Document ID: EPA-HQ-OPP-2005-0491-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-01-11T05:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
November
30,
2005
MEMORANDUM
SUBJECT:
Bitertanol.
Revised
HED
Chapter
of
the
Tolerance
Reassessment
Eligibility
Decision
Document
(
TRED).
PC
Code:
117801,
Decision
#:
343558,
DP
Barcode:
D323894.

Regulatory
Action:
Tolerance
Reassessment
Eligibility
Decision
Risk
Assessment
Type:
Single
Chemical,
No
Aggregate
FROM:
Christina
Jarvis,
Risk
Assessor
Reregistration
Branch
2
Health
Effects
Division
(
7509C)

AND
Dave
Anderson,
Ph.
D.,
Toxicologist
Yvonne
Barnes,
Product
Chemist
Samuel
Ary,
Residue
Chemist/
Dietary
Exposure
Reregistration
Branch
2
Health
Effects
Division
(
7509C)

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

TO:
Rosanna
Louie,
Chemical
Review
Manager
Special
Review
and
Reregistration
Division
(
7508C)
ii
Table
of
Contents
1.0
Executive
Summary
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Page
1
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57
2.0
Ingredient
Profile
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Page
3
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2.1
Summary
of
Registered
Uses
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Page
4
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2.2
Structure
and
Nomenclature
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Page
4
of
57
2.3
Physical
and
Chemical
Properties
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Page
5
of
57
3.0
Metabolism
Assessment
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Page
6
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57
3.1
Comparative
Metabolic
Profile
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Page
6
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57
3.2
Nature
of
the
Residue
in
Foods
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Page
6
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57
3.2.1.
Description
of
Primary
Crop
Metabolism
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Page
6
of
57
3.2.2
Description
of
Livestock
Metabolism
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Page
6
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57
3.2.3
Description
of
Rotational
Crop
Metabolism
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Page
7
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57
3.3
Environmental
Degradation
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Page
7
of
57
3.4
Tabular
Summary
of
Metabolites
and
Degradates
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Page
7
of
57
3.5
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
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Page
7
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57
3.5.1
Tabular
Summary
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Page
7
of
57
4.0
Hazard
Characterization/
Assessment
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Page
8
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57
4.1
Hazard
Characterization
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Page
8
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57
4.2
FQPA
Hazard
Considerations
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Page
17
of
57
4.2.1
Adequacy
of
the
Toxicity
Data
Base
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Page
17
of
57
4.2.2
Evidence
of
Neurotoxicity
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Page
18
of
57
4.2.3
Developmental
Toxicity
Studies
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Page
18
of
57
4.2.3.1
Rat
Developmental
Toxicity
with
Bitertanol
[
Long­
Evans
rats]
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Page
18
of
57
4.2.3.2
Rat
Developmental
Toxicity
with
Bitertanol
[
Sprague
Dawley
rats]
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Page
20
of
57
4.2.3.3
Rabbit
Developmental
Toxicity
with
Bitertanol
[
Chinchilla
rabbits]
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Page
21
of
57
4.2.3.4
Rabbit
Developmental
Toxicity
with
bitertanol
[
Himalayan
rabbits]
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Page
22
of
57
4.2.3.5
Rabbit
Developmental
Toxicity
with
bitertanol
[
Himalayan
rabbits]
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Page
23
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57
4.2.4
Reproductive
Toxicity
Study
Bitertanol
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Page
25
of
57
4.2.5
Additional
Information
from
Literature
Sources
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Page
27
of
57
4.2.6
Pre­
and/
or
Postnatal
Toxicity
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Page
29
of
57
4.2.6.1
Determination
of
Susceptibility
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Page
29
of
57
4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
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Page
29
of
57
4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
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Page
30
of
57
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
iii
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Page
30
of
57
4.3.2
Evidence
that
supports
not
requiring
a
Developmental
Neurotoxicity
study
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Page
30
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57
4.3.2.1
Rationale
for
the
UF
DB
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Page
30
of
57
4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
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Page
30
of
57
4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49
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Page
30
of
57
4.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
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Page
31
of
57
4.4.3
Chronic
Reference
Dose
(
cRfD)
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Page
31
of
57
4.4.4
Incidental
Oral
Exposure
(
Short
Term,
1­
30
days),
and
Intermediate
Term,
1
month­
6
months)
.
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Page
32
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57
4.4.5
Dermal
Absorption
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Page
32
of
57
4.4.6
Dermal
Exposure
(
Short,
Intermediate
and
Long
Term)
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Page
33
of
57
4.4.7
Inhalation
Exposure
(
Short,
Intermediate
and
Long
Term)
Page
33
of
57
4.4.8
Margins
of
Exposure
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Page
33
of
57
4.4.9
Recommendation
for
Aggregate
Exposure
Risk
Assessments
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Page
33
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57
4.4.10
Classification
of
Carcinogenic
Potential
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Page
33
of
57
4.4.10.1
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
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Page
33
of
57
4.4.10.2
Carcinogenicity
Study
in
Mice
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Page
35
of
57
4.5
Special
FQPA
Safety
Factor
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Page
37
of
57
4.6
Endocrine
disruption
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Page
37
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5.0
Public
Health
Data
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Page
38
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5.1
Incident
Reports
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Page
38
of
57
6.0
Exposure
Characterization/
Assessment
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Page
38
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57
6.1
Dietary
Exposure/
Risk
Pathway
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Page
38
of
57
6.1.1
Residue
Profile
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Page
38
of
57
6.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk
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Page
40
of
57
6.2
Water
Exposure/
Risk
Pathway
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Page
41
of
57
6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
.
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Page
41
of
57
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
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Page
41
of
57
8.0
Cumulative
Risk
Characterization/
Assessment
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Page
41
of
57
9.0
Occupational
Exposure/
Risk
Pathway
.
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Page
42
of
57
10.0
Data
Needs
and
Label
Requirements
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Page
42
of
57
10.1
Toxicology
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Page
42
of
57
10.2
Residue
Chemistry
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Page
42
of
57
APPENDICES
A­
C
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Page
48
of
57
iv
Page
1
of
58
1.0
Executive
Summary
Bitertanol
[
beta­([
1,1'­
biphenyl]­
4­
yloxy)­
alpha­(
1,1­
dimethylethyl)­
1H­
1,2,4­
triazole­
1­
ethanol]
is
a
triazole
fungicide
used
to
control
black
sigatoka
on
banana
and
plantain
plants.
Bayer
CropScience
is
the
sole
registrant
of
bitertanol.
Bitertanol
is
marketed
under
the
trade
name
Baycor
®
and
is
formulated
as
an
emulsifiable
concentrate
(
EC)
and
a
suspension
concentrate
(
SC).
The
percentage
of
active
ingredient
in
the
end­
use
formulations
ranges
from
30
percent
(
EC)
to
50
percent
(
SC).
Applications
of
bitertanol
may
be
made
aerially,
by
backpack
sprayer,
and
by
other
types
of
equipment.
The
maximum
single
application
rate
is
0.13
pounds
active
ingredient
per
acre
(
lbs
ai/
A),
and
the
maximum
seasonal
application
rate
is
1.06
lbs
ai/
A.

There
are
no
existing
registrations
for
the
use
of
bitertanol
in
the
United
States;
therefore,
this
assessment
represents
the
tolerance
reassessment
decision
for
bitertanol
use
on
imported
bananas
only.
Major
countries
that
intend
to
export
bananas
or
plantains
that
may
contain
bitertanol
residues
include
Ecuador,
Guatemala,
Costa
Rica,
Columbia,
and
Honduras;
minor
countries
include
Mexico,
Nicaragua,
Peru,
Venezuela,
Dominican
Republic,
and
Panama.
The
toxicological
database
for
bitertanol
is
adequate
when
considered
as
a
whole;
however,
when
reviewed
individually,
many
of
the
studies
are
marginally
adequate
to
inadequate,
with
some
studies
dating
back
to
the
mid­
1970s.
Most
of
the
studies
were
conducted
prior
to
the
publications
of
GLPs,
and
have
other
deficiencies.
However,
the
Health
Effects
Division's
(
HED's)
Risk
Assessment
Review
Committee
(
RARC)
has
determined
that
the
toxicological
database
for
bitertanol
is
adequate
for
risk
assessment
purposes.

Bitertanol
has
low
acute
toxicity
via
the
oral
and
dermal
routes
of
exposure
(
toxicity
categories
IV
and
III,
respectively).
An
acceptable
acute
inhalation
study
is
not
available;
however,
since
bitertanol
is
an
import
tolerance,
none
is
needed
for
registration
in
the
United
States
as
an
import
tolerance.
Bitertanol
is
a
mild
eye
irritant
(
toxicity
category
IV).
It
is
neither
a
dermal
irritant
nor
a
dermal
sensitizer.

Multi­
dose
studies
necessary
for
reregistration,
when
reviewed
in
combination
with
other
studies,
show
sufficient
consistency
to
classify
studies
as
acceptable,
although
the
studies
are
inadequate
when
reviewed
in
isolation.
For
example,
a
combination
of
two
rat
developmental
studies
and
three
rabbit
developmental
studies
are
acceptable
for
developmental
toxicity
in
the
rat
and
rabbit.
Doses
used
and
effects
seen
in
a
three­
generation
reproduction
study
are
similar
to
an
acceptable
90­
day
study
in
rats;
therefore,
when
combined
with
the
90­
day
study
in
rats,
the
three­
generation
reproduction
study
is
considered
acceptable.
Carcinogenicity
studies
in
the
rat
and
mouse
are
acceptable,
and
show
no
treatment­
related
carcinogenicity
at
marginally
toxic
dose
levels.
Bitertanol
is
not
mutagenic.

The
toxicological
database
is
adequate
for
FQPA
hazard
assessment.
In
submitted
developmental
toxicity
studies,
qualitative
susceptibility
was
seen
in
the
rat
and
rabbit
at
the
same
dose
levels
as
maternal
toxicity.
There
is
no
evidence
of
neurotoxicity
among
the
guideline
studies
in
the
toxicity
database;
however,
literature
studies
with
bitertanol
show
limited
neurotoxic
effects.
There
was
no
indication
of
increased
susceptibility
in
the
rat
reproduction
study.

An
acute
reference
dose
(
aRfD)
for
the
general
population
has
not
been
selected
for
bitertanol.
Page
2
of
58
An
appropriate
endpoint
attributable
to
a
single
dose
was
not
available
in
the
toxicity
database,
including
the
developmental
toxicity
studies.
The
aRfD
of
0.05
mg/
kg/
day
for
females
13­
49
years
of
age
is
based
on
a
No­
Observed­
Adverse­
Effect­
Level
(
NOAEL)
of
50
mg/
kg/
day
and
an
uncertainty
factor
of
1000X
(
10X
for
interspecies
extrapolation,
10X
for
intraspecies
variation,
and
10X
database
uncertainty
factor
due
to
lack
of
acute
and
subchronic
neurotoxicity
studies).
There
is
no
residual
uncertainty
with
respect
to
pre­
and
post­
natal
toxicity
based
on
the
submitted
developmental
and
reproduction
studies.
Thus,
the
special
FQPA
safety
factor
has
been
reduced
to
1X.
The
aRfD
is
equivalent
to
the
acute
population
adjusted
dose
(
aPAD).

The
chronic
RfD
(
cRfD)
of
0.00211
mg/
kg/
day
is
based
on
a
NOAEL
of
2.11
mg/
kg/
day
and
the
combined
1000X
uncertainty
factor.
Since
the
special
FQPA
safety
factor
has
been
reduced
to
1X,
the
cRfD
is
equivalent
to
the
chronic
population
adjusted
dose
(
cPAD).

No
endpoints
were
selected
for
short­,
intermediate­,
and
long­
term
incidental
oral,
dermal,
or
inhalation
exposure;
therefore,
these
risk
assessments
were
not
conducted.
Incidental
oral
and
inhalation
exposure
endpoints
are
not
necessary
as
there
are
no
such
exposures
in
the
United
States.
A
dermal
exposure
assessment
is
not
necessary
for
an
import
tolerance.
A
cancer
assessment
is
not
required,
as
no
dose­
related
tumors
were
seen
in
the
rat
or
mouse.
An
aggregate
risk
assessment
is
not
required,
as
there
is
no
exposure
to
residues
of
bitertanol
through
drinking
water
or
residential
uses.

A
rat
metabolism
study
indicates
that
bitertanol,
at
single
low
and
high
doses,
is
rapidly
absorbed,
excreted,
and
extensively
metabolized.
Both
parent
compound
and
numerous
metabolites
were
detected.
No
banana
metabolism
studies
are
available;
however,
acceptable
plant
metabolism
studies
in
apples
and
peanuts
are
available,
as
well
as
recently
submitted
metabolism
studies
in
apples,
cotton,
and
tomatoes.
HED
has
determined
that
the
nature
of
residues
in
bananas
is
likely
similar
to
that
in
apples,
peanuts,
cotton,
and
tomatoes.
Residues
identified
in
these
studies
consist
primarily
of
the
parent
compound,
with
traces
of
the
metabolites
bitertanol
ketone
and
4­
hydroxybiphenyl.
For
risk
assessment
purposes,
HED
has
determined
that
the
bitertanol
residues
of
concern
in/
on
bananas
for
tolerance
expression
and
for
risk
assessment
purposes
are
bitertanol
(
parent
compound
only).

A
single
tolerance
is
established
at
0.20
ppm
for
residues
of
bitertanol
(
parent
only)
in/
on
bananas
(
whole),
which
also
includes
residues
on
plantains
(
40
CFR
§
180.457).
The
Codex
Alimentarius
Commission
(
Codex)
has
established
a
maximum
residue
limit
for
bitertanol
per
se
in/
on
bananas
at
0.50
ppm.
It
is
the
Agency's
policy
to
harmonize
its
tolerances
with
the
levels
established
by
the
Codex,
provided
that
the
Agency
has
sufficient
information
to
make
a
determination
that
the
Codex
maximum
residue
limits
will
be
protective
of
the
health
of
the
U.
S.
public,
and
meet
FFDCA
standards.
In
addition,
the
available
field
trial
studies
suggest
that
a
tolerance
increase
is
advisable.
Therefore,
the
established
tolerance
for
bitertanol
should
be
increased
to
0.50
ppm
to
harmonize
with
Codex.

Since
there
are
no
existing
U.
S.
registrations
for
bitertanol,
the
only
exposure
pathway
considered
in
this
risk
assessment
is
for
acute
and
chronic
dietary
exposure
to
bitertanol
residues
resulting
from
the
consumption
of
whole
bananas.
Conservative
acute
and
chronic
dietary
risk
estimates
were
calculated
using
DEEM­
FCID
 
,
incorporating
the
proposed
tolerance
increase
of
0.50
ppm
Page
3
of
58
(
mg/
kg/
day),
the
DEEM
Version
7.81
default
processing
factor
of
3.9x
for
dried
bananas,
and
an
assumption
of
100%
crop
treated.
For
the
supported
use
of
bitertanol
on
imported
bananas,
acute
and
chronic
dietary
risk
estimates
do
not
exceed
HED's
level
of
concern
(
i.
e.,
risks
are
less
than
100%
of
the
acute/
chronic
population
adjusted
dose)
for
any
population
subgroup.

Data
gaps:
Storage
stability
data
for
bitertanol
in/
on
bananas
have
not
been
submitted
by
the
registrant;
therefore,
storage
stability
data
are
required
to
determine
the
stability
of
residues
in
bananas
during
cold
storage.
Field
trial
data
for
the
suspension
concentrate
(
SC)
formulation
are
required
(
these
field
trials
are
currently
being
conducted
by
the
registrant
and
are
planned
for
completion
in
2006).
Additional
data
(
the
number
of
trials,
location
of
the
trials
within
the
countries,
and
the
formulation
type
used)
are
required
in
order
for
the
submitted
field
trials
conducted
in
Costa
Rica
and
Honduras
to
be
acceptable.

With
regards
to
toxicology
data
needs,
an
acute
neurotoxicity
battery
and
a
90­
day
neurotoxicity
study
with
bitertanol
are
recommended.
The
requirement
for
a
developmental
neurotoxicity
(
DNT)
study
is
held
in
reserve,
pending
the
submission
and
review
of
the
acute
and
subchronic
neurotoxicity
studies.

2.0
Ingredient
Profile
P.
Yvonne
Barnes.
Bitertanol:
Summary
of
Product
Chemistry
Data
for
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
Document.
October
25,
2005.
DP
Barcode
D302878.

Bitertanol
is
a
broad­
spectrum
triazole
fungicide
used
to
control
black
sigatoka
on
banana
and
plantain
plants.
Bayer
CropScience
is
the
sole
registrant
of
bitertanol.
Bitertanol
is
marketed
under
the
trade
name
Baycor
®
and
is
formulated
as
an
emulsifiable
concentrate
(
EC)
and
a
suspension
concentrate
(
SC).
The
percentage
of
active
ingredient
in
the
end­
use
formulations
ranges
from
30
percent
(
EC)
to
50
percent
(
SC).
Applications
of
bitertanol
may
be
made
aerially,
by
backpack
sprayer,
and
by
other
sprayer
equipment.
The
maximum
single
application
rate
is
0.13
pounds
active
ingredient
per
acre
(
lbs
ai/
A),
and
the
maximum
seasonal
application
rate
is
1.06
lbs
ai/
A.
Application
is
foliar
during
fruit
development.
The
minimum
interval
between
treatments
is
seven
days.
Bitertanol
is
intended
for
use
on
bagged
bananas
only;
however,
bananas
are
not
always
bagged
and
plantains
are
rarely
bagged.

There
are
no
existing
registrations
for
the
use
of
bitertanol
in
the
United
States;
therefore,
this
assessment
represents
the
tolerance
reassessment
decision
for
bitertanol
use
on
imported
bananas
only.
Major
countries
that
intend
to
export
bananas
or
plantains
that
may
contain
bitertanol
residues
include
Ecuador,
Guatemala,
Costa
Rica,
Columbia,
and
Honduras;
minor
countries
include
Mexico,
Nicaragua,
Peru,
Venezuela,
Dominican
Republic,
and
Panama.
Page
4
of
58
2.1
Summary
of
Registered
Uses
Table
2.1:
Summary
of
Directions
for
Use
of
Bitertanol.

App.
Timing,
Type,
and
Equip.
Formulation
App.
Rate
(
lb
ai/
A)
Max.
No.
App.
per
Season
Max.
Seasonal
App.
Rate
(
lb
ai/
A)
PHI
(
days)
Use
Directions
and
Limitations
Banana
Apply
as
needed
based
on
speed
of
leaf
emergence
during
fruit
development.
Minimum
retreatment
interval
of
7
days.
Apply
specified
dosage
as
a
foliar
spray
by
air,
tractor
driven
equipment,
or
knapsack
sprayer
in
a
minimum
of
2
gallons
of
water
per
acre.
Baycor
®
30%
EC
0.13
lb
ai/
A
8
1.06
lb
ai/
A
None
 

Baycor
®
50%
SC
0.13
lb
ai/
A
8
1.06
lb
ai/
A
None
 

2.2
Structure
and
Nomenclature
Table
2.2:
Bitertanol
Structure
and
Nomenclature
Chemical
Structure
Empirical
Formula
C20H23N3O2
Common
name
Bitertanol
Trade
name
Baycor
®

IUPAC
name
1­(
biphenyl­
4­
yloxy)­
3,3­
dimethyl­
1­(
1H­
1,2,4­
triazol­
1­
yl)
butan­
2­
ol
CAS
name
[
beta­([
1,1'­
biphenyl]­
4­
yloxy)­
alpha­(
1,1­
dimethylethyl)­
1H­
1,2,4­
triazole­
1­
ethanol]

CAS
Registry
Number
55179­
31­
2
Chemical
Class
Azole
Page
5
of
58
2.3
Physical
and
Chemical
Properties
Table
2.3:
Physicochemical
Properties
Parameter
Value
Reference
Molecular
Weight
337.42
grams/
mole
MRID
46655901
Melting
point/
range
145­
155
°
C
MRID
46655901
Density
1.16
g/
mL
at
20
°
C
MRID
46655901
Water
solubility
1.1
mg/
L
at
20
°
C
(
isomer
A)
MRID
46655901
2.7
mg/
L
at
20
°
C
(
isomer
B)

Solvent
solubility
(
temperature
not
specified)
Propan­
2­
ol
1­
5g/
100g,
toluene
1­
5g/
100g,
cyclohexane
5­
10g/
100g,
methylene
chloride
10­
20g/
100g,
Stable
in
aqueous
acid
and
alkaline
solutions.
Merck
12th
Edition
Vapor
pressure
0.00001
mBar
at
20
°
C
Merck
12th
Edition
Octanol/
water
partition
coefficient,
log
P
K
ow
Kow
logP
=
4.04
at
20
°
C
(
isomer
A)
MRID
46655901
Kow
logP
=
4.1
at
20
°
C
(
isomer
B)

UV/
visible
absorption
spectrum
Peak
maxima
at
255
nm
MRID
46655901
Page
6
of
58
3.0
Metabolism
Assessment
3.1
Comparative
Metabolic
Profile
Based
upon
the
metabolites
identified,
the
investigators
concluded
that
BAYCOR
was
metabolized
in
the
rat
via
mono­
ring
hydroxylation
(
p­
hydroxy
BAYCOR
I
and
p­
hydroxy
BAYCOR
II),
di­
ring
hydroxylation
(
m,
m­
dihydroxy
BAYCOR
I
and
m,
m­
dihydroxy
BAYCOR
I),
aryl
O­
methylation
and
aliphatic
hydroxylation
(
p­
hydroxy­
m­
methoxy
BAYCOR,
BAYCOR
alcohol,
p­
hydroxy
BAYCOR
alcohol
I
and
p­
hydroxy
BAYCOR
alcohol
II),
ether
cleavage
and
aliphatic
oxidation
to
carboxylic
acids.
The
investigators
noted
the
absence
of
metabolites
(
e.
g.,
precursors
to
identified
metabolites)
typically
expected
to
occur
but
hypothesized
that
these
would
likely
be
short­
lived
intermediates
thereby
precluding
accumulation
and
detection.
A
metabolism
pathway
was
proposed
based
upon
the
study
findings
(
Appendix
C).

The
rat
metabolism
study
indicates
that
bitertanol,
at
single
low
and
high
doses,
is
rapidly
absorbed,
excreted
and
extensively
metabolized.
Recovery
of
radioactivity
was
acceptable
(
92­
104%).
The
studies
affirmed
the
relatively
rapid
absorption
of
[
14C­
phenyl­
UL]
BAYCOR
(
Bitertanol)
and
that
excretion
was
primarily
via
the
feces
(
81­
98%
and
92%,
respectively)
over
the
168­
hr
experimental
period.
Urinary
excretion
(
4­
11%)
was
secondary
to
fecal
elimination.
Saturated
absorption
at
the
high
dose
(
1000
mg/
kg)
was
evident
by
a
plateau
in
plasma
radioactivity
levels
(
and
by
estimated
kinetic
parameters)
and
an
increase
in
the
fecal
excretion
of
parent
compound.
A
minor
gender­
related
variance
in
absorption
and
elimination
constants
and
plasma
elimination
halftime
was
observed
for
the
multiple
dose
group
but
not
for
other
treatment
groups.
No
other
gender­
related
variability
was
observed.
The
study
reported
no
excretion
via
expired
air.
Tissue
radioactivity
was
minimal
and
not
suggestive
of
bioaccumulation
of
the
test
material
or
its
metabolites.

Since
the
triazole
ring
was
not
labeled,
the
triazole
metabolite,
if
present,
was
not
detected.
[
Triazole
could
not
be
detected
in
other
triazole
ring
containing
pesticides
when
the
triazole
ring
was
not
labeled.]

3.2
Nature
of
the
Residue
in
Foods
3.2.1.
Description
of
Primary
Crop
Metabolism
The
nature
of
the
residue
in
plants
is
adequately
understood
based
on
acceptable
metabolism
studies
on
apples
and
peanuts.
The
residues
consisted
primarily
of
the
parent
compound
with
traces
of
the
metabolites
bitertanol
ketone
and
4­
hydroxybiphenyl.
The
Agency
has
concluded
that
the
residue
of
concern
is
the
parent
compound
(
S.
Ary,
D302882,
11/
7/
2005).

3.2.2
Description
of
Livestock
Metabolism
Bitertanol
is
not
intended
for
application
to
livestock
exported
to
the
U.
S.
In
addition,
there
are
no
feedstuffs
associated
with
bananas.
Therefore,
no
residue
chemistry
data
are
required
under
this
guideline
topic.
Page
7
of
58
O
N
N
N
O
O
H
3.2.3
Description
of
Rotational
Crop
Metabolism
Rotational
crop
studies
are
not
required
for
uses
of
pesticides
on
bananas
(
HED
SOP
96.6).

3.3
Environmental
Degradation
Bitertanol
is
registered
for
use
on
imported
bananas
only;
therefore,
environmental
fate
data
are
not
required..

3.4
Tabular
Summary
of
Metabolites
and
Degradates
Table
3.4:
Chemical
Names
and
Structures
of
Metabolites
of
Bitertanol.

Common
Name
Chemical
Name
Structure
bitertanol
ketone
1­[(
1,1­
biphenyl)­
4­
yloxy]­
3,3­
dimethyl­
1­(
1H­
1,2,4­
triazole­
1­
yl)­
2­
butanone
p­
hydroxybiphenyl
4­
hydroxybiphenyl
3.5
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
3.5.1
Tabular
Summary
Table
3.5:
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
bitertanol
bitertanol
Rotational
Crop
n/
a
n/
a
Livestock
Ruminant
n/
a
n/
a
Poultry
n/
a
n/
a
Drinking
Water
n/
a
n/
a
Page
8
of
58
4.0
Hazard
Characterization/
Assessment
4.1
Hazard
Characterization
Bitertanol
is
a
triazole
fungicide
used
for
imported
bananas
only,
that
was
registered
about
1994­
1996.
Bitertanol
is
among
a
class
of
over
25
fungicides.
The
literature
noted
that
some
triazole
pesticides
caused
behavioral
effects.
Two
analogs
of
bitertanol,
triadimefon
and
triadimenol
caused
effects
on
operant
behavior.
An
effect
on
operant
behavior
caused
by
acute
dosing
with
bitertanol
differed
from
that
resulting
from
triadimefon
and
triadimenol
exposure.
A
study
in
mice
suggested
hyperactivity
effects
while
other
studies
showing
effects
on
operant
behavior,
suggesting
an
effect
resembling
hyperactivity,
but
no
effects
on
motor
activity
[
Allen
and
MacPhail,
1993,
Crofton,
1996
and
FAO
and
WHO
Working
Groups,
1998].
However,
the
guideline
studies
on
bitertanol
showed
no
evidence
of
neurotoxic
effects.

The
acute
oral
LD50
study
with
bitertanol
show
a
toxicity
category
IV
for
acute
toxicity,
but
toxicity
category
III
for
acute
dermal,
largely
because
of
the
low
highest
dose
tested.
The
acute
inhalation
study
is
unacceptable
because
the
particle
size
in
the
exposure
aerosol
was
not
described.
Eye
and
skin
irritant
were
toxicity
category
IV
and
skin
sensitization
studies
were
negative.

Pre­
natal
studies
showed
no
increased
offspring
quantitative
susceptibility,
but
show
qualitative
susceptibility
in
the
form
of
malformations
and
post
implantation
loss.
The
reproduction
study
showed
no
increased
qualitative
or
quantitative
susceptibility.
In
the
development
toxicity
studies,
although
none
of
the
malformations
were
statistically
significant
in
the
rats
or
rabbits,
in
combination
with
the
increased
resorptions
and
nominally
increased
malformations
in
rabbits
and
nominally
increased
malformations
in
rats,
bitertanol
is
classed
as
a
teratogen
at
maternally
toxic
dose
levels.
The
developmental
toxicity
studies
in
the
rat
show
developmental
effects
in
the
form
of
stunted
fetuses
and
nominally
increased
malformations,
such
as
kinked
tail,
cleft
palate,
rib
malformations
and
delayed
ossification
at
maternally
toxic
dose
levels
in
the
Long­
Evans
rat,
but
the
Sprague
Dawley
rat
developmental
study
conducted
at
lower
doses
showed
only
increased
14th
rib
and
no
malformations.
The
NOAEL
in
the
Long­
Evans
and
Sprague
Dawley
rat
for
developmental
and
maternal
toxicity
were
identical.
In
the
Chinchilla
rabbit,
the
developmental
effects
in
the
from
of
post­
implantation
loss,
decreased
fetal
weights
and
rib
anomalies
occurred
at
the
maternal
toxic
dose
levels.
However,
in
two
Himalayan
rabbits
studies,
decreased
fetal
weight,
increased
resorptions,
and
cleft
palate,
pigeon
chests,
epignathus,
aplasia
of
several
lung
lobes
and
aplasia
of
the
left
lung
and
hypoplasia
of
the
right
lung
were
noted.
The
postimplantation
loss
at
the
LOAEL
is
considered
a
qualitative
susceptibility
for
fetuses
[
more
severe
than
maternal
weight
decrement].
The
study
on
reproduction
showed
pup
weight
decrements
and
parental
weight
decrements
at
the
same
dose
levels.

Subchronic
studies
in
rats
showed
body
weight
decreases
and
elevations
in
clinical
chemistry
parameters
and
liver
effects.
Subchronic
studies
in
dogs
showed
prostate
weight
decrement,
and
skin
and
mucus
membrane
irritation
at
the
LOAEL
and
at
the
HDT
body
weight
and
thymus
weight
decrement.
The
multi­
exposure
inhalation
studies
were
all
unacceptable
due
to
inadequate
explanation
of
the
inhalation
particle
size
and
other
inhalation
conditions.
However,
regardless
of
the
particle
size,
none
to
these
inhalation
studies
in
the
rat
or
dog
showed
the
mucosal
irritation
Page
9
of
58
seen
in
the
90­
day
dog
study.

The
subchronic
studies
showed
effects
at
slightly
lower
dose
levels
than
the
maternal
toxic
dose
levels
in
the
developmental
studies,
but
the
NOAEL
was
comparable
with
that
seen
in
the
chronic
studies.
Effects
on
the
body
weight
and
liver
were
common
effects
seen
in
the
rat,
mouse
and
dog.
However,
the
dog
subchronic
study
was
the
only
study
showing
dose
related
prostate
weight
decrement.
The
prostate
weight
decrement
and
severe
mucosal
irritation
were
not
supported
by
the
chronic
dog
study.

Chronic
studies
in
the
rat,
mouse
and
dog
with
bitertanol
showed
body
weight
decrement
and
food
efficiency
decrement
at
the
LOAEL
and
at
higher
dose
levels
liver
pathology,
stomach
hyperplasia,
and
some
indication
of
unconfirmed
kidney
effects.
In
some
of
the
studies,
liver
enzymes
and
cholesterol
levels
were
increased
at
doses
resulting
in
liver
pathology.
Due
to
dose
selection
the
subchronic
study
in
dogs
showed
a
slightly
lower
NOAEL
than
the
chronic
study
in
dogs.
The
21­
day
dermal
rabbit
study
showed
no
systemic
effects
at
the
highest
dose
tested
and
only
minor
skin
irritation.

Bitertanol
shows
no
dose
related
or
treatment
related
increased
incidence
in
carcinogenicity
in
the
rat
or
mouse
carcinogenicity
studies.
Both
studies
were
classified
as
acceptable.
However,
both
studies
failed
to
analyze
the
dietary
concentration
of
the
test
material.
Marginal
toxicity
at
the
highest
dose
level
shown
by
body
weight
decrement
and
clinical
chemistry
results
indicated
that
the
animals
were
dosed
and
the
effects
were
supported
by
the
90­
day
studies
in
rats.
The
highest
dose
levels
used
were
marginally
adequate
and
all
required
tissues
were
not
evaluated
among
other
deficiencies
that
did
not
negate
the
studies.
Both
studies
were
conducted
prior
to
GLP
publication.

A
battery
of
acceptable
mutagenicity
studies
with
bitertanol
were
universally
negative
for
genetic
damage
and
mutations.
The
dominant
lethal
study
in
mice
was
marginally
acceptable
and
negative.
Only
one
non
toxic
dose
level
was
used
[
1000
mg/
kg,
1/
4
of
the
mouse
LD50].
The
remaining
mutagenicity
studies
meet
the
criteria
for
pre­
1996
guideline
studies.

HED
recommends
that
an
acute
neurotoxicity
battery,
and
a
90­
day
neurotoxicity
study
with
bitertanol
be
submitted.
The
requirement
for
a
developmental
neurotoxicity
toxicity
study
is
held
in
reserve,
pending
the
submission
and
review
of
the
acute
and
subchronic
neurotoxicity
studies.
The
10X
FQPA
factor
is
reduced
to
1X
and
a
10X
database
uncertainty
factor
is
applied
to
acute
and
chronic
dietary
endpoints
to
account
for
the
lack
of
acute
and
subchronic
neurotoxicity
studies.

Bitertanol
is
rapidly
absorbed
and
excreted
in
the
feces
and
urine
of
the
rat.
Only
about
6%­
11%
of
the
absorbed
dose
is
excreted
in
the
urine
while
most
of
the
remaining
dose
is
excreted
through
bile
into
the
feces.
Analysis
of
the
feces
showed
14
metabolites
and
conjugates
including
metabolites
of
the
two
enantiomers
of
bitertanol
[
Appendix
C].
The
metabolic
profile
did
not
differ
between
the
urine
and
feces
except
small
amounts
of
parent
was
excreted
in
feces
but
not
in
the
urine.
About
50%
of
the
dose
remained
unextracted
in
feces
after
attempts
with
multiple
extractants.
No
radioactivity
was
noted
in
the
breath
of
rats.
There
was
evidence
of
metabolic
saturation
at
the
1000
mg/
kg
dose,
but
not
of
accumulation.
Page
10
of
58
Metabolism
studies
with
bitertanol
[
BAYCOR]
showed
extensive
metabolism.
Based
upon
the
metabolites
identified,
the
investigators
concluded
that
BAYCOR
was
metabolized
via
mono­
ring
hydroxylation
(
p­
hydroxy
BAYCOR
I
and
p­
hydroxy
BAYCOR
II),
di­
ring
hydroxylation
(
m,
mdihydroxy
BAYCOR
I
and
m,
m­
dihydroxy
BAYCOR
I),
aryl
O­
methylation
and
aliphatic
hydroxylation
(
p­
hydroxy­
m­
methoxy
BAYCOR,
BAYCOR
alcohol,
p­
hydroxy
BAYCOR
alcohol
I
and
p­
hydroxy
BAYCOR
alcohol
II),
ether
cleavage
and
aliphatic
oxidation
to
carboxylic
acids.
The
investigators
noted
the
absence
of
metabolites
(
e.
g.,
precursors
to
identified
metabolites)
typically
expected
to
occur
but
hypothesized
that
these
would
likely
be
short­
lived
intermediates
thereby
precluding
accumulation
and
detection.
A
metabolism
pathway
was
proposed
based
upon
the
study
findings
(
Appendix
C,
Figure
1).

Table
4.1a:
Acute
Toxicity
Data
on
Bitertanol
(
PC
117801)

Guideline
No./
Study
type
MRID
No.
Results
Toxicity
category
870.1100
Acute
oral
toxicity/
rats
(
95.6%)
00025641,
00025640
[
1977]
[
#
51413]
LD50
>
5000
mg/
kg
IV
870.1200
Acute
dermal
toxicity/
rabbits
(
96.5%)
00025641
[
1977]
[#
51413]
LD50
>
2000
mg/
kg
III
870.1300
Acute
inhalation
toxicity/
rats
(
97%)
79/
ISK034/
387
00025641
[
1977],
00025653
[
1979]
[#
51413]
For
MRID#
0025641;
Study
unacceptable;
undefined
particle
size
&
doses
administered
not
clear.
For
MRID#
00025653;
Study
unacceptable;
undefined
particle
size.
LC50
>
5.16
mg/
L
No
indication
of
mucosal
membrane
irritation.
­

870.2400
Acute
eye
irritation/
rabbit
(
93.3%)
00025641,0
0025640
[
1977]
[#
51413]
Mild
irritation
IV
870.2500
Acute
dermal
irritation/
rabbit
(
93.3%)
79ILK8/
056
00025641,0
0025640
[
1977]
[#
51413]
Non
irritating
IV
870.2600
Skin
sensitization/
GP
(
96.5%)
00114277
[
1981]
[#
80324]
Not
a
dermal
sensitizer
in
the
Magnsson
and
Kligman
Test
­
Page
11
of
58
Table
4.1b:
Subchronic,
Chronic,
Developmental,
Reproductive
and
other
Toxicity
Profile
on
Bitertanol
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
oral
toxicity
(
SD
rat)
Acceptable
00157853
(
1981)
TXR#
0005568
0,
40,
200,
1000
ppm
M/
F
0/
0,
3.1/
3.6,
15.9/
18.6,
81.8/
88.2
mg/
kg/
day.

No
opthalmic
examination
NOAEL
=
40
ppm
(
M/
F:
3.1/
3.6
mg/
kg/
day)
LOAEL
=
200
ppm
(
M/
F:
15.9/
18.6
mg/
kg/
day)
based
on
decreased
body
weight
and
body
weight
gain
in
males
and
females.
At
1000
ppm
(
M/
F:
81.8/
88.2
mg/
kg/
day)
slightly
decreased
hematological
parameters
and
slightly
elevated
LDH,
SGOT,
ALP
(
20%
­
50%)
and
increased
cholesterol
(
117%).
Increased
incidence
of
hyperkeratotic
epithelia
of
the
esophagus
and
glandular
stomach
and
increased
liver
and
adrenal
weights
and
liver
histopathology.

870.3100
90­
Day
oral
toxicity
(
Wistar
rat)
Unacceptable
(
Contractor)
No
need
to
repeat
study.
00025647
(
1976)
TXR#
006018,
p
13
Doses:
0,
30,
100,
300
ppm;
M/
F:
0/
0,
2.46/
3.25,
8.15/
10.15,
24.8/
31.6
mg/
kg/
day
N=
100
ppm
(
M/
F:
8.2/
10.2
mg/
kg/
day)
L=
300
ppm
(
M/
F:
24.8/
31.6
mg/
kg/
day)
based
on
marginal
body
weight
decrease
in
males
and
females
(
6­
8%).
Decreased
body
weight
gain
in
males
and
females
(
8­
12%)
by
week
13.

Non­
guideline
Two
week
oral
toxicity
of
liver
(
rats)
00163455
(
1985)
Acceptable/
Nonguideline:
0,
30,
100,
300
mg/
kg/
day
Body
weight
decrement
was
seen
30
mg/
kg/
day
in
females
and
at
100
mg/
kg/
day
in
males.
Microsomal
enzymes
[
Ndemethylase
and
cytoplasic
granules
were
seen
at
100
mg/
kg/
day
and
higher
in
females.
Councilman
bodies
were
seen
in
liver
from
females
at
100
mg/
kg/
day
and
in
males
at
300
mg/
kg/
day.
Bile
duct
proliferation
was
seen
at
100
mg/
kg/
day
and
higher
doses
and
isolated
mitoses
was
in
male
and
female
livers
at
30
mg/
kg/
day.

870.3200
21/
28­
Day
dermal
toxicity
(
NZ
rabbit)
Acceptable
00149829
(
1984)
TXR#
004638
Supp.
11­
Lner'
88
0,
50,
250
mg/
kg/
day
NOAEL=
250
mg/
kg/
day
for
systemic
effects.
LOAEL=
None,
but
slight
skin
irritation
was
seen
at
250
mg/
kg/
day.

870.3150
90­
Day
oral
toxicity
(
dog)
Acceptable
00025648
(
1979)
TXR#
006018
0,
1,
5,
25
mg/
kg/
day
NOAEL=
1
mg/
kg/
day
LOAEL=
5
mg/
kg/
day
based
on
dose
related
decreased
prostate
weight,
and
dermal,
conjunctival
and
mucosal
irritation
effects
in
males
and
females.

870.3150
21­
Day
Inhalation
toxicity
(
rats)
00025650
(
1977)
TXR#
006018;
Unacceptable/
upgradab
le
on
submission
of
acceptable
particle
size
and
other
data
on
inhalation
characteristics.
Stated
exposure
levels
[
unverified]:
0,
0.0179,
0.0693,
0.1979
mg/
L
At
0.198
mg/
L,
male
body
weight
[
94%]
and
body
weight
gain
[
69%]
were
statistically
significantly
less
than
control.
Male
heart
weights
were
significantly
decreased
at
0.198
mg/
L
No
other
possible
treatment
related
effects
were
supported
by
histopathology
in
males
or
females,
including
irritation
of
the
mucosal
membranes.
The
study
authors
claimed
a
NOAEL/
LOAEL
of
0.0693/
0.198
mg/
L.
Table
4.1b:
Subchronic,
Chronic,
Developmental,
Reproductive
and
other
Toxicity
Profile
on
Bitertanol
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
12
of
58
~
870.3465
21­
Day
Inhalation
toxicity
(
dogs)
00025643
(
1977)
Unacceptable/
upgradab
le
on
submission
of
acceptable
particle
size
and
other
data
on
inhalation
characteristics.
Doses
administered:
0.0288
mg/
L
for
21
days
and
after
10
days
exposed
to
0.0471
mg/
L
for
21
days
in
a
whole
body
chamber.
The
dogs
showed
no
effects
from
either
exposures,
including
irritation
of
the
mucosal
membranes
noted
in
the
90­
day
oral
study
in
dogs.
However,
this
study
is
unacceptable
because
it
was
inadequately
described
and
data
no
particle
sizes
or
concentration
of
the
test
material
in
the
breathing
zone
of
the
dogs
were
submitted
~
870.4100a
Chronic
Toxicity
(
rats)
See
870.4300
870.4100b
Chronic
toxicity
(
Dogs)
00157465,
00157466
(
1983),
401632­
01
(
1986),
02
(
1986),
03
(
1987)
&
40186401
(
1987)
Studies
combined
Acceptable
0,
10,
40
160
ppm
(
0,
2.11,
8.18,
32.24
mg/
kg/
day)
for
2­
years
and
0,
3,
25
ppm
(
0,
0.78,
7.14
mg/
kg/
day
for
1­
year
and
200
ppm
(
50.93
mg/
kg/
day)
for
86
weeks.
NOAEL
=
10
ppm
(
2.11
mg/
kg/
day)
LOAEL
=
40
ppm
(
8.18
mg/
kg/
day)
based
on
adrenal
vacuolation
in
the
2­
year
study,
supported
by
adrenal
vacuolation,
and
160
and
200
ppm
eye
and
liver
effects.

~
870.4200a
Carcinogenicity
(
rats)
See
870.4300
~
870.4200b
Carcinogenicity
(
Mice)
00114280
(
1978)
TXR#
0002588
0,
20,
100,
500
ppm
(
M:
0,
5,
25,
129
mg/
kg/
day;
F:
0,
7,
37,
183
mg/
kg/
day)
NOAEL
=
100
ppm
[
M/
F:
25/
37
mg/
kg/
day]
LOAEL
=
500
ppm
[
M/
F:
129/
183
mg/
kg/
day]
based
on
marginal
body
weight
decrement
in
males
and
females
through
out
the
study
and
other
statistically
significant,
but
marginal
effects,
such
as
eosinophilic
foci
in
livers
of
females.
Increased
liver
wt
&
GPT
in
females
and
increased
ALP
&
urea
in
males.

No
dose
related
carcinogenicity
was
seen.
Table
4.1b:
Subchronic,
Chronic,
Developmental,
Reproductive
and
other
Toxicity
Profile
on
Bitertanol
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
13
of
58
~
870.4300
Combined
chronic/
carcinogeni
city
(
rat)
00114279
(
1981)
TXR#
0002588
0,
20,
100,
500
ppm
[
M:
0,
1.01,
4.89,
25.54
mg/
kg/
day:
F:
0,
1.32,
6.55,
33.53]
mg/
kg/
day]
NOAEL
=
100
ppm
[
M/
F:
4.89/
6.55
mg/
kg/
day]
LOAEL
=
500
ppm
[
M/
F:
25.54/
33.53
mg/
kg/
day]
based
on
nominal
decreased
body
weight
(
8%),
body
weight
gain
(
M/
F
11/
13%)
and
nominal
food
efficiency
in
males
and
females
(
9%)
throughout
the
treatment
period.
Statistically
significant
hematological
effects,
but
within
normal
ranges
were
seen
and
clinical
chemistry
values
were
statistically
significantly
changed,
but
within
normal
ranges,
such
as
decreased
urea,
increased
creatinine.

No
dose
related
tumors
were
seen
in
the
study.

~
Two
rat
developmental
toxicity
studies
in
Long­
Evans
and
Sprague
Dawley
rats
below
00154936
(
1977)
&
00114283
(
1981)
together
are
acceptable
Both
studies
together
are
acceptable.
Analysis
of
doses
were
conducted
in
neither
study,
among
other
deficiencies.
However,
since
both
studies
showed
the
similar
NOAEL/
LOAEL,
it
can
be
concluded
that
the
dose
levels
were
reasonably
accurate,
and
other
deficiencies
are
not
sufficient
to
show
unacceptability.
Malformations
were
seen
at
the
HDT
in
the
Long­
Evans
rat.

~
870.3700a
Prenatal
developmental
in
(
Long­
Evans
rats)
00154936
(
1977)
Acceptable
combined
with
00114283
(
1981)
0,
10,
30,
100
mg/
kg/
day
No
dose
concentration
analysis
Maternal
NOAEL=
10
mg/
kg/
day
LOAEL
=
30
mg/
kg/
day
based
on
dose
related
maternal
weight
gain
decrement.
Devel
NOAEL
=
10
mg/
kg/
day
LOAEL
=
30
mg/
kg/
day
based
on
stunted
fetuses
and
at
100
mg/
kg/
day
malformations,
kinked
tail,
cleft
palate,
rib
malformations
and
delayed
ossification.

~
870.3700a
Prenatal
Development
in
CR
Sprague
Dawley
Japan
rats
Report# ;
80571
00114283
(
1981)
Acceptable
combined
with
00154936
(
1977)
0,
10,
25,
65
mg/
kg/
day
TXR#
002588
Maternal
NOAEL=
10
mg/
kg/
day
LOAEL=
25
mg/
kg/
day
based
on
statistically
significant
decreased
body
weight
gain
decrement
during
dosing
period
(
GD
6­
15).

Devel
NOAEL=
10
mg/
kg/
day.
LOAEL=
25
mg/
kg/
day
increased
14th
rib
32%
and
70%
at
65
mg/
kg/
day.

Three
developmental
toxicity
studies
in
Chinchilla
and
Himalayan
rabbits
below
40490801,
40829401
(
1987),
00149830
&
40163205
[
supp]
(
1983)
&
00154937
SOP
(
1982)
and
00114284
(
1982)
together
with
the
supplementary
information
are
acceptable
for
a
guideline
developmental
toxicity
in
the
rabbit.
Nominal
increases
in
malformations
were
seen
at
100
and
150
mg/
kg/
day.
Table
4.1b:
Subchronic,
Chronic,
Developmental,
Reproductive
and
other
Toxicity
Profile
on
Bitertanol
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
14
of
58
~
870.3700b
Prenatal
developmental
in
(
Chinchilla
rabbits)
Report#
065283:
94704
40490801,
40829401
(
1987)
Acceptable
0,
10,
50,
250,
0
,150
mg/
kg/
day
Maternal
NOAEL
=
50
mg/
kg/
day
LOAEL
=
150
mg/
kg/
day
based
on
decreased
body
weight
gain
and
reduced
food
consumption.
At
250mg/
kg/
day
only
one
dam
showed
8
normal
fetuses,
4/
16
dams
died,
11/
16
of
the
remaining
dams
showed
complete
resorption.

Devel.
NOAEL
=
50
mg/
kg/
day
LOAEL
=
150
mg/
kg/
day
based
increased
post
implantation
loss,
decreased
fetal
weight,
skeletal
anomalies
(
abnormally
ossified
ribs
and
sternebrae
and
fused
ribs).

~
870.3700b
Prenatal
Developmental
in
Himalayan
rabbits
Report#
10979;
82239
Acceptable
00114284
(
1982)
Acceptable
0,
10,
30
,100
mg/
kg/
day
TXR#
002588
Maternal
NOAEL=
30
mg/
kg/
day
LOAEL=
100
mg/
kg/
day
based
on
decreased
maternal
weight
(
85.5g
versus
1.0
g)
GD
6­
18
Devel
NOAEL=
30
mg/
kg/
day
LOAEL=
100
mg/
kg/
day
based
on
decreased
fetal
weight
and
increased
resorptions
and
3
litters
with
nominally
increased
uncommon
malformations
(
epignathus,
aplasia
of
several
lung
lobes
&
aplasia
left
lung
and
hypoplasia
of
right
lung
verus
none
in
controls).

~
870.3700b
Prenatal
Developmental
in
Himalayan
rabbits
Report#
Br11548;
86432
00149830
&
40163205
[
supp]
(
1983)
&
00154937
SOP
(
1982)
Unacceptable
0,
10,
30,100
mg/
kg/
day
TXR#
004683
Maternal
NOAEL=
30
mg/
kg/
day
LOAEL=
100
mg/
kg/
day
based
on
marginal
decreased
maternal
body
weight
GD
6­
18
(
60g
versus
10g
control),
and
GD
6­
9
(­
4.6g
control
verus
­
55.4
g
at
HDT).
Devel
NOAEL=
30
mg/
kg/
day
LOAEL=
100
mg/
kg/
day
based
on
statistically
significant
decreased
fetal
wt,
resorptions
and
suggestive
increase
in
malformations,
2L
cleft
palate
&
3L
pigeon
chests
870.3700
&
870.3460
Inhalation
Developmental
in
rats
00114282
(
1979)
TXR#
003413,002588,00376
4
Unacceptable;
no
particle
size
defined
and
inadequate
description
of
the
test
conditions
and
data
reported.
Stated
test
doses:
Test
1
0,
0.00293,
0.00635,
0.02238,
Test
2;
0,
0.027,
0.060,
0.115
mg/
L
Reported
fetal
weight
decrement
at
0.115
mg/
L.
Reported
increased
incidence
of
runts
at
0.027
mg/
L
and
above
in
one
of
two
tests
could
not
be
verified.

Comment
40490802
Comment
on
3
rabbit
devel
studies:
The
registrant
did
not
believe
that
the
rabbit
studies
suggested
teratogenic
effects,
but
agreed
with
the
NOAEL/
LOAEL
of
50/
150
mg/
kg/
day;
however,
the
increased
post­
implantation
loss
is
considered
in
combination
with
the
nominally
increased
malformations
and
are
considered
to
be
suggestive
of
a
teratogenic
response
at
maternal
toxic
dose
levels
with
NOAEL/
LOAEL
of
50/
150
mg/
kg/
day
for
acute
exposure.
Table
4.1b:
Subchronic,
Chronic,
Developmental,
Reproductive
and
other
Toxicity
Profile
on
Bitertanol
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
15
of
58
~
870.3800
Reproduction
and
fertility
effects
(
Eberfeld
rats,
Sprague
Dawley
derived)
readable
00114281
(
1981)
Acceptable
0,
20,
100,
500
ppm
M/
F:
0,
1.0,
5.0,
25
mg/
kg/
day
Parental
NOAEL
=
20
ppm
(
F:
1.0
mg/
kg/
day)
LOAEL
=
100
ppm
(
5
mg/
kg/
day)
based
on
decreased
female
body
weight
and
body
weight
gain,
premating
and
at
500
ppm
decreased
males
body
weight
and
body
weight
gain.
Offspring:
NOAEL
=
20
mg/
kg/
day
(
1
mg/
kg/
day)
LOAEL
=
100
ppm
(
5.0
mg/
kg/
day)
based
on
reduced
f2
pup
weight
at
birth
and
nominal
dose
related
decreased
at
birth
for
f1,
f3
pups
and
reduced
lactation
or
viability
index
for
f1
and
f2
day
5
­
28
of
lactation.
Reproductive
organs:
NOAEL
=
500
ppm
(
25
mg/
kg/
day)
LOAEL
=
none
~
870.5450
Dominant
Lethal/
Mice
00025646
(
12/
4/
78)
0
and
1000
mg/
kg/
day
about
1/
4
of
the
LD50
in
mice.

Study
was
unacceptable
because
no
toxicity
was
shown
,
but
later
upgraded
to
acceptable.
Mice
(
50/
group)
were
dosed
with
bitertanol
in
a
single
dose
at
0
or
1000
mg/
kg
and
on
the
day
of
dosing
housed
in
a
cage
with
one
untreated
virgin
female
for
4
days.
This
cycle
was
repeated
for
12
females
for
48
days.
Fertility
rate,
corpora
lutea
counts,
pre­
and
post­
implantation
loss
and
live
implants
were
counted.
Although
no
toxicity
was
demonstrated
in
this
study,
the
mice
were
dosed
at
1/
4
of
the
LD50
for
mice,
which
was
probably
close
to
a
toxic
dose
level.

No
dominant
lethal
effects
were
noted
in
any
of
the
parameters
tested.

~
Guideline
870.5100,
Ames/
Salmonella
typhimurium,
reverse
mutation
and
WP2(
hcr)
of
Escherichia
Coli
reverse
mutation
00114286
(
1/
22/
81)
Acceptable,
Study#
MO­
01­
000295
0
to
5000
g./
plate
Bitertanol
was
tested
in
five
strains
of
Salmonella
[
TA
98,
TA
100,
TA
1535,
TA
1537,
TA
1538]
and
WP2(
hcr)
strain
of
Escherichia
Coli
with
and
without
S9
at
0,
1,
5,
10,
50,
100,
500,
1000,
5000
g./
plate.
Cytotoxicity
was
evident
at
500
g./
plate
and
above
with
and
without
S9.
A
Rec
assay
with
strains
H17
and
M45
with
Bacillus
subtilis
conducted
at
0,
20,
100,
200,
500,
100,
2000,
5000
g./
plate
without
S9
was
negative.
No
mutagenic
effects
were
noted
with
none
of
the
tests.

Study
is
acceptable
and
negative
for
reverse
mutation
but
not
for
Rec
assay
with
strains
H17
and
M45
with
Bacillus
subtilis
because
the
test
was
conducted
only
without
S9..

~
Guideline
870.5100,
Ames/
Salmonella
typhimurium,
reverse
mutation
00025651
(
1979)
Mobay#
67959
Unacceptable
0
to
2500
µ
g/
plate
Bitertanol
was
test
in
four
strains
of
Salmonella
[
TA
98,
TA
100,
TA
1535,
TA
1537]
with
S9
at
0,
4,
20,
100,
500,
2500
g./
plate
and
without
S9
at
0
and
2500
g./
plate.
Cytotoxicity
was
shown.
No
mutagenic
effects
were
noted.

Study
is
unacceptable,
but
the
lack
of
mutagenicity
is
supported
by
MRID#
00114286.
Table
4.1b:
Subchronic,
Chronic,
Developmental,
Reproductive
and
other
Toxicity
Profile
on
Bitertanol
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
16
of
58
~
Guideline
870.5300,
Mouse
lymphoma
L5178Y
TK+
test
(
in
vitro)
Acceptable
00149845
(
2/
23/
83)
Lab#
83/
BAG028/
028;
Mobay#
84194
0,1,5,10,15,20
g./
mL
Acceptable
Mouse
lymphoma
L5178YK+/­
cells
(
in
vitro)
were
exposed
4
hours
to
bitertanol
at
0,
1,
5,
10,
15,
20
g./
mL
with
and
without
S9
mix.
Concentrations
were
limited
by
cytotoxicity.

No
increased
mutation
frequency
over
controls
was
seen
at
any
concentration.

~
Guideline
870.5395
Miconucleus/
mice
00025645
(
10/
10/
78)
Lab#
7860;
Mobay#
66652;
0,
1000,
2000
mg/
kg/
day
for
two
days
Unacceptable;
Only
1
sampling
period
&
2
required
In
an
in
vivo
mouse
cytogenetics
test
on
erythrocyte
micronucleous,
5
mice/
group
were
dosed
twice,
24
hours
apart
with
0,
2x
1000
and
2x2000
mg/
kg/
day.
Bone
marrow
was
harvested
6
hours
after
the
last
dose.
One
mouse
at
the
HDT
showed
ruffled
coat.
The
study
was
negative,
possibly
due
to
timing
in
sampling.
Unacceptable
(
Contractor)
because
the
bone
marrow
samples
should
have
been
taken
between
18
hours
and
24
hours
instead
of
6
hours
after
the
last
dose.

~
Guideline
870.5500
Bacterial
DNA
Damage
or
Repair
00114285
(
12/
80)
Lab#
1896,
69099
0,
100,
333.3,
1000,
3300,
33300
g./
well
Acceptable
In
a
DNA
repair
study
(
growth
inhibition/
killing)
in
W3110(
polA+)
and
p3478(
polA­)
strains
of
Escherichia
coli
were
exposed
to
bitertanol
in
DMSO
with
and
without
S9.
Precipitation
was
seen
in
the
333.3
g./
well
and
above
concentration,
but
no
cytotoxicity
and
no
growth
inhibition.

There
was
no
evidence
of
DNA
damage
in
the
(
preferential
growth
inhibition
or
the
cell
killing
in
the
repair­
defective
strain
compared
with
the
repair­
competent
strain)
at
any
concentration
of
bitertanol.

None
Guideline
Aneuploid
induction
in
fungus
00114287
(
7/
78)
Lab#
2034;
Mobay#
80333
0,
0.1,
0.25,
0.5,
1.0,
2.5,
5.0,
10
mg/
L.
Acceptable/
NG
Buff
X
buff
crosses
of
Sordaria
brevicollis
were
exposed
to
bitertanol
in
DMSO
at
0
to
10
mg/
L
Grey
X
grey
crosses
were
exposed
at
0,
0.1,
0.5,
1.0,
2.5,
5.0
mg/
L.
Concentrations
above
2.5
mg/
L
reduced
fertility
and
ascospore
maturation.
Cytotoxicity
was
demonstrated.
Induced
aneuploid
frequency
at
5.0
mg/
L
in
the
buff
x
buffy
crosses,
but
not
in
the
grey
X
grey
crosses
was
attributed
to
selective
maturation
of
black
spores
and
buffy
spores
and
not
to
aneuploid
induction.

There
was
no
evidence
compound
related
changes
in
chromosome
numbers
in
the
study.
Table
4.1b:
Subchronic,
Chronic,
Developmental,
Reproductive
and
other
Toxicity
Profile
on
Bitertanol
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
17
of
58
870.7485
Metabolism
&
Pharmacokinetics
(
Wistar
rats)
00025733
(
1979),
00129560
(
1983)
Acceptable
Rats
were
dosed
with
1
&
1000
mg/
kg
in
a
single
oral
dose
and
multiple
doses
of
100
mg/
kg/
day
and
a
single
i.
v.
dose
of
100
mg/
kg.
Bitertanol
was
labeled
in
the
phenyl
ring
only.
The
studies
affirmed
the
relatively
rapid
absorption
of
[
14C­
phenyl­
UL]
BAYCOR
(
Bitertanol)
and
that
excretion
was
primarily
via
the
feces
(
81­
98%
and
92%,
respectively)
over
the
168­
hr
experimental
period.
Urinary
excretion
(
4­
11%)
was
secondary
to
fecal
elimination.
The
i.
v.
dose
indicated
that
biliary
excretion
was
extensive.
No
radioactive
was
detected
in
breath
samples.
Tissue
levels
were
low
and
indicated
no
bioaccumulation
and
the
1000
mg/
kg
dose
indicated
metabolic
saturation.
There
was
little
gender
differences.
Intestinal
bacterial
metabolism
increased
the
proportions
of
neutral
organic
(
none
acidic)
extracts
in
rats.
Parent
(
both
isomers)
and
12
metabolites
were
indentified
in
the
feces.
About
50%
of
the
radioactivity
remained
unextracted
in
the
feces.
Metabolites
were
p­
hydroxy
Baycor
(
both
isomers
I[
2]
&
II
[
1]),
m,
m­
dihydroxy
Baycor
I
[
8],
phydroxy
m­
methoxy
Baycor
[
5],
Baycor
alcohol
[,
p­
hydroxy
Baycor
alcohol
I
[
10]&
II
[
9],
ether
cleavage
products
among
the
conjugates
and
aliphatic
oxidation
to
carboxylic
acid
[
11,
12,
13,
14].
If
triazole
was
present
it
was
not
detected.
Numbered
structures
in
brackets
can
be
seen
in
the
Appendix.

870.7600
Dermal
absorption
(
rabbit)
00150149
(
1984)
Unacceptable/
not
upgradable
Study
only
accounted
for
8%
and
14%
of
the
dose
applied
in
male
and
female
rabbits,
respectively
and
92%
and
86%
of
the
applied
radio
label
was
not
reported.

4.2
FQPA
Hazard
Considerations
4.2.1
Adequacy
of
the
Toxicity
Data
Base
The
toxicity
data
base
is
old
with
deficiencies;
some
studies
date
back
to
1977.
However,
the
toxicity
data
base
is
adequate
for
FQPA
hazard
assessment
of
bitertanol.
A
combination
of
two
rat
developmental
studies
and
three
rabbit
developmental
studies
are
acceptable
for
developmental
toxicity
in
the
rat
and
rabbit.
The
reproduction
study
in
the
rat
is
acceptable,
since
the
study
showed
a
dose
response
in
body
weight,
which
is
supported
by
the
rat
90­
day
study
at
slightly
higher
dose
levels.
Only
the
developmental
rabbit
study
in
Chinchilla
rabbits
was
conducted
after
GLP
publication.

90­
Day
studies
in
the
rat
and
dog
and
the
chronic
dog
are
acceptable.
However,
the
chronic/
carcinogenicity
studies
were
dosed
at
marginally
adequate
dose
levels
showing
marginal
toxicity.
The
dietary
concentration
of
test
material
was
not
verified,
such
that
there
is
no
Page
18
of
58
verification
of
the
dosage
administered
to
the
rats
or
mice.
However,
both
studies
were
classed
as
acceptable,
since
some
toxicity
was
demonstrated
and
the
dose
levels
approached
an
adequate
dose
level.
In
addition,
the
rat
and
mouse
were
less
sensitive
to
bitertanol
toxicity
than
the
dog
and
the
chronic
RfD
was
based
on
a
lower
NOAEL
in
a
chronic
dog
study.
A
battery
of
adequate
and
negative
mutagenicity
studies
support
the
lack
of
cancer
in
carcinogenicity
studies.

4.2.2
Evidence
of
Neurotoxicity
There
was
no
evidence
of
neurotoxicity
among
the
guideline
studies
in
bitertanol
toxicity
data
base.
However,
literature
studies
with
bitertanol
show
limited
neurotoxic
effects.
Bitertanol
is
a
triazole
fungicide
with
structural
similarities
with
triadimefon
and
triadimenol.
Triadimefon
showed
hyperactivity,
but
bitertanol
did
not
in
that
study.
Bitertanol
showed
an
effect
on
a
certain
type
of
operant
behavior,
which
may
have
suggested
a
slight
hyperactivity.
The
difference
between
bitertanol
and
triadimefon
in
operant
behavior
is
complex,
but
bitertanol
has
no
effect
on
motor
activity
where
as
triadimefon
increases
motor
activity
[
Allen
and
MacPhail,
1993].
Another
reference
noted
the
difference
in
neurotoxic
effects
from
bitertanol
exposure
and
from
triadimefon
exposure
[
Crofton,
1996].
Crofton
speculated
that
benzene
ring
substitution
in
bitertanol
for
the
chlorine
in
triadimefon
sterically
hindered
the
effect.

4.2.3
Developmental
Toxicity
Studies
In
submitted
developmental
toxicity
studies,
qualitative
susceptibility
was
seen
in
the
rat
and
rabbit
at
the
same
dose
levels
as
maternal
toxicity.
A
nominal
increase
in
malformations
was
seen
in
the
Long­
Evans
rat
but
not
in
the
Sprague
Dawley
rat.
No
increase
in
malformations
was
seen
in
the
Chinchilla
rabbit,
but
nominally
increased
malformations
(
some
of
which
where
rare)
were
seen
in
the
two
Himalayan
rabbit
studies
at
the
HDT.
However,
in
all
3
rabbits
studies
postimplantation
loss
was
seen
at
the
HDT.
The
post­
implantation
loss
combined
with
nominally
increased
malformations
in
rabbits
and
nominally
increased
malformations
in
the
rat
suggests
that
bitertanol
exposure
results
in
terata
at
maternally
toxic
dose
levels.
There
was
no
indication
of
increased
susceptibility
in
the
rat
reproduction
study.

4.2.3.1
Rat
Developmental
Toxicity
with
Bitertanol
[
Long­
Evans
rats]

EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
(
MRID
00154936)
KWG
0599
(
96.5%
a.
i.,
lot/
batch
#
16001/
76)
was
administered
to
20­
22
female
Long­
Evans
rats/
dose
by
gavage
at
dose
levels
of
0,
10,
30,
or
100
mg/
kg
bw/
day
from
days
6
through
15
of
gestation.
On
gestation
day
(
GD)
20,
dams
were
sacrificed
and
all
fetuses
examined
externally.
Approximately
one­
third
of
the
fetuses
were
examined
viscerally,
and
the
remaining
two­
thirds
of
the
fetuses
were
examined
for
skeletal
malformations/
variations.
The
total
number
of
fetuses
(
number
of
litters)
examined
was
225(
20),
238(
20),
223(
20),
and
213(
19)
for
the
0,
10,
30,
and
100
mg/
kg
bw/
day
groups,
respectively.

Treatment
with
30
or
100
mg/
kg
bw/
day
of
KWG
0599
statistically
reduced
mean
body
weight
gain
of
the
dams
over
the
treatment
interval
of
GD
6­
15
(
80
and
48%
of
controls,
respectively;
p<
0.05).
Dams
in
the
mid­
dose
group
were
able
to
recover
during
the
5
day
post­
dose
interval,
with
overall
body
weight
gain
for
GDs
0­
20
comparable
to
controls,
while
high­
dose
group
dams
Page
19
of
58
had
reduced
body
weight
gain
over
the
entire
interval
of
GD
0­
20
(
84%
of
controls;
p<
0.05).
Feed
consumption
was
not
measured
in
this
study.
Gross
necropsy
was
not
conducted
on
the
dams,
so
it
is
not
known
if
treatment
resulted
in
any
gross
lesions.

Therefore,
the
maternal
toxicity
LOAEL
for
KWG
0599
in
rats
is
30
mg/
kg
bw/
day
based
on
reduced
body
weight
gain,
and
the
maternal
toxicity
NOAEL
is
10
mg/
kg
bw/
day.

No
treatment­
related,
statistically
significant
effects
on
pregnancy
rate,
resorptions/
dam,
fetuses/
litter,
or
fetal
sex
ratio
were
observed
in
the
treated
groups
compared
with
the
controls.
An
increase
in
the
total
number
of
resorptions
in
the
high­
dose
group
is
a
consequence
of
one
high­
dose
dam
that
had
complete
litter
resorption.
The
number
of
corpora
lutea
was
not
provided.

Treatment
with
30
and
100
mg/
kg
bw/
day
resulted
in
delayed
fetal
growth
as
evidenced
by
a
dose­
related
decrease
in
fetal
body
weight
(
3.72
and
3.29
g,
respectively
vs.
3.83
g
for
controls;
p<
0.05
for
high
dose)
and
an
increase
in
the
incidence
of
stunted
fetuses
[
fetuses(
litters)
affected:
8(
5)
and
50(
8),
respectively,
vs.
1(
1)
for
controls].
The
high­
dose
group
had
an
increased
fetal
incidence
of
delayed
overall
ossification
(
115/
146
fetuses
vs.
56/
158
for
controls)
and
of
vertebrae
(
98/
146
fetuses
vs.
33/
158
for
controls)
and
sternebrae
(
39/
146
fetuses
vs.
5/
158
for
controls).
Although
likely
an
effect
of
treatment,
the
reviewer
could
not
definitively
assign
significance
to
the
delayed
ossification
because
the
study
author
did
not
report
the
litter
incidences
of
these
delays.

Treatment
with
100
mg/
kg
bw/
day
resulted
in
an
increased
incidence
of
malformations.
A
total
of
five
litters
from
the
high­
dose
group
had
fetuses
with
malformations
compared
with
two
litters
each
in
the
low­
and
mid­
dose
groups
and
one
from
the
control
group.
Cleft
palate
was
considered
an
effect
of
treatment
with
100
mg/
kg
bw/
day
because
it
was
clearly
related
to
dose
[
fetuses(
litters)
affected:
4(
3)
vs.
0(
0)
for
all
other
groups]
and
was
above
the
historical
control
range.
Other
malformations
noted
in
the
high­
dose
group
were
of
low
incidence
but
were
not
seen
in
the
other
groups
and
included:
a
hydrocephalus,
a
kinked
tail,
rib
dysplasia
and
synostoses,
and
multiple
malformations
of
the
ribs,
spinal
column
and
tail.

Therefore,
the
developmental
toxicity
LOAEL
for
KWG
0599
in
rats
is
30
mg/
kg
bw/
day
based
on
delayed
fetal
growth,
and
at
100
mg/
kg/
day
nominally
increased
malformations
and
other
developmental
toxicity.
NOAEL
is
10
mg/
kg
bw/
day.

The
combined
developmental
toxicity
studies
in
the
rat
(
MRID#
00154936
&
00114283)
are
classified
Acceptable/
Guideline
and
do
satisfy
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
the
rat.
Main
deficiencies
include
data
pertaining
to
the
stability
of
KWG
0599;
homogeneity,
stability,
and
concentration
analyses
of
the
test
substance
in
the
dosing
medium;
and
summary
litter
incidences
of
skeletal
examination
data.
However,
another
unacceptable
study
in
Sprague
Dawley
rats
for
similar
reasons
showed
a
developmental
NOAEL/
LOAEL
of
10/
25
mg/
kg/
day
and
a
maternal
NOAEL/
LOAEL
of
10/
25
mg/
kg/
day
(
MRID#
00114283).
[
Note
this
study
was
considered
acceptable
in
August
10,
1982
memo
from
Gary
Bruin
to
Henry
Jacoby
(
HED
File
Code
13000
Tox
Reviews).]
Page
20
of
58
4.2.3.2
Rat
Developmental
Toxicity
with
Bitertanol
[
Sprague
Dawley
rats]

EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
(
MRID
00114283)
KWG
0599
(
95%
a.
i.,
lot/
batch
#
not
provided)
was
administered
to
25
female
Sprague­
Dawley
rats/
dose
by
gavage
at
dose
levels
of
0,
10,
25,
or
65
mg/
kg
bw/
day
from
days
6
through
15
of
gestation.
On
gestation
day
(
GD)
20,
dams
were
sacrificed
and
all
fetuses
examined
externally.
Approximately
one­
half
of
the
fetuses
were
examined
viscerally,
and
the
remaining
one­
half
of
the
fetuses
were
examined
for
skeletal
malformations/
variations.
The
total
numbers
of
fetuses
examined
(
number
of
litters)
were
315(
22),
305(
23),
321(
22),
and
311(
23)
for
the
0,
10,
25,
and
65
mg/
kg
bw/
day
groups,
respectively.
Two
dams
from
the
control
group
died
due
to
gavage
error.

Dams
treated
with
25
or
65
mg/
kg
bw/
day
of
KWG
0599
had
statistically
reduced
mean
body
weight
gain
over
the
treatment
interval
of
GD
6­
15
(
81
and
69%
of
controls,
respectively;
p<
0.05).
The
high­
dose
group
also
had
decreased
absolute
body
weight
on
GD
15
(
96%
of
controls;
p<
0.05).
Mid­
and
high­
dose
dams
were
able
to
recover
during
the
5
day
post­
dose
interval,
with
overall
body
weight
gain
for
GDs
0­
20
comparable
to
controls.
Feed
consumption
was
not
adversely
affected
by
treatment
as
measured
on
GD
1,
6,
15,
or
20.
However,
it
is
not
known
if
the
mid­
and
high­
dose
groups
had
reduced
feed
consumption
early
in
the
dosing
interval
since
feed
consumption
was
not
measured
at
any
intermediate
time
points.
Gross
necropsy
was
not
conducted
on
the
dams.

Therefore,
the
maternal
toxicity
LOAEL
for
KWG
0599
in
rats
is
25
mg/
kg
bw/
day
based
on
reduced
body
weight
gain
during
the
dosing
period,
and
the
maternal
toxicity
NOAEL
is
10
mg/
kg
bw/
day.

No
treatment­
related,
statistically
significant
effects
on
pregnancy
rate,
number
of
corpora
lutea,
pre­
or
post
implantation
loss,
resorptions/
dam,
fetuses/
litter,
or
fetal
sex
ratio
were
observed
in
the
treated
groups
compared
with
the
controls.
No
dams
had
complete
litter
resorption.
No
treatment­
related
malformations
or
external
or
visceral
variations
were
observed
in
any
group.

A
statistically
significant
increase
in
the
litter
incidence
of
the
presence
of
a
14th
rib
was
noted
in
the
mid­
and
high­
dose
groups
(
16/
21
and
22/
23
litters
affected,
respectively,
compared
to
7/
22
control
litters;
p<
0.05).
It
was
not
possible
to
assess
the
effect
of
treatment
on
other
skeletal
variations
from
the
summary
data
as
presented.
Although
the
number
of
fetuses
affected
was
provided,
the
number
of
litters
affected
was
not.
The
reviewer
did
not
calculate
the
litter
incidence
for
the
remaining
skeletal
variations,
including
the
degree
of
ossification
of
the
sternum,
coccygeal,
metacarpals,
and
metarsals.

Therefore,
the
developmental
toxicity
LOAEL
for
KWG
0599
in
rats
is
25
mg/
kg
bw/
day
based
on
a
dose
related
increased
incidence
of
a
14th
rib,
and
the
developmental
toxicity
NOAEL
is
10
mg/
kg
bw/
day.

The
combined
developmental
toxicity
studies
in
the
rat
(
MRID#
00114283
and
00154936)
are
Page
21
of
58
classified
Acceptable/
Guideline
and
do
satisfy
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
the
rat.
Although,
major
deficiencies
include
the
following:
stability
of
KWG
0599;
homogeneity,
stability,
and
concentration
analyses
of
the
test
substance
in
the
dosing
medium,
another
study
conducted
in
Germany
with
Long­
Evans
rats
showed
similar
endpoints.
It
should
be
noted
that
another
study
unacceptable
for
similar
reasons
in
Long­
Evans
rats
showed
malformations
at
100
mg/
kg/
day
and
showed
developmental
toxicity
with
a
NOAEL/
LOAEL
of
10/
30
mg/
kg/
day
with
a
maternal
NOAEL/
LOAEL
of
10/
30
mg/
kg/
day
(
MRID#
00154936),
but
was
considered
acceptable
when
combined
with
MRID#
00114283.

There
were
missing
fetuses
in
MRID#
00114283
with
no
explanation
(
7,
10,
7
and
0
from
control,
10,
25
and
65
mg/
kg/
day
dose
groups,
respectively,
but
no
fetuses
were
missing
from
the
HDT
where
the
effects
would
be
expressed
if
present.

4.2.3.3
Rabbit
Developmental
Toxicity
with
Bitertanol
[
Chinchilla
rabbits]

EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
(
MRID
40490801)
KWG
0599
(
96.9%
a.
i.,
batch/
lot
#
203
501
018)
was
administered
to
16
female
Chinchilla
rabbits/
dose
by
oral
gavage
at
dose
levels
of
0,
10,
50,
or
250
mg/
kg
bw/
day
from
days
6
through
18
of
gestation.
Due
to
excessive
toxicity
at
the
high
dose,
supplementary
groups
of
0
or
150
mg/
kg/
day
were
added.
Does
were
sacrificed
on
GD
28
and
subjected
to
gross
necropsy.
Fetuses
were
removed,
weighed
and
examined
for
external
and
visceral
malformations.
The
head
was
removed
and
examined
by
cross­
section
after
fixation.
All
carcasses
were
processed
for
skeletal
evaluation.
Analysis
on
a
litter
basis
of
data
obtained
during
skeletal
examination
was
presented
in
MRID
40829401.

At
150
and
250
mg/
kg/
day,
one
and
two
female(
s)
died,
respectively.
All
remaining
animals
survived
to
scheduled
sacrifice.
Clinical
signs
of
toxicity
in
the
250
mg/
kg/
day
group
included
six
does
with
hair
loss
in
the
throat
region
or
between
the
hind
legs,
bloody
toes
on
one
animal,
another
doe
with
mucoid,
yellowish
flux
from
the
vagina.
Absolute
body
weight
was
similar
between
the
treated
and
control
groups
throughout
the
study.
The
mean
body
weight
gain
and
food
consumption
by
the
does
at
10
mg/
kg/
day
were
not
affected
by
treatment.
At
50
mg/
kg/
day,
no
change
in
body
weight
was
noted
during
the
first
three
days
of
treatment;
thereafter,
the
mean
body
weight
gain
was
similar
to
that
of
controls.
In
groups
treated
with
250
mg/
kg/
day
or
150
mg/
kg/
day,
dose­
related
effects
on
the
body
weight
gain
were
noted.
During
the
treatment
interval,
the
250­
mg/
kg/
day
group
had
a
net
weight
loss
compared
to
a
net
gain
by
the
control
group
and
in
the
150­
mg/
kg/
day
group
weight
gain
was
28%
of
the
control
level.
Pre­
and
posttreatment
the
mean
body
weight
gain
for
all
treated
groups
was
similar
to
the
respective
control.
Food
consumption
at
50
mg/
kg/
day
was
84­
88%
of
the
control
level
during
gestational
days
6­
15
or
93%
of
control
during
gestational
days
6­
19
of
treatment
and
was
slightly
higher
than
control
amounts
for
the
remainder
of
the
study.
[
The
same
period,
gestational
days
6­
19,
showed
an
increase
in
body
weight
gain.]
Food
consumption
by
the
150­
mg/
kg/
day
group
was
63­
76%
of
controls
during
the
first
and
third
weeks
of
treatment
and
similar
to
or
slightly
higher
than
controls
at
other
times.
In
the
250­
mg/
kg/
day
group,
food
consumption
was
17­
26%
of
the
control
level
during
the
treatment
interval,
remained
53%
of
the
control
level
immediately
post
Page
22
of
58
treatment
(
GDs
19­
24)
and
rebounded
to
137%
of
the
control
level
during
the
last
four
days
of
the
study.

At
necropsy,
does
in
the
250­
mg/
kg/
day
group
were
observed
with
an
enlarged
liver
which
corresponded
to
an
increase
in
liver
weight
of
36.8%
compared
to
the
control
group.

The
maternal
toxicity
LOAEL
for
KWG
0599
in
mated
female
Chinchilla
rabbits
is
150
mg/
kg/
day,
based
on
reduced
food
consumption
and
decreased
body
weight
gain.
The
maternal
toxicity
NOAEL
is
50
mg/
kg
bw/
day.

No
test
article­
related
effects
were
noted
at
cesarean
section
or
fetal
examination
up
to
and
including
50
mg/
kg/
day.
In
the
250­
and
150­
mg/
kg/
day
groups
post­
implantation
losses
were
increased
in
a
dose­
related
manner
(
93.6%
vs.
4.9%
in
controls;
16.1%
vs.
5.0%
in
controls).
The
250­
mg/
kg/
day
group
had
a
total
of
15
complete
litter
resorptions,
resulting
in
only
one
litter
available
for
evaluation.
Empty
implantation
sites
were
also
found
in
the
250­
mg/
kg/
day
does
with
complete
litter
resorption,
but
no
evidence
of
abortion
was
observed.
In
the
150­
mg/
kg/
day
group,
two
does
had
complete
litter
resorption.
Mean
fetal
body
weight
for
the
one
live
litter
in
the
250­
mg/
kg/
day
group
and
for
the
150­
mg/
kg/
day
group
was
slightly
less
than
that
of
their
respective
control
group.

A
total
of
117(
15),
122(
15),
116(
15),
8(
1),
114(
15),
and
73(
11)
fetuses
(
litters)
were
available
for
evaluation,
respectively.
No
treatment­
related
external
or
visceral
malformations/
variations
were
seen
in
any
fetus
from
any
group.
In
the
150­
and
250­
mg/
kg/
day
groups,
the
quota
of
incompletely
or
non­
ossified
phalangeal
nuclei
of
fore­
and
hind­
limbs
and
calcanea
was
increased
in
a
dose­
related
manner
with
a
shift
towards
a
higher
percentage
of
fetuses
and
litters
showing
reduced
ossification.

The
developmental
toxicity
LOAEL
for
KWG
0599
in
mated
female
Chinchilla
rabbits
is
150
mg/
kg
bw/
day,
based
on
increased
post­
implantation
loss,
decreased
body
weight
and
reduced
ossification
of
the
fore­
and
hind­
limb
digits.
The
developmental
toxicity
NOAEL
is
50
mg/
kg
bw/
day.

The
developmental
toxicity
study
in
the
rabbit
is
classified
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
Chinchilla
rabbits.
Some
minor
study
deficiencies
are
listed
in
Section
III.
C.

4.2.3.4
Rabbit
Developmental
Toxicity
with
bitertanol
[
Himalayan
rabbits]

EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
(
MRID
00114284)
Bitertanol
[
96.7%
a.
i.;
composite
sample
of
5
batches
(
lot/
batch
numbers
not
reported)]
was
administered
to
12
mated
female
Himalayan
(
CHBB:
HM)
rabbits/
dose
by
gavage
in
aqueous
0.5%
Cremophor
EL
at
dose
levels
of
0,
10,
30,
or
100
mg/
kg
bw/
day
on
gestation
days
(
GDs)
6­
18,
inclusive.
On
GD
29,
the
surviving
does
were
sacrificed
and
subjected
to
cesarean
section,
and
the
numbers
of
implantation
sites,
male
and
female
fetuses,
and
"
losses,"
the
combined
weight
of
all
placentae
and
of
all
fetuses,
and
the
number
of
stunted
fetuses
(
weighing
less
than
25
g)
were
recorded
for
each
Page
23
of
58
doe.
Each
fetus
was
sexed
externally,
examined
for
external
malformations
and
malformations
of
the
abdominal
and
thoracic
organs
and
brain,
and
subjected
to
skeletal
evaluation
of
the
trunk
and
extremities
for
malformations
or
"
slight
skeletal
changes."

One
high­
dose
female
died
on
GD
29
after
exhibiting
diarrhea
and
weight
loss,
beginning
on
GD
10;
the
death
could
not
be
definitively
attributed
to
treatment.
Three
high­
dose
animals
had
hematuria
(
vs.
none
in
controls).
High­
dose
females
had
decreased
body
weight
gain
during
the
treatment
interval
(
1.0
vs.
85.5
g
for
controls;
p<
0.05)
and
over
the
entire
gestation
period
due
to
decreased
gravid
uterine
weight
(
65%
of
controls;
n.
s.).
Food
consumption
was
not
measured
and
gross
necropsy
findings
were
not
reported.

The
maternal
toxicity
LOAEL
for
bitertanol
in
Himalayan
rabbits
is
100
mg/
kg
bw/
day,
based
on
clinical
signs
(
hematuria)
and
decreased
body
weight
gain
(
GD
6­
18).
The
maternal
toxicity
NOAEL
is
30
mg/
kg
bw/
day.

At
the
highest
dose
level
there
was
a
decreased
mean
number
of
live
fetuses
per
litter
(
5.1
vs.
6.7
for
controls)
due
to
increased
postimplantation
loss
(
25.0%
and
1.7
"
losses"/
litter
vs.
7.5%
and
0.6
"
losses"/
litter
for
controls).
[
Note:
the
"
losses"
were
not
further
characterized
as
early/
late
resorptions
or
dead
fetuses.]
No
total
litter
resorptions
were
reported.
Mean
fetal
weight
and
placental
weight
were
decreased
at
the
highest
dose
level
(
86%
and
89%
of
controls,
respectively;
p<
0.05
for
fetal
weight).
In
the
control,
low­,
mid­,
and
high­
dose
groups,
respectively
a
total
of
74
(
11),
88
(
12),
89
(
12),
and
51
(
10)
fetuses
(
and
litters)
were
evaluated,
and
there
were
a
total
of
3
(
2),
0
(
0),
0
(
0),
and
3
(
3)
fetuses
(
litters)
with
malformations.
Two
of
the
affected
high­
dose
fetuses
had
the
rare
malformation
of
epignathus
or
pulmonary
hypoplasia
and
the
third
affected
high­
dose
fetus
had
aplasia
of
a
lung
or
lung
lobes
which
was
also
noted
in
the
fetuses
with
pulmonary
hypoplasia;
these
findings
may
be
treatment­
related.

The
developmental
LOAEL
for
bitertanol
in
Himalayan
rabbits
is
100
mg/
kg
bw/
day,
based
on
decreased
fetal
weight,
decreased
placental
weight,
decreased
live
litter
size,
increased
post­
implantation
loss,
and
rare
malformations.
The
developmental
toxicity
NOAEL
is
30
mg/
kg
bw/
day.

The
developmental
toxicity
study
in
the
rabbit
is
classified
Acceptable/
Guideline
and
does
satisfy
the
guideline
requirement
for
a
developmental
toxicity
study
in
the
rabbit
[
OPPTS
870.3700b;
OECD
414].
Although,
data
on
the
homogeneity
and
stability
of
the
dosing
solutions
were
not
submitted,
they
were
stated
to
be
confirmed.
In
addition,
this
study
shows
the
same
NOAEL/
LOAEL
for
maternal
and
developmental
toxicity
as
MRID#
00149830;
suggesting
that
the
doses
were
as
stated.
Submitted
historical
control
data
indicated
that
skeletal
variations
in
the
strain
of
rabbit
used
was
very
low
and
that
the
study
was
acceptable
(
TXR#
0004442).
It
should
be
noted
that
the
study
was
conducted
prior
to
the
implementation
of
the
Good
Laboratory
Practice
standards
and
the
current
guidelines.
This
study
also
can
be
used
as
weight­
of­
evidence
support
of
the
conclusions
in
MRID
40490801.

4.2.3.5
Rabbit
Developmental
Toxicity
with
bitertanol
[
Himalayan
rabbits]
Page
24
of
58
EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
(
MRID
149830)
KWG
0599
(
93.9%
a.
i.,
mixed
batch
from
June­
Oct
1978)
was
administered
orally
to
15
female
Himalayan
rabbits
/
dose
in
0.5%
aqueous
Cremophor
emulsion
at
dose
levels
of
0,
10,
30,
or
100
mg/
kg
bw/
day
from
gestation
days
(
GD)
6­
18,
inclusive.
Body
weight
was
measured
on
GD
0,
6­
18,
and
29.
On
GD
29,
dams
were
sacrificed
with
T61
and
subjected
to
caesarian
section.
Examination
at
sacrifice
consisted
of:
number
of
implantation
sites,
number
of
male
and
female
fetuses,
number
of
"
losses",
and
placental
weight.
Gross
examination
of
the
dams
was
not
described.
Food
consumption
was
not
reported.
Fetuses
were
examined
for
external
malformations
and
alterations.
The
litter
weight,
mean
fetal
weight
per
litter,
number
of
stunted
(<
25
grams)
fetuses,
and
the
sex
of
each
fetus
were
determined.
All
fetuses
were
subjected
to
visceral
examination.
Fetuses
were
examined
for
cerebral
malformations
following
severance
of
the
head
from
the
corner
of
the
mouth
to
the
base
of
the
ear,
and
for
skeletal
malformations
following
staining
with
Alizarin
Red
S.
Additional
details
of
the
methods
were
given
in
MRID
00154937
and
limited
historical
control
data
were
provided
in
MRID
40163205.

At
doses
up
to
and
including
30
mg/
kg/
day
there
were
no
treatment
related
effects
on
maternal
survival,
clinical
signs,
body
weight,
food
consumption,
or
caesarean
parameters.
However,
at
100
mg
KWG
0599
/
kg
bw/
day,
the
dams
reportedly
ate
less,
although
no
data
are
presented
to
confirm
the
magnitude
of
effect.
Further,
two
dams
bled
occasionally
from
the
vagina.
Absolute
body
weight
was
similar
between
the
treated
and
control
groups
throughout
the
study.
The
mean
weight
gain
of
the
control
group
and
the
treated
groups
did
not
differ
significantly
from
each
other,
however,
weight
gain
by
the
high­
dose
group
during
the
treatment
interval
was
60%
of
the
control
group
level.
All
groups
including
controls
lost
weight
during
the
first
three
days
of
treatment
with
the
greatest
magnitude
in
the
high­
dose
group
(­
55.6
g
vs
­
4.6
g
for
controls).
The
evidence
for
maternal
toxicity
is
an
unsupported
statement
by
the
authors
that
rabbits
at
100
mg/
kg/
day
ate
less
and
past
fewer
stools
than
other
groups,
one
abortion
occurred,
vaginal
bleeding
was
reported
for
two
rabbits
during
the
study
and
the
body
weight
gain
decrement
during
GD
6­
9.
The
evidence
for
maternal
toxicity
is
marginal
at
best.

The
tentative
maternal
toxicity
LOAEL
for
KWG
0599
in
Himalayan
rabbits
is
100
mg/
kg
bw/
day
based
on
reduced
body
weight
gain.
The
tentative
maternal
toxicity
NOAEL
is
30
mg/
kg/
day.

At
doses
up
to
and
including
30
mg/
kg/
day,
there
were
no
treatment
related
effects
on
developmental
parameters.
The
high
dose
of
100
mg/
kg/
day
was
embryotoxic
and
teratogenic;
dams
in
this
dose
group
had
a
significantly
higher
resorption
rate
(
postimplantation
loss:
64.2%
vs
21.0%
in
controls)
due
to
seven
high­
dose
animals
with
complete
liter
loss
[
one
abortion
and
6
litters
with
complete
resorption.
In
addition,
one
high­
dose
doe
aborted
on
GD
23.
The
total
number
of
fetuses
(
litters)
evaluated
was
81
(
14)
control,
90
(
15)
low­
dose,
86
(
15)
mid­
dose,
and
34
(
8)
high­
dose.
Mean
fetal
body
weight
in
the
high­
dose
group
was
significantly
lower
than
controls
(
34.94
g
vs
39.38
g
for
controls).
Finally,
there
was
a
greater
incidence
of
fetal
malformations
in
the
100
mg/
kg
dose
group
compared
to
controls
(
1
fetus
in
the
control
group
had
one
type
of
malformation;
6
fetuses
from
4
high­
dose
litters
had
one
or
two
types
of
malformations).
Fetal
malformations
in
the
100
mg/
kg/
day
dose
group
included
cleft
palate
(
2
fetuses;
2
litters),
"
pigeon
chest"
(
4
fetuses;
2
litters),
arthrogryposis
(
1
fetus),
abnormal
posture
of
the
hind
extremities
(
1
fetus),
and
rib
and
spinal
column
adhesions
(
1
fetus).
In
the
control
Page
25
of
58
group,
only
one
fetus
was
observed
with
a
malformation
(
arthrogryposis)
and
2
fetuses
from
2
litters
in
the
10
mg/
kg/
day
dose
group
had
malformations
(
rib
and
spinal
column
adhesions;
umbilical
hernia
and
fusion
of
ribs);
no
malformations
were
observed
in
the
30
mg/
kg/
day
dose
group.

The
tentative
developmental
toxicity
LOAEL
for
KWG
0599
in
Himalayan
rabbits
is
100
mg/
kg
bw/
day,
based
on
increased
resorption
rate,
decreased
body
weight,
and
increased
incidence
of
fetal
malformations.
The
tentative
developmental
toxicity
NOAEL
is
30
mg/
kg
bw/
day.

The
developmental
toxicity
study
in
the
rabbit
is
classified
Unacceptable/
Guideline
and
does
not
satisfy
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
rabbits.
Major
deficiencies
include
lack
of
analyses
of
homogeneity,
stability,
and
concentration
of
the
dosing
solutions.
The
lack
of
analysis
of
dosing
concentrations
could
be
mitigated
by
the
similar
NOAEL/
LOAEL
to
MRID#
00114284,
but
the
omission
of
data
requested
that
could
verify
some
of
the
effects,
prevents
this
study
form
being
acceptable.
The
data
requested
should
be
submitted.
For
a
list
of
other
study
deficiencies,
refer
to
Section
III.
C.
This
study
can
be
used
as
weight­
of­
evidence
support
of
the
conclusions
in
MRID
40490801.
[
This
study
was
unacceptable
in
TXR#
0006528,
but
concluded
that
fetal
toxicity
in
the
form
of
fetal
weight
decrement,
fetal
lose/
dam
and
decreased
number
of
litters
was
shown
at
100
mg/
kg/
day.]

4.2.4
Reproductive
Toxicity
Study
Bitertanol
EXECUTIVE
SUMMARY:
In
a
3­
generation
reproduction
study
(
MRID
00114281),
bitertanol
[
95.0%
a.
i.;
batch
nos.
16012/
77
and
16001­
16004/
78
(
mixed
sample)]
was
administered
to
10
male
and
20
female
FB
30
(
Elberfeld)(
Sprague
Dawley
derived)
rats/
group
in
the
diet
at
concentrations
of
0,
20,
100,
and
500
ppm
(
equivalent
to
0,
1,
5,
and
25
mg/
kg
bw/
day
using
a
food
factor
of
0.05
for
the
rat).
Parental
animals
were
administered
the
treated
or
control
diets
for
56
days
(
F
0
)
or
70
days
(
F
1
and
F
2
)
prior
to
mating,
throughout
mating,
gestation,
and
lactation,
and
until
necropsy.
Two
litters
(
A
and
B)
were
produced
by
each
generation,
and
the
parental
animals
for
the
next
generation
were
selected
from
the
B
litters.
In
the
absence
of
analytical
data
for
the
diet
formulations
and
lack
of
food
consumption
data,
the
actual
dosages
to
the
study
animals
are
unknown;
therefore
the
LOAELs
and
NOAELs
set
below
are
tentative
ones.

There
was
no
treatment­
related
effect
on
mortality,
and
no
treatment­
related
clinical
signs
were
reported.
High­
dose
males
and
females
of
all
three
generations
consistently
had
decreased
body
weight
gain
during
the
first
2­
3
weeks
of
premating
(
F
0
,
F
1
,
and
F
2
males:
45­
89%,
81­
83%,
and
71­
80%
of
controls,
respectively;
F
0
,
F
1
,
and
F
2
females:
44­
81%,
75%,
and
65­
77%).
The
significant
decreases
in
absolute
body
weight
persisted
throughout
premating,
but
tended
to
decrease
in
magnitude
over
time
(
F
0
,
F
1
,
and
F
2
males:
76­
91%,
69­
88%,
and
66­
92%
of
controls;
F
0
,
F
1
,
and
F
2
females:
77­
91%,
71­
89%,
and
68­
87%).
F
1
mid­
dose
females
had
marginally
decreased
absolute
body
weight
during
weeks
9­
14
(
91­
92%)
after
gaining
3­
4
g
less
per
week
than
controls
during
weeks
5­
9
and
had
decreased
weight
gain
during
weeks
9­
11
(
87%
of
controls).
F
2
mid­
dose
females
also
had
significant
decreases
in
absolute
body
weight
throughout
premating
(
84­
89%;
p<
0.01)
along
with
slightly
decreased
body
weight
gain
during
most
Page
26
of
58
intervals.
No
treatment­
related
gross
changes
were
noted
at
necropsy
of
the
F
2
adults,
and
there
were
no
treatment­
related
effects
on
organ
weight.
Microscopic
examination
of
tissues
from
F
2
adults
revealed
bile
duct
proliferation
at
increasing
severity
in
mid­
and
high­
dose
males
and
at
increasing
incidence
and
severity
in
high­
dose
females.
In
males,
this
finding
was
seen
in
2/
5
controls,
1/
5
low­,
1/
5
mid­,
and
2/
5
high­
dose
males,
with
average
grades
of
1.0,
1.0,
2.0,
and
2.5,
respectively.
In
females
this
finding
was
seen
in
1/
5
and
4/
5
mid­
and
high­
dose
animals,
respectively
(
vs.
0/
5
controls)
with
average
grades
of
1.0
and
2.3,
respectively.
However,
since
microscopic
evaluation
was
limited
to
5
F
2
animals/
sex/
dose,
these
data
are
of
limited
usefulness
and
were
not
used
to
set
toxicity
levels.

The
parental
systemic
LOAEL
for
bitertanol
in
FB
30
(
Elberfeld)
rats
is
100
ppm
for
females
(
approximately
5
mg/
kg
bw/
day)
and
500
ppm
for
males
(
approximately
25
mg/
kg
bw/
day),
based
on
decreased
body
weight
and
body
weight
gain
during
premating.
The
parental
systemic
NOAEL
is
20
ppm
for
females
(
approximately
1
mg/
kg
bw/
day)
and
100
ppm
for
males
(
approximately
5
mg/
kg
bw/
day).

Treatment­
related
effects
on
offspring
body
weight
and
body
weight
gain
were
noted
in
high­
dose
pups
from
all
generations
and
litters,
in
the
mid­
dose
F
2a
and
F
2b
pups,
and
the
mid­
dose
F
3a
pups.
The
high­
dose
F
3b
pups
had
significantly
decreased
mean
body
weight
beginning
on
LD
5,
postcull
and
continuing
through
the
remainder
of
lactation
(
79­
87%
of
controls),
while
all
of
the
other
high­
dose
pups
had
significantly
decreased
mean
weight
at
birth
and
throughout
lactation
(
F
1a
:
75­
80%;
F
1b
:
70­
90%;
F
2a
:
76­
86%;
F
2b
:
62­
76%;
F
3a
:
84­
89%
of
controls).
In
high­
dose
pups,
the
greatest
effect
on
body
weight
gain
was
during
LD
0­
5;
cumulative
weight
gain
during
the
LD
0­
28
interval
was
also
decreased
(
F
1a
and
F
1b
:
78%
and
68%;
F
2a
and
F
2b
:
80%
and
64%;
F
3a
and
F
3b
:
88%
and
78%
of
controls,
respectively).
Mid­
dose
F
2
pups
had
significantly
decreased
body
weight
throughout
lactation
(
F
2a
:
78­
93%;
F
2b
:
71­
84%);
the
F
2a
pups
mainly
had
decreased
weight
gain
during
LD
0­
5
(
60%),
with
absolute
body
weight
showing
evidence
of
recovery
by
LD
28,
whereas
the
F
2b
pups
had
decreased
weight
gain
throughout
lactation
(
LD
0­
5:
57%;
LD
5­
28:
79%)
and
did
not
show
recovery.
The
mid­
dose
F
3a
pups
had
decreased
weight
gain
at
the
beginning
of
lactation
(
82%);
absolute
pup
weight
was
not
affected
until
LDs
7
and
14
(
86­
88%
of
controls),
and
recovery
had
occurred
by
LD
21.
Additional
evidence
of
offspring
toxicity
seen
at
the
highest
dose
level
included
decreased
pup
survival
(
decreased
viability
index
and/
or
lactation
index)
in
all
high­
dose
litters
of
all
generations.
Correspondingly,
decreased
litter
size
occurred
in
the
high­
dose
F
1
A
litters
on
LDs
0
and
5,
pre­
cull
(
81%
and
73%
of
controls,
respectively),
and
in
the
high­
dose
F
3
A
litters
throughout
lactation
(
LD
0:
77%;
LD
5,
pre­
cull:
67%;
LD
28:
69%
of
controls).

The
offspring
LOAEL
for
bitertanol
in
FB
30
(
Elberfeld)
rats
is
100
ppm
(
approximately
5
mg/
kg
bw/
day),
based
on
decreased
body
weight
and
body
weight
gain.
The
offspring
NOAEL
is
20
ppm(
approximately
1
mg/
kg
bw/
day).

No
clear
treatment­
related
effects
on
reproductive
performance
(
fertility
and
gestation
indices)
were
seen
in
any
generation
or
litter.
Ovarian
and
testicular
weights
of
the
F
2
animals
were
not
affected
by
treatment,
and
no
gross
changes
of
the
testes,
epididymides,
ovaries
or
uteri
of
the
F
2
adults
and
F
3b
weanlings
(
10/
sex/
group)
were
reported.
Histopathological
evaluation
of
testes
and
ovaries
from
5
F
2
animals/
sex/
group
and
testes,
ovaries,
and
uteruses
from
10
F
3b
Page
27
of
58
weanlings/
sex/
group
did
not
reveal
any
clear
treatment­
related
changes.

Under
the
conditions
of
this
study,
the
reproductive
LOAEL
for
bitertanol
in
FB
30
(
Elberfeld)
rats
is
not
identified,
and
the
reproductive
NOAEL
is
greater
than
or
equal
to
500
ppm
(
approximately
25
mg/
kg
bw/
day).

This
study
is
Acceptable/
Guideline
and
does
satisfy
the
guideline
requirement
for
a
2­
generation
reproductive
study
[
OPPTS
870.3800;
OECD
416]
in
rats.
Although
there
were
no
analyses
for
concentration,
homogeneity
and
stability
of
the
test
material
in
the
diet,
the
study
is
acceptable
for
the
following
reasons:
(
1)
A
dose
related
response
was
noted
in
several
parameters,
indicating
that
the
animals
were
dosed.
(
2)
The
body
weight
decrement
data
is
supported
by
an
acceptable
90­
day
study
in
a
similar
strain
of
rat
with
a
NOAEL/
LOAEL
=
3.6/
18.6
mg/
kg/
day
(
MRID#
00157853)
and
an
acceptable
90­
day
study
in
dogs
with
a
NOAEL
/
LOAEL
of
1/
5
mg/
kg/
day
(
MRID#
00025648).

Although
there
were
a
number
of
other
deficiencies
in
the
conduct
of
this
study
[
see
deficiency
section],
the
study
was
conducted
prior
to
the
implementation
of
the
guidelines
and
these
deficiencies
did
not
adversely
affect
the
quality
of
the
data
that
was
attained.
However,
rotating
each
female
with
3
males
without
an
evaluation
of
each
mating
as
was
done
in
this
study
is
not
a
recommended
practice.

4.2.5
Additional
Information
from
Literature
Sources
Several
papers
considered
aspects
of
bitertanol
toxicity
were
found
in
the
literature.
FAO
and
WHO
working
groups
[
1983]
&
[
1987]
reviewed
toxicity
data
of
bitertanol.
In
general
the
review
of
the
toxicity
data
agreed
with
the
results
in
the
DERs
by
EPA,
including
the
rabbit
dermal
study,
the
rat
chronic
study,
the
chronic
dog
study
and
the
metabolism
study
in
rats.
These
references
indicated
the1000
mg/
kg
dose
level
resulted
in
saturation
of
the
metabolic
system,
which
showed
reduced
absorption
and
increased
unmetabolized
parent
material
in
the
feces.

Another
FAO
and
WHO
working
group
paper
[
1998]
reviewed
more
completely
the
toxicity
and
metabolism
data
on
bitertanol
than
did
the
1983
paper.
The
review
of
the
toxicity
data
confirmed
the
interpretation
of
similar
studies
by
EPA.
Metabolism
studies
of
bitertanol
showed
that
84%
of
the
orally
administered
dose
was
rapidly
absorbed,
metabolized
and
excreted
through
the
bile
into
the
feces.
The
terminal
phase
of
elimination
from
the
plasma
showed
a
½
life
was
26
hours.
Parent
compound
was
not
detected
in
bile
or
urine.
Parent
was
found
only
in
the
feces
of
which
15%
of
the
administered
dose
probably
represented
unabsorbed
material.
Radiolabel
was
excreted
in
the
urine
[
4%­
11%]
and
the
remaining
material
in
the
feces.
Para­
hydroxy­
bitertanol
was
the
only
metabolite
identified
in
the
bile.
Smaller
amounts
of
para­
hydroxybitertanol
acid,
parabitertanol
alcohol
and
bitertanol
acid
were
identified.
Ring
dihydroxylation,
aryl­
0­
methylation,
ether
cleavage
products,
and
aliphatic
hydroxylation
and
oxidation
to
acid
with
gluronide
and
sulfate
conjugates
were
tentatively
identified.

The
1998
reference
also
reviewed
studies
of
central
nervous
system.
Mice
administered
single
doses
of
bitertanol
at
0.075,
0.6
or
4.8
mg/
kg.
The
results
showed
no
significant
effects
with
Page
28
of
58
potentiation
of
anesthesia,
stimulation
of
spontaneous
motility,
open
field
test,
reserpine
ptosis,
potentiation
of
amphetamine
effects
or
antagonism
to
reserpine
ptosis.
Mice
administered
single
oral
doses
of
0.02,
0.2,
2,
20
or
200
mg/
kg
showed
significantly
increased
spontaneous
motor
activity
at
200
mg/
kg
only.
Rats
showed
increased
spontaneous
motor
activity
at
single
dose
of
200
mg/
kg,
but
not
at
100
mg/
kg
orally
or
intraparitoneally.

A
radiolabeled
50%
formulation
of
bitertanol
administered
dermally
to
rabbits
showed
a
10%
dermal
penetration.
The
1998
reference
cited
Hixson,
1984.
[
Study
was
classified
by
OPP
as
unacceptable
because
only
one
dose
level
was
used
and
the
study
did
not
account
for
86
to
92%
of
radio­
label
applied.]

Four
references
were
found
relative
to
the
developmental
toxicity
of
bitertanol.
Schardien
(
1993)
referred
to
a
short
note
by
Vergieva
(
1990)
in
stating
that
bitertanol
resulted
in
microacardia
and
acaudia
and
in
rare
cases
exophtalamus,
hypgnathia
and
cleft
palate.
The
short
note
stated
that
a
clear
dose
effect
relationship
was
established
from
single
doses
at
100,
500
and
1000
mg/
kg
on
gestational
day
9,
10,
11
or
13.
The
two
other
developmental
toxicity
studies
in
the
rat
were
TSCA
Section
8(
e)
submissions
already
discussed
under
MRID#
00154936
(
studied
by
gavage
dosing)
and
00114282
(
studied
through
inhalation
dosing).
The
latter
study
was
inadequate
because
no
particle
sizes
were
discussed.
The
study
(
MRID#
00154936),
which
used
doses
by
gavage
at
0,
10,
30
or
100
mg/
kg/
day,
showed
maternal
weight
reduction
and
stunted
fetal
growth
at
NOAEL/
LOAEL
of
10/
30
mg/
kg/
day.
Bone
anomalies
were
statistically
increased
in
a
treatment
related
manner
at
100
mg/
kg/
day
when
sternebrae
(
delayed
ossification)
and
vertebrae
(
dumb­
bell)
anomalies
were
added
together.

Lewalther
and
Korallus
(
1986)
advocated
testing
for
exposure
to
bitertanol
by
detecting
4­
hydroxyphenylphenol
aducts
to
erythrocytes.

Allen
and
MacPhail
[
1993]
noted
that
Long­
Evan
rats
showed
increases
in
operant
responding
behavior,
but
not
motor
activity.
Operant
Behavior:
Operant
chambers
using
milk
delivery
for
reinforcement
and
3
multicolored
cue
lights
centered
a
lever
on
the
front
panel
and
a
house
light
was
mounted
at
the
top
of
the
panel
above
a
speaker.
Below
the
speaker
was
a
Sonalert
device
that
was
briefly
activated
following
a
response.
The
rats
were
trained
to
consume
milk
from
the
dipper
and
then
to
press
the
lever.
After
all
the
rats
performed
on
a
FR­
2
schedule
for
one
session,
the
multiple
FI
1­
min
F1
5­
min
schedule
(
with
a
60­
s
limited
hold
in
each
component)
was
initiated.
Discriminative
stimuli
were
illumination
of
either
the
house
light
(
F1
1­
min)
or
the
cue
lights
(
F1
5­
min).
Motor
Activity:
Motor
activity
chambers
were
used
with
a
platform
that
housed
5X8
matrix
of
photodetectors
that
were
illuminated
by
a
single
overhead
incandescent
lamp.
Each
movement
that
occluded
a
photodetector
was
recorded
as
a
horizontal
activity
count
(
6
rats/
group).

Operant
behavior
results
were
recorded
as
a
percentage
of
the
control
response
rate.
Bitertanol
was
administered
orally
in
a
single
dose
at
0,
10,
30,
56,
100
or
300
mg/
kg.
Bitertanol
showed
no
effect
on
overall
response
rates
or
index
of
curvature
(
IOC)
at
lowest
dose[
10
mg/
kg],
but
response
rates
increased
for
both
F1
components,
but
were
greater
in
F1
5­
min
than
the
F1
1­
min
component
at
the
three
intermediate
doses
[
30,
56,
and
100
mg/
kg]
and
then
fell
to
control
levels
at
300
mg/
kg.
Unlike
triadimefon,
bitertanol
administration
had
no
effect
on
motor
activity
in
Page
29
of
58
these
rats.
These
response
patterning
were
similar
to
triademifon
and
other
stimulants,
and
dissimilar
from
those
reported
for
most
other
pesticides.
Bitertanol
response
patterning
in
the
operant
behavior
tests
resembled
the
effects
of
triadimefon,
but
the
response
was
not
as
great.
The
data
were
reported
as
a
percentage
of
control
and
did
not
clearly
state
the
number
of
animals
used/
group
to
test
for
operant
behavior.

Crofton
[
1996]
noted
that
the
triazole
pesticide
triadimefon
exposure
affects
the
CNS
catecholamines
and
introduces
a
transient
hyperactivity
and
sterotyped
behaviors
in
rats.
Of
the
16
triazole
pesticides
studied
for
hyperactivity
in
a
figure­
eight­
maze
with
photodetectors,
only
triadimefon
and
triadimenol
showed
hyperactivity
when
dosed
acutely.
Crofton
suggested
that
the
SAR
for
triazole­
induced
hyperactivity
is
fairly
rigid
and
requires
the
ether
linkage
between
the
phenyl
group
and
the
aliphatic
group
for
activity;
and
the
lack
of
effect
of
bitertanol,
which
has
this
ether
linkage,
was
the
result
of
stearic
hindrance
from
the
benzene
ring
substituted
for
a
chlorine
of
triadimefon
and
triadimenol.

The
1998
FAO
and
WHO
reference
indicated
the
acute
toxicity
of
metabolites
of
bitertanol.
A
ketone
metabolite
of
bitertanol,
1­(
triazol­
1­
yl)­
1­(
4'­
phenyphenoxy)­
3,3­
dimethylbutan­
2­
one,
induced
signs
of
effects
on
the
CNS,
with
initial
sedation
and
respiratory
disturbances
and
later
stimulation.
The
highest
oral
dose
technically
administrable
was1750
mg/
kg,
which
caused
no
deaths.
A
metabolite
not
seen
in
rat
studies,
bitertanol
benzoic
acid
at
an
oral
acute
dose
of
5000
mg/
kg
showed
no
toxicity.
1,2,4­
triazole
given
orally
in
an
acute
dose
showed
an
LD50
of
1600
mg/
kg.
When
administered
dermally
the
acute
LD50
was
4200
mg/
kg.
1,2,4­
triazole
was
strongly
irritating
to
the
mucus
membranes
of
rabbit
eyes.
In
a
90­
day
subchronic
study
at
0,
100,
500,
or
2500
ppm,
1,2,4­
triazole
administration
orally
resulted
in
temporary
reduction
in
food
intake,
body
weight
and
transient
palmospasms
in
isolated
animals.
Significant
decreases
in
hemoglobin,
hematocrit,
mean
corpuscular
volume
and
mean
corpuscular
hemoglobin
in
male
rats
at
2500
ppm.
Fat
accumulation
was
seen
in
the
3/
15
male
livers
at
2500
ppm.
The
NOAEL
was
500
ppm
(
38
mg/
kg/
day).
In
developmental
toxicity
in
the
Wistar
rat,
the
triazole
metabolite
administration
resulted
in
reduced
fetal
weight,
increased
resorption,
and
malformations
including
cleft
palate
and
malformed
extremities
at
maternal
toxic
dose
levels.
The
NOAEL
was
30
mg/
kg/
day,
which
was
higher
than
the
NOAEL
of
10
mg/
kg/
day
with
bitertanol
in
Long­
Evans
and
Sprague
Dawley
rats
at
maternally
toxic
doses.

4.2.6
Pre­
and/
or
Postnatal
Toxicity
4.2.6.1
Determination
of
Susceptibility
Qualitative
susceptibility
was
seen
in
two
developmental
toxicity
studies
[
1982­
1983]
in
Himalayan
rabbits
and
qualitative
susceptibility
was
seen
in
one
developmental
toxicity
study
in
Chinchilla
rabbits
[
MRID#
40490801,
1987]
that
showed
increased
resorptions
at
dose
levels
causing
slight
maternal
weight
gain
decrement.
These
studies
showed
no
increased
quantitative
susceptibility.
The
two
rat
developmental
toxicity
studies
showed
stunted
fetuses
and
increased
incidence
of
14th
rib
at
maternally
toxic
dose
levels,
and
at
higher
dose
levels
nominally
increased
incidence
of
malformations
in
one
rat
study,
but
no
increased
susceptibility.
No
offspring
pre­
or
postnatal
susceptibility
was
seen
in
a
3­
generation
reproduction
study.
Page
30
of
58
4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
There
was
evidence
of
malformations
at
high
doses
in
two
developmental
toxicity
studies
in
rats,
but
no
quantitative
susceptibility
and
NOAELs
were
clearly
defined.
In
rabbits
there
were
three
developmental
studies
which,
when
combined,
clearly
delineated
developmental
toxicity
in
the
rabbit.
Although
there
were
some
deficiencies
in
the
rat
reproduction
study,
the
study
is
considered
acceptable
and
indicates
that
there
are
adequately
defined
NOAELs
and
no
evidence
of
susceptibility.
There
is
no
residual
uncertainty
with
respect
to
pre­
and
post­
natal
toxicity
based
on
the
submitted
developmental
and
reproduction
studies.

4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
The
literature
refers
to
single
dose
studies
showing
effects
on
operant
behavior
(
Allen
and
MacPhail,
1993).
The
effect
on
operant
behavior
was
distinguishable
from
and
less
than
with
triadimefon
and
triadimenol
and
unlike
the
latter
two
pesticides
showed
no
effects
on
motor
activity.
However,
decreased
motor
activity
was
seen
in
mouse
and
rat
single
dose
studies
at
200
mg/
kg
(
FAO
and
WHO
working
group,
1998).
No
multi­
dose
studies
related
to
neurotoxicity
have
been
seen
with
bitertanol.
One
fetus
in
one
litter
showed
hydrocephalus
in
a
developmental
toxicity
study.

4.3.2
Evidence
that
supports
not
requiring
a
Developmental
Neurotoxicity
study
No
neurotoxicity
or
CNS
developmental
toxicity
was
seen
in
the
developmental
toxicity
studies
in
the
rat
or
rabbit
or
in
the
study
on
reproduction.
No
neurotoxicity
was
seen
in
the
subchronic
or
chronic
guideline
studies
in
rats,
mice
or
dogs.

4.3.2.1
Rationale
for
the
UFDB
A
DNT
study
is
not
recommended
at
this
time.
A
data
base
uncertainty
factor
of
10X
was
assessed
due
to
the
uncertainty
caused
by
the
lack
of
multi­
dose
neurotoxicity
studies
with
bitertanol.
Acute
neurotoxicity
battery
and
90­
day
neurotoxicity
studies
are
necessary
to
resolve
the
conflicting
literature
reports
and
to
determine
NOAELs
from
guideline
studies.
A
DNT
study
recommendation
is
held
in
reserve
pending
review
of
the
acute
and
90­
day
neurotoxicity
studies.

4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49
Selected
Study:
Developmental
toxicity
in
rabbits
(
MRID#
40490801).
GDL#
870.3500.
For
an
Executive
Summary
see
Section
4.2.3.3
Page
31
of
58
Dose
and
Endpoint
for
Establishing
an
aRfD:
NOAEL
is
50
mg/
kg/
day.
LOAEL
is
150
mg/
kg/
day
based
on
developmental
effects
of
nominal
increased
incidence
of
malformations
,
increased
resorptions,
post­
implantation
loss,
decreased
fetal
weight
and
delayed
ossification.

Uncertainty
Factor
(
UF):
1000X.
This
includes
10X
for
interspecies
extrapolation,
10x
for
intraspecies
variation,
and
a
10X
database
uncertainty
factor
the
lack
of
neurotoxicity
studies.

Comments
about
the
Study/
Endpoint/
uncertainty
Factor:
The
nominal
increase
in
malformations,
resorptions
and
post
implantation
loss
is
presumed
to
be
a
single
dose
effect.
The
developmental
endpoint
is
appropriate
for
females
13­
49
and
is
of
the
appropriate
duration.
The
endpoint
is
supported
by
a
two
rat
studies
with
bitertanol
with
NOAEL/
LOAEL
of
10/
25
&
10/
30
mg/
kg/
day.

4.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
An
appropriate
acute
endpoint
attributable
to
a
single
dose
was
not
available
in
the
toxicity
data
base
including
the
developmental
toxicity
studies.

4.4.3
Chronic
Reference
Dose
(
cRfD)

Selected
Study:
The
chronic
study
in
dogs
(
MRIDs
00157466
and
00157465
and
supplemental
MRIDs
40163203,
40163202,
40163201,
and
40186401)
GDL:
870.4100
EXECUTIVE
SUMMARY:
In
chronic
toxicity
studies
(
MRIDs
00157466
and
00157465
and
supplemental
MRIDs
40163203,
40163202,
40163201,
and
40186401),
KWG
0599
[
Bitertanol;
MRID
00157466:
1616001/
78
(
97.3%
a.
i.);
Composite
of
Batch
Nos.
16012/
77
and
16001­
16004/
78
(
95%
a.
i.);
MRID
11457465:
Composite
of
Batch
Nos.
816164054,
0816164056,
816164067,
816164079,
and
816164083
(
96.7%
a.
i.);
Composite
of
Batch
Nos.
233296089,
233296233,
233296296,
233296989,
and
233296992
(
96.3%
a.
i.)]
was
administered
in
the
diet
to
beagle
dogs.
In
MRID
00157466,
the
test
material
was
provided
to
groups
of
four
male
and
four
female
dogs
at
concentrations
of
0,
10,
40,
or
160
ppm
(
equivalent
to
0,
2.11,
8.18,
and
32.24
mg/
kg/
day)
for
104
weeks.
In
MRID
00157465
the
test
material
was
provided
in
the
diet
to
groups
of
six
male
and
six
female
dogs
at
concentrations
of
0,
3,
or
25
ppm
(
equivalent
to
0,
0.78,
and
7.14
mg/
kg/
day)
for
52
weeks
and
to
a
group
of
six
male
and
six
female
dogs
at
200
ppm
(
equivalent
to
50.93
mg/
kg/
day)
for
86
weeks.

Treatment
with
the
test
material
had
no
effect
on
mortality,
body
weight,
reflexes,
pulse,
food
intake,
hematological
parameters,
or
urinalysis
parameters.
Treatment
did
induce
slight
increases
in
the
enzyme
activities
of
ALP
and
ALT,
enzymes
associated
with
the
liver.
No
increases
were
found
in
the
liver
activity
of
total
cytochrome
P­
450
or
N­
demethylase.
In
MRID
00157466,
slight
increases
in
the
absolute
and/
or
relative
to
body
weight
of
the
liver
of
high­
dose
dogs
were
observed
while
in
MRID
00157465,
the
absolute
and
relative
adrenal
weights
of
200
ppm
male
dogs
were
increased.
In
both
studies,
treatment
with
160
ppm
for
two
years,
or
200
ppm
for
86
weeks
increased
the
incidence
(
3/
8
at
160
ppm
and
3/
11
at
200
ppm)
of
corneal
opacity.
These
liver,
ocular,
and
adrenal
effects
were
considered
KWG
0599­
related.
Page
32
of
58
In
MRID
00157466,
minimal
to
moderate
adrenal
vacuolation
was
found
in
all
160
ppm
dogs,
7/
8
40
ppm
dogs
had
very
minimal
to
moderate
adrenal
vacuolation
and
3/
8
10
ppm
dogs
had
very
minimal
adrenal
vacuolation.
Adrenal
vacuolation
was
not
observed
in
control
dogs.
In
MRID
00157465,
all
male
and
female
dogs
treated
with
200
ppm
test
material
developed
slight
to
medium
adrenal
vacuolation
by
86
weeks
of
treatment.
The
vacuoles
were
characterized
as
large
amyloid
droplets
in
the
epithelia
of
the
inner
cortical
layer
close
to
the
medulla.
Medium
to
severe
thymic
involution
was
found
in
4/
6
200
ppm
male
and
2/
6
200
ppm
female
dogs.
Thymic
atrophy
was
not
found
in
control,
3
ppm
or
25
ppm
male
and
female
dogs
and
was
not
reported
in
MRID
00157466.

The
86
weeks
study
at
200
ppm
[
MRID
00157465]
confirmed
the
slight
liver
effects
at
160
ppm
in
the
104
week
study
[
MRID#
00157466]
and
the
adrenal
effects
in
the
104
week
study
at
40
ppm.
The
adrenal
vacuolation
at
10
ppm
was
minimal
and
of
doubtful
toxicological
significance.
However,
the
lack
of
adrenal
vacuolation
at
25
ppm
in
a
52
week
study
can
not
be
used
as
a
NOAEL
for
a
2­
year
study.
Therefore
the
NOAEL
for
the
2­
year
study
is
considered
to
be
10
ppm.

The
LOAEL
for
MRID#
00157466
&
157465
with
bitertanol
in
male
and
female
dogs
is
40
ppm
(
8.18
mg/
kg/
day)
based
on
adrenal
vacuolation
and
at
160
and
200
ppm,
adrenal
vacuolation,
eye
and
liver
effects.
The
NOAEL
is
10
ppm
(
2.11
mg/
kg/
day).

This
chronic
study
in
the
dog
is
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
chronic
oral
study
[
OPPTS
870.4100,
OECD
452]
in
the
dog.

Dose
and
Endpoint
for
Establishing
a
cRfD:
NOAEL
is
2.11
mg/
kg/
day.
The
LOAEL
is
8.18
mg/
kg/
day
for
male/
female
based
on
adrenal
vacuolation.

Uncertainty
Factor
(
UF):
1000X.
This
includes
10X
for
interspecies
extrapolation,
10X
for
intraspecies
variation,
and
a
10X
database
uncertainty
factor
for
the
lack
of
neurotoxicity
studies.

Comments
about
the
Study/
Endpoint/
uncertainty
Factor:
The
study
is
the
right
duration.
The
dose
levels
in
the
chronic
dog
study
were
considered
more
acceptable
than
those
in
the
90­
day
dog
or
the
reproduction
study.
Although,
the
90­
day
dog
study
and
the
3­
generation
study
on
reproduction
showed
a
NOAEL
of
1
mg/
k/
day,
the
90­
day
study
was
not
chosen
due
to
spacing
of
the
doses,
and
the
reproduction
study
was
not
chosen
because
the
dose
levels
were
calculated
from
standard
tables
and
not
measured.

4.4.4
Incidental
Oral
Exposure
(
Short
Term,
1­
30
days),
and
Intermediate
Term,
1
month­
6
months)

These
endpoints
are
not
required
since
there
are
no
residential
exposures.

4.4.5
Dermal
Absorption
A
1998
FAO
and
WHO
report
stated
that
dermal
absorption
was
about
10%
[
MRID#
00150149].
However,
OPP
reviewed
the
data
and
found
the
study
unacceptable
because
it
did
not
account
Page
33
of
58
for
86%
to92%
of
the
radio­
label
applied
to
the
test
animals.

4.4.6
Dermal
Exposure
(
Short,
Intermediate
and
Long
Term).

These
endpoints
are
not
required
for
an
import
tolerance.

4.4.7
Inhalation
Exposure
(
Short
Term,
1­
30
days,
Intermediate
Term,
30
day
­
6
months
or
Long
Term,
>
6
months)

This
parameter
is
unnecessary
because
there
is
no
inhalation
exposure
in
the
United
States.

4.4.8
Margins
of
Exposure
Not
applicable.

Occupational
exposure:
An
occupational
exposure
assessment
is
not
required
for
an
import
tolerance.

Residential
exposure:
There
are
no
residential
exposures
for
this
risk
assessment.

4.4.9
Recommendation
for
Aggregate
Exposure
Risk
Assessments
Not
applicable.

4.4.10
Classification
of
Carcinogenic
Potential
Bitertanol
has
not
been
reviewed
by
the
Cancer
Assessment
Review
Committee
[
CARC],
however,
no
dose
related
carcinogenicity
was
seen
in
the
rat
[
MRID#
00114279]
or
mouse
[
MRID#
00114280]
carcinogenicity
studies.

The
carcinogenicity
studies
in
the
rat
and
mouse
were
conducted
at
a
marginally
toxic
dose
levels
and
neither
study
analyzed
test
material
concentration
in
the
feed.
However,
both
studies
showed
some
toxicity
at
the
HDT,
where
no
treatment
related
carcinogenicity
was
seen.
The
toxicity
seen
at
the
HDT
in
both
studies
is
evidence
that
the
animals
were
dosed
and
the
effects
in
rats
are
consistent
with
subchronic
studies
in
rats
where
doses
were
analyzed.
Although,
both
carcinogenicity
studies
could
have
used
higher
doses,
both
studies
were
classified
as
acceptable,
because,
(
1)
Bitertanol
appears
to
be
less
toxic
in
the
rat
than
in
the
dog,
which
was
used
to
set
the
RfD,
(
2)
No
treatment
related
carcinogenicity
were
seen
in
the
rat
or
the
mouse
studies
at
marginally
toxic
dose
levels,
(
3)
Bitertanol
is
negative
in
a
battery
of
mutagenicity
studies,
(
4)
Bitertanol
is
used
on
import
bananas
only,
thus
exposure
is
limited
to
residues
on
bananas.
(
5)
Both
studies
were
listed
as
acceptable
in
1988.

4.4.10.1
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
(
MRID#
00114279)
GDL#
870.4300
EXECUTIVE
SUMMARY:
In
a
combined
chronic
toxicity/
carcinogenicity
study
(
MRID
Page
34
of
58
00114279),
KWG
0599
(
bitertanol;
94­
95%;
batch/
lot
#
1616001/
78
and
16012/
77
&
16001­
16004/
78
composite)
was
administered
in
feed
to
groups
of
50
male
and
50
female
Wister
TNO/
W
74
rats
at
concentrations
of
0,
20,
100,
or
500
ppm
for
2
years.
The
equivalent
doses
were
0,
1.01,
4.89,
and
25.54
mg/
kg
bw/
day,
respectively,
for
males
and
0,
1.32,
6.55,
and
33.53
mg/
kg
bw/
day,
respectively,
for
females.
An
interim
sacrifice
group
was
not
included
in
this
study.

No
treatment­
related
effect
was
observed
on
clinical
signs
or
mortality.
Adequate
numbers
of
male
and
female
rats
were
alive
at
the
end
of
the
study
for
evaluation
of
late­
developing
lesions.
High­
dose
male
and
female
rats
weighed
11%
and
9%
less,
respectively,
than
controls
at
the
end
of
the
first
week
of
treatment
and
body
weight
was
within
10%
of
control
weight
for
the
remaining
weeks
except
for
a
12%
decrease
in
the
high­
dose
female
group
at
week
91.
High­
dose
males
gained
42%
less
weight
than
controls
during
the
first
week
of
treatment,
8%
less
during
the
first
year,
and
77%
less
during
the
second
year
resulting
in
an
11%
decrease
in
weight
gain
for
the
entire
study.
High­
dose
females
gained
41%
less
weight
than
controls
during
the
first
week
of
treatment,
15%
less
during
the
first
year,
an
amount
similar
to
that
of
controls
during
the
second
year,
resulting
in
a
13%
decrease
in
weight
gain
for
the
entire
study.
Body
weight
and
weight
gain
were
similar
among
the
low­
dose
and
mid­
dose
and
control
groups.
Weekly
food
consumption
by
high­
dose
male
and
female
rats
fluctuated
considerably
throughout
the
study,
but
total
food
consumption/
group
and
average
daily
food
consumption/
rat
were
similar
to
those
of
the
control
group.
Food
efficiency
calculated
for
the
entire
study
was
reduced
by
9%
in
high­
dose
male
and
female
rats,
suggesting
that
the
reduced
weight
gain
was
likely
due
to
a
slightly
toxic
effect
of
the
test
material.

Statistically
significant
decreases
were
seen
at
the
HDT
in
hematological
and
changes
in
clinical
chemistry
parameters,
which
were
within
the
normal
range.
Thus,
no
treatment­
related
effects
were
observed
on
hematologic,
clinical
chemistry,
or
urinalysis
parameters.
Postmortem
examination
showed
no
treatment­
related
effects
on
the
incidences
of
gross
or
microscopic
lesions.
It
is
noted
that
the
statistically
significant
lung
alveolar
macrophage
aggregation
in
males
and
females
at
500
ppm
may
have
resulted
from
inspiration
of
dietary
dust.
The
tracheitis/
peritracheitis
at
the
two
highest
doses
may
be
related
to
test
material
irritation
from
diet
consumption.

The
lowest­
observed­
adverse­
effect
level
(
LOAEL)
for
KWG
0599
in
rats
is
500
ppm
(
25.54
mg/
kg/
day
for
males
and
33.53
mg/
kg/
day
for
females)
based
on
decreased
weight
gain
and
food
efficiency.
The
no­
observed­
adverse­
effect
level
(
NOAEL)
is
100
ppm
(
4.89
mg/
kg/
day
for
males
and
6.55
mg/
kg/
day
for
females).

At
the
doses
tested,
there
was
no
treatment
related
increase
in
tumor
incidence
in
male
or
female
rats
receiving
any
dose
of
the
test
material
when
compared
to
controls.
Although
the
high­
dose
caused
a
notable
decrease
in
weight
gain
in
male
and
female
rats
during
either
the
first
or
second
year
of
the
study,
these
animals
could
have
tolerated
a
higher
dose,
because
absolute
body
weight
remained
within
10%
of
that
of
the
control
group
and
no
increase
in
mortality,
adverse
clinical
pathologic
effects,
or
histopathologic
lesions
were
observed
that
could
be
attributed
to
treatment
with
the
test
material.
Page
35
of
58
This
chronic/
carcinogenicity
study
in
the
rat
is
Acceptable/
Guideline
and
does
satisfy
the
guideline
requirement
for
a
chronic
toxicity/
carcinogenicity
study
OPPTS
870.4300);
OECD
453]
in
the
rat.
Although
analyses
of
concentration
of
test
material
in
the
diet
was
not
done,
the
study
showed
sufficient
toxicity
to
show
that
the
animals
were
dosed,
the
weight
of
evidence
would
suggest
that
this
study
can
be
classified
as
acceptable.
(
1)
The
effects
noted
in
this
study
are
consistent
with
effects
in
an
acceptable
90­
day
study
in
Sprague
Dawley
rats
and
a
reproduction
study.
(
2)
A
battery
of
mutagenicity
studies
are
all
negative.
(
3)
The
HDT
showed
some
toxicity
and
was
close
to
an
adequate
dose.
(
4)
There
was
no
indication
of
dose
related
increased
tumor
incidence
at
any
dose
including
the
top
dose.
(
5)
An
acceptable
Chronic
Dog
study
showed
a
lower
NOAEL.
(
6)
The
study
is
used
to
support
a
limited
exposure
on
imported
bananas
only.
(
7)
The
study
is
listed
as
acceptable
in
TXR#
0002588.
Additional
deficiencies,
which
do
not
negate
the
study
are
listed
in
Section
IIIC
of
this
DER.

4.4.10.2
Carcinogenicity
Study
in
Mice
(
MRID#
00114280)
GDL#
870.4200
EXECUTIVE
SUMMARY:
In
a
24­
month
oral
carcinogenicity
study
(
MRID
00114280),
KWG
0599
(
97.3%
a.
i.,
Batch
#
s
1616001/
78,
16012/
77,
and
16001
­
16004/
78)
was
administered
to
a
total
of
50
SPF
CF
1
/
W
74
®
mice/
sex/
dose
in
the
diet
at
concentrations
of
0,
20,
100,
or
500
ppm
(
equivalent
to
0,
5,
25,
or
129
mg/
kg
bw/
day
for
males
and
0,
7,
37,
or
183
mg/
kg
bw/
day
for
females).

There
were
no
significant
treatment­
related
effects
on
mortality,
clinical
signs,
food
intake,
or
hematology
parameters.
At
500
ppm,
mean
weekly
body
weights
of
males
were
within
95%
of
controls
at
most
weighing
periods
throughout
the
study,
and
of
females
were
within
95%
of
controls
during
the
first
12
months.
The
final
body
weights
of
the
500
ppm
males
and
females
were
97%
and
92%
of
controls,
respectively,
and
the
overall
body
weight
gains
were
92%
and
79%
of
controls,
respectively.
The
overall
food
efficiency
in
males
was
decreased
by
21%
in
females
at
500
ppm,
suggesting
a
treatment­
related
decrease
in
body
weight
in
500
ppm
females.
Although
the
body
weight
decrement
was
slight
in
males
and
females,
it
was
consistently
decreased
in
the
500
ppm
group
from
the
controls,
20
and
100
ppm
groups
throughout
the
study,
suggesting
that
the
500
ppm
groups
were
affected
by
treatment
and
that
the
500
ppm
dose
level
was
close
to
a
toxic
dose
level
even
in
males.
Other
studies
with
bitertanol
have
shown
toxicity
from
histopathological
findings,
but
only
marginal
body
weight
decrement.

The
mean
alkaline
phosphatase
activity
was
statistically
significantly
increased
at
100
and/
or
500
ppm
in
males
and
females
after
12
months
only.
The
mean
glutamate­
pyruvate­
transaminase
(
GPT)
activity
was
statistically
increased
in
all
male
dose
groups
after
12
months,
and
in
females
at
500
ppm
after
24
months.
The
enzyme
activity
increases
were
not
dose­
dependent
and
largely
due
to
outliers
with
very
high
levels
of
enzyme
activity.
The
mean
absolute
and
relative
(
to
body
weight)
liver
weights
were
increased
at
500
ppm
in
males
(
16%
and
19%,
respectively)
and
females
(
60%
and
69%,
respectively)
although
only
the
latter
differed
statistically
from
the
controls.
An
increased
incidence
of
greenish
liver
discoloration
occurred
in
500
ppm
females,
being
seen
only
in
those
that
survived
to
terminal
sacrifice.
Microscopic
examination
revealed
that
females
had
an
increased
incidence
of
liver
altered
cell
foci
(
basophilia,
eosinophilia,
vacuolation)
that
was
not
clearly
dose­
related
(
16%,
40%,
26%,
and
54%
at
0,
20,
100,
and
500
ppm,
respectively).
The
lack
of
histopathological
findings
indicates
that
the
liver
weight
increase
Page
36
of
58
in
500
ppm
females
was
a
non­
specific
adaptive
response
to
treatment
with
a
xenobiotic.
Significant
increases
found
in
both
sexes
in
blood
urea
concentration
and
in
the
incidence
of
kidney
cortical
cysts
were
not
dose­
related,
and
were
not
considered
treatment­
related.

A
LOAEL
was
500
ppm
(
M/
F:
129/
183
mg/
kg/
day)
based
marginal
body
weight
decrement
in
males
and
females
(
not
statistically
significant)
throughout
the
study,
and
other
statistically
significant
marginal
effects,
such
as
eosinphilic
foci
in
livers
of
females.
Increased
liver
wt
&
GPT
in
females
and
increased
ALP
&
urea
in
males.
The
corresponding
NOAEL
is
100
ppm
(
25/
37
mg/
kg/
day).

Treatment
of
SPF
CF
1
/
W
74
®
male
and
female
mice
with
a
dietary
levels
up
to
and
including
500
ppm
KWG
0599
for
24
months
did
not
result
in
a
significant
increase
in
neoplasms
compared
to
the
control
group.

This
carcinogenicity
study
in
the
mice
is
Acceptable/
Guideline
for
a
carcinogenicity
study
[
OPPTS
870.4200b;
OECD
451]
in
mice.
Although
tests
for
homogeneity
or
stability
and
analyses
of
concentration
of
test
material
in
the
diet
was
not
done
such
that
dose
levels
can
not
be
verified,
the
weight
of
evidence
would
suggest
that
this
study
can
be
classified
as
acceptable
because
(
1)
A
battery
of
mutagenicity
studies
are
all
negative;
(
2)
The
HDT
approached
an
adequate
dose;
(
3)
There
was
indications
of
increased
incidence
of
liver
adenomas,
but
not
carcinomas
at
the
top
dose;
(
4)
An
acceptable
Chronic
Dog
study
showed
a
lower
NOAEL;
(
5)
The
study
supports
a
pesticide
with
limited
exposure
(
import
tolerance
on
bananas
only);
and
(
6)
The
study
is
listed
as
acceptable
TXR#
0002588.
Additional
deficiencies,
which
do
not
negate
the
study
are
listed
in
Section
IIIC
of
the
DER.

Table
4.4:
Summary
of
Toxicological
Doses
and
Endpoints
for
Chemical
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
of
age)
NOAEL
=
50
mg/
kg/
day
UF
=
1000
Acute
RfD
=
0.05
mg/
kg/
day
FQPA
SF
=
1X
aPAD
=
acute
RfD
FQPA
SF
=
0.05
mg/
kg/
day
Developmental
Toxicity
in
rabbits
MRID
40490801
Maternal;
LOAEL
=
150
mg/
kg/
day
based
on
decreased
body
weight
gain
and
food
consumption.
Developmental;
LOAEL
=
150
mg/
kg/
day
based
on
increased
potimplantation
loss,
decreased
fetal
weight,
and
reduced
ossification.

Acute
Dietary
(
General
population
No
endpoint
from
a
single
dose
was
seen
in
an
appropriate
study.
Table
4.4:
Summary
of
Toxicological
Doses
and
Endpoints
for
Chemical
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
Page
37
of
58
Chronic
Dietary
(
All
populations)
NOAEL=
2.11
mg/
kg/
day
UF
=
1000
Chronic
RfD
=
0.00211
mg/
kg/
day
FQPA
SF
=
1X
cPAD
=
chronic
RfD
FQPA
SF
=
0.00211
mg/
kg/
day
Chronic/
dog
[
MRID
00157466
&
00157465]
LOAEL
=
8.18
mg/
kg/
day
based
on
based
on
adrenal
vacuolation..

Incidental
Short
and
Intermediate
oral
exposure
There
is
no
incidental
oral
short
or
intermediate
exposure
in
US.

Short,
Intermediate
&
Long
term
Dermal
Endpoint
not
necessary
for
an
import
tolerance
All
Inhalation
exposures
No
endpoint
is
necessary
since
there
is
no
inhalation
exposure
in
United
States.

Cancer
(
oral,
dermal)
"
E,"
Unlikely
human
carcinogen.
No
dose
related
tumors
in
the
rat
or
mouse.

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.

4.5
Special
FQPA
Safety
Factor
Because
there
is
no
residual
uncertainty
with
respect
to
pre­
and
post­
natal
toxicity
based
on
the
submitted
developmental
and
reproduction
studies,
the
Special
FQPA
Factor
is
reduced
to
1X.
There
is
some
uncertainty
for
potential
neurotoxicity
based
on
some
literature
studies.
Because
acute
and
subchronic
neurotoxicity
studies
are
not
available,
a
10X
database
uncertainty
factor
(
UF
DB
)
is
retained
to
account
for
the
lack
of
data.

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
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
Page
38
of
58
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).

In
the
available
toxicity
studies
with
bitertanol,
no
evidence
of
agonistic
or
antagonistic
estrogen
or
androgen
or
thyroid
activity
was
seen.
A
potential
hormonal
antagonistic
effects
was
seen
as
a
prostate
weight
decrement
in
a
subchronic
dog
study,
but
not
in
dog
chronic
studies.
The
change
in
prostate
weight
not
seen
at
1­
year
or
2­
years
in
the
chronic
dog
studies
suggest
that
the
effect
in
the
90­
day
dog
study
was
specific
to
the
dogs
tested
and
not
to
bitertanol
treatment.
However,
the
reason
for
the
difference
in
the
90­
day
and
chronic
dog
studies
is
unknown.

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

5.0
Public
Health
Data
5.1
Incident
Reports
An
incident
report
for
bitertanol
is
not
available.

6.0
Exposure
Characterization/
Assessment
S.
Ary.
Bitertanol:
Summary
of
Analytical
Chemistry
and
Residue
Data
for
the
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
Document.
November
7,
2005.
DP
Barcode
D302882.

6.1
Dietary
Exposure/
Risk
Pathway
6.1.1
Residue
Profile
The
nature
of
residues
in
plants
is
adequately
understood
based
on
acceptable
plant
metabolism
studies
in
apples
and
peanuts
conducted
with
bitertanol
labeled
in
the
biphenyl
ring
system
and
additional
studies
submitted
recently
in
apples,
cotton,
and
tomatoes
conducted
with
bitertanol
labeled
in
the
triazole
ring
system.
The
recently
submitted
studies
are
currently
under
review
by
the
Agency;
however,
it
is
noted
that
after
initial
review
of
the
newly
submitted
studies,
the
data
support
the
conclusions
drawn
from
the
two
previous
submissions.
The
residues
identified
in
these
studies
consisted
primarily
of
the
parent
compound
with
traces
of
the
metabolites
bitertanol
ketone
and
4­
hydroxybiphenyl.
Although
no
metabolism
studies
for
bananas
are
available,
HED
has
concluded
that
the
nature
of
residues
in
bananas
is
likely
similar
to
that
in
apples,
cotton,
peanuts,
and
tomatoes.
Therefore,
HED
has
determined
that
the
bitertanol
residue
of
concern
in/
on
bananas
for
tolerance
expression
and
for
risk
assessment
is
bitertanol
(
parent
only).
Page
39
of
58
An
analytical
method
for
analysis
of
residues
of
bitertanol
has
been
submitted
and
found
acceptable
for
data
collection
purposes.
The
submitted
method
is
a
modification
of
Mobay
Chemical
Corporation's
Method
54166
for
the
analysis
of
bitertanol
in
apples.
Analysis
is
by
gas
chromatography
using
a
nitrogen­
phosphorus
flame
ionization
detector.
The
limit
of
detection
is
0.01
ppm.
A
method
trial
was
successfully
performed
on
banana
pulp
and
peels
at
fortification
levels
of
0.1
ppm
and
0.2
ppm.
Recoveries
ranged
from
78
to
88%
for
pulp
samples,
and
from
70
to
98%
for
peel
samples.
The
method
was
approved
by
the
Agency
for
the
enforcement
of
tolerance
in/
on
bananas
and
the
results
were
forwarded
to
FDA
for
inclusion
in
the
Pesticide
Analytical
Manual
(
PAM)
Volume
II.

The
FDA
PESTDATA
database
dated
11/
2001
(
PAM
Volume
I,
Appendix
I)
indicates
that
bitertanol
was
completely
recovered
using
Multiresidue
Method
Section
302
(
Protocol
D).

Storage
stability
data
for
bitertanol
in/
on
bananas
have
not
been
submitted
by
the
registrant;
therefore,
storage
stability
data
are
required.

As
indicated
in
the
tolerance
petition,
bitertanol
was
originally
marketed
for
use
on
bananas
in
Costa
Rica
and
Honduras,
but
has
expanded
to
include
Ecuador,
Guatemala,
Honduras,
Mexico,
Nicaragua,
Peru,
Venezuela,
Dominican
Republic,
and
Panama.
Residue
data
from
trials
conducted
in
Costa
Rica
and
Honduras
have
been
submitted
and
reviewed
by
the
Agency.
Bitertanol
was
applied
to
both
bagged
and
unbagged
bunches
of
green
and
ripe
bananas
at
a
rate
of
0.26
lb
ai/
A/
application
(
2x
the
current
rate
per
application),
the
maximum
rate
per
application
indicated
on
the
product
label
at
that
time.
Samples
of
peel,
pulp
and
whole
fruit
were
collected
3
days
after
the
last
of
9
treatments
and
0
days
after
the
last
of
12
treatments.
Washed
and
unwashed
samples
were
analyzed
for
bitertanol
by
Method
54166,
with
modifications.
The
number
of
trials,
the
location
of
the
trials
within
Costa
Rica
and
Honduras,
and
the
formulation
type
were
not
specified.
No
data
were
provided
on
how
long
the
samples
were
stored
prior
to
analysis.
Residues
found
in
samples
of
whole
fruit
from
unbagged
and
bagged
bunches
of
ripe
and
green
bananas
were
all
below
the
recommended
tolerance
level
of
0.5
ppm.
The
residue
data
are
deemed
adequate
to
support
a
tolerance
of
0.5
ppm
in/
on
bananas.

The
SC
formulation
will
be
supported
with
additional
field
trials
that
are
currently
being
conducted
by
the
registrant.
The
studies
are
planned
for
completion
in
2006.

Regulatory
Recommendations
and
Residue
Chemistry
Deficiencies:

°
Revise
tolerance
to
0.50
ppm
to
harmonize
with
Codex.

°
Storage
stability
data
are
required
to
determine
the
stability
of
residues
in
bananas
during
cold
storage.
No
data
were
provided
on
how
long
the
banana
samples
from
submitted
field
trial
studies
were
stored
prior
to
analysis.

°
Field
trial
data
for
the
SC
formulation
are
required.

°
Additional
data
are
required
in
order
for
the
submitted
field
trials
conducted
in
Costa
Rica
and
Honduras
to
be
acceptable:
the
number
of
trials,
location
of
the
trials
within
the
Page
40
of
58
countries,
and
the
formulation
type
used
A
tolerance
has
been
established
under
40
CFR
§
180.457
for
residues
of
bitertanol
in/
on
bananas
imported
into
the
U.
S.
Field
trials
conducted
in
Costa
Rica
and
Honduras
showed
residues
below
the
existing
tolerance
level
of
0.2
ppm.
In
order
to
harmonize
with
Codex,
the
established
tolerance
should
be
increased
to
0.5
ppm.

Since
the
tolerance
for
bitertanol
is
an
import
tolerance,
it
should
be
listed
in
a
separate
subsection
of
40
CFR
indicating
that
there
are
no
U.
S.
registrations
for
bitertanol.
A
summary
of
the
bitertanol
tolerance
reassessment
for
bananas
is
presented
in
the
following
table:

Table
6.1(
a):
Tolerance
Summary
for
Bitertanol.

Commodity
Established/
Proposed
Tolerance
(
ppm)
Recommended
Tolerance
(
ppm)
Comments
[
correct
commodity
definition]

Banana
(
whole)
0.20
(
established)
0.5
Tolerance
should
be
listed
in
a
separate
subsection
of
40
CFR
indicating
that
there
are
no
U.
S.
registrations
associated
with
bitertanol.
[
Banana]

Codex/
International
Harmonization
The
Codex
Alimentarius
Commission
has
established
a
maximum
residue
limit
(
MRL)
for
bitertanol
residues
in/
on
bananas
at
0.5
mg/
kg.
The
Codex
MRL
for
bitertanol
is
expressed
in
terms
of
residues
of
bitertanol
only,
as
is
the
U.
S.
tolerance
expression.
Various
enforcement
methods
are
listed
for
bitertanol
under
the
Codex
system
including
PAM
Multiresidue
Method
Section
302
(
Protocol
D).

It
is
EPA's
policy
to
harmonize
its
tolerances
with
the
levels
established
by
Codex
provided
that
the
Agency
has
sufficient
information
to
make
a
determination
that
the
Codex
MRLs
will
be
protective
of
the
health
of
the
U.
S.
public
and
meet
FFDCA
standards.
FQPA
requires
EPA
to
publish
a
notice
for
public
comment
whenever
the
Agency
establishes
a
tolerance
that
differs
from
an
established
Codex
MRL.
The
established
tolerance
should
be
increased
to
0.50
ppm
to
harmonize
with
Codex
as
the
dietary
exposures
and
risks
are
not
of
concern
(
S.
Ary,
D302880,
11/
7/
2005).

6.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk
S.
Ary.
Acute
and
Chronic
Dietary
Exposure
Assessments
for
the
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
Document.
November
7,
2005.
DP
Barcode
D302880.

Acute
dietary
risk
estimates
are
provided
for
females
13­
49
years
of
age
only.
For
the
general
population
there
is
no
study
to
support
an
effect
from
a
single
dose.
The
acute
dietary
risk
assessment
concludes
that
for
the
supported
use
of
bitertanol
on
imported
bananas,
the
acute
Page
41
of
58
dietary
risk
estimate
does
not
exceed
HED's
level
of
concern
(
i.
e.,
dietary
risk
is
less
than
100%
of
the
aPAD)
at
the
95th
exposure
percentile
for
females
13­
49
years
old
(
2%
of
the
aPAD).

Chronic
dietary
risk
estimates
do
not
exceed
HED's
level
of
concern
(
i.
e.,
dietary
risks
are
less
than
100%
of
the
cPAD)
for
the
U.
S.
population
(
9%
of
the
cPAD)
and
all
population
subgroups.
The
highest
exposed
population
subgroup
is
children
1­
2
years
of
age,
at
43%
of
the
cPAD.

The
results
of
the
acute
and
chronic
dietary
exposure
analysis
are
presented
in
the
following
table.

Table
6.1(
b):
Summary
of
Acute
and
Chronic
Dietary
Exposure
and
Risk
for
Bitertanol.

Population
Subgroup
a
Acute
Dietary
(
95th
Percentile)
Chronic
Dietary
Cancer
Dietary
aPAD,
mg/
kg
Exposure,
mg/
kg/
da
y
%
aPAD
cPAD,
mg/
kg/
da
y
Exposure,
mg/
kg/
day
%
cPAD
Exposure
mg/
kg/
da
y
Risk
General
U.
S.
Population
Not
Applicable
0.00211
0.000179
9
Not
Applicable
All
Infants
(<
1
yr)
0.00211
0.000731
35
Children
1­
2
yrs
0.00211
0.000917
43
Children
3­
5
yrs
0.00211
0.000467
22
Children
6­
12
yrs
0.00211
0.000192
9
Youth
13­
19
yrs
0.00211
0.000064
3
Adults
20­
49
yrs
0.00211
0.000104
5
Adults
50+
yrs
0.00211
0.000177
8
Females
13­
49
yrs
0.05
0.000964
2
0.00211
0.000105
5
a
The
values
for
the
population
with
the
highest
risk
for
each
type
of
risk
assessment
are
bolded.

6.2
Water
Exposure/
Risk
Pathway
Bitertanol
has
no
registered
uses
in
the
United
States;
therefore,
a
drinking
water
assessment
has
not
been
conducted.

6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
Bitertanol
has
no
registered
uses
in
the
United
States;
therefore,
a
residential
exposure
assessment
has
not
been
conducted.

7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
In
accordance
with
the
FQPA,
HED
must
consider
and
aggregate
(
add)
pesticide
exposures
and
risks
from
three
major
sources:
food,
drinking
water,
and
residential
exposures.
However,
as
bitertanol
is
an
import
tolerance
only,
there
are
no
exposures
via
drinking
water
or
residential
sources.
Therefore,
an
aggregate
risk
assessment
has
not
been
conducted.
Page
42
of
58
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
made
a
common
mechanism
of
toxicity
finding
as
to
bitertanol
and
any
other
substances
and
bitertanol
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
bitertanol
has
a
common
mechanism
of
toxicity
with
other
substances.
For
information
regarding
EPA's
efforts
to
determine
which
chemicals
have
a
common
mechanism
of
toxicity
and
to
evaluate
the
cumulative
effects
of
such
chemicals,
see
the
policy
statements
released
by
EPA's
Office
of
Pesticide
Programs
concerning
common
mechanism
determinations
and
procedures
for
cumulating
effects
from
substances
found
to
have
a
common
mechanism
on
EPA's
website
at
http://
www.
epa.
gov/
pesticides/
cumulative/.

9.0
Occupational
Exposure/
Risk
Pathway
Bitertanol
has
no
registered
uses
in
the
United
States;
therefore,
an
occupational
exposure
assessment
has
not
been
conducted.

10.0
Data
Needs
and
Label
Requirements
10.1
Toxicology
HED
recommends
that
an
acute
neurotoxicity
battery,
and
a
90­
day
neurotoxicity
study
with
bitertanol
be
submitted.
The
requirement
for
a
developmental
neurotoxicity
toxicity
study
is
held
in
reserve,
pending
the
submission
and
review
of
the
acute
and
subchronic
neurotoxicity
studies.

10.2
Residue
Chemistry
The
tolerance
should
be
increased
to
0.50
ppm
to
harmonize
with
Codex.

Storage
stability
data
are
required
to
determine
the
stability
of
residues
in
bananas
during
cold
storage.
No
data
were
provided
on
how
long
the
banana
samples
from
submitted
field
trial
studies
were
stored
prior
to
analysis.

Field
trial
data
for
the
suspension
concentrate
formulation
are
required
(
these
field
trials
are
currently
being
conducted
by
the
registrant
and
are
planned
for
completion
in
2006).
a
Additional
data
are
required
in
order
for
the
submitted
field
trials
conducted
in
Costa
Rica
and
Honduras
to
be
acceptable:
the
number
of
trials,
the
location
of
the
trials
within
the
countries,
and
the
formulation
type
used.
Page
43
of
58
Page
44
of
58
REFERENCES:

Literature
References:

1.
AR
Allen
&
RC
MacPhail
[
1993]
Bitertanol,
a
triazole
fungicide,
increases
operant
responding
but
not
motor
activity.
Neurotoxicology
and
Teratology
Vol
15
No.
4
pages
237­
242.
2.
KM
Crofton
[
1996]
A
Structure­
activity
relationship
for
neurotoxicity
of
triazole
fungicides.
Toxicology
Letters
84
(
3)
155­
159
3.
EPA/
OTS
Doc
#
88­
920006908
[
Initial
submission:
(
1,2,4­
triazole­
1)­
3,3­
dimethylbutan­
2­
ol
studies
of
embryo
&
teratogenic
effects
in
rats
following
oral
administration
with
cover
letter
&
attachments]
4.
FAO
and
WHO
working
groups
[
1983]
Bitertanol.
FAO
Plant
production
and
protection
paper
Vol
61
pages
47­
57.
5.
FAO
and
WHO
working
groups
[
1987].
Bitertanol.
FAO
Plant
production
and
protection
paper.
Vol
86/
2
page
19­
23.
6.
FAO
and
WHO
working
groups
[
1998]
Bitertanol.
Pesticide
residues
in
food.
Toxicological
evaluations
page
39­
61.
7.
J
Lewalter
and
U
Korallus
[
1986]
Erythrocyte
protein
conjugates
as
a
principle
of
biological
monitoring
for
pesticides.
Toxicology
Letters
Vol
33
Nos
1/
3
153­
165.
8.
P
Mineau,
DC
Boersma
and
B
Collins
[
1994]
An
analysis
of
avian
reproduction
studies
submitted
for
pesticide
registration.
Ecotoxicology
and
Environmental
Safety
29(
3)
304­
329.
9.
M
Peterka,
M
Tucek
and
D
Vesely
[
1996]
Embryotoxicity
of
none
mordants
in
chick
embryo:
The
chest
method.
Acta
Veterinaria
Brno
65(
3)
213­
217.
10.
JL
Schardien
[
1993]
Pesticides.
In
Chemically
Induced
Birth
Defects.
Published
1993.
International
Standard
book
Number:
0­
8247­
8775­
7.
2:
675­
721
11.
T
Vergieva
[
1990]
Triazoles
teratogenicity
in
rats.
Teratology
Aug:
42
(
2)
27A­
28A
12.
T
Yamano
and
S
Morita
[
1995]
Effects
of
pesticides
on
isolated
rat
hepatocytes,
mitocondria,
and
microsomes
II.
Archives
of
Environmental
Contamination
and
Toxicology
28:
(
1)
1­
7.

References
to
Toxicity
Studies
on
Bitertanol:

MRID:
00025640
Mobay
Chemical
Corporation
(
1979)
Synopsis
of
the
Human
Safety
of
Baycor
(
Formerly
Bay
KWG
0599).
Summary
of
studies
099184­
B
through
099184­
Q.
(
Unpublished
study
received
Dec
21,
1979
under
3125­
EX­
168;
CDL:
099184­
A)

MRID:
00025641
Thyssen,
J.;
Kimmerle,
G.;
Lorke,
D.
(
1977)
KWG
0599:
Acute
Toxicity
Studies:
Report
No.
6546;
Report
No.
51413.
(
Unpublished
study
received
Dec
21,
1979
under
3125­
EX­
168;
prepared
by
Bayer,
AG,
submitted
by
Mobay
Chemical
Corp.,
Kansas
City,
Mo.;
CDL:
099184­
B)

MRID:
00025645
Herbold,
B.;
Lorke,
D.
(
1978)
KWG
0599:
Micronucleus
Test
on
Mouse
to
Evaluate
KWG
0599
for
Potential
Mutagenic
Effects:
Report
No.
7860;
Report
No.
66652.
(
Unpublished
study
received
Dec
21,
1979
under
3125­
EX­
168;
prepared
by
Bayer,
AG,
submitted
by
Mobay
Chemical
Corp.,
Kansas
City,
Mo.;
CDL:
099184­
F)

MRID:
00025646
Herbold,
B.;
Lorke,
D.
(
1978)
KWG
0599:
Dominant
Lethal
Study
on
Page
45
of
58
Male
Mouse
To
Test
for
Mutagenic
Effects:
Report
No.
7964;
Report
No.
67067.
(
Unpublished
study
received
Dec
21,
1979
under
3125­
EX­
168;
prepared
by
Bayer,
AG,
submitted
by
Mobay
Chemical
Corp.,
Kansas
City,
Mo.;
CDL:
099184­
G)

MRID:
00025647
F.;
Bomhard,
E.;
Loser,
E.;
et
al.
(
1978)
KWG
0599:
Subchronic
Toxicity
Study
on
Rats:
Report
No.
8002;
Report
No.
67074.
(
Unpublished
study
received
Dec
21,
1979
under
3125­
EX­
168;
prepared
by
Bayer,
AG,
submitted
by
Mobay
Chemical
Corp.,
Kansas
City,
Mo.;
CDL:
099184­
H)

MRID:
00025648
Hoffman,
K.;
Schilde,
B.;
Lorke,
D.
(
1979)
KWG
0599:
Subchronic
Toxicity
Study
on
Dogs:
Report
No.
8053;
Report
No.
67374.
(
Unpublished
study
received
Dec
21,
1979
under
3125­
EX­
168;
prepared
by
Bayer,
AG,
submitted
by
Mobay
Chemical
Corp.,
Kansas
City,
Mo.;
CDL:
099184­
I)

MRID:
00025651
Herbold,
B.;
Lorke,
D.
(
1979)
KWG
0599:
Salmonella/
Microsome
Test
for
Detection
of
Point­
Mutagenic
Effects:
Report
No.
8152;
Re­
port
No.
67959.
(
Unpublished
study
received
Dec
21,
1979
under
3125­
EX­
168;
prepared
by
Bayer,
AG,
submitted
by
Mobay
Chemical
Corp.,
Kansas
City,
Mo.;
CDL:
099184­
L)

MRID:
00025733
Puhl,
R.
J.;
Obrist,
J.
J.;
Pither,
K.
M.
(
1979)
The
Excretion
of
Baycor(
TM)­
phenyl­
UL­
14C
following
Administration
of
a
Single
Oral
Dose
to
Rats:
Report
No.
68307.
(
Unpublished
study
received
Dec
21,
1979
under
3125­
EX­
168;
submitted
by
Mobay
Chemical
Corp.,
Kansas
City,
Mo.;
CDL:
099185­
Q)

MRID:
00114277
Flucke,
W.;
Lorke,
D.
(
1981)
KWG
0599:
Evaluation
for
Sensitization
in
Guinea
Pigs
(
Maximization
Test
after
Magnusson
and
Kligman):
Report
No.
9934;
80324.
(
Unpublished
study
received
Sep
15,
1982
under
2E2756;
prepared
by
Bayer
AG,
W.
Ger.,
submitted
by
Mobay
Chemical
Corp.,
Kansas
City,
MO;
CDL:
071090­
C)

MRID:
00114279
Bomhard,
E.;
Loeser,
E.;
Lorke,
D.;
et
al.
(
1981)
KWG
0599:
Chronic
Toxicity
Study
on
Rats
(
2­
year
Feeding
Experiment):
Bayer
Report
No.
10104;
69985.
(
Unpublished
study
received
Sep
15,
1982
under
2E2756;
prepared
by
Bayer
AG,
W.
Ger.,
submitted
by
Mobay
Chemical
Corp.,
Kansas
City,
MO;
CDL:
071090­
E)

MRID:
00114280
Bomhard,
E.;
Loeser,
E.;
Lorke,
D.;
et
al.
(
1981)
KWG
0599:
(
Bitertanol,
the
Active
Ingredient
of
Baycor)
Chronic
Toxicity
Study
on
Mice
(
2­
year
Feeding
Experiment):
Bayer
Report
No.
10103;
69095.
(
Unpublished
study
received
Sep
15,
1958
under
2E2756;
prepared
by
Bayer
AG,
W.
Ger.,
submitted
by
Mobay
Chemical
Corp.,
Kansas
City,
MO;
CDL:
071091­
A)

MRID:
00114281
Loser,
E.;
Eiben,
R.;
Lorke,
D.;
et
al.
(
1981)
KWG
0599:
Multigeneration
Reproduction
Study
on
Rats:
Report
No.
10024;
69096.
(
Unpublished
study
received
Sep
15,
1982
under
2E2756;
prepared
by
Bayer
AG,
W.
Ger.,
submitted
by
Mobay
Chemical
Corp.,
Kansas
City,
MO;
CDL:
071091­
B)
Page
46
of
58
MRID:
00114283
Nagumo,
K.;
Teraki,
Y.;
Chiba,
T.;
et
al.
(
1981)
Teratogenicity
Test
of
KWG
0599
in
Pregnant
Rats:
(
Submitter)
80571.
(
Unpublished
study
received
Sep
15,
1982
under
2E2756;
prepared
by
St.
Marianna
Univ.,
First
Dept.
of
Anatomy,
Laboratory
of
Embryology,
Japan,
submitted
by
Mobay
Chemical
Corp.,
Kansas
City,
MO;
CDL:
071091­
D)

MRID:
00114284
Roetz,
R.;
Lorke,
D.
(
1982)
KWG
0599
(
Bitertanol,
the
Active
Ingredient
of
Baycor):
Study
of
Embryotoxic
(
and
Teratogenic)
Effects
on
Rabbits
after
Oral
Administration:
Bayer
Report
No.
10979;
82239.
(
Unpublished
study
received
Sep
15,
1982
under
2E2756;
prepared
by
Bayer
AG,
W.
Ger.,
submitted
by
Mobay
Chemical
Corp.,
Kansas
City,
MO;
CDL:
071091­
E)

MRID:
00114285
Riach,
C.;
Harris,
W.
(
1980)
KWG
0599:
Testing
the
Modification
of
Cellular
DNA
in
Escherichia
coli:
Report
No.
1896;
69099.
(
Unpublished
study
received
Sep
15,
1982
under
2E2756;
prepared
by
Inveresk
Research
International,
Scot.,
submitted
by
Mobay
Chemical
Corp.,
Kansas
City,
MO;
CDL:
071091­
F)

MRID:
00114286
Shirasu,
Y.;
Moriya,
M.;
Ohta,
T.
(
1981)
Bitertanol:
Microbial
Mutagenicity
Study:
(
Submitter)
80331.
(
Unpublished
study
received
Sep
15,
1982
under
2E2756;
prepared
by
Institute
of
Environmental
Toxicology,
Japan,
submitted
by
Mobay
Chemical
Corp.,
Kansas
City,
MO;
CDL:
071091­
G)

MRID:
00114287
Bond,
J.;
McGregor,
D.;
McMillan,
L.;
et
al.
(
1981)
Bitertanol:
Testing
for
Aneuploid
Induction
of
HE
1004
in
Sordaria
brevicollis:
IRI
Project
No.
416594;
80333.
(
Unpublished
study
received
Sep
15,
1982
under
2E2756;
prepared
by
Inveresk
Research
International,
Scot.,
submitted
by
Mobay
Chemical
Corp.,
Kansas
City,
MO;
CDL:
071091­
H)

MRID
00129560
Puhl,
R.;
Hurley,
J.
(
1983).
The
Absorption,
Excretion,
and
Metabolism
of
Baycor­
phenyl­
UL­
14C
by
Rats:
85832.
(
Unpublished
study
received
August
1,
1983
under
2E2756;
submitted
by
Mobay
Chemical
Corp.,
Kansas
City,
MO;
CDL:
071760­
A.

MRID:
00149829
Heimann,
K.;
Vogel,
O.
(
1984)
Subacute
Study
of
Dermal
Toxicity
To
Rabbits:
KWG
0599:
Report
No.
12571.
Unpublished
Mobay
study
No.
86863
prepared
by
Bayer
AG,
Institute
of
Toxicology.
67
p.
MRID:
00149830
Schluter,
G.
(
1983)
Study
to
Determine
Embryotoxic
and
Teratogenic
Effects
on
Rabbits
Following
Oral
Administration:
KWG
0599:
Re­
port
No.
11548.
Unpublished
Mobay
study
No.
86432
prepared
by
Bayer
AG,
Institute
of
Toxicology.
21
p.

MRID:
00150149
Hixson,
E.
(
1984)
Dermal
Absorption
of
[
Carbon­
14]­
Baycor
Applied
As
a
50%
Wettable
Powder:
Study
No.
83­
723­
01;
86638.
Unpublished
study
prepared
by
Mobay
Chemical
Corp.
16
p.

MRID:
00154936
Machemer,
L.;
Lorke,
D.
(
1977)
Studies
of
Embryotoxic
and
Teratogenic
Effects
on
Rats
following
Oral
Administration:
KWG
0599:
Report
No.
6697;
53072.
Unpublished
study
prepared
by
Bayer
AG.
61
p.

MRID:
00154937
Roetz,
R.
(
1982)
Examination
for
Embryotoxic
Effects
on
Rabbits:
Procedure
(
S.
O.
P)
No.
1360;
82­
T­
215.
Unpublished
study
prepared
by
Reproduction
Tox.
Lab.,
Bayer
AG.
11
p.
Page
47
of
58
MRID:
00157465
Hoffmann,
K.;
Vogel,
O.
(
1983)
Second
Chronic
Toxicity
Study
with
Dogs
on
Oral
Administration:
(
Feeding
Study,
0­
3­
25
ppm
12
Months,
200
ppm
20
Months):
KWG
0599
(
Bitertanol):
Report
No.:
12328.
Unpublished
study
prepared
by
Bayer
AG.
302
p.

MRID:
00157466
Hoffmann,
K.;
Groening,
P.
(
1983)
Chronic
Oral
Toxicity
Study
on
Dogs:
(
2­
Year
Feeding
Experiment):
(
Common
Name:
Bitertanol):
KWG
0599:
Report
No.:
12307:
Mobay
Agchem
No.:
86304.
Unpublished
study
prepared
by
Bayer
Ag
Institut
fuer
Toxikologie.
299
p.

MRID:
00157853
Yonemura,
H.;
Shimazaki,
M.;
Yamazaki,
K.;
et
al.
(
1981)
Subacute
Toxicity
Tests
with
Bitertanol
(
KWG
0599)
in
Rats:
Report
No.
90891.
Unpublished
study
prepared
by
Mobay
Chemical
Corp.
145
p.

MRID:
00163455
Mihail,
F.;
Luckhaus,
G.
(
1986)
Subacute
Oral
Toxicity
Study
with
Special
Attention
to
Effect
on
the
Liver:
[
September
9,
1986]:
KWG
0599
(
c.
n.
Bitertanol):
Report
No.
13230.
Unpublished
Mobay
Report
No.
90496.
12
p.

MRID:
40163201
Hoffmann,
K.;
Groening,
P.
(
1986)
Chronic
Oral
Toxicity
Study
on
Dogs
(
2­
year
Feeding
Experiment):
Supplemental
Submission
...:
(
Common
Name:
Bitertanol):
Bayer
Report
No.:
12307:
Mobay
AgChem
No.:
86304.
Unpublished
study
prepared
by
Bayer
Ag
Institut
Fuer
Toxikologie.
12
p.

MRID:
40163202
Hoffmann,
K.;
Vogel,
O.
(
1986)
Second
Chronic
Toxicity
Study
with
Dogs
on
Oral
Administration:
(
Feeding
Study,
0­
3­
25
ppm
12
months,
200
ppm
20
months):
Supplemental
Submission
...
Mobay
Report
No.
86298:
KWG
0599
(
Bitertanol):
Report
No.:
12328.
Unpublished
study
prepared
by
Bayer
Ag
Institute
of
Toxicology.
12
p.

MRID:
40163203
Hoffmann,
K.;
Vogel,
O.
(
1987)
Second
Chronic
Toxicity
Study
with
Dogs
on
Oral
Administration:
(
Feeding
Study,
0­
3­
25
ppm
12
months,
200
ppm
20
months):
Supplemental
Submission
...
KWG
0599
(
Bitertanol):
Report
No.:
12328:
86298­
3.
Unpublished
study
prepared
by
Bayer
Ag
Institute
of
Toxicology.
19
p.

MRID:
40163205
Schluter,
G.
(
1987)
Study
to
Determine
Embryotoxic
and
Teratogenic
Effects
on
Rabbits
following
Oral
Administration:
Supplemental
Submission
...:
Mobay
Report
No.
86432:
KWG
0599:
Bericht­
Nr.:
11548.
Unpublished
study
prepared
by
Bayer
Ag
Institut
fur
Tox­
ikologie.
18
p.

MRID:
40186401
Hoffmann,
K.;
Groening,
P.
(
1987)
Chronic
Oral
Toxicity
Study
on
Dogs:
(
2­
year
Feeding
Experiment):
[
Using
Baycor]:
Bayer
Report
No.
12307.
Unpublished
Mobay
AgChem
Report
No.
86304
prepared
by
Bayer
AG
Institut
Fuer
Toxikologie.
19
p.

MRID:
40490801
Becker,
H.;
Mueller,
E.;
Vogel,
W.;
et
al.
(
1987)
Embryotoxicity
Page
48
of
58
(
Including
Teratogenicity)
Study
with
KWG
0599
in
Rabbits:
Project
065283;
94704.
Unpublished
study
prepared
by
Research
and
Consulting
Co.,
AG.
281
p.

MRID:
40829401
Machemer,
L.
(
1987)
Embryotoxicity
(
including
Teratogenicity)
Study
with
KWG
0599
in
the
Rabbit:
Project
No.
065283,
Report
No.
94704,
94704­
1.
Unpublished
study
prepared
by
Research
&
Consulting
Co.
AG.
10
p.
Page
49
of
58
APPENDICES
A­
C
APPENDIX
A:
TOXICOLOGY
DATA
REQUIREMENTS
The
requirements
(
40
CFR
158.340)
for
food
use
for
{
Bitertanol}
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.

Table
1:
Toxicity
data
requirements
for
Bitertanol
(
PC
117801).

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
No
yes
yes
yes
yes
yes
yes
a
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
yes
no
no
870.3700a
Developmental
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3700b
Developmental
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
870.3800
Reproduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
870.4100a
Chronic
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4100b
Chronic
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200a
Oncogenicity
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200b
Oncogenicity
(
mouse)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4300
Chronic/
Oncogenicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
b
yes
yes
b
yes
yes
b
870.5100
Mutagenicity 
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
870.5300
Mutagenicity 
Gene
Mutation
­
mammalian
.
.
.
.
.
.
870.5450
Mutagenicity 
Structural
Chromosomal
Aberrations
NG
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.
Neuroc
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
yes
yes
no
­
­
yes
yes
no
870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
no
yes
no
Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Subchronic
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Six­
month
Oral
(
dog)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
Page
50
of
58
a
There
is
no
inhalation
exposure
in
the
United
States.
Bitertanol
is
a
non­
volatile
pesticide
used
on
imported
bananas.
b
Not
required
where
Guideline
870.4300
satisfies
guideline
870.4100a
and
870.4200a.
c
Held
in
reserve
pending
review
of
the
acute
and
90­
day
neurotoxicity
studies.

APPENDIX
B:
TOXICOLOGY
STUDIES
[
Executive
Summaries]

Subchronic
Studies
with
Bitertanol
90­
day
feeding
study
in
Sprague
Dawley
rats
(
MRID#
00157853)

EXECUTIVE
SUMMARY:
In
a
90­
day
oral
toxicity
study
(
MRID
00157853),
bitertanol
(
BAYCOR,
95%,
a.
i.,
Batch
No.
Pt
161600478)
was
administered
in
feed
at
concentrations
of
0,
40,
200
or
1000
ppm
to
15
Sprague­
Dawley
rats/
sex/
group.
Mean
test
substance
consumption
was
3.1,
15.9
and
81.8
mg/
kg/
day
in
males
and
3.6,
18.6
and
88.2
mg/
kg/
day
in
females.
Concentrations
administered
were
based
on
data
from
a
previous
four­
week
preliminary
dosage
study.
Controls
were
fed
untreated
feed.

One
male
in
the
control
group
died
at
ten
weeks
from
a
circulatory
disturbance;
no
deaths
occurred
in
the
treated
animals.
No
treatment­
related
clinical
signs
were
observed
in
any
animals.

Mean
body
weight
and
body
weight
gain
indicated
a
dose­
dependent
decrease
in
the
treated
animals.
While
low­
dose
male
and
female
rats
had
slight
decreases
in
body
weight
and
body
weight
gain
compared
to
controls,
the
values
were
not
of
a
magnitude
to
be
considered
toxicologically
significant
with
values
$
94%
of
controls.
Mid­
dose
males
and
females
had
a
decrease
in
body
weight
and
body
weight
gain
that
was
toxicologically
significant.
Mid­
dose
male
and
female
body
weight
started
to
decrease
compared
to
controls
at
week
three,
remained
lower
than
controls
for
the
remainder
of
the
study,
with
decreases
within
10%
of
controls.
Mean
body
weight
gain
in
the
mid­
dose
males
remained
at
84­
91%
of
controls
with
the
lowest
weight
gain
observed
at
weeks
3­
6.
Mid­
dose
females
had
a
mean
body
weight
gain
in
weeks
0­
3
that
was
88%
of
controls,
then
decreased
to
79%
of
controls
in
weeks
6­
9,
but
was
the
same
as
controls,
thereafter.
The
high­
dose
male
body
weight
was
81%
of
controls
in
the
first
week,
dropped
to
80%
of
controls
through
week
six
and
averaged
about
83%
of
controls
through
week
thirteen.
Total
mean
body
weight
gain
in
the
high­
dose
males
for
the
entire
thirteen
weeks
was
74%
of
controls
and
ranged
from
56
to
115%
with
no
trend
in
time
established.
High­
dose
female
mean
body
weight
was
85%
of
controls
during
week
one,
then
decreased
to
83%
of
controls
for
the
remainder
of
the
study.
Mean
body
weight
gain
for
high­
dose
females
was
the
lowest
in
weeks
0­
3
at
58%
of
controls
and
increased
to
88%
of
controls
during
weeks
9­
13.

Low
and
mid­
dose
male
and
female
rats
had
values
similar
to
controls
for
food
and
water
consumption,
and
low­
dose
animals
were
similar
to
controls
in
food
efficiency.
In
high­
dose
males,
food
consumption
was
decreased
(
77
%
of
controls)
during
week
one
but
then
improved
to
approximately
90%
of
the
control
values
for
the
remainder
of
the
study.
Food
consumption
in
high­
dose
females
was
also
decreased
compared
to
controls
(
76%)
in
week
one
but
increased
to
83%
of
controls
by
study
termination.
Water
consumption
for
the
high­
dose
male
and
female
rats
was
the
lowest
in
week
one,
71
and
77%
of
controls,
respectively,
and
never
increased
above
80%
of
controls
in
males
or
86%
in
females
for
the
remainder
of
the
study.
Overall,
food
efficiency
was
88
and
90%
of
controls
in
mid­
dose
male
and
female
rats,
respectively
and
87
and
86%
in
high­
dose
male
and
female
rats,
respectively.

Hematology
results
showed
both
the
high­
dose
male
and
female
rats
had
a
statistically
significant
decrease
(
p
<
0.05)
in
the
number
of
red
blood
cells
with
a
corresponding
increase
in
reticulocytes.
The
hematocrit
was
significantly
decreased
in
the
female
rats
in
the
high­
dose
but
Page
51
of
58
not
in
the
males.
These
differences;
however,
did
not
demonstrate
any
dose­
related
trends.
Treated
males
were
not
observed
to
have
any
dose­
related
differences
in
their
clinical
chemistry
values.
However,
in
high­
dose
females,
clinical
chemistry
values
for
lactate
dehydrogenase
(
LDH),
aspartate
aminotransferase
(
AST,
SGOT)
and
alkaline
phosphatase
(
ALP)
values
showed
a
statistically
significant
increase
(
p
<
0.05).
In
mid­
dose
females,
SGOT
and
ALP
were
also
significantly
increased.

Organ
weight
differences
were
observed
only
in
the
high­
dose
animals.
Relative
liver
and
spleen
organ
weights
were
increased,
+
23
and
+
26
%
of
controls,
respectively,
in
high­
dose
males.
Absolute
and
relative
liver
and
spleen
organ
weights
were
statistically
increased
in
the
high­
dose
female
rats;
absolute
weights
by
+
16%
for
both
liver
and
spleen
and
relative
by
+
39
and
+
37%,
respectively.
Gross
examination
of
the
animals
found
a
slight
enlargement
of
the
liver
and
adrenals
in
both
the
male
and
females
in
the
high­
dose
group.
Histopathology
examination
found
lesions
related
to
these
enlargements;
however,
severity
of
the
lesions
was
not
provided.
Liver
changes
indicating
hepatotoxicity
included:
swelling
of
hepatocytes
(
9/
15
males
and
10/
15
females),
fatty
degeneration
of
liver
cells
(
1/
15
males
and
8/
15
females)
and
bile
duct
hyperplasia
(
1/
15
males
and
5/
15
females).
In
the
adrenal,
there
were
enlarged
cortical
cells
(
14/
15
males
and
15/
15
females)
with
increased
fatty
deposition
(
6/
15
males
and
10/
15
females).
Other
lesions
found
in
the
highdose
group
were
keratosis
of
the
mucosal
epithelium
of
the
esophagus
(
9/
15
males
and
11/
15
females)
and
stomach
(
10/
15
males
and
6/
15
females).
Few,
if
any,
differences
in
organ
weights,
gross
or
histopathological
lesions
associated
with
treatment
were
seen
in
any
animals
in
the
control,
low­
or
mid­
dose
groups.

The
lowest­
observed­
adverse­
effect­
level
(
LOAEL)
for
oral
systemic
toxicity
in
rats
for
bitertanol
is
200
ppm,
(
15.9
or
18.6
mg/
kg/
day
in
males
and
females,
respectively),
based
on
a
decrease
in
body
weight
and
body
weight
gain.
The
no­
observed­
adverse­
effect­
level
(
NOAEL)
for
systemic
toxicity
is
40
ppm,
(
3.1
or
3.6
mg/
kg/
day
in
males
and
females,
respectively).

This
study
is
Acceptable/
Guideline
and
satisfies
the
requirements
for
a
subchronic
oral
toxicity
study
in
rats
[
OPPTS
870.3100
(
§
82­
1)].
Although
ophthalmological
examinations
were
not
conducted,
eye
were
examined
histologically
and
individual
animal
histopathology
was
acceptable.

Comments:
This
is
a
revised
Executive
Summary.
This
reviewer
disagrees
with
the
previous
reviewer
on
the
NOAEL
and
LOAEL
values.
The
previous
reviewer
set
the
LOAEL
at
40
ppm
and
the
NOAEL
to
be
undetermined.
This
reviewer
agrees
that
there
is
a
dose­
related
decrease
to
body
weight
and
body
weight
gain
but
the
values
are
not
toxicologically
significant
at
the
40
ppm
concentration,
especially
in
the
females.
A
table
with
the
addition
of
body
weight
gain
with
additional
time
points
was
added
to
this
revision
to
support
this
evaluation.

90­
day
feeding
study
Wister
rats
(
MRID#
00025647)

EXECUTIVE
SUMMARY:
In
a
90­
day
oral
toxicity
study
(
MRID
00025647),
KWG
0599
(
purity
not
provided;
batch
no.
16001/
77)
was
administered
to
15
Wistar
W.
74
rats/
sex/
dose
in
the
diet
at
concentrations
of
0,
30,
100
or
300
ppm
(
equivalent
to
0,
2.46,
8.16
or
24.84
mg/
kg/
day,
respectively,
for
males
and
0,
3.25,
10.15
or
31.60
mg/
kg/
day,
respectively,
for
females).

There
were
no
significant
compound­
related
effects
based
on
the
assessment
of
mortality,
clinical
signs
of
toxicity,
behavior,
body
weights,
food
consumption,
urinalysis,
hematology,
clinical
chemistry,
gross
necropsy
and
histopathology.
The
test
animals
could
have
tolerated
higher
dosages
of
KWG
0599.
However,
there
was
a
nominal
body
weight
gain
decrement
in
males
and
females
through
out
treatment
at
300
ppm
of
upto
8%
and
12%
by
termination.

The
tentative
NOAEL
is
100
ppm
[
M/
F:
8.2/
10.2
mg/
kg/
day].
The
tentative
LOAEL
is
300
ppm
Page
52
of
58
[
M/
F:
24.8/
31.6
mg/
kg/
day]
based
on
a
consistent
body
weight
gain
decrement
of
upto
8%
and
12%
in
males
and
females
by
termination,
respectively.

This
90­
day
oral
toxicity
study
in
the
rat
is
Unacceptable/
Guideline/
not
upgradable
and
does
no
satisfy
the
guideline
requirement
for
a
90­
day
oral
toxicity
study
(
OPPTS
870.3100;
OECD
408)
in
rat.
Although
no
concentration
analysis
for
test
material
in
the
feed
was
conducted,
the
effects
from
this
study
are
similar
to
the
NOAEL/
LOAEL
and
effects
from
MRID#
00157853
where
analysis
of
test
material
in
the
feed
was
conducted.
MRID#
0002547
supports
MRID#
00157853.
Since
the
same
lot#/
batch#
was
used
in
MRID#
0002548
where
purity
was
reported
as
used
in
MRID#
0002547,
the
purity
is
not
an
issue.
However,
the
diet
preparation,
concentration,
stability,
and
homogeneity
data
were
not
provided.
Repeating
the
study
is
unnecessary
because
another
90­
day
study
in
rats
with
bitertanol
is
acceptable.

COMPLIANCE:
Signed
and
dated
GLP,
Quality
Assurance,
and
Data
Confidentiality
statements
were
not
provided.
This
study
was
done
prior
to
the
and
the
guideline
requirements
of
OPPTS
870.3100
and
publication
of
FIFRA
GLP
Standards
(
11/
29/
83).
The
pesticide
is
sufficiently
stable,
and
the
limits
on
the
purity
indicate
that
the
purity
is
satisfactory,
but
the
lack
of
validation
of
the
dose
levels
used
is
more
problematic.

90­
day
feeding
study
in
dogs
(
MRID#
00025648)

EXECUTIVE
SUMMARY:
In
a
90­
day
oral
toxicity
study
(
MRID
00025648)
KWG
0599
[
Bitertanol
(
90.2%
a.
i.,
batch/
lot
16001/
77)]
was
administered
by
capsule
to
groups
of
4
male
and
4
female
beagle
dogs/
group
at
concentrations
of
0,
1.0,
5.0,
or
25.0
mg/
kg/
day.

Treatment
with
the
test
material
at
concentrations
$
5
mg/
kg/
day
induced
a
dose­
and
timedependent
effect
on
the
physical
appearance
of
male
and
female
dogs.
Skin
redness,
alopecia,
scale
and
scab
formation,
and
mucosal
irritation
developed
on
most
mid­
and
high­
dose
dogs.
conjunctivitis
was
found
on
most
mid­
and
high­
dose
dogs
and
was
often
accompanied
with
lacrimation.
Three
high­
dose
dogs
developed
conjunctival
keratitis
by
study
end.
The
body
weight
of
high­
dose
male
and
female
dogs
was
significantly
decreased
from
week
7
through
the
end
of
the
study,
although
food
intake
was
not
decreased.
Likewise,
a
net
decrease
of
total
weight
gain
of
male
and
female
high­
dose
dogs
was
statistically
significant
from
control.
No
biologically
significant
differences
in
body
weight
gain
were
found
in
the
low­
and
mid­
dose
treatment
groups.

Treatment
with
the
test
material
induced
a
slight
increases
in
the
activity
of
ALT
and
ALP
in
highdose
animals.
However,
other
liver­
related
activities,
such
as
glutamate
dehydrogenase
and
AST
were
not
significantly
increased.
A
slight
increase
in
liver
total
cytochrome
P450
activity
was
found.
No
clearly
demonstrable
increase
in
the
tissue
activity
of
N­
demethylase
activity
or
other
significant
treatment­
related
effects
were
found.
At
necropsy,
all
female
dogs
in
the
5
mg/
kg
group
and
all
male
and
female
dogs
in
the
25
mg/
kg/
day
group
had
thin
hair
coats,
particularly
on
the
chest
and/
or
stomach.
The
coat
of
all
female
high­
dose
dogs
was
dirty
and
sticky,
particularly
on
the
edges
of
the
ears.
The
prostate
gland
of
high­
dose
male
dogs
was
noted
to
be
small,
and
the
thymus
gland
of
three
high­
dose
female
dogs
was
severely
atrophied.
Consistent
with
the
increased
total
cytochrome
P450
activity
in
both
sexes
of
high­
dose
dogs,
the
relative
weight,
but
not
the
absolute
liver
weight
was
statistically
increased
~
13%
in
males
and
22%
in
females,
suggestive
of
an
adaptive
response.

Treatment
of
male
and
female
dogs
with
25
mg/
kg
KWG
0599
decreased
the
absolute
thymus
weight
and
both
absolute
and
relative
prostate
weight
of
mid­
and
high­
dose
male
dogs.
Microscopically,
the
prostate
gland
of
all
high­
dose
dogs
and
one
mid­
dose
dog
was
only
slightly
developed
with
the
tubuloalveolar
section
having
a
small
lumen
and
containing
no
secretions.
No
treatment­
related
effects
were
noted
microscopically
in
the
thymus.
The
stratum
epithelium
was
Page
53
of
58
minimally
distended
in
high­
dose
male
and
female
dogs
and
one
mid­
dose
male
and
female
dog.
In
many
cases,
minimal
cornification,
particularly
in
follicles
where
the
hair
had
fallen
out,
was
observed.

Based
on
the
prostatic
effects
in
mid­
and
high­
dose
male
dogs
and
the
dermal
and
conjunctival
effects
on
mid­
and
high­
dose
male
and
female
dogs,
the
KWG
0599
LOAEL
is
5
mg/
kg/
day.
The
NOAEL
for
KWG
0599
is
1
mg/
kg/
day.

This
90­
day
oral
toxicity
study
in
the
dog
is
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
90­
day
oral
toxicity
study
(
OPPTS
870.3150;
OECD
409)
in
the
dog.
Signed
and
dated
GLP,
Quality
Assurance,
and
Confidentiality
statements
were
not
included
since
the
study
was
done
prior
to
the
original
publication
of
FIFRA
GLP
Standards
(
11/
29/
83).
However,
sufficient
numbers
of
animals
were
used/
group
and
individual
animal
data
were
provided.

COMPLIANCE:
Signed
and
dated
GLP,
Quality
Assurance,
and
Data
Confidentiality
statements
were
not
provided.

21/
28­
Day
dermal
study
in
NZW
rabbits
(
MRID#
00149829)

EXECUTIVE
SUMMARY:
In
a
21­
day
dermal
toxicity
study
(
MRID
00149829),
KWG
0599
(
bitertanol,
95.8%,
a.
i.,
Batch
No.
233296990)
was
applied
to
the
shaved
skin
of
six
New
Zealand
White
rabbits/
sex/
dose
at
concentrations
of
0
(
controls),
50,
or
250
mg/
kg
bw/
day,
6
hours/
day,
5
days/
week
for
three
consecutive
weeks.
Skin
in
three
rabbits
in
each
group
was
abraded
prior
to
treatment
and
three
were
left
intact.
MRID
40163204
was
provided
as
a
supplemental
submission
on
the
technical
problems
associated
with
application
of
higher
doses
in
the
original
study.

There
were
no
treatment­
related
deaths
or
clinical
signs
of
systemic
toxicity
in
the
rabbits.
No
effects
on
body
weight,
hematology,
clinical
chemistry,
urinalysis,
liver
homogenate
examination,
or
organ
weight
were
observed
in
either
treated
or
control
animals.
The
histopathological
examination
showed
lesions
that
were
related
only
to
dermal
irritation.

Based
on
the
results
of
this
study,
the
systemic
LOAEL
for
KWG
0599
(
bitertanol)
in
male
and
female
rabbits
can
not
be
identified,
and
the
systemic
NOAEL
is
$
250
mg/
kg/
day.

Evidence
of
mild
dermal
irritation
in
the
form
of
redness
was
observed.
Scoring
for
redness
severity
ranged
from
0
(
no
redness)
to
4
(
deep
redness
with
some
corrosion).
Dermal
irritation
was
never
scored
greater
than
3
(
moderate
to
severe
redness)
in
any
group.
Treated
male
rabbits
were
observed
to
have
a
dose­
related
difference
in
severity
of
redness
with
scores
being
slightly
higher
for
abraded
skin.
In
the
first
five
days,
high­
dose
male
rabbits
with
abraded
skin
had
a
mean
redness
score
of
3
versus
the
low­
dose
group
with
a
mean
of
2
(
slight
to
moderate
redness).
Male
rabbits
with
intact
skin
had
mean
scores
of
<
1
to
1
(
slight,
barely
perceptible
redness)
on
days
4­
7
in
the
low­
dose
group
and
1­
2
in
the
high­
dose
group
during
the
same
time
period.
Females
had
slightly
higher
redness
scores
in
abraded
skin
compared
to
intact
skin
but
there
was
not
a
doseresponse
All
treated
rabbits
had
dermal
scores
of
#
1
by
day
7
of
the
study.
Control
animals
with
abraded
skin
had
redness
scores
of
1­
3
for
days
0­
3
due
to
the
physical
act
of
abrading
done
pretreatment,
but
redness
was
not
observed
in
the
controls
with
intact
skin.
No
treatment­
related
effect
on
skin
thickness
was
observed
in
any
of
the
rabbits,
treated
or
controls,
when
measured
with
calipers.

Gross
examination
at
necropsy
showed
no
treatment­
related,
systemic
or
dermal
lesions
in
any
rabbits.
Histopathological
examination
showed
lesions
limited
to
treated
skin
in
the
treated
animals.
No
lesions
were
observed
in
the
control
group
or
in
the
untreated
skin
of
the
treated
animals.
The
histopathological
lesion
observed
from
treatment
was
a
mild
epithelial
proliferation
Page
54
of
58
of
the
epidermis
in
the
form
of
acanthosis
with
slight
hyperkeratosis.
This
effect
was
seen
in
all
treated
animals
(
intact
and
abraded
skin)
at
the
same
severity
level,
mild.

Based
on
the
results
of
this
study,
the
dermal
LOAEL
for
KWG
0599
(
bitertanol)
in
male
and
female
rabbits
is
50
mg/
kg/
day,
and
the
dermal
NOAEL
is
not
identified.

This
21­
day
dermal
toxicity
study
in
rabbits
is
Acceptable/
Guideline.
It
satisfies
the
guideline
requirement
for
a
21/
28­
day
dermal
toxicity
study
(
OPPTS
870.3200;
OECD
410)
in
rabbits.
This
study
is
believed
to
be
adequate
to
show
no
systemic
effects,
although
previously
classified
as
Supplementary
in
TXR#
0004638
and
0006528
because
the
explanation
of
the
upper
dose
level
was
inadequate.
The
following
explanation
was
accepted;
"
increasing
the
dose
level
would
have
exceeded
the
capacity
for
a
stationary
film
on
the
treated
area."

COMPLIANCE:
Signed
and
dated
GLP,
and
Data
Confidentiality
statements
were
provided.
No
Quality
Assurance
statements
were
provided.

Two
week
non­
guideline
liver
toxicity
study
in
Wister
rats
(
MRID#
00149829)

EXECUTIVE
SUMMARY:
In
a
14­
day
study
(
MRID
00163455),
suspensions
of
KWG
0599
(
95.8%;
Batch
No.
233296990)
were
administered
to
10
Wistar
(
Bor
WISW)
(
SPF­
Cpb)
rats/
sex/
dose
by
gavage
at
concentrations
of
0,
30,
100
or
300
mg/
kg/
day.
The
study
was
designed
to
assess
the
potential
effects
of
orally
administered
KWG
0599
on
the
liver
of
rats;
therefore,
a
limited
number
of
parameters
were
investigated.

There
were
no
significant
treatment­
related
effects
on
mortality,
clinical
signs,
behavior,
hematology
or
gross
pathology.
A
treatment­
related
decrease
in
terminal
body
weight
was
statistically
significant
beginning
at
30
mg/
kg/
day
in
females
and
100
mg/
kg/
day
in
males;
corresponding
body
weight
gain
was
decreased
in
both
sexes.

Slight
induction
of
liver
microsomal
enzymes
beginning
at
100
mg/
kg/
day
was
based
on
increased
O­
demethylase
(
p#
0.01)
activity
in
males
and
N­
demethylase
activity
in
females
as
well
as
increased
total
cytochrome
P­
450
activity
and
increased
absolute
and/
or
relative
liver
weights
in
both
sexes.
Hepatocellular
hypertrophy
with
cytoplasmic
granules
was
also
reported
at
this
dosage.

Additional
significant
treatment­
related
effects
in
the
liver
include
isolated
Councilman
bodies
at
100
mg/
kg/
day
in
females
and
300
mg/
kg/
day
in
males,
bile
duct
proliferation
at
$
100
mg/
kg/
day
in
both
sexes,
and
isolated
mitoses
at
300
mg/
kg/
day
in
females.
No
treatment­
related
effects
were
seen
in
liver
of
males
and
females
receiving
30
mg
KWG
0599/
kg/
day.

This
subacute
oral
toxicity
study
in
the
rat
is
Acceptable/
Non­
guideline
and
satisfies
the
intent
of
the
study.
Signed
and
dated
GLP
and
Quality
Assurance
statements
were
not
included
since
the
study
was
done
prior
to
the
original
publication
of
FIFRA
GLP
Standards
(
11/
29/
83).
However,
sufficient
numbers
of
animals
were
used/
group
and
individual
animal
data
were
provided.

COMPLIANCE:
Signed
and
dated
GLP,
Quality
Assurance,
and
Data
Confidentiality
statements
were
not
provided.

Dermal
Penetration
in
New
Zealand
White
Rabbits
(
MRID#
00150149]

EXECUTIVE
SUMMARY:
In
a
dermal
absorption
study
(
MRID#
00150149)
200
mg
of
50%
formulation
of
bitertanol
and
50
µ
Ci
of
radiolabled
bitertanol
were
applied
to
the
shaved
backs
of
4
NZW
rabbits/
sex/
group
for
24
hours
and
occluded
[
about
2.5
mg/
cm2].
After
24
hours
the
sites
Page
55
of
58
were
washed
and
urine
and
feces
were
collected
over
each
24
hour
period
for
13
days
and
processed
for
counting
and
the
amount
of
radio­
label
excreted
in
male
and
female
urine
and
feces
during
each
24
hour
period
counted.
At
the
end
of
13
days,
skin
from
the
application
site
was
removed
and
processed
for
radio­
label
counting.

During
the
first
24
hours
only
0.73%
of
the
dose
applied
was
excreted
from
males
and
0.53%
of
the
dose
applied
was
excreted
from
females.
Excretion
was
complete
in
13
days.

The
author
calculated
the
amount
adsorbed
as
a
percentage
of
the
mean
of
the
total
excreted
in
the
urine
and
feces
of
male
and
female
rabbits
and
reported
as
follows.
The
total
excreted
after
13
days
from
males
ranged
from
3.18
to
5.98
µ
Ci
or
6%
to
12%
of
the
dose
applied.
The
total
excreted
after
13
days
from
females
ranged
from
5.21
to
11.67
µ
Ci
or
10
to
23%
of
the
dosed
applied.
The
author
estimated
that
about
10%
absorption
represents
a
worst
case
scenario.

Using
the
mean
of
the
total
excreted
in
the
urine,
feces
and
remaining
in
the
skin
of
males
and
female
rabbits
the
reviewer
calculated
that
a
mean
of
4.13
µ
Ci
or
8.1%
of
the
dose
applied
to
males
and
7.02
µ
Ci
or
13.8%
of
the
dose
applied
to
females
was
accounted
for.
This
left
92%
of
the
dose
to
males
and
86%
of
dose
to
females
that
was
not
accounted
for.
[
Although
most
of
this
unaccount
for
radiolabel
was
probably
washed
from
the
skin
24
hours
after
application,
this
is
an
unverifible
assumption.]
This
percentage
of
unaccounted
for
radio­
label
is
unsatisfactory
in
a
dermal
penetration
study
where
the
dermal
penetration
could
be
as
high
as
about
90%
or
as
low
as
about
10%.

The
study
is
unacceptable/
not
upgradeable
for
a
guideline
dermal
absorption
study.
The
study
lack
multiple
dose
levels
and
did
not
account
for
the
radio­
label
applied.

COMPLIANCE:
Signed
and
dated
GLP,
and
Data
Confidentiality
statements
were
provided.
Quality
Assurance
statements
were
provided.

Metabolism
and
Pharmacokinetics
in
Wister
rats
(
MRID#
0025733
&
00129560)

EXECUTIVE
SUMMARY:
Two
studies
were
conducted
to
assess
the
metabolism
and
disposition
of
[
14C­
phenyl­
UL]
BAYCOR
(
Bitertanol)
in
rats
[
MRID
00129560
&
00025733].
In
MRID
00129560,
groups
of
five
male
and
female
rats
were
given
single
or
multiple
low
(
100
mg/
kg)
oral
doses,
a
single
low
(
100
mg/
kg)
intravenous
dose,
or
a
single
high
(
1000
mg/
kg)
dose
of
[
14C­
phenyl­
UL]
BAYCOR
(>
99%
radiochemical
purity;
no
lot/
batch
no.)
combined
with
nonlabeled
material
(
93.9%
chemical
purity,
no
lot/
batch
no).
The
metabolism
and
disposition
of
the
test
material
was
assessed
over
a
168­
hour
time
frame.
An
earlier
study
(
MRID
00025733)
examined
the
metabolism
and
disposition
of
[
14C­
phenyl­
UL]
BAYCOR
(>
99%
radiochemical
purity;
no
lot/
batch
no.)
and
non­
labeled
material
(
93.9%
chemical
purity,
no
lot/
batch
no)
in
five
male
and
five
female
rats.
Unfortunately
neither
study
used
bitertanol
labeled
in
the
triazole
group.

Recovery
of
radioactivity
was
acceptable
in
both
studies
(
92­
104%
and
99%).
Both
studies
affirmed
the
relatively
rapid
absorption
of
[
14C­
phenyl­
UL]
BAYCOR
(
Bitertanol)
and
that
excretion
was
primarily
via
the
feces
(
81­
98%
and
92%,
respectively)
over
the
168­
hr
experimental
period.
Urinary
excretion
(
4­
11%
and
­
8%
in
the
two
studies)
was
secondary
to
fecal
elimination.
Saturated
absorption
at
the
high
dose
(
1000
mg/
kg)
was
evident
by
a
plateau
in
plasma
radioactivity
levels
(
and
by
estimated
kinetic
parameters)
and
an
increase
in
the
fecal
excretion
of
parent
compound.
A
minor
gender­
related
variance
in
absorption
and
elimination
constants
and
plasma
elimination
halftime
was
observed
for
the
multiple
dose
group
but
not
for
other
treatment
groups.
No
other
gender­
related
variability
was
observed.
Neither
study
reported
excretion
via
expired
air.
In
both
studies,
tissue
radioactivity
was
minimal
and
not
suggestive
of
bioaccumulation
of
the
test
material
or
its
metabolites.
Page
56
of
58
Both
studies
provided
information
on
the
identification
of
metabolites
(
MRID
00025733
lacked
details
and
a
data
table
pertaining
to
metabolite
quantification)
that
implied
extensive
metabolism
of
BAYCOR.
Both
parent
compound
and
numerous
metabolites
(
of
which
12
were
identified
in
addition
to
two
isomers
of
BAYCOR)
were
detected.
The
metabolites
identified
in
fecal
samples
appeared
to
account
for
­
34­
72%
of
radioactivity
recovered
in
the
feces
(­
81­
98%
of
the
dose)
in
that
matrix.
A
notable
amount
of
administered
radioactivity
(­
50%
of
total)
remained
unidentified
and
probably
unextractable
in
the
feces.
Since
the
triazole
ring
was
not
labeled,
the
triazole
metabolite
if
present
was
not
detected.
[
Triazole
could
not
be
detected
in
other
triazole
ring
containing
pesticides
when
the
triazole
ring
was
not
labeled.]
For
the
urine,
the
metabolite
profile
was
less
complex
but
contained
similar
metabolites
as
found
in
the
feces.
The
urinary
metabolites,
however,
were
quantitatively,
less
significant
due
to
urinary
excretion
accounting
for
only
4­
11%
of
the
total
dose.
The
effort
to
extract
and
subsequently
characterize
the
radioactivity
in
the
excreta
appeared
to
have
been
thorough,
however.
Fecal
excretion
in
males
and
females
was
as
high
in
the
i.
v.
as
the
oral
dosing
studies
showing
high
biliary
excretion
of
the
test
material.

These
studies
(
MRID
00025733
and
00129560)
on
the
metabolism
and
disposition
of
[
14Cphenyl
UL]
BAYCOR
(
Bitertanol)
are
classified
Acceptable/
Guideline
and
satisfy
the
85­
1
Guideline
Requirement
for
a
metabolism
study
[
OPPTS
870.7485
OECD
417].
However,
failure
to
label
the
triazole
ring
may
require
additional
metabolic
data.
Although
conducted
prior
to
GLP
guidelines,
the
reviewed
studies
utilized
and
adequate
number
of
animals
of
each
gender,
demonstrated
acceptable
mass
balance
accounting
of
radioactivity,
and
adequately
described
the
metabolism
and
disposition
of
the
BAYCOR
(
Bitertanol)
in
rats
following
multiple
dose
regimens
including
single
low
(
100
mg/
kg)
oral
and
intravenous
doses,
multiple
low
doses,
and
a
single
high
(
1000
mg/
kg)
oral
dose.

COMPLIANCE:
These
studies
were
conducted
in
1979
(
MRID
00025733)
and
1979­
1983
(
MRID
00129560),
both
prior
to
GLP
Guideline
requirements.
No
quality
Assurance
or
Data
Confidentiality
Claim
statements
were
provided.
Page
57
of
58
APPENDIX
C:
Names
and
Structures
of
Rat
Metabolites
in
MRID#
00129560
&
00025733
TABLE
C­
1.
Fecal
metabolites
(%
of
total
recovered)
in
rats
given
[
14C­
phenyl­
UL]
BAYCOR
Metabolite
Metabolite
#
a
A
100
mg/
kg
iv
B
100
mg/
kg
oral
C
100
mg/
kg
oral,
repeat
D
1000
mg/
kg
oral
Male
Female
Male
Female
Male
Female
Male
Female
BAYCOR
II
1
0.7
0.7
4.3
2.2
3.9
1.5
28.8
31.0
BAYCOR
I
2
1.1
0.7
4.2
2.1
2.9
1.4
26.5
28.1
p­
hydroxy
BAYCOR
II
3
4.0
4.1
3.2
3.8
2.7
3.5
1.6
1.4
p­
hydroxy
BAYCOR
I
4
4.2
3.2
3.0
2.3
1.8
1.8
2.2
1.4
p­
hydroxy­
m­
methoxy
BAYCOR
I
5
3.0
1.8
5.0
1.9
0.1
­
1.6
0.8
BAYCOR
alcohol
II
6
1.5
1.2
1.6
1.0
1.0
1.1
0.7
0.3
m,
m­
dihydroxy
BAYCOR
II
7
1.7
3.4
1.9
4.6
1.9
3.0
0.7
1.3
m,
m­
dihydroxy
BAYCOR
I
8
2.1
5.0
3.3
5.3
4.5
6.0
1.4
2.0
p­
hydroxy
BAYCOR
alcohol
II
9
2.3
1.7
3.5
2.7
4.2
1.8
0.8
0.7
p­
hydroxy
BAYCOR
alcohol
I
10
1.5
1.2
1.9
1.9
1.9
1.3
0.7
0.7
BAYCOR
acid
II
11
0.6
0.5
0.6
1.5
0.6
0.9
0.2
0.3
BAYCOR
acid
I
12
4.3
1.5
2.5
1.7
3.6
2.4
1.1
0.7
p­
hydroxy
BAYCOR
acid
II
13
2.8
2.0
0.9
2.3
0.7
1.8
1.2
1.1
p­
hydroxy
BAYCOR
acid
I
14
5.5
5.9
5.4
6.9
4.4
6.2
2.3
2.4
Conjugates
0.6
1.1
0.6
0.9
0.8
1.1
0.6
0.7
Total
identified
b
35.9
34.0
41.9
41.1
35.0
33.8
70.4
72.9
Unidentified
b
64.1
66.0
58.1
58.9
65.0
66.2
29.6
27.1
Total
accounted
b
100
100
100
100
100
100
100
100
a
Refers
to
the
number
under
the
structures
in
the
figure
on
the
following
page.
b
percent
of
radioactivity
recovered
in
feces.
Page
58
of
58
Figure
1.
Proposed
metabolic
pathway
for
[
14C­
phenyl­
UL]
BAYCOR
(
Bitertanol)
in
rats.
Figure
taken
from
page
48
of
MRID
00129560.