental
Toxicity
Studies
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15
4.2.4
Reproductive
Toxicity
Studies
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18
4.2.5
Pre­
and/
or
Postnatal
Toxicity
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19
4.2.6
Recommendation
for
a
Developmental
Neurotoxicity
Study
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19
4.3
Data
Base
Uncertainty
Factor
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19
4.4
Safety
Factor
for
Infants
and
Children
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20
4.5
Hazard
Identification
and
Toxicity
Endpoint
Selection
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20
4.5.1
Acute
Reference
Dose
­
General
Population
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20
4.5.2
Chronic
Reference
Dose
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21
4.5.3
Classification
of
Carcinogenic
Potential
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22
4.5.4
Summary
of
Endpoints
Selected
for
Risk
Assessment
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22
4.6
Endocrine
Disruption
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23
5.0
DIETARY
EXPOSURE
ASSESSMENT
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24
5.1
Dietary
Profile
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24
5.2
Magnitude
of
the
Residue
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24
5.3
Residue
Analytical
Method
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25
5.4
Acute
and
Chronic
Dietary
Exposure
and
Risk
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25
6.0
CUMULATIVE
RISK
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26
7.0
DATA
NEEDS
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27
7.1
Residue
Chemistry
Data
Requirements
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27
7.2
Toxicology
Data
Requirements
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27
APPENDICES
1.0
GUIDELINE
TOXICOLOGY
DATA
SUMMARY
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28
2.0
REFERENCES
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29
Page
3
of
30
1.0
EXECUTIVE
SUMMARY
This
assessment
provides
information
to
support
the
issuance
of
a
risk
management
decision
document
known
as
a
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
Document
for
tridemorph.
EPA's
pesticide
reregistration
process
provides
for
the
review
of
older
pesticides
(
those
initially
registered
prior
to
November
1984)
under
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA)
to
ensure
that
they
meet
current
scientific
and
regulatory
standards.
The
process
considers
the
human
health
and
ecological
effects
of
pesticides
and
incorporates
a
reassessment
of
tolerances
(
pesticide
residue
limits
in
food)
to
ensure
that
they
meet
the
safety
standard
established
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.

Use
Profile
Tridemorph
(
2,6­
dimethyl­
4­
tridecylmorpholine)
is
a
systemic
fungicide
used
to
treat
black
and
yellow
sigatoka
on
banana
and
plantain
plants.
It
belongs
to
the
morpholine
group
of
compounds
(
e.
g.,
fenpropimorph).
Calixin
86
OL
Fungicide,
the
only
known
formulation
product,
contains
86%
tridemorph
as
the
active
ingredient.
A
tolerance
has
been
established
under
40
CFR
§
180.372
for
residues
of
tridemorph
in
or
on
bananas
imported
into
the
U.
S.
at
0.1
ppm.
This
tolerance
was
established
in
1978.
Major
countries
that
intend
to
export
tridemorph
treated
bananas
or
plantains
are
Guatemala,
Belize,
Honduras,
Nicaragua,
Costa
Rica,
Panama,
Dominican
Republic,
Ecuador,
Columbia,
Mexico,
and
Venezuela.
There
are
currently
no
U.
S.
registrations
for
tridemorph.
BASF
is
the
sole
U.
S.
company
supporting
tolerances
for
tridemorph.
A
petition
was
submitted
by
BASF
Wyandotte
Corporation
to
establish
a
tolerance
of
50
ppm
for
the
residues
of
tridemorph
in/
on
dried
tea.
We
are
in
the
process
of
evaluating
new
toxicity
data
and
will
consider
the
BASF
petition
once
we
have
done
so.

Hazard
Identification
The
toxicology
database
for
tridemorph
is
incomplete.
All
the
available
toxicity
studies
were
conducted
during
the
late
1960s
or
early
part
of
the
1970s
and
do
not
meet
the
current
guideline
standards.
Most
of
the
toxicity
studies
available
in
the
EPA
Files
are
only
summaries
and
do
not
provide
adequate
information
to
determine
the
quality
of
the
studies,
lack
GLP/
Quality
Assurance
Statements
and
often
the
compound
tested
whether
technical
or
formulation
is
unknown.
However,
the
available
toxicological
database
for
tridemorph
is
considered
adequate
to
characterize
potential
hazards
for
this
tolerance
reassessment
given
that
it
is
an
import
tolerance
with
a
very
limited
use.

Based
on
available
toxicity
data,
tridemorph
has
low
acute
toxicity
(
Category
III)
for
oral
exposure
and
higher
acute
toxicity
for
dermal
and
inhalation
exposure
routes
(
Category
II).
It
exhibits
high
acute
toxicity
(
Category
I)
for
eye
and
skin
irritation.
There
are
no
acute
dermal
sensitization
studies
available
for
tridemorph.
Page
4
of
30
The
majority
of
subchronic
and
chronic
studies
available
for
tridemorph
are
unacceptable
guideline
studies
due
to
lack
of
actual
data
for
verification
of
conclusions
(
only
summary
information
is
available).
In
four­
week
subchronic
toxicity
studies,
testicular
toxic
effects
were
reported
in
rats
and
dogs.
However,
these
effects
were
not
observed
at
similar
dose
levels
in
the
90
day
subchronic
studies
using
rats
and
dogs.
The
reason
for
this
discrepancy
is
not
clear.
Sedation,
nervousness
and
slight
decrease
in
body
weight
during
first
the
six
months
were
reported
in
the
chronic
rat
oral
toxicity
study.

The
available
developmental
toxicity
information
indicates
increased
quantitative
and
qualitative
susceptibility
(
increased
incidence
for
developmental
anomalies)
in
rats
and
increased
quantitative
susceptibility
(
reduction
in
fetal
weight)
in
mice
since
the
developmental
findings
occurred
in
the
absence
of
maternal
toxicity.
There
is
no
developmental
study
available
in
rabbits.
The
developmental
toxic
effects
in
rodents
are
severe
for
tridemorph
compared
to
fenpropimorph,
a
structural
homologue.
For
example,
the
incidences
for
cleft
palate
are
higher
and
occur
at
lower
doses
for
tridemorph
compared
to
fenpropimorph.
Based
on
the
developmental
effect
concerns
(
e.
g.,
cleft
palate),
tridemorph
is
currently
banned
in
the
United
Kingdom.
The
database
for
tridemorph
lacks
an
acceptable
two­
generation
reproduction
toxicity
study.

The
degree
of
concern
for
the
prenatal
susceptibility
effects
in
rabbits
and
post
natal
susceptibility
effects
in
rats
could
not
be
determined
due
to
the
data
gaps.
To
address
the
potential
degree
of
concern
for
infants
and
children,
a
10X
database
uncertainty
factor
was
added
to
the
acute
reference
dose
derivation
and
a
30X
data
base
uncertainty
factor
was
added
to
the
chronic
reference
dose
derivation.
The
addition
of
a
10X
database
uncertainty
factor
also
protects
for
effects
to
infants
and
children.
Therefore,
an
additional
FQPA
safety
factor
is
not
required
and
the
FQPA
safety
factor
may
be
reduced
to
1X.

Mutagenicity
data
are
inadequate
or
lacking.
Based
on
the
data
available,
there
is
no
evidence
of
tumors
in
rats
treated
with
tridemorph
for
2
years.
The
structural
analogue,
fenpropimorph
tested
negative
in
mutagenicity
studies
and
it
is
classified
as
`
not
likely
to
be
carcinogenic
to
humans'.

Based
on
the
open
literature
information,
tridemorph
appears
to
be
rapidly
excreted
in
urine
and
feces
with
the
half­
life
of
~
15
hours.
Metabolites
of
tridemorph
in
rats
are
not
characterized,
but
evidence
suggests
oxidation
in
the
tridecyl
side
chain
or
in
methyl
side
groups
of
the
morpholine
ring.
Glucuronide
conjugates
are
found
in
urine,
bile
and
feces.
The
mode
of
action
for
the
toxic
effects
of
tridemorph
in
mammals
is
not
known.
It
appears
to
inhibit
synthesis
of
lipids
(
e.
g.,
sterols)
and
interfere
with
RNA,
DNA
and
protein
synthesis
in
fungi.
It
is
possible
that
tridemorph
might
interfere
with
synthesis
of
macromolecules
in
mammalian
cells.

BASF
is
in
the
process
of
submitting
a
series
of
toxicity
studies
(
acute
battery,
subchronic
oral
toxicity
in
rats,
chronic
oral
toxicity
in
rats,
mice
and
dogs,
developmental
toxicity
studies
in
rats
and
rabbits
and
two
generation
reproduction
study
in
rats,
and
a
battery
of
mutagenic
tests).
The
current
hazard
assessment
does
not
include
the
review
of
the
recent
studies.
EPA
is
Page
5
of
30
requesting
these
as
confirmatory
toxicity
studies
as
part
of
this
assessment.

Dose
Response
Assessment
Toxicological
endpoints
were
selected
for
the
dietary
exposure
route
only
as
this
is
the
only
exposure
scenario
expected
for
tridemorph
since
it
is
not
registered
for
use
in
the
U.
S.
The
acute
reference
dose
(
RfD)
is
based
on
developmental
effects
observed
in
the
rat
developmental
study.
An
acute
RfD
was
selected
for
the
subpopulation
females
13­
49
only.
An
acute
RfD
was
not
selected
for
the
general
population
or
other
population
subgroups
because
no
effect
attributable
to
a
single
(
or
few)
day(
s)
oral
exposure
was
observed
in
available
animal
studies.
The
chronic
RfD
is
based
on
the
subchronic
toxicity
study
in
dogs.
An
uncertainty
factor
(
UF)
of
100
was
applied
to
the
acute
and
chronic
RfDs
based
on
the
conventional
100X
(
10X
for
intraspecies
extrapolation
and
10X
for
interspecies
variation).
An
additional
10X
UF
was
added
to
address
the
data
gaps
for
the
acute
and
chronic
reference
dose
derivation
for
tridemorph.
The
special
FQPA
safety
factor
was
reduced
to
1X
for
tridemorph.

Risk
Assessment
and
Characterization
Risk
assessments
were
conducted
for
the
dietary
pathway
only
as
there
are
no
current
registrations/
uses
for
tridemorph
in
the
U.
S.
HED
conducted
an
unrefined
Tier
1
acute
and
chronic
dietary
exposure
analyses
using
the
Dietary
Exposure
Evaluation
Model
with
the
Food
Commodity
Intake
Database
(
DEEM­
FCID
 
)
.
The
dietary
exposure
assessment
indicates
that
the
highly
conservative
Tier
1
acute
and
chronic
dietary
exposure
estimates
are
below
HED's
level
of
concern.

2.0
INGREDIENT
PROFILE
2.1
Summary
of
Registered
and
Proposed
Uses
There
are
no
U.
S.
registrations
for
tridemorph.
Tridemorph
which
is
contained
in
the
enduse
product,
Calixin
86
OL
Fungicide,
is
a
emulsifiable
concentrate
containing
6.26
lb
ai/
A
registered
for
use
on
bananas
in
Columbia,
Costa
Rica,
Dominican
Republic,
Ecuador,
and
Guatemala.
It
is
also
proposed
for
use
in
Honduras,
but
no
registration
is
required
for
this
country.
Calixin
is
manufactured
by
BASF
Corporation.

2.2
Structure,
Nomenclature,
and
Physical/
Chemical
Properties
The
nomenclature
and
physicochemical
properties
of
tridemorph
are
provided
in
Tables
1
and
2.
Page
6
of
30
TABLE
1.
Tridemorph
Nomenclature
Compound
Chemical
Structure
Common
name
Tridemorph
Company
experimental
name
NA
IUPAC
name
2,6­
dimethyl­
4­
tridecylmorpholine
CAS
name
CAS:
2,6­
dimethyl­
4­
tridecylmorpholine
CAS
#
24602­
86­
6
Current
Food/
Feed
Site
Registration
No
U.
S.
registrations.
Registered
for
use
in/
on
bananas
TABLE
2.
Physicochemical
Properties
of
the
Technical
Grade
Tridemorph
Parameter
Value
Reference
Melting
point/
range
NA
pH
NA
Density
NA
Water
solubility
(
20
/

C)
11.7
mg/
L
EEE
Branch
Review,
R.
Ney,
10/
20/
75,
00067847.

Solvent
solubility
(
mg/
L
at20
/

C)
Miscible
with
ordinary
organic
solvents
at
any
rate.
EEE
Branch
Review,
R.
Ney,
10/
20/
75,00067847.

Vapour
pressure
(
mPa)
at
20
/

C
6.4
Dissociation
constant
(
pKa)
NA
Octanol/
water
partition
coefficient
Log(
KOW)
NA
UV/
visible
absorption
spectrum
NA
3.0
METABOLISM
ASSESSMENT
Based
on
open
literature
information,
tridemorph
appears
to
be
rapidly
excreted
in
urine
and
feces
with
the
half­
life
of
~
15
hours.
Metabolites
of
tridemorph
in
rats
are
not
characterized,
but
evidence
suggests
oxidation
in
the
tridecyl
side
chain
or
in
methyl
side
groups
of
the
morpholine
ring.
Using
the
formulation
product,
glucuronide
conjugates
are
found
in
urine,
bile
and
feces.

The
nature
of
terminal
residue
in
bananas
is
considered
adequately
defined
based
on
data
Page
7
of
30
O
NH
C
H
3
CH
3
submitted
to
the
Agency.
To
determine
whether
tridemorph
is
systemic,
ring­
labeled
14Ctridemorph
was
applied
to
the
leaves
of
barley,
cucumbers
and
bananas.
Plants
were
sampled
at
various
intervals
and
analyzed
autoradiometrically.
While
tridemorph
was
absorbed
and
translocated
rapidly
in
barley
and
cucumbers,
translocation
was
slow
in
bananas
as
a
result
of
slow
penetration
of
the
leaf
surface.
A
banana
translocation
study
conducted
in
Costa
Rica
in
which
banana
leaves
were
treated
with
either
unlabeled
or
ring­
labeled
14C­
tridemorph..
Tridemorph
was
found
to
rapidly
penetrate
into
leaves
and
remain
at
levels
>
2
ppm
for
at
least
4
weeks
after
treatment.
However,
partial
treatment
of
leaves
indicated
that
translocation
to
untreated
portions
of
the
leaves
was
relatively
slow.
Additionally,
a
field
metabolism
study
using
ring­
labeled
14C­
tridemorph
was
conducted
on
a
banana
plantation
in
Costa
Rica.
Tridemorph
was
applied
in
a
manner
which
simulated
commercial
practice.
Shortly
after
the
last
application,
the
treated
leaves
and
fruiting
stems
were
harvested;
the
fruit
was
essentially
mature
and
at
a
stage
typical
of
commercial
harvest.
Leaves,
peels,
and
pulp
were
analyzed
for
total
activity
by
radiometric
techniques.
The
major
component
of
the
total
radioactive
residue
(
TRR)
was
found
to
be
the
parent
compound
with
a
small
amount
of
polar
material.
The
majority
of
the
aqueous
soluble
activity
was
found
to
be
2,6­
dimethyl
morpholine
(
DMM).
The
residues
in
the
peel
were
also
found
to
be
primarily
tridemorph,
per
se,
with
traces
of
2,6­
dimethyl
morpholine
found
in
the
aqueous
phase.
No
attempt
was
made
to
characterize
the
trace
amount
of
residue
(
0.02
­
0.04
ppm)
in
the
pulp.
Tridemorph
per
se
is
the
residue
of
concern.
As
there
are
no
animal
feed
items
proposed,
the
Agency
concluded
that
the
metabolism
in
animals
was
adequately
understood,
and
the
intended
use
will
be
in
Category
3
of
40
CFR
Section
180.6(
a)
with
respect
to
secondary
residues
in
meat,
milk,
poultry
and
eggs
(
i.
e.,
there
is
no
reasonable
expectation
of
finite
residues).

A
summary
of
tridemorph
parent
and
metabolite
matrices
is
provided
in
Table
3.

Table
3.
Tabular
Summary
of
Metabolites
and
Degradates
Chemical
Name
Commodity
Matrices­
Major
Residue
(>
10%
TRR)
Matrices­
Minor
Residue
(<
10%
TRR)
Chemical
Structure
Tridemorph
2,6­
dimethyl­
4­
tridecylmorpholine
Banana
leaves
&
peel
87%
NA
See
Table
1
Banana
pulp
NA
trace
amounts
DMM
2,6­
dimethylmorpholine
Banana
remainder
(
aqueous
phase)
13%
NA
A
summary
of
compounds
included
in
the
risk
assessment
and
tolerance
expression
is
provided
in
Table
4.
Page
8
of
30
Table
4.
Metabolites
and
Degradates
to
be
included
in
the
Risk
Assessment
and
Tolerance
Expression
Matrix
Residues
included
in
Risk
Assessment
Residues
included
in
Tolerance
Expression
Plant
Primary
Crop
Tridemorph
Tridemorph
Livestock
Ruminant
&
Poultry
NA
NA
NA
NA
Drinking
Water
NA
NA
New
residue
data
indicate
the
established
tolerance
must
be
increased
to
1.0
ppm.
The
current
tolerance
was
determined
using
only
4
studies.
Reassessed
tolerances
are
provided
in
Table
5.

TABLE
5.
Tolerance
Summary
for
Tridemorph
Commodity
Established/
Proposed
Tolerance
(
ppm)
Recommended
Tolerance
(
ppm)
Comments
/(
correct
commodity
definition)

Bananas
0.1
(
established)
1.0
The
tolerance
should
be
footnoted
to
indicate
that
there
are
no
U.
S.
registrations
associated
with
tridemorph./
banana
4.0
HAZARD
CHARACTERIZATION
AND
DOSE
RESPONSE
ASSESSMENT
4.1
Hazard
Characterization
The
toxicology
database
for
tridemorph
is
incomplete.
All
the
toxicity
studies
were
conducted
during
the
late
1960s
or
early
part
of
the
1970s
and
do
not
meet
the
current
guideline
standards.
Most
of
the
toxicity
studies
available
in
the
EPA
Files
are
only
summaries
and
do
not
provide
adequate
information
to
determine
the
quality
of
the
studies,
lack
GLP/
Quality
Assurance
Statements
and
often
the
compound
tested
whether
technical
or
the
formulation
is
unknown.

Based
on
available
acute
oral
toxicity
data,
tridemorph
is
classified
as
Category
III
compound.
Tridemorph/
Calixin
is
classified
as
Category
II
by
both
dermal
route
and
inhalation
route.
Tridemorph/
Calixin
is
classified
as
Category
I
eye
irritant
as
well
as
skin
irritant.
There
is
no
dermal
sensitization
study
available
for
tridemorph.

The
developmental
toxicity
study
using
the
technical
ingredient
in
mice
and
rats
(
Merkle
et
al.,
1984),
and
Calixin
in
two
strains
of
rats,
subchronic
toxicity
study
using
Beagle
dogs
(
00151325)
are
all
classified
as
Acceptable/
Non­
Guideline
studies
and
provide
sufficient
information
for
choosing
the
endpoints.
All
other
subchronic
and
chronic
studies
are
Unacceptable
Non­
Guideline
studies
due
to
lack
of
actual
data
for
verification
of
conclusions
(
only
summary
information
is
available).
Page
9
of
30
The
available
developmental
toxicity
information
indicates
increased
quantitative
and
qualitative
susceptibility
(
increased
incidence
for
developmental
anomalies)
in
rats
and
increased
quantitative
susceptibility
(
reduction
in
fetal
weight)
in
mice
since
the
developmental
findings
occurred
in
the
absence
of
maternal
toxicity.
There
is
no
developmental
study
available
in
rabbits.
The
developmental
toxic
effects
in
rodents
are
severe
for
tridemorph
compared
to
fenpropimorph,
a
structural
homologue.
For
example,
the
incidences
for
cleft
palate
are
more
and
occur
at
lower
doses
for
tridemorph
compared
to
that
for
fenpropimorph.
The
database
for
tridemorph
also
lacks
an
acceptable
two­
generation
reproduction
toxicity
study.
Based
on
the
developmental
effect
concerns
(
e.
g.,
cleft
palate),
tridemorph
is
currently
banned
in
the
United
Kingdom
(
http://
www.
pan­
uk.
org/
pestnews/
actives/
tridemor.
htm).

Based
on
the
open
literature
information,
tridemorph
appears
to
be
rapidly
excreted
in
urine
and
feces
with
the
half­
life
of
~
15
hours.
Metabolites
of
tridemorph
in
rats
are
not
characterized,
but
evidence
suggests
oxidation
in
the
tridecyl
side
chain
or
in
methyl
side
groups
of
the
morpholine
ring.
Glucuronide
conjugates
are
found
in
urine,
bile
and
feces.

The
mode
of
action
for
the
toxic
effects
of
tridemorph
in
mammals
is
not
known.
It
appears
to
inhibit
synthesis
of
lipids
(
e.
g.,
sterols)
and
interfere
with
RNA,
DNA
and
protein
synthesis
in
fungi.
It
is
possible
that
tridemorph
might
interfere
with
synthesis
of
macromolecules
in
mammalian
cells.

In
four
week
subchronic
toxicity
studies,
testicular
toxic
effects
were
reported
in
rats
and
dogs.
Degeneration
of
testes
with
oligospermia
and
azoospermia
in
rats
and
cryptorchidism
(
testes
failed
to
descend),
dysplasia
and
atrophy
of
the
left
testes
were
reported
in
dogs,
both
after
28
days
of
exposure.
However,
these
effects
were
not
observed
at
similar
dose
levels
in
the
90
day
subchronic
studies
using
rats
and
dogs
and
the
reason
for
this
discrepancy
is
not
clear.
Sedation,
nervousness
and
slight
decrease
in
body
weight
during
first
six
months
were
reported
in
the
chronic
rat
oral
toxicity
study.

Mutagenicity
of
tridemorph
is
unknown.
Based
on
inadequate
data,
no
evidence
of
tumors
was
reported
in
rats
treated
with
tridemorph
for
2
years.
The
structural
analogue,
fenpropimorph
tested
negative
in
mutagenicity
studies
and
it
is
classified
as
`
not
likely
to
be
carcinogenic
to
humans'.

BASF
is
in
the
process
of
submitting
a
complete
series
of
toxicity
studies
(
acute
battery,
subchronic
oral
toxicity
in
rats,
chronic
oral
toxicity
in
rats,
mice
and
dogs,
developmental
toxicity
studies
in
rats
and
rabbits
and
two
generation
reproduction
study
in
rats,
and
a
battery
of
mutagenicity
tests).
These
studies
were
conducted
between
the
1970s
and
1990s
and
the
current
hazard
assessment
does
not
include
the
review
of
these
recently
submitted
studies.

Tables
6
and
7
provide
the
acute
and
subchronic/
chronic
toxicity
profile
of
tridemorph,
respectively.
Page
10
of
30
Table
6
­
8
Acute
Toxicity
Profile
of
Tridemorph
Study/
Species
MRID
or
Publication
(
Year)
Results
Classificatio
n
870.1100
Acute
Oral,
Rats
Rats
Rabbits
Rats
Guinea
Pigs
Rabbits
Mice
No
MRID*
(
1969)
00151305a
(
1969)
No
MRID*
(
1970)
No
MRID*
(
1971)
00151310a
(
1970)
No
MRID*
(
1969)
No
MRID*
(
1971)
LD50=
1900
mg/
kg
bw
(
Technical
&
7
days)
LD50
=
~
1000
mg/
kg
bw
(
Technical)
LD50
=
~
2000
mg/
kg
bw
(
Technical)
LD50
=
~
1100
mg/
kg
bw
(
Calixin­
75%
Formulation)
LD50
=
~
1000
mg/
kg
bw
(
Calixin­
75%
Formulation)
LD50
=
~
750
mg/
kg
bw
(
Calixin­
75%
Formulation?)
LD50
=
950
mg/
kg
bw
(
Calixin­
75%
Formulation)
Category
III
Category
III
Category
III
Category
III
Category
III
Category
III
Category
III
870.1200
Acute
Dermal,
Rabbits
Acute
Dermal,
Rabbits
Acute
Dermal,
Dogs
No
MRID*
(
1970)
No
MRID*
(
1970)
No
MRID*
(
1970)
LD50
=
~
1600
mg/
kg
bw
(
Technical/
Calixin­
75%
Formulation?)
LD50
=
1800
mg/
kg
bw
(
Technical/
Calixin­
75%
Formulation?)
LD50
=
>
3200
mg/
kg
bw(
Technical/
Calixin­
75%
Formulation?)
Category
II
Category
II
Category
III
870.1300
Acute
Inhalation,
Rats
Cats
00151318a
(
1970)
No
MRID*
(
1970)
LC50(
6h):
>
0.12
mg/
L?
(
Calixin­
1%)
LC50(
6h):
>
16
mg/
L
(
Calixin­
1%)
Category
II
Category
IV
870.2400
Primary
Eye
Irritation,
Rabbits
No
MRID*
Slight
erythema,
moderate
milky
corneal
inflammation,
pus
and
hemorrhage
at
day
8
(
Calixin­
Undiluted/
75%
Formulation?)
Slight
erythema
up
to
2
hours
and
normal
at
8
days
(
Calixin­
1%
and
10%
Formulation)
Category
I
Category
IV
870.2500
Primary
Skin
Irritation,
Rabbits
Note:
Exposure
period
varies
from
1,
5,
15
minutes
to
20
hours.
The
current
guidelines
call
for
maximum
4
hours
exposure.
Not
known
what
duration
produced
skin
irritant
effects.
00151315a
(
1973)
Corrosive
(
Calixin­
75%
Formulation
0.5­
50%
aqueous
emulsion)
Marked
erythema
and
necrosis
at
8
days
Moderate
Irritation
Calixin
­
0.25%
aqueous
emulsion)
Slight
erythema
during
first
24
hours
and
returned
to
normal
after
24h.
Category
I
Category
IV
870.2600
Dermal
Sensitization,
Guinea
Pigs
No
Study
Identified
­
­

870.6200
Acute
Neurotoxicity,
Rats
No
Study
Identified
­
­

8
All
the
acute
studies
are
classified
as
Unacceptable
/
Non­
Guideline
and
do
not
meet
the
current
standards.
*
Original
Study
Reports
could
not
be
located.
Only
summary
information
was
available
in
the
R.
Coberly
Review
of
3/
10/
76
So
the
results
could
not
be
verified.
Often
it
is
not
clear
whether
technical
or
formulation
was
tested.
No
GLP
or
QA
statements
provided.
aNo
GLP
or
QA
statements
provided.
Page
11
of
30
Table
7:
Subchronic,
Chronic
Toxicity
Studies
­
Tridemorph
Study/
Species
MRID/
Publication
Doses
Results/
Classification
Developmental/
Reproduction
Toxicity
870.3700a
Developmental
Toxicity,
NMRI
Mice
Merkle
et
al.,
1984**
and
No
MRID*
(
1973)
Doses
(
Gavage):
Control,
vehicle
control
(
olive
oil),
27.5,
81.7,
and
245.1
mg/
kg/
day,
GD6­
15
Technical
N=
22­
29
dams/
group
Maternal
NOAEL:
81.7
mg/
kg/
day
Maternal
LOAEL:
245.1
mg/
kg/
day
Reduction
in
placental
weight
(
12.5%)

Developmental
NOAEL:
27.5
mg/
kg/
day
Developmental
LOAEL:
81.7
mg/
kg/
day
Reduction
in
fetal
weight
(
7.9%)

Highest
Dose
Tested
(
HDT):
Cleft
palate
(
127/
305),
reduced
fetal
weight.
Also,
reduced
fetal
length
and
30
cases
of
runts
were
reported.
R.
Coberly
review
(
3/
10/
76)

Acceptable/
Non­
Guideline
Note:
The
doses
in
the
low
mid
and
high
doses
differed
in
R.
Coberly
review
(
3/
10/
76)
compared
to
that
reported
in
Merkle
et
al.,
publication.
The
doses
in
the
EPA
Summary
Report
were
32,
95
and
285
mg/
kg
for
low,
mid
and
high
doses,
respectively
and
may
not
have
been
adjusted
for
percent
purity.
Also,
there
were
slight
differences
in
the
incidences
in
fetal
effects
(
127/
305
versus
127/
309
for
cleft
palate).
Since
the
original
study
submitted
to
EPA
could
not
be
verified,
the
information
from
the
open
literature
was
used
for
the
hazard
assessment.
870.3700a
Developmental
Toxicity,
Sprague
Dawley
Rats
Merkle
et
al.,
1984**
and
No
MRID*
(
1973)
Doses
(
Gavage):
Control,
vehicle
control
(
olive
oil),
20.6,
60.2,
and
189.2
mg/
kg/
day,
GD6­
15
Technical
N=
21­
30
dams/
group
Maternal
NOAEL:
60.2
mg/
kg/
day
Maternal
LOAEL:
189.2
mg/
kg/
day
Decreased
body
weight
gain
(
910.0%),
presence
of
clinical
signs
such
as
apathy,
and
accelerated
respiration,
increased
mortality
during
GD10­
13
(
55.1%),
increased
placental
weight
(
818.5%),
increased
resorption
(
14.19
±
11.74%
versus
7.47
±
7.11%
in
vehicle
controls)

Developmental
NOAEL:
20.6
mg/
kg/
day
Developmental
LOAEL:
60.2
mg/
kg/
day
Increased
percent
of
fetal
incidences
for
overall
anomalies,
and
variations;
presence
of
cleft
palate,
(
191/
370),
brachygnathia
inferior
(
96/
370),
fused
vertebral
arches
as
compared
to
none
in
vehicle
or
untreated
controls;
increased
incidences
for
cleft
thoracic
vertebral
centrum/
centra
(
36/
370
versus
10/
332
in
vehicle
controls).
In
R.
Coberly
review
(
3/
10/
76),
in
addition,
reduced
fetal
weight,
length
and
incompletely
descended
testes
(
9
cases),
fusion
of
individual
sternebrae
(
22
cases)
and
numerous
cases
of
skeletal
retardation
were
reported
at
MDT,
however,
Table
7:
Subchronic,
Chronic
Toxicity
Studies
­
Tridemorph
Study/
Species
MRID/
Publication
Doses
Results/
Classification
Page
12
of
30
these
data
can
not
be
verified
since
the
original
report
is
not
available.

HDT:
Reduced
fetal
survival
(
163
versus
332
in
vehicle
controls),
decreased
fetal
weight
(
910%),
increased
percent
of
fetuses
with
overall
anomalies,
variations/
retardations,
fetal
incidences
for
cleft
palate
(
54/
163),
brachygnathia
inferior
(
2/
163),
syndactyly
(
13/
163),
oligodactyly
(
2/
163),
pseudoankylosis
(
3/
163),
kinky
tail
(
6/
163),
dilated
renal
pelvis
and
hydroureter
(
3/
163)
were
seen
as
compared
to
none
of
these
in
vehicle
or
untreated
controls.
Also,
increased
incidences
for
cleft
thoracic
vertebral
centrum/
centra
(
42/
163
versus
10/
332
in
vehicle
controls)
were
reported.
In
the
R.
Coberly
Review
(
3/
10/
76),
in
addition,
decreased
fetal
length,
anasarca,
(
edema)
(
3
cases),
fusion
of
individual
vertebrae
(
13
cases),
spina
bifida
of
individual
sternebrae
(
3
cases),
incompletely
descended
testes
(
6
cases)
were
reported,
however,
these
data
can
not
be
verified
since
the
original
report
is
not
available.

Acceptable/
Non­
Guideline
Note:
The
fetal
incidences
for
cleft
palate,
brachygnathia
inferior
were
greater
for
MDT
compared
to
HDT,
probably
due
to
poor
fetal
survival
in
HDT.
The
doses
in
the
low
mid
and
high
doses
differed
in
EPA
file
compared
to
that
reported
in
Merkle
et
al.,
publication.
The
doses
in
the
EPA
Summary
Report
(
R.
Coberly
Review
(
3/
10/
76))
were
24,
70,
and
220
mg/
kg
for
low,
mid
and
high
doses,
respectively
and
may
not
have
been
adjusted
for
percent
purity.
Also,
there
were
slight
differences
in
the
incidences
in
fetal
effects
(
e.
g.,
191/
370
versus
191/
371
for
cleft
palate).
Since
the
original
study
submitted
to
EPA
could
not
be
verified,
the
information
from
the
open
literature
was
used
for
the
hazard
assessment.
870.3700a
Developmental
Toxicity,
Wistar
Rats
Merkle
et
al.,
1984**
Doses
(
Gavage):
Control,
vehicle
control
(
Tween
60),
0.13,
0.6,
and
3.25
mg/
kg/
day,
GD7­
15,
GD1­
19
Calixin
75%
Formulation
Maternal
NOAEL:
3.25
mg/
kg/
day
Maternal
LOAEL:
Not
Determined
Developmental
NOAEL:
3.25
mg/
kg/
day
Developmental
LOAEL:
Not
Determined
Acceptable/
Non­
Guideline
(
Developmental
Study
using
the
formulation
is
not
required).
Note:
Doses
are
adjusted
to
a.
i.
in
the
formulation
N=
26­
27
dams/
group
GD7­
15
Table
7:
Subchronic,
Chronic
Toxicity
Studies
­
Tridemorph
Study/
Species
MRID/
Publication
Doses
Results/
Classification
Page
13
of
30
N=
21­
24
dams/
group
GD1­
19
870.3700a
Developmental
Toxicity,
Sprague
Dawley
Rats
Merkle
et
al.,
1984**
Doses
(
Gavage):
Control,
vehicle
control
(
Tween
60),
0.13,
0.6,
and
3.25
mg/
kg/
day
GD7­
15,
GD1­
19
Calixin
75%
Formulation
Maternal
NOAEL:
3.25
mg/
kg/
day
Maternal
LOAEL:
Not
Determined
Developmental
NOAEL:
3.25
mg/
kg/
day
Developmental
LOAEL:
Not
Determined
Acceptable/
Non­
Guideline
(
Developmental
Study
using
the
formulation
is
not
required).
Note:
Doses
are
adjusted
to
a.
i.
in
the
formulation
N=
22­
25
dams/
group
GD7­
15
N=
24­
25
dams/
group
GD1­
19
870.3800
Three
Generation
Reproduction
Toxicity,
Sprague
Dawley
Rats
No
MRID*
(
1972)
Doses
(
diet):
0,
0.25,
0.5,
1.0
mg/
kg/
day
0,
5,
10,
20
ppm
Calixin/
Technical?
NOAEL:
1.0
mg/
kg/
day
LOAEL:
Not
Determined
Unacceptable/
Non­
Guideline
Subchronic
Oral
Toxicity
870.3100
Subchronic
Toxicity,
Rats,
Sprague
Dawley
Rats,
28
days
No
MRID*
(
1975)
Doses
(
diet):
0,
50,
100
mg/
kg/
day
0,
500,
1000
ppm
(
Technical)
NOAEL:
Not
determined
LOAEL:
50
mg/
kg/
day
Reduction
in
food
consumption
in
females
and
decreased
body
weight
in
both
sexes,
degeneration
of
the
testes
with
oligospermia
and
azoospermia
Unacceptable/
Non­
Guideline
Note:
30/
sex/
group
870.3100
Subchronic
Toxicity,
Sparague
Dawley
Rats,
90
days
No
MRID*
(
1968)
Doses
(
diet):
0,
5,
10,
20,
40
mg/
kg/
day
0,
50,
100,
200,
400
ppm
(
Technical)
NOAEL:
20
mg/
kg/
day
LOAEL:
40
mg/
kg/
day
Decreased
body
weight
gain
in
females
and
increased
liver
weight
in
both
males
and
females
and
increased
heart
and
kidney
weight
of
females
Unacceptable/
Non­
Guideline
Note:
n=
20­
25sex/
group
870.3150
Subchronic
Toxicity,
Beagle
dogs,
28
days
No
MRID*
(
1968)
Doses
(
diet):
0,
20,
40
mg/
kg/
day
0,
500,
1000
ppm
(
Technical)
NOAEL:
20
mg/
kg/
day
LOAEL:
40
mg/
kg/
day
Cryplorchidism
(
testes
failed
to
descend),
dysplasia
and
atrophy
of
the
left
testes
Unacceptable/
Non­
Guideline
Note:
n=
1/
sex/
group
870.3150
Subchronic
Toxicity,
Beagle
Dogs,
90
days
00151325**
(
1968)
Doses
(
diet):
0,
7.8,
15.6,
31.3
mg/
kg/
day
0,
200,
400,
800
ppm
(
Technical)
NOAEL:
31.3
mg/
kg/
day
LOAEL:
>
31.3
mg/
kg/
day
Acceptable/
Non­
Guideline
Note:
n=
3/
sex/
group
Subchronic
Dermal
Toxicity
870.3200
21­
Day
Dermal
Toxicity
No
acceptable
study
identified
Dermal
Absorption
No
Study
Identified
Table
7:
Subchronic,
Chronic
Toxicity
Studies
­
Tridemorph
Study/
Species
MRID/
Publication
Doses
Results/
Classification
Page
14
of
30
Chronic
Oral
Toxicity
870.4300
Chronic
Toxicity,
Sprague
Dawley
Rats,
2
years
No
MRID*
(
1972)
Doses
(
diet):
0,
0.5,
1.5,
4.5
mg/
kg/
day
0,
10,
30,
and
90
ppm
Technical
NOAEL:
1.5
mg/
kg/
day
LOAEL:
4.5
mg/
kg/
day
Sedation,
nervousness
and
slight
decrease
in
body
weight
during
first
6
months
No
increased
evidence
of
tumors.
Unacceptable/
Non­
Guideline
Metabolism
870.7485
Metabolism
in
Sprague
Dawley
Rats
00151334*
(
1973)
or
Hawkins
et
al.,
1974**
A
single
oral
dose
of
14C 
Tridemorph
was
administered
by
oral
intubation
to
4
rats/
sex.
Whole
body
autoradiography
was
used
to
establish
the
distribution
of
radioactivity
in
the
rat
tissues.
Urine
and
feces
samples
were
collected
every
24
hours
for
5
days.
The
radioactivity
in
expired
air
was
trapped
for
5
days.
The
bile
ducts
of
2
separate
rats
(
1/
sex)
were
cannulated
and
radioactivity
was
measured
at
24
hour
intervals
for
2
days.
Tridemorph
is
rapidly
absorbed
and
excreted
with
a
half­
life
of
15
hours.
The
majority
of
the
radioactivity
was
excreted
in
urine
(
39%
in
males;
36%
in
females)
and
feces
(
30%
in
males
and
34%
in
females)
during
24
hours.
Bile
contained
21.7%
and
26.4%
of
the
administered
radioactivity
after
2
days.
At
5
days,
43.5%
(
m)
and
41.8%
(
f)
of
radioactivity
in
urine
and
45.7%
(
m)
and
47.8%
(
f)
of
radioactivity
in
feces
were
found.
The
percent
of
dose
administered
was
1.6%
and
1.3%
in
air
and
3.5%
and
3.3%
in
carcass
and
viscera
for
males
and
females,
respectively.
The
autoradiography
revealed
radioactivity
in
the
stomach,
small
intestine
and
liver
at
2
hours
post
treatment;
significant
amounts
in
multiple
tissues
at
6
hours
post
treatment,
large
amounts
of
radioactivity
in
the
large
intestine
at
24
hours
post
treatment
and
traces
of
radioactivity
in
the
body
at
72
hours
post
treatment.
Four
metabolites
were
detected
in
urine
and
two
in
bile
and
fecal
extracts
by
thin
layer
chromatography.
The
major
urinary
metabolite
was
also
present
in
bile
and
feces
but
in
lesser
amounts.
Negligible
amount
of
radioactivity
was
excreted
unchanged.
Detection
of
radioactivity
in
the
expired
air
indicates
some
breakdown
of
the
morpholine
ring.
Based
on
preliminary
mass
spectrometry
findings,
the
major
metabolite
in
24
hour
urine
accounting
for
22.3%
of
the
radioactivity
was
identified
as
side
chain
hydroxylated
derivative.
However,
the
individual
metabolites
were
not
further
characterized.
Note:
The
test
compound
was
found
to
contain
mixtures
of
isomers.
Acceptable/
Non­
Guideline
870.7485
Metabolism
in
Wistar
Rats
Waring
(
1974)**
3H­
Calixin
(
75%
a.
i.)
was
administered
orally
by
intubation
to
female
Wistar
rats
and
urine
and
feces
samples
were
collected
daily
for
3
days.
The
radioactivity
in
bile
was
measured
over
25
hours.
Autoradiography
was
performed
to
measure
the
radioactivity
in
tissues.
Majority
of
the
radioactivity
was
excreted
during
24
hours
(
48.3%
in
urine
and
9.2%
in
feces).
Considerable
amount
of
the
radio
activity
in
the
urine
sample
was
associated
with
glucuronide
(
18.1%)
and
sulphate
conjugates
(
4.8%).
About
10%
of
the
administered
radioactivity
was
found
in
bile
during
25
hours.
About
30%
of
the
radioactivity
was
fairly
distributed
among
different
tissues
with
slightly
higher
concentrations
in
liver,
kidney,
and
gut.
Only
small
amounts
of
the
administered
dose
(
1.5%)
was
recovered
unchanged.
Table
7:
Subchronic,
Chronic
Toxicity
Studies
­
Tridemorph
Study/
Species
MRID/
Publication
Doses
Results/
Classification
Page
15
of
30
Preliminary
mass
spec
findings
suggest
the
possible
hydroxylation
at
the
tridecyl
side
chain
and
in
the
methyl
side
chain
of
the
morpholine
ring.
Note:
The
study
is
done
with
formulation
and
the
metabolites
are
not
adequately
characterized.
Acceptable/
Non­
Guideline
Mutation/
Genotoxicity
No
Study
Identified
*
Only
summary
information
was
available
in
the
R.
Coberly
review
of
3/
10/
76.
So
the
results
could
not
be
verified.
No
GLP
or
QA
statements
available
in
the
summary
information
**
No
GLP
or
QA
statements
provided.
Studies
are
classified
as
Acceptable/
Non­
Guideline
4.2
FQPA
Hazard
Considerations
4.2.1
Adequacy
of
the
Toxicity
Data
Base
The
database
for
tridemorph
is
incomplete
to
assess
the
potential
risk
for
infants
and
children.
The
only
acceptable
Non­
Guideline
studies
are
developmental
toxicity
in
rats
and
mice
and
90­
day
subchronic
toxicity
study
in
dogs.
There
are
no
Acceptable/
Guideline
acute
toxicity
studies
available.
The
subchronic
and
chronic
toxicity
studies
in
rats,
chronic
toxicity
study
in
nonrodents
and
carcinogenicity
studies
in
rodents,
developmental
toxicity
study
in
nonrodents
and
two­
generation
reproduction
toxicity
study
in
rats
are
all
datagaps.
However,
given
that
this
is
an
import
tolerance
with
a
very
limited
use,
the
available
toxicological
database
for
tridemorph
is
considered
adequate
to
characterize
potential
hazards
for
this
tolerance
reassessment.
Also,
HED
is
requiring
submission
of
confirmatory
toxicological
data.

4.2.2
Evidence
of
Neurotoxicity
The
database
is
inadequate
to
determine
any
neurotoxic
effects.
No
acute
and
subchronic
neurotoxicity
studies
are
available.
The
clinical
signs
such
as
apathy,
accelerated
respiration
in
dams
are
identified
as
frank
toxic
signs
associated
with
mortality.
HED
is
requiring
submission
of
acute
and
subchronic
neurotoxicity
studies.

4.2.3
Developmental
Toxicity
Studies
4.2.3.1
Rat
Study
­
Technical
Product
In
a
developmental
study
(
Merkle
et
al.,
1984,
R.
Coberly
Review
(
3/
10/
76)),
pregnant
Sprague­
Dawley
rats
(
21­
30/
group)
were
administered
tridemorph
(
purity
unspecified)
in
olive
oil
by
gavage
at
20.6,
60.2,
189.2
mg/
kg
body
weight/
day
during
GD6­
15.
The
control
animals
included
the
untreated
as
well
as
the
vehicle
treated
groups.
The
doses
were
administered
in
a
volume
of
5
ml/
kg.
The
maternal
survival
in
the
high
dose
group
was
poor
as
only
13/
29
dams
were
available
for
sacrifice
on
GD20
(
i.
e.,
55%
of
dams
died
between
GD10­
13)
and
the
high
dose
dams
exhibited
clinical
signs
such
as
apathy
and
accelerated
respiration.
The
mean
body
Page
16
of
30
weight
of
the
high
dose
dams
were
slightly
decreased
(
10%)
as
compared
to
vehicle
controls
(
128.26
±
17.68g
versus
115.62
±
34.46g)
and
the
results
were
not
statistically
significant
at
p=
0.01.
The
percent
resorptions
was
slightly
higher
in
mid
dose
and
twice
as
great
in
high
dose
animals
as
compared
to
vehicle
treated
controls
(
7.47
±
7.11,
7.92
±
14.76,
9.33
±
18.98,
14.19
±
11.74
in
vehicle
control,
low,
mid
and
high
dose
groups
respectively)
and
was
not
statistically
significant
at
p=
0.01.
The
fetal
viability
was
poor
in
the
high
dose
group
(
163
in
HDT
versus
332
in
controls)
possibly
due
to
decreased
dam
survival
since
the
number
of
fetuses
per
litter
was
not
affected
due
to
treatment.
The
study
lacks
food
consumption
data
for
dams.

The
MDT
had
increased
percent
of
fetal
incidences
for
overall
anomalies,
and
variations.
The
fetal
incidences
for
cleft
palate,
(
191/
370),
brachygnathia
inferior
(
96/
370),
fused
vertebral
arches
were
high
as
compared
to
none
in
vehicle
or
untreated
controls.
Also,
increased
fetal
incidence
for
cleft
thoracic
vertebral
centrum/
centra
(
36/
370
versus
10/
332
in
vehicle
controls)
was
observed
in
mid
dose
group.

In
the
HDT,
reduced
fetal
survival
(
163
versus
332
in
vehicle
controls),
decreased
fetal
weight
(
10%),
increased
percent
of
fetuses
with
overall
anomalies,
variations
and
retardations
were
noticed.
The
fetal
incidences
for
cleft
palate
(
54/
163),
brachygnathia
inferior
(
2/
163),
syndactyly
(
13/
163),
oligodactyly
(
2/
163),
pseudoankylosis
(
3/
163),
kinky
tail
(
6/
163),
dilated
renal
pelvis
and
hydroureter
(
3/
163)
were
high
as
compared
to
none
in
vehicle
or
untreated
controls.
Also,
increased
incidences
for
cleft
thoracic
vertebral
centrum/
centra
(
42/
163
versus
10/
332
in
vehicle
controls)
were
reported.

The
standard
deviations
were
not
reported
for
several
fetal
parameters
such
as
fetal
survival,
and
developmental
effects.
Also,
the
statistical
comparison
was
not
done
to
the
vehicle
controls
and
often
limited
to
p
value
of
0.01
level
and
therefore,
statistical
significance
at
the
often
used
0.05
level
could
have
been
missed
in
treatment
groups.

The
maternal
LOAEL
is
189.2
mg/
kg/
day
based
on
decrease
in
body
weight
gain,
clinical
signs,
increased
mortality
of
dams,
and
increased
resorption.
The
maternal
NOAEL
is
60.2
mg/
kg/
day.
The
developmental
NOAEL
is
20.6
mg/
kg/
day.
The
developmental
LOAEL
is
60.2
mg/
kg/
day
based
on
increased
percent
of
fetal
incidences
for
over
all
malformations
and
variations,
presence
of
cleft
palate,
brachygnathia,
fused
vertebral
arches,
and
increased
incidence
for
cleft
thoracic
vertebral
centrum/
centra.

The
study
is
classified
as
Acceptable/
Non­
Guideline
and
does
not
meet
the
guideline
requirement
for
the
developmental
toxicity
study.

Note:
The
fetal
incidences
for
cleft
palate,
brachygnathia
inferior
were
greater
for
MDT
compared
to
the
HDT,
probably
due
to
poor
fetal
survival
in
HDT.
In
the
R.
Coberly
Review
(
3/
10/
76),
the
doses
were
24,
70,
and
220
mg/
kg
for
low,
mid
and
high
doses,
respectively.
In
addition
to
the
fetal
effects
mentioned
in
Merkle
et
al.,
1984,
reduced
fetal
length
and
incompletely
descended
testes
(
9
cases),
fusion
of
individual
sternebrae
(
22
cases)
and
numerous
Page
17
of
30
cases
of
skeletal
retardation
were
reported
at
MDT.
Decreased
fetal
length,
anasarca,
(
edema)
(
3
cases),
fusion
of
individual
vertebrae
(
13
cases),
spina
bifida
of
individual
sternebrae
(
3
cases),
incompletely
descended
testes
(
6
cases)
were
reported
at
HDT.
Also,
there
were
slight
differences
in
the
incidences
in
fetal
effects
(
e.
g.,
191/
370
versus
191/
371
for
cleft
palate).
However,
these
data
can
not
be
verified
since
the
original
report
is
not
available.

4.2.3.2Mouse
Study
­
Technical
Product
In
a
developmental
study
(
Merkle
et
al.,
1984,
R.
Coberly
Review
(
3/
10/
76)
pregnant
NMRI
mice
(
22­
29/
group)
were
administered
with
tridemorph
(
purity
unspecified)
in
olive
oil
at
27.5,
81.7,
245.1
mg/
kg
body
weight/
day
during
GD6­
15.
The
control
animals
received
vehicle
alone.
The
doses
were
administered
in
a
volume
of
2
ml/
kg.
The
study
included
three
untreated
controls
and
three
vehicle
treated
controls
(
one
set
for
each
dose).

There
were
no
treatment
related
effects
on
body
weight
gain
in
dams,
number
of
implantations,
or
percent
resorptions
per
dam.
Weight
of
the
placentas
was
decreased
in
high
dose
dams
compared
to
controls
(
0.08
±
0.01
versus
0.07
±
0.01;
12.5%,
p<
0.01).

The
percent
of
fetuses
with
anomalies
were
2.98%,
2.29%,
39.15%
in
low,
mid
and
high
dose
groups
compared
to
0.29
to
2.74%
in
control
and
vehicle
controls.
There
is
a
reduction
in
fetal
weight
in
MDT
(
1.17
±
0.11
g;
7.9%)
and
HDT
(
1.13
±
0.17
g;
11.7%)
compared
to
vehicle
controls
(
1.28
±
0.13
g).
There
was
no
overall
change
in
the
percent
of
fetuses
with
variations
or
retardations
between
controls
and
the
treatment.
The
incidences
for
cleft
palate
were
5/
298,
3/
259,
and
27/
305
in
low,
mid
and
high
dose
groups
compared
to
1/
248
or
0/
285
in
appropriate
untreated
and
vehicle
controls.

The
study
is
classified
as
Acceptable/
Non­
Guideline
and
does
not
meet
the
guideline
requirement
for
the
developmental
toxicity
study.

The
maternal
NOAEL
is
81.7
mg/
kg/
day
and
the
maternal
LOAEL
is
245.1
mg/
kg/
day
based
on
reduction
in
placental
weight
.
The
developmental
NOAEL
is
27.5
mg/
kg/
day.
The
developmental
LOAEL
is
81.7
mg/
kg/
day
based
on
reduction
in
fetal
weight.

Note:
In
the
R.
Coberly
review
(
3/
10/
76),
the
doses
in
the
low,
mid
and
high
doses
differed
in
EPA
file
compared
to
that
reported
in
Merkle
et
al.,
publication.
The
doses
in
the
EPA
file
were
32,
95
and
285
mg/
kg
for
low,
mid
and
high
doses,
respectively.
In
addition
to
the
fetal
effects
mentioned
above,
30
cases
of
runts
were
reported
in
HDT
and
there
were
slight
differences
in
the
incidences
for
fetal
effects
(
127/
305
versus
127/
309
for
cleft
palate).
Since
the
original
study
submitted
to
EPA
could
not
be
verified,
the
information
from
the
open
literature
was
used
for
the
hazard
assessment.

4.2.3.3
Rabbit
Study
­
Technical
Product
Page
18
of
30
No
study
identified
in
the
available
database.
Anecdotal
evidence
indicates
that
rabbits
are
not
sensitive
compared
to
rats
as
cleft
palates
were
not
observed
in
the
rabbit
developmental
study
(
http://
www.
pan­
uk.
org/
pestnews/
actives/
tridemor.
htm).
However,
the
doses
tested
were
unknown
and
the
information
could
not
be
verified.

4.2.3.4
Rat
Study
­
Formulation
Product
In
a
developmental
study
(
Merkle
et
al.,
1984)
pregnant
Wistar
rats
or
Sprague­
Dawley
rats
(
21­
27/
group)
were
administered
with
Calixin
(
83%
a.
i.)
orally
at
dose
levels
of
0
(
control),
0
(
vehicle
control),
0.156,
0.722,
3.909
mg/
kg
in
a
dosing
volume
of
5
ml/
kg
during
GD1­
19
or
GD7­
15.
The
concentration
of
the
vehicle
(
Tween
60)
used
was
not
provided.
The
test
doses
after
correction
for
the
active
ingredient
corresponded
to
0.13,
0.6,
and
3.25
mg/
kg
body
weight/
day,
respectively.
There
were
no
significant
changes
in
the
mean
body
weights,
number
of
implantations
per
dam,
percent
resorptions,
number
of
live
fetuses
per
litter,
or
weight
of
the
placentas
in
treated
groups
as
compared
to
either
controls.
Also,
there
are
no
significant
changes
for
fetal
survival,
fetal
weight,
fetal
or
litter
incidence
for
anomalies
or
variations
or
retardations
in
either
strain
of
the
animals
for
both
exposure
durations.
However,
there
was
increased
number
of
fetuses
with
cleft
thoracic
vertebral
centra
in
high
dose
Sprague
Dawley
rats
for
GD7­
15
(
2
in
untreated
controls
versus
6
in
high
dose
group).
Similarly,
the
number
of
fetuses
with
cleft
thoracic
vertebral
centra
in
the
low
dose
Wistar
rats
was
higher
as
compared
to
controls
(
3
in
each
controls
versus
6
in
the
low
dose
group),
however,
no
dose
response
effects
were
seen.
The
study
lacks
food
consumption
data
for
dams.
No
standard
deviations
were
provided
for
developmental
effects.

The
maternal
and
developmental
NOAEL
was
determined
as
3.25
mg/
kg
body
weight/
day
(
for
both
strain
of
rats).
The
LOAEL
is
not
established.
This
study
is
classified
as
Acceptable/
Non­
Guideline
and
does
not
meet
the
guideline
requirement
for
the
developmental
toxicity
study.
No
GLP/
QA
Statements
are
available.

4.2.3.5
Other
Developmental
Toxicity
Studies
In
one
earlier
report
by
Schtenberg
et
al.,
1981
(
as
cited
in
Merkle
et
al.,
1984),
75%
tridemorph
(
presumably
the
formulation
product,
Calixin)
was
reported
to
produce
developmental
toxic
effects
in
rats
(
strain
unspecified)
as
low
as
0.6
mg/
kg.
The
compound
was
administered
from
GD7­
15
or
GD1­
20
up
to
65
mg/
kg.
Hemorrhages
and
hydronephrosis
in
the
lower
doses
(
exact
dose
levels
unspecified)
and
cleft
palate
and
micrognathia
in
the
highest
dose
were
the
common
findings
observed
in
rat
fetuses.
However,
this
secondary
reference
published
in
a
foreign
language
could
not
be
verified.
Further
this
observation
was
not
reproduced,
when
two
strains
of
rats
(
Wistar
and
Sprague
Dawley)
were
tested
using
Calixin(
75%
a.
i.)
in
the
dose
range
of
0.156­
3.909
mg/
kg
during
GD7­
15,
or
GD1­
19
as
mentioned
above
(
Merkle
et
al.,
1984).

4.2.4
Reproduction
Toxicity
Studies
Page
19
of
30
In
the
R
Coberly
reivew
(
3/
10/
76),
no
maternal
or
reproductive
or
offspring
effects
were
observed
when
Sprague
Dawley
rats
were
administered
technical
tridemorph
in
diet
at
0,
5,
10
or
20
ppm
(
0,
0.25,
0.5,
1.0
mg/
kg/
day
determined
based
on
5%
conversion)
for
three
generations.
No
changes
were
observed
in
body
weights,
food
consumption,
water
consumption,
fertility,
litter
size,
litter
weight,
pup
survival,
hearing,
eye
examination,
and
gross
and
histopathological
examination.

The
NOAEL
is
determined
as
1.0
mg/
kg/
day
(
HDT).
The
LOAEL
is
not
established.
This
study
is
Unacceptable/
Non­
Guideline
and
does
not
meet
the
guideline
requirement
(
OPPTS
870.3800)
for
s
two
generation
reproduction
study.
No
GLP/
QA
Statements
are
available.
This
information
presented
in
the
EPA
file
could
not
be
verified
since
the
original
data
are
not
available.

4.2.5
Pre­
and/
or
Postnatal
Toxicity
4.2.5.1
Determination
of
Susceptibility
There
is
a
quantitative
and
qualitative
susceptibility
observed
in
rat
fetuses
and
quantitative
susceptibility
observed
in
mice
fetuses
upon
in
utero
exposures
(
Merkle
et
al.,
1984).
In
rats,
developmental
malformations
(
cleft
palate,
brachygnathia
inferior,
cleft
thoracic
vertebral
centrum/
centra,
and
fused
vertebral
arches)
and
increased
percent
of
fetal
incidences
for
overall
anomalies
were
observed
at
doses
that
did
not
produce
any
maternal
toxic
effects.
In
mice,
a
slight
reduction
in
fetal
weight
was
observed
at
doses
that
did
not
produce
any
maternal
toxic
effects.
Susceptibility
in
rabbits
could
not
be
adequately
ascertained
due
to
the
absence
of
a
rabbit
developmental
study.
Post
natal
susceptibility
could
not
be
determined
since
there
is
no
acceptable
two­
generation
reproduction
study.

4.2.5.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
The
degree
of
concern
for
the
quantitative
and/
or
qualitative
susceptibility
effects
seen
in
rodents
after
in
utero
exposures
is
low.
The
developmental
findings
are
of
low
residual
concern
due
to
the
fact
that:
1)
the
developmental
NOAELs
in
both
the
mice
and
rat
studies
are
clearly
defined
(
no
developmental
effects
were
observed
at
doses
of
27.5
and
20.6
mg/
kg/
day
in
the
mice
and
rat
studies
respectively);
2)
the
dose
response
curve
is
clearly
understood
(
developmental
effects
were
observed
at
the
next
highest
dose
tested
both
rats
(
NOAEL
of
60.2
mg/
kg/
day)
and
mice
(
LOAEL
of
81.7
mg/
kg/
day));
and
3)
the
developmental
endpoint
was
selected
as
the
point
of
departure
for
risk
assessment
and
is
therefore
protective
of
developmental
effects.
Consequently,
there
is
no
additional
need
for
a
proposed
special
FQPA
safety
factor
for
residual
uncertainty.

The
degree
of
concern
for
the
prenatal
susceptibility
effects
in
rabbits
and
post
natal
susceptibility
effects
in
rats
could
not
be
determined
due
to
data
gaps.
A
10X
database
Page
20
of
30
uncertainty
factor
was
added
to
the
acute
reference
dose
derivation
and
a
30X
was
added
to
the
chronic
reference
dose
derivation
to
address
gaps
in
the
tridemorph
toxicology
data
base.
The
10X
database
uncertainty
factors
address
the
potential
degree
of
concern
for
infants
and
children.
Therefore,
the
Special
FQPA
Safety
Factor
was
reduced
to
1X.

4.2.6
Recommendation
for
a
Developmental
Neurotoxicity
Study
Clinical
signs
such
as
apathy
and
accelerated
respiration
were
observed
in
dams
in
the
developmental
rat
toxicity
study.
Since
dams
had
high
mortality
at
the
same
dose
that
exhibited
clinical
signs,
these
are
interpreted
as
frank
toxic
signs.
For
the
structural
analogue,
fenpropimorph,
there
was
little
or
no
evidence
to
support
requiring
a
neurotoxicity
study
at
this
time
since
the
neurotoxic
effects
occurred
at
much
higher
doses
than
those
causing
developmental
or
systemic
effects.
However,
the
database
is
inadequate
to
determine
any
neurotoxic
effects.
An
acute
and/
or
subchronic
neurotoxicity
study
is
required.
A
developmental
neurotoxicity
study
is
held
in
reserve.

4.3
Data
Base
Uncertainty
Factor
There
is
a
data
gap
in
the
toxicology
database
for
tridemorph
(
developmental
toxicity
study
in
rabbits,
two­
generation
reproduction
study
in
rats
and
chronic
oral
toxicity
study
in
rodents
and
non­
rodents
and
acute
and
subchronic
neurotoxicity
studies).
This
necessitates
the
use
of
10X
database
uncertainty
factor
(
UF
DB
)
for
acute
and
chronic
dietary
risk
assessment.

4.4
Safety
Factor
for
Infants
and
Children
Based
on
the
discussion
in
4.2.5,
and
the
addition
of
a
10X
database
uncertainty
factor
which
protects
for
effects
to
infants
and
children,
the
special
FQPA
Safety
Factor
was
reduce
to
1X
for
tridemorph.
It
is
assumed
that
the
exposure
databases
are
complete
and
the
risk
assessment
does
not
underestimate
the
potential
risks
for
infants
and
children.

4.5
Hazard
Identification
and
Toxicity
Endpoint
Selection
Endpoints
were
selected
for
dietary
exposure
routes
only
because
there
are
currently
no
U.
S.
registrations/
uses
for
tridemorph
and
therefore
no
exposures
to
workers
and/
or
homeowners
via
other
routes
of
exposure
(
i.
e.,
incidental
oral,
dermal,
inhalation).

4.5.1
Acute
Reference
Dose
(
aRfD)

4.5.1.1
Females
13­
49
Years
An
aRFD
for
females
13­
49
years
was
selected
based
on
the
developmental
toxicity
study
in
rats
combined
chronic
toxicity/
carcinogenicity
study
in
rats
in
the
technical
product.
Refer
to
Section
4.2.3.1
for
a
summary
of
the
study
and
endpoint
selection.
Page
21
of
30
Acute
RfD
(
Females
13­
49
years)
=
20.6
mg/
kg/
day
(
NOAEL)
=
0.02
mg/
kg/
day
1000
(
UF)
Dose
and
Endpoint
Selected
for
Establishing
Acute
RfD
(
Females
13­
49
years):
The
NOAEL
of
20.6
mg/
kg/
day)
based
on
developmental
malformations
at
60.2
mg/
kg/
day.

Uncertainty
Factor
(
UF):
1000X
(
10X
interspecies
extrapolation,
10X
intraspecies
variation
and
10X
database
uncertainty
factor
for
the
data
gaps
in
toxicity
studies).

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
The
study
is
considered
appropriate
for
the
population
of
concern.
The
developmental
effects
(
cleft
palate,
cleft
thoracic
vertebral
centrum/
centra
and
brachygnathia
inferior
)
could
be
attributed
to
a
single
dose.
The
endpoint
selected
is
protective
of
the
developmental
effects
seen
in
rats
and
mice.
For
example,
cleft
palate
was
the
only
developmental
abnormality
reported
in
mice
fetuses
and
that
occurred
at
high
dose
tested
(
245.1
mg/
kg/
day).
In
rats
several
developmental
abnormalities
including
cleft
palate
were
reported
at
much
lower
dose
(
60.2
mg/
kg/
day).

4.5.1.2
General
Population
Based
on
available
data
an
acute
RfD
for
the
general
population
was
not
selected
because
no
effect
attributable
to
a
single
(
or
few)
day(
s)
oral
exposure
was
observed
in
animal
studies.

4.5.2
Chronic
Reference
Dose
(
cRfD)

The
chronic
RfD
was
selected
based
on
a
subchronic
oral
toxicity
study
(
00151325),
in
which
beagle
dogs
(
3/
sex/
group)
were
administered
orally
with
0,
200,
400
and
800
ppm
tridemorph
(
purity
unknown)
in
diet
for
90
days.
The
mean
dose
levels
determined
in
the
study
for
low
mid
and
high
dose
groups
were
7.8,
15.6,
31.3
mg/
kg/
day,
respectively.
Observations
included
clinical
signs
and
measurements
in
body
weight,
food
consumption,
hematology,
clinical
chemistry,
urinalysis,
organ
weights
and
histopathology.
No
effects
were
observed
in
any
of
the
above
parameters.
The
NOAEL
is
determined
as
31.3
mg/
kg/
day,
(
HDT).
The
LOAEL
is
not
established.

The
study
is
classified
as
Acceptable/
Non­
Guideline
and
does
not
meet
the
guideline
requirement
for
870.3150,
OPP
82­
1
due
to
absence
of
GLP/
QA
statements
and
the
lack
of
information
on
purity
of
the
technical
compound
tested.

Dose
and
Endpoint
Selected
for
Establishing
Chronic
RfD
(
Gen
Population):
The
NOAEL
of
31.3
mg/
kg/
day.

Uncertainty
Factor
(
UF):
3000X
(
10X
interspecies
extrapolation,
10X
intraspecies
variation,
10X
database
uncertainty
factor
for
the
data
gaps
in
toxicity
studies,
3X
uncertainty
Page
22
of
30
Chronic
RfD
(
General
Population)
=
31.3
mg/
kg/
day
(
NOAEL)
=
0.01
mg/
kg/
day
3000
(
UF)
factor
for
the
extrapolation
of
subchronic
to
chronic
study
effects).

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
The
study
selected
is
appropriate
for
the
route
of
exposure.
This
was
the
only
Acceptable
Non­
Guideline
study
available
for
estimating
chronic
dietary
risk
for
tridemorph.
Since
the
study
did
not
test
high
enough
and
the
LOAEL
is
not
established.
A
database
factor
of
10X
was
added
since
there
is
no
acceptable
two
generation
reproduction
toxicity
study
or
chronic
toxicity
study
in
rodent
and
non
rodents.
Since
the
endpoint
is
based
on
the
subchronic
study,
3X
uncertainty
factor
was
deemed
necessary
for
the
extrapolation
from
subchronic
to
chronic
effects.

4.5.3
Classification
of
Carcinogenic
Potential
In
a
two
year
dietary
study,
Sprague
Dawley
rats(
30/
sex/
group)
were
fed
with
0,
10,
30
and
90
ppm
tridemorph
(
not
clear
whether
technical
or
calixin
was
the
compound
tested)
(
R.
Coberly
review
(
3/
10/
76)).
The
dose
levels
based
on
5%
conversion
corresponds
to
0.5,
1.5,
4.5
mg/
kg/
day
for
low
mid
and
high
dose
groups,
respectively
(
assuming
100%
a.
i.
was
tested).
Observations
included
clinical
signs
and
measurements
in
body
weight,
food
consumption,
hematology,
clinical
chemistry,
urinalysis,
organ
weights
and
histopathology.
The
mortality
rate
for
the
0,
10,
30
and
90
ppm
levels
was
40%,
30%,
35%,
and
36.6%,
respectively.
Sedation,
nervousness
and
slight
decrease
in
body
weight
during
first
6
months
were
the
only
effects
reported.
The
incidence
of
tumors
(
organ
not
specified)
for
the
0,
10,
30
and
90
ppm
levels
was
20%,
20%,
18.4%,
and
16.7%
respectively.
No
increased
evidence
of
tumors
found.

The
NOAEL
is
determined
as
31.3
mg/
kg/
day,
(
HDT).
The
LOAEL
is
not
established.
The
study
is
classified
as
Unacceptable/
Non­
Guideline
and
does
not
meet
the
guideline
requirement
for
870.4300,
§
OPP
83­
5.
The
summary
information
found
in
EPA
file
could
not
be
verified.
The
information
on
purity
of
the
technical
compound
tested
is
not
known
and
no
GLP/
QA
statements
are
available.

The
structural
analogue,
fenpropimorph
is
classified
as
`
not
likely
to
be
carcinogenic
to
humans'.
No
mutagenicity
studies
are
identified
in
the
available
database.
Fenpropimorph,
the
structural
analogue,
tested
negative
for
point
mutations
in
bacteria,
for
chromosomal
aberrations
in
Chinese
hamster
lung
cells,
for
increased
frequency
in
micronuclei
in
mice
and
for
unscheduled
DNA
synthesis
in
primary
rat
hepatocytes.

4.5.4
Summary
of
Endpoints
Selected
for
Risk
Assessment
Toxicological
doses/
endpoints
selected
for
the
maleic
hydrazide
risk
assessment
are
provided
in
Table
8.
Page
23
of
30
Table
8:
Summary
of
Toxicological
Doses
and
Endpoints
for
Tridemorph
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
Acute
Dietary
(
Females,
13­
49
years)
NOAEL
=
20.6
mg/
kg/
day
UF
=
1000
Acute
RfD
=
0.02
mg/
kg/
day
FQPA
SF
=
1X
aPAD
=
acute
RfD
FQPA
SF
=
0.02
mg/
kg/
day
Developmental
Toxicity,
Rats
(
Merkle
et
al.,
1984)
Developmental
LOAEL:
60.2
mg/
kg/
day
Increased
percent
of
fetal
incidences
for
overall
anomalies,
and
variations;
presence
of
cleft
palate,
(
191/
370),
brachygnathia
inferior
(
96/
370),
fused
vertebral
arches;
increased
incidences
for
cleft
thoracic
vertebral
centrum/
centra
(
36/
370
versus
10/
332
in
vehicle
controls).

Acute
Dietary
(
General
populations)
No
endpoint
of
concern
is
found
suitable
to
assess
risk
for
this
population
Chronic
Dietary
(
All
populations)
NOAEL
=
31.3
mg/
kg/
day
UF
=
3000
Chronic
RfD
=
0.01
mg/
kg/
day
FQPA
SF
=
1X
cPAD
=
chronic
RfD
FQPA
SF
=
0.01
mg/
kg/
day
Subchronic
Toxicity,
Beagle
Dogs
(
00151325)
LOAEL:
Not
established
Incidental
Oral,
Dermal,
Inhalation
(
all
durations)
Endpoints
for
these
exposure
routes
were
not
selected
as
tridemorph
is
reregistered
for
import
tolerance
only
Cancer
(
Oral)
No
data
to
determine
any
cancer
effects.

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
*
Refer
to
Section
4.3
4.5
Endocrine
Disruption
EPA
is
required
under
the
FFDCA,
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
pesticide
active
and
other
ingredients)
"
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
recommendations
of
its
Endocrine
Disruptor
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
a
scientific
basis
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC's
recommendation
that
the
Program
include
evaluations
of
potential
effects
in
wildlife.
For
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).

Based
on
the
available
information,
tridemorph
was
reported
to
cause
degeneration
of
the
testes
with
oligospermia
and
azoospermia
in
the
subchronic
rat
and
cryptorchidism
(
testes
failed
to
descend),
dysplasia
and
atrophy
of
the
testes
in
the
subchronic
dog
study.
However,
these
findings
are
preliminary
and
need
to
be
confirmed.
When
additional
appropriate
screening
and/
or
Page
24
of
30
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
tridemorph
may
be
subjected
to
further
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.

5.0
DIETARY
EXPOSURE
ASSESSMENT
5.1
Dietary
Profile
A
tolerance
of
0.1
ppm
has
been
established
under
40
CFR
§
180.372
for
residues
of
tridemorph
in
or
on
bananas
imported
into
the
U.
S.
Currently,
there
are
no
U.
S.
registrations
for
tridemorph.
New
residue
data
indicates
the
established
tolerance
must
be
increased
to
1.0
ppm.
The
qualitative
nature
of
the
residues
in
plants
is
adequately
understood.
The
residue
of
concern
in
plants
is
tridemorph
per
se.
(
G.
Otakie,
D322129,
10/
05)

5.2
Magnitude
of
the
Residue
The
existing
tolerance
is
based
on
residue
data
on
bananas
submitted
in
1976
from
three
plantations
in
Costa
Rica.
In
one
study,
bananas
were
sampled
from
1
hour
to
20
days
after
the
last
of
10
to
20
applications
of
tridemorph
at
a
rate
of
0.33
lb
ai/
A
(
0.83x
maximum
proposed
rate).
In
a
second
study,
bananas
were
sampled
1
to
20
days
after
the
last
of
11
to
19
applications
of
tridemorph
at
the
maximum
proposed
rate.
In
the
third
study,
bananas
were
sampled
4
to
18
days
after
the
last
of
11
to
21
treatments
of
tridemorph
at
0.83x
the
maximum
proposed
rate.
In
all
three
studies,
fruit
were
protected
by
bagging
in
polyethylene.
No
detectable
residues
of
tridemorph
(<
0.05
ppm)
were
found
in
either
the
peels
or
pulp
in
the
first
two
studies.
In
the
third
study,
tridemorph
residues
ranged
from
nondetectable
(<
0.01
ppm)
to
0.01
ppm
in
the
pulp
and
from
<
0.01
to
0.1
ppm
in
the
peels.

At
the
time
the
import
tolerance
for
tridemorph
on
bananas
was
established,
HED
provided
case­
by­
case
advice
on
requirements
for
field
trials
for
import
tolerances.
EPA
guidance
has
since
been
issued
(
2000).
In
2002,
12
field
trials
were
conducted
in
Columbia
(
2
tests),
Guatemala
(
1
test),
Costa
Rica
(
2
tests),
Mexico
(
1
test),
Ecuador
(
2
tests),
Honduras
(
2
tests),
and
Martinique
(
2
tests).
Tridemorph
was
applied
to
bananas
as
multiple
foliar
applications.
At
each
test
site,
a
single
plot
of
bananas,
containing
both
bagged
and
unbagged
fruit
clusters,
received
10
foliar
applications
of
tridemorph
at
1x
the
maximum
proposed
rate.
Applications
were
made
beginning
4­
5
months
prior
to
harvest,
at
retreatment
intervals
of
9­
14
days.
Applications
were
made
using
ground
equipment
in
all
cases
but
one
in
which
applications
were
made
above
the
plant
canopy
to
simulate
aerial
application.
Residues
of
tridemorph
in
the
main
tests
were
<
0.05
ppm
(<
LOQ)
in/
on
all
samples
of
bagged
whole
bananas
(
n=
12)
harvested
at
0
days
after
treatment
(
DAT)
and
in
all
associated
subsamples
of
pulp.
For
unbagged
fruit
samples
harvested
at
0­
DAT,
residues
of
tridemorph
were
<
0.05
ppm
in/
on
7
out
of
12
samples
of
whole
fruit;
residues
in/
on
the
remaining
5
samples
were
0.054­
0.628
ppm.
In
pulp
from
unbagged
fruits,
residues
were
<
0.05
ppm
in/
on
11
subsamples
and
0.066
ppm
in
one
subsample.
In
peel
from
unbagged
fruits,
residues
were
<
0.05
ppm
in/
on
7
subsamples
and
0.052­
0.907
ppm
in
5
Page
25
of
30
subsamples.
Average
tridemorph
residues
were
0.114
and
0.025
ppm
in/
on
unbagged
and
bagged
samples
of
whole
bananas,
respectively,
and
0.028
and
0.025
ppm
in
pulp
samples
from
unbagged
and
bagged
fruits.

The
North
American
Free
Trade
Agreement
(
NAFTA)
issued
guidance
on
the
establishment
of
import
tolerances
in
2003.
The
NAFTA
guidance
document
is
consistent
with
the
2000
U.
S.
guidance.
Based
on
this
new
guidance,
12
field
trials
from
Columbia
(
2),
Ecuador
(
3),
Honduras
(
2),
and
Guatemala
(
2)
are
required
for
a
banana
import
tolerance
in
the
U.
S.
Although
the
distribution
of
the
banana
field
trials
does
not
exactly
match
the
distribution
recommended
by
the
Agency,
the
12
field
trails
conducted
at
1x
during
2002
are
considered
adequate.
Based
on
data
from
these
tests,
however,
the
established
tolerance
of
0.1
ppm
in/
on
banana
must
be
increased
to
1.0
ppm.
Storage
stability
data,
which
have
not
been
provided
by
the
registrant,
must
be
submitted.

5.3
Residue
Analytical
Method
Adequate
tolerance
enforcement
methods
are
listed
in
PAM
Volume
II
for
the
determination
of
tridemorph
residues
of
concern.
The
analytical
enforcement
method
is
a
colorimetric
method
based
on
the
formation
of
a
chloroform
soluble
tridemorph/
methyl
orange
addition
complex.
Residues
of
tridemorph
are
confirmed
through
a
GC/
MS
procedure.
The
analytical
method
is
also
suitable
for
the
determination
of
2,6­
dimethylmorpholine
(
DMM),
a
metabolite
of
tridemorph.

There
was
no
information
in
the
review
documents
regarding
submission
of
data
for
FDA
multiresidue
methods
by
the
petitioner.
Tridemorph
is
not
listed
in
the
FDA
PESTDATA
database
dated
11/
01
(
PAM
Volume
I,
Appendix
I).

5.4
Acute
and
Chronic
Dietary
Exposure
and
Risk
Acute
and
chromic
dietary
risk
assessments
were
conducted
using
the
DEEM
(
DEEMFCID
 
,
Ver
2.03)
Model
which
use
food
consumption
data
from
the
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.
In
these
analyses
the
dietary
exposure
and
risk
estimates
resulting
from
food
intake
were
determined
for
the
general
U.
S.
population
and
various
population
subgroups.
The
DEEM
 
program
converts
raw
agricultural
commodity
(
RAC)
residues
into
residues
in/
on
foods
as
eaten
or
consumed
based
on
recipes
of
raw
ingredients
for
each
food
item.
For
acute
exposure
assessments,
individual
oneday
food
consumption
data
are
used
on
an
individual­
by­
individual
basis.
The
reported
consumption
amounts
of
each
food
item
are
"
matched"
in
multiple
random
pairings
with
residue
values
and
then
summed
in
a
probabilistic
assessment.
The
resulting
distribution
of
exposures
is
expressed
as
a
percentage
of
the
acute
Population
Adjusted
Dose
(
aPAD).
Chronic
dietary
exposure
is
estimated
by
estimating
the
residue
level
in
each
treated
food/
food
form,
multiplying
that
estimate
by
the
average
daily
consumption
estimate
for
that
food/
food
form,
and
summing
residue
intake
estimates
for
all
food/
food
forms
to
arrive
at
a
total
average
estimated
exposure.
Page
26
of
30
The
average
estimated
exposure
is
expressed
as
a
percent
of
the
cPAD
for
the
U.
S.
population
and
various
population
subgroups.

The
acute
and
chronic
dietary
exposure
analyses
for
tridemorph
were
conducted
using
unrefined
Tier
1
dietary
exposure
assumptions
for
all
uses.
The
Tier
1
analysis
assumes
tolerance
level
residues,
100%
crop
treated
for
all
commodities,
and
DEEM­
FCID
 
(
ver
7.81)
default
processing
factors
for
the
processed
commodities.

Results
of
the
DEEM
acute
and
chronic
dietary
exposure
analyses
are
presented
in
Tables
8
and
9.
The
results
of
both
the
acute
and
chronic
dietary
exposure
analyses
for
tridemorph
indicate
that,
for
all
supported
commodities,
the
dietary
exposure
estimates
are
below
HED's
level
of
concern.
The
95th
percentile
acute
exposure
estimates
were
<
100%
of
the
acute
Population
Adjusted
Dose
(
aPAD).
The
acute
dietary
exposure
estimates
for
the
population
subgroup
females
13­
49
years
at
the
95th
percentile
is
9%
of
the
aPAD.
The
mean
chronic
dietary
exposure
estimate
for
the
highest
exposed
population
subgroup,
children
1­
2
years
of
age,
is
18%
of
the
cPAD.

Table
8.
Tridemorph
DEEM
Tier
1
Acute
Dietary
Exposure
Analysis
Population
Subgroup
aPAD
(
mg/
kg/
day)
95th
%
ile
Exposure
(
mg/
kg/
day)
%
aPAD
(
95th
%)
99th
%
ile
Exposure
(
mg/
kg/
day)
%
aPAD
(
99th
%)
99.9th
%
ile
Exposure
(
mg/
kg/
day)
%
aPAD
(
99.9th
%)

Females
13­
49
years
0.02
0.0019
9
0.0025
12
0.0043
21
Table
9.
Tridemorph
Tier
1
Chronic
Dietary
Exposure
Analysis
Population
Subgroup
cPAD
(
mg/
kg/
day)
Exposure
(
mg/
kg/
day)
%
cPAD
General
U.
S.
Population
0.01
0.0004
4
All
Infants
(<
1
year
old)
0.0012
12
Children
1­
2
years
old
0.0018
18
Children
3­
5
years
old
0.0009
9
Children
6­
12
years
old
0.0004
4
Youth
13­
19
years
old
0.0001
1
Adults
20­
49
years
old
0.0002
2
Females
13­
49
years
old
0.0002
2
Adults
50+
years
old
0.0004
4
6.0
CUMULATIVE
RISK
Section
408(
b)(
2)(
D)(
v)
of
FFDCA
requires
that,
when
considering
whether
to
establish,
modify,
or
revoke
a
tolerance,
the
Agency
consider
"
available
information"
concerning
the
cumulative
effects
of
a
particular
pesticide's
residues
and
"
other
substances
that
have
a
common
mechanism
of
toxicity."
Page
27
of
30
EPA
does
not
have,
at
this
time,
available
data
to
determine
whether
tridemorph
has
a
common
mechanism
of
toxicity
with
other
substances.
Unlike
other
pesticides
for
which
EPA
has
followed
a
cumulative
risk
approach
based
on
a
common
mechanism
of
toxicity,
EPA
has
not
made
a
common
mechanism
of
toxicity
finding
as
to
tridemorph
and
any
other
substances
and,
tridemorph
does
not
appear
to
produce
a
toxic
metabolite
produced
by
other
substances
which
have
tolerances
in
the
U.
S.
For
the
purposes
of
this
tolerance
reassessment
action,
therefore,
EPA
has
not
assumed
that
tridemorph
has
a
common
mechanism
of
toxicity
with
other
substances.
For
information
regarding
EPA's
efforts
to
determine
which
chemicals
have
a
common
mechanism
of
toxicity
and
to
evaluate
the
cumulative
effects
of
such
chemicals,
see
the
policy
statements
released
by
EPA's
OPP
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/
fedrgstr/
EPA­
PEST/
2002/
January/
Day­
16/.

7.0
DATA
NEEDS
7.1
Residue
Chemistry
Data
Requirements
°
Data
are
required
on
FDA
multiresidue
methods.
Tridemorph
was
not
listed
in
the
FDA
PESTDATA
database
dated
11/
01
(
PAM
Volume
I,
Appendix
I).
°
Storage
stability
data
for
tridemorph
must
be
submitted.
°
Product
Chemistry
data
must
be
provided.

7.2
Toxicology
Data
Requirements
°
870.1100
Acute
oral
toxicity
°
870.1200
Acute
dermal
toxicity
°
870.1300
Acute
inhalation
toxicity
°
870.2400
Acute
eye
irritation
°
870.2500
Acute
dermal
irritation
°
870.2600
Skin
sensitization
°
870.6200
Neurotoxicity
screening
battery
°
870.3700b
Rabbit
developmental
toxicity
study
°
870.3800
Reproduction
and
fertility
effects
°
870.3100
Subchronic
oral
toxicity
study,
rodents
°
870.4300
Combined
chronic
toxicity/
carcinogenicity­
oral
(
rodent)
°
870.4100b
Chronic
toxicity­
oral
(
nonrodent)
°
870.5100
Bacterial
reverse
mutation
test
°
870.5300
Gene
Mutation
­
mammalian
°
870.5375
Mammalian
chromosomal
aberrations
°
870.5395
Mammalian
erythrocyte
micronucleus
test
°
870.5550
Unscheduled
DNA
synthesis
in
mammalian
cells
in
culture
°
870.5900
In
vitro
sister
chromatid
exchange
assay
°
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
Page
28
of
30
°
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
°
870.7485
Metabolism
and
pharmacokinetics
Page
29
of
30
APPENDICES
1.0
TOXICOLOGY
DATA
REQUIREMENTS
Data
requirements
(
40
CFR
158.340)
for
tridemporph
are
provided
in
the
following
table.
Use
of
the
new
guideline
numbers
does
not
imply
that
new
(
1998)
guidelines
were
used
for
studies
conducted
prior
to
the
establishment
of
new
guidelines.

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
no
no
no
no
no
­

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
no
yes
no
no
no*
­
­
­

870.3700a
Developmental
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3700b
Developmental
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
870.3800
Reproduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
no*
no
no
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
­
no
­
no
no
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
no
no
no
no
870.6100a
Acute
Delayed
Neurotox.
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6100b
90­
Day
Neurotoxicity
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
.
.
870.6300
Develop.
Neuro
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
no
no
­
­
yes
yes
reserved
870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
no
¶
no
­

Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Subchronic
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Six­
month
Oral
(
dog)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
yes
­
­
­

*
Acceptable
Non­
Guideline
Studies
available.
Page
30
of
30
2.0
REFERENCES
MRID
00151305
Zeller,
H.,
Hofmann,
H.
(
1972)
Acute
Oral
Toxicity
of
Technical
Grade
N­
tridecyl­
2,6­
dimethylmorpholine
to
the
Rat.
Unpublished
study
prepared
by
BASF.
1
p.

MRID
00151310
Zeller,
H.,
and
Magoley,
J.
(
1975)
Acute
Oral
Toxicity
of
Calixin
to
Guinea
Pigs.
Unpublished
study
prepared
by
BASF.
2
p.

MRID
00151318
Zeller,
H.,
and
Hofmann,
H.
(
1975)
Acute
Inhalation
Toxicity
of
a
1%
Aqueous
Calixin
Emulsion
in
the
Form
of
a
Spray
to
Rats.
Unpublished
study
prepared
by
BASF.
2
p.

MRID
00151315
BASF
Wyandotte
Corp.
(
1973)
Primary
Dermal
Irritation
of
BAS
2205
F
(
Calixin)
to
the
Dorsal
Skin
of
White
Rabbits.
Unpublished
study.
8
p.

MRID
00151325
Leuschner,
F.,
Leuschner,
A.,
Schwerdtfeger,
W.,
et.
al.
(
1968)
Subacute
Oral
Toxicity
of
BAS
220
F
to
Beagles.
Unpublished
study
prepared
by
BASF
Wyandotte
Corp.
84
p.

MRID
00151334
Hawkins,
D.,
Down,
W.,
Chasseaud,
L.,
et.
al.
(
1974)
The
metabolic
fate
of
tridemorph
in
rats
Pestic.
Sci.
5:
535­
542.

Open
Literature
Merkle,
J.,
Schulz,
V
and
Gelbke,
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