UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
Date:
July
18,
2005
MEMORANDUM
SUBJECT:
Iprovalicarb
HED
Human
Health
Risk
Assessment
to
Support
Tolerance
on
Imported
Tomatoes
(
Petition
No.
3E6578).

PC
Code:
098359,
DP
Barcode:
D317045
Regulatory
Action:
Tolerance
without
Registration
Risk
Assessment
Type:
Single
Chemical
No
Aggregate
Trade
Names:
Melody
Med
WP
66,
Melody
Med
WP
69,
and
Melody
Compact
WP
24.5.
Chemical
Class:
Amino
Acid
Amide
Carbamate
Fungicide
FROM:
Margarita
Collantes,
Biologist
Registration
Action
Branch
2
Health
Effects
Division
(
7509C)

AND
William
Drew,
Chemist
Alan
Levy,
Toxicologist
Registration
Action
Branch
2
Health
Effects
Division
(
7509C)

THROUGH:
Richard
Loranger,
Branch
Senior
Scientist
Registration
Action
Branch
2
Health
Effects
Division
(
7509C)

TO:
Lisa
Jones/
Mary
Waller
Fungicide
Branch
Registration
Division
(
7505C)
ii
Table
of
Contents
1.0
Executive
Summary
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1
2.0
Ingredient
Profile
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5
2.1
Summary
of
Registered/
Proposed
Uses
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5
2.2
Structure
and
Nomenclature
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8
2.3
Physical
and
Chemical
Properties
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9
3.0
Metabolism
Assessment
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9
3.1
Comparative
Metabolic
Profile
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9
3.2
Nature
of
the
Residue
in
Foods
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11
3.2.1.
Description
of
Primary
Crop
Metabolism
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11
3.2.2
Description
of
Livestock
Metabolism
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11
3.2.3
Description
of
Rotational
Crop
Metabolism,
including
identification
of
major
metabolites
and
specific
routes
of
biotransformation
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11
3.3
Environmental
Degradation
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11
3.4
Toxicity
Profile
of
Major
Metabolites
and
Degradates
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11
3.5
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
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12
3.5.1
Rationale
for
Not
Including
Metabolites
and
Degredates
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12
4.0
Hazard
Characterization/
Assessment
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12
4.1
Hazard
Characterization
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13
4.2
FQPA
Hazard
Considerations
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22
4.2.1
Adequacy
of
the
Toxicity
Data
Base
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22
4.2.2
Evidence
of
Neurotoxicity
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22
4.2.3
Developmental
Toxicity
Studies
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23
4.2.4
Reproductive
Toxicity
Study
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24
4.2.5
Additional
Information
from
Literature
Sources
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25
4.2.6
Pre­
and/
or
Postnatal
Toxicity
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25
4.2.6.1
Determination
of
Susceptibility
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25
4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
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26
4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
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26
4.3.1
Evidence
that
supports
not
requiring
a
Developmental
Neurotoxicity
study
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26
4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
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27
4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49
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27
4.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
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27
4.4.3
Chronic
Reference
Dose
(
cRfD)
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27
4.4.4
Incidental
Oral,
Dermal
and
Inhalation
Exposure
(
All
Durations)
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29
4.4.5
Recommendation
for
Aggregate
Exposure
Risk
Assessments
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29
4.4.6
Classification
of
Carcinogenic
Potential
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29
4.5
Special
FQPA
Safety
Factor
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32
4.6
Endocrine
disruption
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32
iii
5.0
Public
Health
Data
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33
5.1
Incident
Reports
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33
6.0
Exposure
Characterization/
Assessment
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33
6.1
Dietary
Exposure/
Risk
Pathway
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33
6.1.1
Residue
Profile
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33
6.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk
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34
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
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35
Water
and
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
8.0
Cumulative
Risk
Characterization/
Assessment
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35
9.0
Occupational
Exposure/
Risk
Pathway
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36
10.0
Data
Needs
and
Label
Requirements
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36
10.1
Toxicology
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36
10.2
Residue
Chemistry
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36
10.3
Occupational
and
Residential
Exposure
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36
References:
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37
Appendices
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38
1
1.0
Executive
Summary
The
registrant,
Bayer
CropScience
Ag,
has
requested
the
establishment
of
a
permanent
tolerance
for
residues
of
iprovalicarb
on
imported
tomatoes
without
a
United
States
registration
(
PP#
3E6578).
Iprovalicarb
(
also
known
as
Melody
Med
WP
66,
Melody
Med
WP
69,
and
Melody
Compact
WP
24.5.
)
is
a
systemic
fungicide
active
ingredient
that
is
proposed
for
use
in
the
European
Union
to
prevent
and
control
downy
mildew
in/
on
tomatoes.
Iprovalicarb
is
a
systemic
plant
protectant
with
a
mono­
site
mode
of
action,
which
inhibits
spore
germination,
mycelial
growth
and
sporulation
and
has
protective,
curative
and
fungus
eradicative
properties.
There
are
no
products
containing
iprovalicarb
registered
for
us
in
the
United
States,
but
there
is
a
2
ppm
tolerance
for
residues
in
imported
grapes,
established
in
2002.

Toxicology
The
toxicology
data
base
for
iprovalicarb
is
adequate
to
support
the
proposed
tolerance
on
imported
tomatoes,
and
there
are
no
data
gaps
at
this
time.
The
scientific
quality
of
the
database
for
iprovalicarb
is
relatively
high,
and
the
toxicity
profile
can
be
characterized
for
all
effects,
including
potential
developmental,
reproductive
and
neurotoxic
effects.

As
the
studies
submitted
are
to
support
only
the
tolerance
on
imported
tomatoes,
the
only
acute
studies
submitted
to
EPA
were
the
acute
oral
studies
on
the
technical
(
98.4%
a.
i.)
and
a
50%
a.
i.
(
50WG)
in
the
rat.
The
acute
oral
toxicity
study
with
the
50WG
formulation
was
tested
only
at
500
mg/
kg
(
both
sexes)
and
no
clinical
signs
or
mortality
were
noted
("
moderate
acute
oral
toxicity";
Toxicity
Category
II).
Other
acute
studies
with
the
technical
grade,
though
not
received
by
EPA,
were
considered
to
have
been
Toxicity
Category
IV
(
acute
dermal
rabbit,
acute
inhalation
rat,
primary
eye
irritation
rabbit
and
primary
skin
irritation
rabbit).
Dermal
sensitization
in
the
guinea
pig
was
negative.
The
metabolite
p­
methylphenethylamine
had
an
acute
oral
LD
50
of
300­
500
mg/
kg
(
Toxicity
Category
II).

In
dogs
and
rats,
the
liver
was
the
primary
target
organ
with
dogs
being
more
sensitive.
In
a
oneyear
dog
study,
the
NOAEL
was
2.6
mg/
kg/
day.
The
following
liver­
related
findings
were
noted
in
rats
and
dogs:
swelling;
enlargement;
distinct
lobulation;
discoloration;
increases
in
absolute
and
relative
weights;
increased
ALT
and
ALP
values;
and
hepatocellular
hypertrophy
as
well
as
periportal
fatty
change.
In
90­
day
and
28­
day
dog
studies,
similar
liver­
related
effects
were
noted
at
LOAELs
of
62.5
and
31.5
mg/
kg/
day,
respectively.
Rat
studies
of
28
days,
90
days
or
2
years
duration
showed
similar
liver
findings,
but
at
higher
LOAELs
than
for
dogs.
In
mice,
no
liverrelated
effects
were
observed
over
a
2­
year
period;
but,
in
a
90­
day
study,
there
were
increases
in
liver
weights
at

limit
doses
(
M:
1724.6
mg/
kg/
day
and
F:
3599.5
mg/
kg/
day).

No
appropriate
endpoint
attributable
to
a
single
exposure
was
identified
from
the
oral
toxicity
studies,
including
the
developmental
toxicity
studies
in
rats
and
rabbits
and
there
were
no
neurotoxic
effects
in
the
neurotoxicity
studies.
Therefore,
an
acute
reference
dose
(
aRfD)
was
not
established
for
the
general
population,
females
or
children.
The
chronic
one­
year
dog
study
was
used
to
select
the
dose
and
endpoint
for
establishing
the
chronic
reference
dose
(
cRfD)
of
0.026
mg/
kg/
day.
The
cRfD
is
derived
from
the
NOAEL
of
2.6
mg/
kg/
day
based
on
biochemical
and
morphological
liver
effects
(
increased
weight,
increased
enzyme
levels
and
hepatocellular
2
hyperplasia)
observed
at
the
LOAEL
of
24.69
mg/
kg/
day.
Since
this
petition
is
for
a
tolerance
on
imported
tomatoes
only,
endpoints
were
not
selected
for
residential
and
occupational
exposure
and
risk
assessments.

In
accordance
with
the
EPA
Draft
Guidelines
for
Carcinogen
Risk
Assessment
(
July,
1999),
the
Cancer
Assessment
Review
Committee
(
CARC)
classified
iprovalicarb
as
"
Likely
to
be
carcinogenic
to
humans".
The
CARC
further
recommended
using
a
linear
low­
dose
extrapolation
(
Q*)
approach
for
estimating
the
human
cancer
risk
based
on
the
most
potent
tumor
in
rats.
The
most
potent
unit
risk,
Q*
(
mg/
kg/
day)­
1,
for
iprovalicarb
was
determined
to
be
4.5
x
10­
4
in
human
equivalents,
based
on
combined
follicular
cell
adenomas
and
carcinomas
in
the
thyroid
gland
of
female
rats.
A
complete
battery
of
mutagenicity
studies
was
negative.

There
is
no
evidence
of
neurotoxicity
or
neuropathology
in
the
hazard
database.
The
Hazard
Identification
Assessment
Review
Committee
(
HIARC
TXR
No.
0050515;
March
1,
2002)
determined
that
a
developmental
neurotoxicity
study
was
not
required
for
this
chemical
and
no
additional
safety
factors
are
needed
to
account
for
data
deficiencies.

In
the
rat
and
rabbit
developmental
toxicity
studies,
no
apparent
maternal
or
developmental
effects,
for
developmental
and
maternal
toxicity
were
noted
at
the
limit
dose
of
1000
mg/
kg/
day.
In
the
2­
generation
reproduction
study,
limit
doses
resulted
in
a
decrease
in
body
weight
gain
in
males
and
an
increase
in
liver
weights
in
both
sexes.
No
effects
on
reproductive
parameters
were
reported
at
any
dose.
Regarding
offspring,
at
the
highest
dose
tested
(
M:
=
1838
mg/
kg/
day;
F
=
2944.1
mg/
kg/
day
>
limit
dose),
there
was
a
decrease
in
mean
litter
weight
on
day
28
(
F
1
and
F
2),
reduced
body
weight
in
F
1
and
F
2
during
lactation
and
increased
pup
relative
liver
weights
as
well
as
reduced
lactation
index
in
F
1
pups.
The
laction
index
was
low
in
all
groups
(
including
control)
in
the
F
2
pups.

Two
rat
metabolism
studies
(
MRIDs
44865733
and
44865734)
were
performed.
Following
oral
administration,
there
was
rapid
absorption
of
radioactivity,
wide
distribution
with
minimal
tissue
residence
time,
extensive
metabolism
and
rapid
elimination,
which
was
independent
of
sex,
rate
or
frequency
of
dosing.
Twelve
metabolites
were
identified.
The
main
metabolite
pair
was
the
diastereomers
of
iprovalicarb­
carboxylic
acid
(
MO3).
This
metabolite
pair
accounted
for
more
than
58%
of
the
administered
dose
(
AD).
Small
amounts
of
eight
other
metabolites
were
also
found
in
the
urine.
These
minor
metabolites
accounted
for
less
than
2%
each
or
7%
AD
when
combined.
A
quantitative
analysis
of
the
excreta
was
focused
on
the
parent
compound,
iprovalicarb,
the
main
metabolite
iprovalicarb
carboxylic
acid
(
MO3),
the
two
minor
metabolites,
4­(
1­
hydroxyethyl)­
benzoic
acid
(
M02)
and
PMPA
(
p­
methylphenethylamine,
M10).
The
proposed
biotransformation
pathway
was
via
oxidation
of
the
methyl
group
on
the
aromatic
ring,
leading
to
the
carboxylic
acid
metabolite
via
the
hydroxylmethyl­
derivative.

Rationale
for
Inclusion
of
Metabolites
and
Degredates
The
acute
oral
toxicity
study
in
the
rat
(
MRID
44865707)
identified
that
the
metabolite
pmethylphenethylamine
had
an
acute
oral
LD
50
of
300
­
500
mg/
kg
(
Toxicity
category
II).
Although
this
is
a
significantly
lower
oral
LD
50
than
that
of
iprovalicarb,
the
Risk
Assessment
team
has
concluded,
based
on
findings
from
the
Pest
Management
Regulatory
Agency's
3
Monograph
and
the
submitted
tomato
metabolism
study,
that
the
parent
compound
comprises
almost
all
of
the
residue
(
98.7%
TRR).
Therefore,
the
residue
of
concern
for
tolerance
enforcement
and
dietary
risk
purposes
is
the
parent
compound
only.
It
is
also
noted
that
the
major
metabolic
pathway
in
both
plants
and
rats
involves
the
oxidation
of
the
aromatic
methyl
group.

FQPA
and
Uncertainty
Factors
The
toxicological
database
for
iprovalicarb
is
complete
and
adequate
for
FQPA
assessment.
There
are
developmental
toxicity
studies
in
two
species,
the
rat
and
the
rabbit,
as
well
as
a
multigeneration
study
in
the
rat.
There
is
no
evidence
of
neurotoxicity
or
neuropathology
in
the
hazard
database.
The
HIARC
determined
that
a
developmental
neurotoxicity
study
was
not
required
for
this
chemical.
Furthermore,
the
FQPA
Safety
Factor
Committee
(
TXR
No.
0050633;
April
2,
2002)
concluded
that
the
data
indicate
there
are
no
(
residual)
concerns
for
pre­
and/
or
postnatal
toxicity
following
exposure
to
iprovalicarb
and
therefore,
no
additional
safety
factors
are
necessary
to
protect
the
safety
of
infants
and
children.
The
Iprovalicarb
Risk
Assessment
Team
reaffirms
this
conclusion.

Residue
Chemistry
HED
has
evaluated
the
residue
chemistry
database
for
iprovalicarb.
There
are
no
residue
chemistry
deficiencies
in
this
petition
that
would
preclude
establishing
a
tolerance
for
iprovalicarb
on
imported
tomatoes.
The
nature
of
the
residue
in
tomatoes
is
adequately
understood,
based
on
an
acceptable
metabolism
study
in
tomato
fruit
and
foliage.
The
degree
of
metabolism
is
very
low
as
the
parent
represents
>
90%
of
the
total
residues.
Similar
results
were
obtained
in
a
grape
metabolism
study.
The
metabolism
of
iprovalicarb
which
does
occur
in
plants
primarily
involves
hydroxylation
of
the
aromatic
methyl
group
to
form
4­
hydroxymethyl­
iprovalicarb,
which
is
subsequently
conjugated
with
glucose.
A
minor
pathway
in
plants
also
involves
direct
hydroxylation
of
the
phenyl
group
to
form
3­
hydroxyphenyl­
iprovalicarb
which
also
forms
a
glucose
conjugate.
These
studies
are
adequate
for
delineating
the
major
residues.
For
purposes
of
tolerance
and
risk
assessment,
the
terminal
residue
of
concern
in
plants
is
parent
iprovalicarb
(
PMRA
Monograph,
September
2001,
and
reaffirmed
by
HED
in
the
current
assessment).
There
are
no
significant
livestock
feed
items
associated
with
this
petition;
therefore,
the
nature
of
the
residue
in
livestock
does
not
need
to
be
addressed.
There
is
an
established
Canadian
MRL
of
2.0
ppm
for
the
use
of
iprovalicarb
on
grapes,
which
was
established
on
9/
25/
2004.

Dietary
Exposure
Both
the
Dietary
Exposure
Evaluation
Model
(
DEEM­
FCID
 
)
and
the
LifeLine
 
assessments
utilized
tolerance­
level
residues
in/
on
grape
commodities,
anticipated
residue
(
AR)
values
for
tomato
commodities,
DEEM
default
processing
factors,
and
100%
crop
treated
(
100%
CT)
assumptions.
The
AR
used
for
tomatoes
was
0.5
ppm,
or
half
the
proposed
tolerance
level
of
1.0
ppm
for
harmonization
purposes.
ARs
were
utilized
for
tomato
commodities
because
use
of
tolerance­
level
residues
in
the
chronic
dietary
analysis
resulted
in
a
cancer
risk
slightly
above
HED's
level
of
concern.
4
The
two
models
provided
similar
estimates
of
chronic
dietary
exposure
and
risk.
The
most
highly
exposed
population
subgroup
was
children
1­
2
years
old.
The
chronic
exposure
estimate
of
approximately
0.00972
mg/
kg/
day
corresponds
to
37
%
cPAD.
Risks
for
the
general
US
population
and
all
other
population
subgroups
were
lower.

The
cancer
dietary
exposure
analysis
was
based
on
the
same
assumptions
as
the
chronic
analysis.
The
esitmated
lifetime
cancer
risk
for
the
general
US
population
is
9.74
x
10­
7,
which
is
below
HED's
level
of
concern.

Drinking
Water
Exposure/
Residential
(
Non­
occupational)
Exposure/
Occupational
Exposure
Since
this
action
is
for
a
tolerance
on
imported
tomatoes
only,
there
are
no
registered
uses
in
the
United
States.
There
is
no
expectation
that
exposure
to
iprovalicarb
residues
would
occur
via
water
consumption,
residential
or
occupational
exposure.
Therefore,
assessment
of
drinking
water,
residential,
or
occupational
exposure
and
risk
is
not
required.

Aggregate
Risk
Estimates
Since
there
are
no
registered
(
agricultural,
occupational
nor
residential)
uses
associated
with
iprovalicarb,
the
only
route
of
exposure
is
dietary.
Dietary
exposure
will
be
limited
to
residues
from
imported
tomatoes.
There
will
be
no
additional
risks
resulting
from
residential
or
drinking
water
exposure;
therefore,
an
aggregate
risk
estimate
is
not
required
for
this
assessment.

Recommendation
HED
recommends
in
favor
of
the
proposed
tolerance
for
use
for
iprovalicarb
residues
on
imported
tomatoes.
There
are
no
residue
chemistry
deficiencies
in
this
petition
that
would
preclude
establishing
a
tolerance
for
iprovalicarb
on
imported
tomatoes.
The
available
tomato
field
trial
data
are
adequate
and
would
support
a
tolerance
of
0.50
ppm
for
iprovalicarb
residues
in/
on
imported
tomatoes;
however,
HED
is
recommending
a
1.0
ppm
tolerance
for
tomato
in
order
to
harmonize
with
the
existing
1.0
mg/
kg
provisional
maximum
residue
limit
(
MRL)
for
iprovalicarb
on
tomatoes
in
the
European
Union
(
scheduled
to
be
permanently
established
in
July
2007).
5
Table
1:
Tolerance
Summary
for
Iprovalicarb
Commodity
Proposed
Tolerance
Recommended
Tolerance
Comments
Tomato
1.0
ppm
1.0
ppm
The
available
residue
data
would
support
a
tolerance
of
0.50
ppm
on
tomatoes.
However,
a
tolerance
of
1.0
ppm
is
being
recommended
in
order
to
harmonize
with
the
existing
1.0
mg/
kg
MRL
in
Europe.

The
CFR
entry
should
also
state
that
there
are
no
U.
S.
registrations
for
use
on
tomatoes.

2.0
Ingredient
Profile
Iprovalicarb
is
an
amino
acid
amide
carbamate
that
belongs
to
a
class
of
chemicals
derived
from
natural
amino
acids
and
is
a
1:
1
mixture
of
distereoisomers
(
SR:
SS).
Iprovalicarb
acts
both
as
a
contact
and
systemic
fungicide
for
control
of
Oomycete
fungi,
such
as
downy
mildew.
Iprovalicarb
is
a
plant
protectant
with
a
mono­
site
mode
of
action,
which
inhibits
spore
germination,
mycelial
growth
and
sporulation,
and
which
has
protective,
curative
and
fungus
eradicative
properties.

2.1
Summary
of
Proposed
Uses
A
tolerance
has
been
established
under
40
CFR
§
180.581(
a)
for
residues
of
iprovalicarb
in/
on
imported
grapes
at
2.0
ppm
(
PP#
9E6020,
67
FR
54351,
8/
22/
2002).
In
the
current
petition
(
PP#
3E6578),
Bayer
CropScience
AG
is
requesting
a
tolerance
of
1.0
ppm
for
residues
of
iprovalicarb
in/
on
tomatoes
imported
into
the
US.
Bayer
has
established
registrations
or
pending
registrations
on
several
wettable
powder
(
WP)
formulations
of
iprovalicarb
in
countries
that
export
tomatoes
or
processed
tomato
products
to
the
US.

Bayer
is
not
proposing
any
uses
for
iprovalicarb
on
tomatoes
grown
in
the
US.
However,
there
are
three
End­
Use
Products
(
EUPs)
containing
iprovalicarb
that
Bayer
has
either
registered
or
proposed
for
use
on
tomatoes
that
may
be
exported
to
the
US.
These
three
WPs
are
multiple
active
ingredient
(
MAI)
formulations
containing
iprovalicarb
(
4.2,
6,
and
9%)
along
with
either
20.3%
copper
oxychloride
(
MELODY
®
COMPACT
WP
24.5)
or
60%
mancozeb
(
MELODY
MED
®
66
WP
and
MELODY
®
MED
69
WP),
respectively.
There
is
currently
a
US
tolerance
of
4
ppm
for
mancozeb
residues
in/
on
tomatoes
[
40CFR
§
180.176]
and
an
exemption
from
tolerances
for
copper
oxychloride
[
40CFR
§
180.1021].
These
three
WP
formulations
are
either
registered
or
proposed
for
registration
in
Mexico,
Italy,
Chile,
Portugal,
and
Greece
(
see
Table
2.1,
below)
for
use
as
multiple
foliar
applications
to
fresh
and
processing
tomatoes.
During
1999
to
2001,
these
five
countries
together
accounted
for
roughly
83%
of
the
fresh
tomatoes
and
54%
of
the
processed
tomato
products
imported
into
the
US.

Of
the
use
patterns
being
supported
for
imported
tomatoes
(
Table
2.1),
the
use
in
Mexico
is
likely
6
to
result
in
the
highest
residues
in/
on
tomatoes
as
it
includes
the
highest
single,
and
seasonal
application
rates
and
the
shortest
PHI
(
4
days).
Of
the
use
patterns
in
Southern
Europe,
the
pattern
in
Italy
has
the
highest
single,
and
seasonal
application
rates,
with
a
7­
day
(
greenhouse)
or
20­
day
(
field)
PHI.

Several
other
MAI
WP
formulations
containing
iprovalicarb
(
5.5
to
9%)
are
also
registered
for
use
on
tomatoes
in
Israel,
the
Dominican
Republic,
Morocco,
and
Peru,
which
together
account
for
less
than
1%
of
the
fresh
tomatoes
and
approximately
16%
of
the
processed
tomato
products
imported
into
the
US.
However,
as
the
other
active
ingredient
(
propineb)
in
these
formulations
does
not
have
a
US
tolerance,
the
petitioner
stated
that
tomatoes
treated
with
these
formulations
are
unlikely
to
be
imported
into
the
US.

Due
to
efficacy
and
marketing
concerns,
Bayer
is
also
not
planning
on
registering
iprovalicarb
for
use
on
tomatoes
in
the
other
countries
that
are
major
exporters
of
tomatoes
or
tomato
products
to
the
US,
such
as
Canada,
Netherlands,
Spain,
Belgium
and
China.
7
TABLE
2.1
Summary
of
Current
Use
Directions
for
Iprovalicarb
on
Tomato
(
by
Country).

Country
1
EUPs
2
[%
Iprovalicab]
Applications
Type,
Timing
Maximum
Single
Rate
(
kg
ai/
ha)
Maximum
Number
per
Season
Maximum
Seasonal
Rate
(
kg
ai/
ha)
RTI
3
(
Days)
PHI
3
(
Days)

Mexico
MELODY
MED
WP
66
(
6%)
Foliar
spray,
fruit
development.
0.21
5
1.05
7
4
Italy
MELODY
COMPACT
WP
24.5
(
4.2%)
Foliar
spray,
fruit
development.
0.168
5
0.84
7
7,
20
4
Chile
MELODY
MED
WP
69
(
9%)
Foliar
spray,
fruit
development.
0.18
3
0.54
7
5
Israel
5
MELODY
DUO
WP
66.75
(
5.5%)
Foliar
spray,
fruit
development.
0.192
2
0.385
7
14
Dominican
Republic
5
POSITRON
WP
69
(
9%)
Foliar
spray,
fruit
development.
0.225
6
1.35
5
7
Morocco
5
MELODY
DUO
WP
66.75
(
5.5%)
Foliar
spray,
fruit
development.
0.137
4
0.54
10
14
Peru
5
INVENTO
WP
66.75
(
5.5%)
Foliar
spray,
fruit
development.
0.164
3
0.492
14
20
Portugal
MELODY
COMPACT
WP
24.5
(
4.2%)
Foliar
spray,
fruit
development.
0.126
3
0.378
7
Pending
Greece
MELODY
COMPACT
WP
24.5
(
4.2%)
Foliar
spray,
fruit
development.
0.168
3
0.504
7
7,
20
6
1.
Countries
with
current
or
pending
uses
for
iprovalicarb
on
tomatoes.
There
are
no
current
uses
for
iprovalicarb
in
the
US.

2.
All
formulations
are
MAI
WP
formulations
containing
iprovalicarb
(
4.2
to
9%)
in
combination
with
either
mancozeb
(
60%),
propineb
(
60
to
61.25%)
or
copper
oxychloride
(
20.3%).
There
is
currently
a
US
tolerance
on
tomatoes
for
mancozeb
and
an
exemption
from
tolerances
for
copper
oxychloride.

3.
RTI
=
minimum
Re­
Treatment
Interval;
PHI
=
minimum
Pre­
Harvest
Interval.

4.
In
Italy
the
PHI
is
20
days
for
field­
grown
tomatoes
and
7
days
for
those
grown
in
greenhouses.

5.
The
formulations
registered
for
use
in
Israel,
Dominican
Republic,
Morocco,
and
Peru
all
contain
propineb,
which
has
no
tolerance
on
tomatoes
in
the
US;

therefore,
these
formulations
will
not
be
used
on
tomatoes
destined
for
the
US.

6.
In
Greece
the
PHI
is
7
days
for
field­
grown
fresh
or
greenhouse
tomatoes
and
20
days
for
field­
grown
processing
tomatoes.
8
CH
3
N
H
CH
3
O
C
H
3
CH
3
NH
O
O
C
H
3
CH
3
2.2
Structure
and
Nomenclature
TABLE
2.2
Nomenclature
of
Iprovalicarb.

Chemical
Structure
Empirical
Formula
C18H28N2O3
Common
Name
Iprovalicarb
Company
Experimental
Names
SZX
0722,
SZX
722,
TM­
210
IUPAC
Name
Isopropyl
2­
methyl­
1­[(
1­
p­
tolylethyl)
carbamoyl]­(
S)­
propylcarbamate
CAS
Name
1­
methylethyl
[(
1S)­
2­
methyl­
1­[[[
1­(
4­
methylphenyl)
ethyl]
amino]
carbonyl]
propyl]
carbamate
CAS
Number
140923­
17­
7
(
unspecified
stereochemistry)

Chemical
Class
Amino
acid
amide
carbamate
fungicide
Known
Impurities
of
Concern
None
EUPs*
MELODY
MED
66
WP
(
6%
iprovalicarb),
MELODY
MED
69
WP
(
9%
iprovalicarb),
MELODY
COMPACT
WP
24.5
(
4.2%
iprovalicarb)
*
In
addition
to
iprovalicarb,
these
MAI
WP
formulations
also
contain
either
60%
mancozeb
(
MELODY
MED)
or
20.3%
copper
oxychloride
(
MELODY
COMPACT).
9
2.3
Physical
and
Chemical
Properties
TABLE
2.3
Physicochemical
Properties.

Parameter
Value
1
Reference
2
Melting
Point/
Range
(

C)
SR:
183
SS:
199
Mix:
163­
165
PMRA
Monograph
(
September
2001)

pH
Not
available.

Density
at
20

C
(
g/
cm3)
1.11
Water
Solubility
at
20

C
(
mg/
L)
SR:
11
SS:
6.8
Solvent
Solubility
at
20

C
(
g/
L)
Solvent
n­
hexane
toluene
DCM
2­
propanol
1­
octanol
polyethylene
glycol
polyethylene
gylcol
+
ethanol
acetone
dimethylformamide
ethylacetate
acetonitrile
dimethylsuloxide
SR
0.06
2.9
97
15
11
2.0
7.1
22
63
13
8.1
27
SS
0.04
2.4
35
13
9.3
1.8
6.3
19
55
7.0
11
15
Vapor
Pressure
at
25

C
(
PA)
SR:
4.4
x
10­
8
SS:
3.5
x
10­
8
Mix:
7.7
x
10­
8
Dissociation
Constant
(
pKa)
Does
not
dissociate.

Octanol/
Water
Partition
Coefficient
(
Log
[
KOW])
SR:
3.18
SS:
3.20
UV/
Visible
Absorption
Not
available.

1.
When
available,
physicochemical
properties
are
reported
for
each
distereoisomer
(
SR
and
SS)
and
the
mixture.
2.
Pest
Management
Regulatory
Agency
(
PMRA)
product
monograph
for
iprovalicarb
on
grapes
grown
in
Europe
and
imported
into
Canada
(
September
2001).

3.0
Metabolism
Assessment
3.1
Comparative
Metabolic
Profile
In
the
rat
metabolism
and
pharmacokinetics
study
(
MRID
44865733),
following
oral
administration,
there
was
rapid
absorption
of
radioactivity,
wide
distribution
with
minimal
tissue
residence
time,
extensive
metabolism,
and
rapid
elimination,
which
was
independent
of
sex,
rate
or
frequency
of
dosing.
Peak
plasma
levels
occurred
20­
90
minutes
after
exposure
to
the
low
10
dose,
or
within
8
hours
of
exposure
at
the
high
dose.
In
intraduodenally
dosed
animals,
>
91%
was
absorbed
from
the
gastro­
intestinal
tract
within
48
hours.
Different
absorption
profiles
were
seen
for
individual
diastereomers:
S,
S
absorbed
more
rapidly
and
reached
a
plasma
level
4x
as
high
as
S,
R
isomer.
One
hour
post
administration,
liver
and
kidney
contained
significantly
higher
radioactivity
than
blood,
indicating
rapid
elimination.
There
was
little
tissue
bioaccumulation.
The
material
was
metabolized
extensively;
a
small
percent
of
the
parent
passed
through
the
rat
unchanged.
Twelve
metabolites
were
identified.
The
main
metabolite
pair
was
the
diastereomers
of
iprovalicarb­
carboxylic
acid
(
M03).
This
metabolite
pair
accounted
for
more
than
58%
of
administered
dose
(
AD).
Small
amounts
of
8
other
metabolites
were
found
in
the
urine.
These
minor
metabolites
accounted
for
less
than
2%
each
or
7%
AD
when
combined.
In
the
bilefistulation
experiment,
the
main
radioactive
components
identified
in
the
bile
were
iprovalicarbcarboxylic
acid
(
MO3)
and
two
conjugates
thereof
(
iprovalicarb­
carbonylglycine
(
MO5)
and
iprovalicarb­
carbonyltaurine
(
MO6).
These
three
metabolites
accounted
for
about
87%
of
the
radioactivity
in
the
bile
and
about
73%
of
the
administered
dose.
The
proposed
biotransformation
pathway
is
via
oxidation
of
the
methyl
group
on
the
aromatic
ring,
which
leads
to
the
carboxylic
acid
metabolite
via
the
hydroxylmethyl­
derivative.
Metabolites
noted
in
the
study
were
not
affected
by
long­
term
feeding.

In
another
rat
metabolism
and
pharmacokinetics
following
subchronic
feeding
study
(
MRID
44865734),
absorption
and
excretion
were
similar
to
what
was
seen
in
the
standard
metabolism
study
(
MRID
44865733).
Females
had
less
radioactivity
in
plasma
than
males
after
being
dosed
with
20,000
ppm,
equal
to
1,000
mg/
kg/
day.
Whole
body
autoradiography
4
hours
postadministration
confirmed
rapid
absorption
and
distribution
(
found
mainly
in
liver,
stomach,
kidney
and
small
intestine).
Up
to
99%
of
the
parent
compound
was
excreted
via
urine
and
feces
within
72
hours.
Feces
was
the
major
route
of
excretion
for
males
(
70%).
In
females,
excretion
of
the
parent
compound
was
similar
in
feces
and
urine.
There
was
little
activity
outside
the
gastrointestinal
tract.
Identification
of
residues
was
not
performed
in
this
study.

Adequate
plant
metabolism
studies
with
[
14C]­
iprovalicarb
on
grapes,
potatoes,
and
tomatoes
have
been
reviewed
(
PMRA
Monograph,
September
2001).
The
results
of
these
studies
indicate
that
the
metabolism
of
iprovalicarb
is
similar
in
the
three
crops
investigated.
Following
multiple
foliar
applications
of
[
14C]­
iprovalicarb
(
WP),
total
radioactive
residues
(
TRR)
were
comprised
almost
entirely
of
parent
compound
in
grapes
(
96.1%
TRR)
and
tomatoes
(
98.7%
TRR)
harvested
10
to
35
days
after
the
final
application,
with
the
majority
of
parent
being
surface
residues
(
95
to
97%
TRR).
Minor
amounts
(
less
than
5%
TRR)
of
4­
hydroxymethyliprovalicarb
and
its
glucose
conjugate
were
also
identified
in
tomatoes
and
grapes,
along
with
3­
hydroxyphenyl­
iprovalicarb
glucoside
in
tomatoes.
Translocation
experiments
with
examination
of
treated
tomato
leaves
and
the
adjacent
fruits
also
indicated
that
the
translocation
of
iprovalicarb
is
limited.
In
the
potato
metabolism
study,
iprovalicarb
was
also
identified
as
the
principal
[
14C]­
residue
in
both
vines
(
82.9%
TRR)
and
tubers
(
30.5%
TRR)
harvested
14
days
after
the
final
application.
In
tubers,
the
metabolites
4­
hydroxymethyl­
iprovalicarb
(
13.1%
TRR)
and
4­
hydroxymethyl­
iprovalicarb
glucoside
(
12.8%
TRR)
also
accounted
for
a
substantial
portion
of
the
TRR.
However,
in
vines,
these
metabolites
accounted
for
only
2.5
to
3.2%
of
the
TRR.

Since
there
are
no
significant
livestock
feed
items
associated
with
this
petition,
there
is
no
11
concern
for
livestock
metabolites
and
or
pathways.

Based
on
the
above
results
of
the
various
metabolism
studies,
the
major
metabolic
pathway
in
both
plants
and
rats
involves
the
oxidation
of
the
aromatic
methyl
group.

3.2
Nature
of
the
Residue
in
Foods
3.2.1.
Description
of
Primary
Crop
Metabolism
Based
on
the
three
plant
metabolism
studies
mentioned
above,
the
metabolism
of
iprovalicarb
in
plants
primarily
involves
hydroxylation
of
the
aromatic
methyl
group
to
form
4­
hydroxymethyliprovalicarb
which
is
subsequently
conjugated
with
glucose.
A
minor
pathway
in
plants
also
involves
direct
hydroxylation
of
the
phenyl
group
to
form
3­
hydroxyphenyl­
iprovalicarb
which
also
forms
a
glucose
conjugate.
These
studies
are
adequate
for
delineating
the
major
residues.
For
purposes
of
tolerance
and
risk
assessment,
the
terminal
residue
of
concern
in
plants
is
parent
iprovalicarb
(
PMRA
Monograph,
September
2001).

3.2.2
Description
of
Livestock
Metabolism
There
are
no
significant
livestock
feed
items
associated
with
this
petition;
therefore,
the
nature
of
the
residue
in
livestock
does
not
need
to
be
addressed.

3.2.3
Description
of
Rotational
Crop
Metabolism
Per
the
NAFTA
Guidance
Document
on
Data
Requirements
for
Tolerances
on
Imported
Commodities
(
dated
April
2003),
rotational
crop
data
are
not
required
to
support
the
proposed
tolerances
on
imported
tomatoes.

3.3
Environmental
Degradation
Since
iprovalicarb
is
proposed
for
use
only
on
imported
tomato
commodities,
with
neither
existing
nor
proposed
US
registration,
there
is
no
expectation
that
iprovalicarb
residues
would
occur
in
surface
or
ground
water.

3.4
Toxicity
Profile
of
Major
Metabolites
and
Degradates
An
acute
oral
toxicity
study
was
performed
in
the
rat
(
MRID
44865707).
The
metabolite
pmethylphenethylamine
had
an
acute
oral
LD
50
of
300
­
500
mg/
kg
and
was
classified
as
Toxicity
Category
II.

Two
rat
metabolism
studies
(
MRIDs
44865733
and
44865734)
were
performed.
There
was
very
little
accumulation
of
the
parent
compound
iprovalicarb.
Parent
compound
was
extensively
metabolized,
with
only
a
small
percent
of
parent
compound
passing
through
rat
unchanged.
Twelve
metabolites
were
identified.
The
main
metabolite
pair
was
the
diastereomers
of
iprovalicarb­
carboxylic
acid
(
M03).
This
metabolite
pair
accounted
for
more
than
58%
of
administered
dose
(
AD).
Small
amounts
of
8
other
metabolites
were
found
in
the
urine.
These
12
minor
metabolites
accounted
for
less
than
2%
each
or
7%
AD
when
combined.
In
the
bilefistulation
experiment,
the
main
radioactive
components
identified
in
the
bile
were
iprovalicarbcarboxylic
acid
(
MO3)
and
two
conjugates
thereof
(
iprovalicarb­
carbonylglycine
(
MO5)
and
iprovalicarb­
carbonyltaurine
(
MO6).
These
three
metabolites
accounted
for
about
87%
of
the
radioactivity
in
the
bile
and
about
73%
of
the
administered
dose.

Adequate
plant
metabolism
studies
with
[
14C]­
iprovalicarb
on
grapes,
potatoes,
and
tomatoes
have
been
reviewed
(
PMRA
Monograph,
September
2001).
The
results
of
these
studies
indicate
that
the
metabolism
of
iprovalicarb
is
similar
in
the
three
crops
investigated.
Following
multiple
foliar
applications
of
[
14C]­
iprovalicarb
(
WP),
total
radioactive
residues
(
TRR)
were
comprised
almost
entirely
of
parent
compound
in
grapes
(
96.1%
TRR)
and
tomatoes
(
98.7%
TRR)
harvested
10
to
35
days
after
the
final
application,
with
the
majority
of
parent
being
surface
residues
(
95
to
97%
TRR).
Minor
amounts
(
less
than
5%
TRR)
of
4­
hydroxymethyliprovalicarb
and
its
glucose
conjugate
were
also
identified
in
tomatoes
and
grapes,
along
with
3­
hydroxyphenyl­
iprovalicarb
glucoside
in
tomatoes.
In
the
potato
metabolism
study,
iprovalicarb
was
also
identified
as
the
principal
[
14C]­
residue
in
both
vines
(
82.9%
TRR)
and
tubers
(
30.5%
TRR)
harvested
14
days
after
the
final
application.
In
tubers,
the
metabolites
4­
hydroxymethyliprovalicarb
(
13.1%
TRR)
and
4­
hydroxymethyl­
iprovalicarb
glucoside
(
12.8%
TRR)
also
accounted
for
a
substantial
portion
of
the
TRR.
However,
in
vines,
these
metabolites
accounted
for
only
2.5
to
3.2%
of
the
TRR.

3.5
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
TABLE
3.5
Summary
of
Metabolites
and
Degradates
to
be
included
in
the
Risk
Assessment
and
Tolerance
Expression.

Crop
[
Matrix]
Residue
in
Risk
Assessment
Residue
in
Tolerance
Expression
Tomato
[
Fruit,
Puree,
Paste]
Parent
compound
only,
iprovalicarb
per
se.
Parent
compound
only,
iprovalicarb
per
se.

3.5.1
Rationale
for
Not
Including
Metabolites
and
Degredates
In
Tolerance
Expression
The
acute
oral
toxicity
study
in
the
rat
(
MRID
44865707)
identified
that
the
metabolite
pmethylphenethylamine
had
an
acute
oral
LD
50
of
300
­
500
mg/
kg
(
Toxicity
Category
II).
Although
this
is
a
significantly
lower
oral
LD
50
than
that
of
iprovalicarb,
the
Risk
Assessment
team
has
concluded,
based
on
findings
from
the
Pest
Management
Regulatory
Agency's
Monograph
and
the
submitted
tomato
metabolism
study,
that
the
parent
compound
comprises
almost
all
of
the
residue
(
98.7%
TRR).
Therefore,
the
residue
of
concern
for
tolerance
enforcement
and
dietary
risk
purposes
is
the
parent
compound
only.
It
is
also
noted
that
the
major
metabolic
pathway
in
both
plants
and
rats
involves
the
oxidation
of
the
aromatic
methyl
group.

4.0
Hazard
Characterization/
Assessment
The
Registrant
has
requested
the
establishment
of
a
permanent
tolerance
for
iprovalicarb
on
13
tomatoes
without
a
United
States
registration.
Iprovalicarb
(
also
known
as
Melody
Med
WP
66,
Melody
Med
WP
69,
and
Melody
Compact
WP
24.5)
is
a
new
systemic
fungicide
active
ingredient
that
is
proposed
for
use
in
the
European
Union
to
prevent
and
control
downy
mildew
in/
on
tomatoes.
Iprovalicarb
is
a
systemic
plant
protectant
with
a
new,
mono­
site
mode
of
action,
which
inhibits
spore
germination,
mycelial
growth
and
sporulation
and
has
protective,
curative
and
fungus
eradicative
properties.

4.1
Hazard
Characterization
On
January
31,
2002,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
iprovalicarb
with
regard
to
the
acute
and
chronic
Reference
Doses
(
RfDs)
and
the
toxicological
endpoint
selection
for
acute
and
chronic
risk
assessments.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
iprovalicarb
was
also
evaluated
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.

Technical
grade
iprovalicarb
(
also
known
as
TM­
210,
SZX
0722,
and
MELODY),
a
white
powder,
had
an
acute
oral
LD
50
in
male
and
female
rats
>
5000
mg/
kg;
Toxicity
Category
IV.
Since
these
studies
were
submitted
in
support
for
the
import
tolerance
on
grapes
and
raisins,
this
acute
oral
study
(
98.4%
a.
i.)
and
an
acute
oral
in
rats
at
about
50%
a.
i.
(
50WG)
were
the
only
acute
studies
submitted
to
EPA.
The
50WG
acute
oral
toxicity
was
tested
only
at
500
mg/
kg
(
both
sexes)
and
no
clinical
signs
or
mortality
were
noted
("
moderate
acute
oral
toxicity";
Toxicity
Category
II).
Other
acute
studies
with
the
technical
grade,
though
not
received
by
EPA,
were
considered
to
have
been
Toxicity
Category
IV
(
acute
dermal
rabbit,
acute
inhalation
rat,
primary
eye
irritation
rabbit
and
primary
skin
irritation
rabbit).
Dermal
sensitization
in
the
guinea
pig
was
negative.
The
metabolite
p­
methylphenethylamine
had
an
acute
oral
LD
50
of
300­
500
mg/
kg
(
Toxicity
Category
II).

In
dogs
and
rats,
the
liver
was
the
primary
target
organ
with
dogs
being
more
sensitive.
In
a
one­
year
dog
study,
the
NOAEL
was
2.6
mg/
kg/
day.
The
following
liver­
related
findings
were
noted:
swelling;
enlargement;
distinct
lobulation;
discoloration;
increases
in
absolute
and
relative
weights;
increased
alanine
aminotransaminase
phosphotase
(
ALT)
and
alkaline
phosphotase
(
ALP)
values;
and
hepatocellular
hypertrophy
as
well
as
periportal
fatty
change.
In
90­
day
and
28­
day
dog
studies,
similar
liver­
related
effects
were
noted
at
LOAELs
of
62.5
mg/
kg/
day
and
31.5
mg/
kg/
day
respectively.
Rat
studies
of
28
days,
90
days
or
2
years
duration
showed
similar
liver
findings,
but
at
higher
LOAELs
than
for
dogs.
In
mice,
no
liver­
related
effects
were
observed
over
a
2­
year
period;
but,
in
a
90­
day
study,
there
were
increases
in
liver
weights
at

limit
doses
(
LOAEL
M:
1724.6
and
F:
3599.5
mg/
kg/
day).

In
the
rat
and
rabbit
developmental
studies,
there
were
no
apparent
maternal
or
developmental
effects
at
the
limit
dose.
In
the
2­
generation
reproduction
study,
limit
doses
resulted
in
a
decrease
in
body
weight
gain
in
males
and
an
increase
in
liver
weights
in
both
sexes.
No
effects
on
reproductive
parameters
were
reported
at
any
dose.
Regarding
offspring,
at
the
highest
dose
tested
(

limit
dose),
there
was
a
decrease
in
mean
litter
weight
on
day
28
(
F
1
and
F
2),
reduced
body
weight
in
F
1
and
F
2
during
lactation
and
increased
pup
relative
liver
weights
as
well
as
14
reduced
lactation
index
in
F
1
pups.
The
laction
index
was
low
in
all
groups
(
including
control)
in
the
F
2
pups.

In
accordance
with
the
EPA
Draft
Guidelines
for
Carcinogen
Risk
Assessment
(
July,
1999),
the
Cancer
Assessment
Review
Committee
(
CARC)
classified
iprovalicarb
as
"
Likely
to
be
carcinogenic
to
humans".
The
CARC
further
recommended
using
a
linear
low­
dose
extrapolation
(
Q
1*)
approach
for
estimating
the
human
cancer
risk
based
on
most
potent
tumor
in
rats.
The
most
potent
unit
risk,
Q
1*
(
mg/
kg/
day)­
1,
for
iprovalicarb
was
determined
to
be
4.5
x
10­
4
in
human
equivalents,
based
on
combined
follicular
cell
adenomas
and
carcinomas
in
the
thyroid
gland
of
female
rats.

A
complete
battery
of
mutagenicity
studies
was
negative.

In
the
rat
metabolism
and
pharmacokinetics
study
(
MRID
44865733),
following
oral
administration,
there
was
rapid
absorption
of
radioactivity,
wide
distribution
with
minimal
tissue
residence
time,
extensive
metabolism,
and
rapid
elimination,
which
was
independent
of
sex,
rate
or
frequency
of
dosing.
Peak
plasma
levels
occurred
20­
90
minutes
after
exposure
to
the
low
dose,
or
within
8
hours
of
exposure
at
the
high
dose.
In
intraduodenally
dosed
animals,
>
91%
was
absorbed
from
the
gastro­
intestinal
tract
within
48
hours.
Different
absorption
profiles
were
seen
for
individual
diastereomers:
S,
S
absorbed
more
rapidly
and
reached
a
plasma
level
4x
as
high
as
S,
R
isomer.
One
hour
post
administration,
liver
and
kidney
contained
significantly
higher
radioactivity
than
blood,
indicating
rapid
elimination.
There
was
little
tissue
bioaccumulation.
The
material
was
metabolized
extensively;
a
small
percent
of
the
parent
passed
through
the
rat
unchanged.
Twelve
metabolites
were
identified.
The
main
metabolite
pair
was
the
diastereomers
of
iprovalicarb­
carboxylic
acid
(
M03).
This
metabolite
pair
accounted
for
more
than
58%
of
administered
dose
(
AD).
Small
amounts
of
8
other
metabolites
were
found
in
the
urine.
These
minor
metabolites
accounted
for
less
than
2%
each
or
7%
AD
when
combined.
In
the
bile­
fistulation
experiment,
the
main
radioactive
components
identified
in
the
bile
were
iprovalicarb­
carboxylic
acid
(
MO3)
and
two
conjugates
thereof
(
iprovalicarb­
carbonylglycine
(
MO5)
and
iprovalicarb­
carbonyltaurine
(
MO6).
These
three
metabolites
accounted
for
about
87%
of
the
radioactivity
in
the
bile
and
about
73%
of
the
administered
dose.
The
proposed
biotransformation
pathway
is
via
oxidation
of
the
methyl
group
on
the
aromatic
ring,
which
leads
to
the
carboxylic
acid
metabolite
via
the
hydroxylmethyl­
derivative.
Some
minor
metabolites
originated
from
cleavage
of
the
parent
molecule.

In
another
rat
metabolism
and
pharmacokinetics
following
subchronic
feeding
study
(
MRID
44865734),
absorption
and
excretion
were
similar
to
what
was
seen
in
the
standard
metabolism
study
(
MRID
44865733).
Based
on
the
results
from
the
standard
metabolism
study
(
MRID
44865733)
the
quantitative
analysis
of
the
excreta
was
focused
on
the
parent
compound,
iprovalicarb,
the
main
metabolite,
iprovalicarb
carboxylic
acid
(
M03),
and
two
minor
metabolites
4­(
1­
hydroxyethyl)­
benzoic
acid
(
M20)
and
PMPA
(
p­
methylphenethylamine
(
M10).
Females
had
less
radioactivity
in
plasma
than
males
after
being
dosed
with
20,000
ppm,
equal
to
1,000
mg/
kg/
day.
Whole
body
autoradiography
4
hours
post­
administration
confirmed
rapid
absorption
and
distribution
(
found
mainly
in
liver,
stomach,
kidney
and
small
intestine).
Up
to
99%
of
the
parent
compound
was
excreted
via
urine
and
feces
within
72
hours.
Feces
was
the
major
route
of
excretion
for
males
(
70%).
In
females,
excretion
of
the
parent
compound
was
15
similar
in
feces
and
urine.
There
was
little
activity
outside
the
gastrointestinal
tract.
Metabolites
noted
in
the
standard
study
were
not
affected
by
long­
term
feeding.

Table
4.1a
Acute
Toxicity
Profile
­
Test
Substance
Guideline
No.
Study
Type
MRID(
s)
Results
Toxicity
Category
870.1100
Acute
Oral
­
Rats
98.4%
44865706
M
:
LD50
=
>
5000
mg/
kg
F:
LD
50
=
>
5000
mg/
kg
No
systemic
toxicity.
IV
870.1100
Acute
Oral
­
Rats
50
WG
(
about
50%
a.
i)
44865708
M:
LD50
=
500
mg/
kg
F:
LD50
=
500
mg/
kg
500
mg/
kg
=
only
dose
No
clinical
signs
or
mortality
"
Moderate
Acute
Oral
Toxicity"
II
[
II
=
>
50
thru
500,
III
=
>
500
thru
5000]

870.1100
Acute
Oral
­
Rats
METABOLITE:
p­
Methylphenethylamine
44865707
3/
sex/
dose,
200
mg/
kg;
F
only
at
2000
mg/
kg:
LD50
=
300­
500
mg/
kg
signs:
incoordination,
increased
movement,
labored
breathing,
spasmodic
state,
tonical
cramps,
rolling
over,
convulsions,
increased
salivation
and
dyspnea;
deaths
within
15
min.
at
2000
"
High
Acute
Oral
Toxicity"
II
870.1200
Acute
Dermal
­
Rabbits
N/
A
M:
LD50
=
>
5000
mg/
kg
F:
LD50
=
>
5000
mg/
kg
No
systemic
or
dermal
toxicity.
IV
870.1300
Acute
Inhalation
­
Rats
N/
A
M:
LC50
=
>
4.977
mg/
L
F:
LC50
=
>
4.977
mg/
L
No
systemic
or
inhalation
toxicity.
IV
870.2400
Primary
Eye
Irritation
­
Rabbits
N/
A
Not
irritating.
IV
870.2500
Primary
Skin
Irritation
­
Rabbits
N/
A
500
mg
IV
870.2600
Dermal
Sensitization
­
Guinea
Pig
N/
A
Negative
N/
A
870.6200
Neurotoxicity
Screening
Battery
­
Rats
44865731
No
systemic
or
neurotoxic
effects
at
2000
mg/
kg
N/
A
(
N/
A)
=
No
MRID
Numbers
were
assigned
as
this
information
was
received
from
the
Registrant.
16
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
oral
toxicity
(
4­
week
recovery)
­
Rat
98.1­
98.7%
44865710
(
1996)

0,
1250,
5000
or
20000
ppm:

M:
0,
87.4,
372.7
or
1524.0
mg/
kg/
day:
F:
0,
133.9,
561.4
or
2585.9
mg/
kg/
day:
NOAEL
=
M:
372.7
mg/
kg/
day
F:
561.4
mg/
kg/
day
LOAEL
=
M:
1524.0
mg/
kg/
day,
F:
2585.9,
mg/
kg/
day
based
on
increased
food
intake
with
decrease
in
body
weight
gain
and
food
efficiency,
and
increased
plasma
cholesterol
levels
in
females,
decrease
in
plasma
triglycerides
and
increases
in
leukocyte
counts,
alkaline
phosphatase
levels
and
incidence
of
pale
livers
in
males,
as
well
as
increased
relative
liver
weights,
in
both
sexes
870.3100
28­
Day
oral
toxicity
­
Rat
99.4%
44865709
(
1995)

0,
2000,
6000
or
20000
ppm
M:
0,
195.8,
579.3
or
1973.9
mg/
kg/
day
F:
0,
198.7,
572.8
or
1934.4
mg/
kg/
day:
NOAEL
=
M:
579.3
mg/
kg/
day
F:
195.8
mg/
kg/
day
LOAEL
=
M:
1973.9
mg/
kg/
day
based
on
increased
alkaline
phosphatase,
cholesterol
and
relative
liver
weight
LOAEL
=
F:
572.8
mg/
kg/
day
based
on
increased
cholesterol
and
triglycerides
as
well
as
increased
absolute
and
relative
liver
weight
870.3100
90­
Day
oral
toxicity
­
Mice
98.1­
98.7%
44865711
(
1996)

0,
280,
1400,
7000
or
14000
ppm
M:
0,
63.9,
325.0,
1724.6
or
3473.1
mg/
kg/
day
F:
0,
125.2,
696.5,
3599.5
or
6869.0
mg/
kg/
day
NOAEL
=
M:
325.0
mg/
kg/
day
F:
696.5
mg/
kg/
day
LOAEL
=
M:
1724.6
mg/
kg/
day,
F:
3599.5
mg/
kg/
day,
based
on
elevated
water
intake
and
changes
in
hematological
parameters
(
erythrocyte
count,
MCV)
in
males;
increases
in
liver
weights
and
plasma
cholesterol
in
females
870.3150
90­
Day
oral
toxicity
(
Dog)
95.8%
44865714
(
1995)

0,
250,
2500
or
50000
ppm
(
both
sexes):
0,
9.1,
62.5
or
1250
mg/
kg/
day
NOAEL
=
M
&
F:
9.1
mg/
kg/
day
LOAEL
=
M
&
F:
62.5
mg/
kg/
day,
based
on
increased
absolute
and
relative
liver
weight,
hepatocellular
hypertrophy,
increased
serum
activity
of
alkaline
phosphatase
and
decreased
plasma
protein
levels
870.3150
28­
Day
oral
toxicity
(
Dog)
[
2/
sex/
group]
97.9%
44865712
(
1993)

0,
100,
1000,
10000
or
50000
ppm
M:
0,
3.0,
31.5,
280
or
1322
mg/
kg/
day:
F:
0,
3.4,
35.0,
269.5,
or
1164.5
mg/
kg/
day
NOAEL
=
M:
3.0
mg/
kg/
day
F:
3.4
mg/
kg/
day
LOAEL
=
M
=
31.5
mg/
kg/
day;
F
=
35.0
mg/
kg/
day;
based
on
hepatocellular
hypertrophy,
vacuolated
hepatocytes
and
increased
alkaline
phosphatase
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
17
870.3150
28­
Day
oral
toxicity
+
28­
day
Recovery
(
Dog)
[
3/
sex/
group]

97.9%
44865713
(
1997)

0,
10,
20,
40,
80
ppm,
and
28­
day
dosing
followed
by
28­
day
recovery
ppm
(
0,
80
ppm)

Both
sexes:
0,
0.41,
0.77,
1.61,
2.93
­
3.01
or
0
+
2.93
­
3.01
recovery
mg/
kg/
day
{
N­
DEM
=
N­
Demethylase
O­
DEM
=
O­
Demethylase
P­
450
=
Cytochrome
P­
450}
NOAEL
=
M
+
F
Systemic:
2.93­
3.01
mg/
kg/
day
Liver
Microsomal
Enzymes
N­
DEM,
P­
450
&
O­
DEM=
1.6
LOAEL
=
M
+
F
Systemic:
not
attained
Liver
Microsomal
Enzymes
N­
DEM
=
1.61
P­
450
=
1.61
O­
DEM
=
3.01
AFTER
RECOVERY
=
all
normal
870.3700a
Prenatal
developmental
in
(
Rat)
Gavage
95.8%
44865716
(
1996)

0,
100,
300
or
1000
mg/
kg/
day
Maternal
NOAEL
=
1000
mg/
kg/
day
LOAEL
>
1000
mg/
kg/
day
based
on
absence
of
treatment
related
toxicity
in
the
dams
or
in
the
fetuses
at
the
highest
dose
tested.
Developmental
NOAEL
=
1000
mg/
kg/
day
LOAEL
>
1000
mg/
kg/
day
based
on
absence
of
treatment
related
toxicity
in
the
dams
or
in
the
fetuses
at
the
highest
dose
tested.

870.3700b
Prenatal
developmental
in
(
Rabbit)
Gavage
95.8%
44865718
(
1995)

0,
100,
300
or
1000
mg/
kg/
day:
Maternal
NOAEL
=
1000
mg/
kg/
day
LOAEL
>
1000
mg/
kg/
day
based
on
absence
of
treatment
related
toxicity
in
the
dams
or
in
the
fetuses
at
the
highest
dose
tested.
Developmental
NOAEL
=
1000
mg/
kg/
day
LOAEL
>
1000
mg/
kg/
day
based
on
on
absence
of
treatment
related
toxicity
in
the
dams
or
in
the
fetuses
at
the
highest
dose
tested.
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
18
870.3800
2­
Generation
Reproduction
(
Rat)
99.2%
44865720
(
1997)

0,
100,
2000
or
20000
ppm
M:
F0
=
0,
7.3,
146.3
or
1514.3
mg/
kg/
day
F1
=
0,
7.7,
155.3
or
1838.0
mg/
kg/
day
F:
F0
=
0,
9.6,
190.4
or
2074.0
mg/
kg/
day
F1
=
0,
10.8,
239.5
or
2944.1
mg/
kg/
day
Parental/
Systemic
NOAEL
=
M:
(
F0)
146.3
/
(
F1)
155.3
mg/
kg/
day:
F:
(
F0)
190.4
/
(
F1)
239.5
/
(
mean
of
F0
&
F1
)
214.95
mg/
kg/
day
LOAEL
=
M:
1514.3
mg/
kg/
day
based
on
decreased
body
weights
(
F1)
and
increased
liver
weights
and
bile
duct
proliferation
(
F0
and
F1).
F:
2074.0
mg/
kg/
day
based
on
increased
relative
liver
weights
Reproductive
NOAEL
=
M:
1514.3,
1838.0
mg/
kg/
day
F:
2074.0,
2944.1
mg/
kg/
day
LOAEL
=
not
attained
Offspring
NOAEL
=
214.9
mg/
kg/
day
(
mean
of
F0
&
F1
)
LOAEL
=
2509.1
mg/
kg/
day
(
mean
of
F0
&
F1
)
based
on
decreased
mean
litter
weight
day
28
(
F1
and
F2),
reduced
body
weight
F1
and
F2
during
lactation,
increased
pup
relative
liver
weights
and
reduced
lactation
index
in
F1
pups.

NOTE:
NOAELs
and/
or
LOAELs
may
appear
as
a
value
using
the
mean
of
F0
and
F1.

870.4100b
12­
Month
Chronic
toxicity
(
Dog)
98.7%
44865721
(
1997)

0,
80,
800
or
8000
ppm
M:
0,
2.62,
24.69
or
256.21
mg/
kg/
day
F:
0,
2.68,
28.10
or
261.70
mg/
kg/
day
NOAEL
=
M:
2.62
mg/
kg/
day
F:
2.68
mg/
kg/
day
LOAEL
=
M:
24.69
mg/
kg/
day,
F:
28.10
mg/
kg/
day,
based
on
biochemical
and
morphological
liver
effects
(
swelling,
enlargement,
distinct
lobulation
and
discoloration,
increases
in
absolute
and
relative
liver
weights,
and
activities
of
ALT
and
ALP,
hepatocellular
hypertrophy
and
periportal
fatty
change).
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
19
870.4200
2­
Year
Carcinogenicity
(
rat)
95.8­
98.5%
44865723
(
1998)

0,
500,
5000
or
20000
ppm
(
LIMIT
DOSE)

M:
0,
26.0,
262.5
or
1109.6
mg/
kg/
day:
F:
0,
31.7,
326.3
or
1379.7
mg/
kg/
day
NOAEL
=
M
=
26.0
mg/
kg/
day
F
=
31.7
mg/
kg/
day
LOAEL
=
M
=
262.5
mg/
kg/
day
based
on
histopathological
changes
in
liver
(
bile
duct
hyperplasia)

F
=
326.3
mg/
gk/
day
based
on
increases
in
plasma
cholesterol,
relative
liver
weights,
hepatocellular
hypertrophy
and
bile
duct
hyperplasia;
uterine
Muellerian
tumor
and
a
positive
trend
for
thyroid
adenomas
CARCINOGENICITY:
effects
seen
at
262.5
mg/
kg/
day
(
M)
and
326.3
mg/
kg/
day
(
F)

870.4300
2­
Year
Carcinogenicity
(
mouse)
95.8­
98.5%
44865722
(
1997)

0,
280,
1400
or
7000
ppm
M:
0,
58.5,
283.4
or
1566.8
mg/
kg/
day:
F:
0,
97.4,
503.1
or
2544.0
mg/
kg/
day
NOAEL
=
M
=
58.5mg/
kg/
day
F
=
97.4
mg/
kg/
day
LOAEL
=
M
=
283.4
mg/
kg/
day;
F
=
503.1
mg/
kg/
day,
based
on
increased
blood
urea
concentrations
(
both
sexes)
and
decreased
kidney
weights
(
males),
as
well
as
histological
kidney
changes
in
males
no
evidence
of
carcinogenicity
870.5100
Reverse
Gene
Mutation
Assay
(
Salmonella
typhimurium)
44865724
No
evidence
of
induced
mutant
colonies
over
background
870.5100
Reverse
gene
mutation
assay
(
Salmonella
typimurium)
44865725
P­
Methyl­
phenethylamine
was
non­
mutagenic
in
the
Ames
assay,
using
Salmonella
typhimurium
strains.

870.5375
In
vitro
Chinese
Hamster
lung
fibrolblast
44865727
No
evidence
of
induced
mutant
colonies
over
background;
therefore,
under
the
conditions
of
this
in
vitro
mammalian
cell
gene
mutation
assay,
iprovalicarb
was
considered
to
be
non­
mutagenic
870.5375
Cytogenetic
assay
(
chromosomal
aberrations
in
Chinese
Hamster
ovary
cells)
44865726
No
evidence
of
chromosomal
aberrations
induced
over
background
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
20
870.5375
Mouse
bone
marrow
micronucleus
assay
44865728
No
significant
increase
in
the
frequency
of
micronucleated
polychromatic
erythocytes
in
bone
marrow
after
any
treatment
time.

870.5375
Unscheduled
DNA
synthesis,
primary
rat
hepatocyte
cultures
44865729
No
evidence
that
unscheduled
DNA
synthesis,
as
determined
by
radioactive
tracer
procedures
was
induced.

In
vivo
32
Ppostlabelling
assay,
possible
DNA
adduct
formation
44865730
Iprovalicarb
was
assessed
as
negative
870.6200a
Acute
neurotoxicity
screening
battery
(
Rat)
44865731
(
1997)

0,
200,
800
or
2000
mg/
kg
(
single
gavage
dose)]
NOAEL
=
2000
mg/
kg/
day
(
Systemic
and
Neurotox)
LOAEL
>
2000
mg/
kg/
day
(
no
effects).

870.6200b
13­
Week
Subchronic
neurotoxicity
(
Rat)
97.3­
97.7
44865732
(
1997)

0,
1250,
5000
or
20000
ppm
M:
0,
86,
342
or
1434
mg/
kg/
day
F:
0,
131,
476
or
2314
mg/
kg/
day
NOAEL
=
SYSTEMIC
=
M:
86
mg/
kg/
day;
F:
476
mg/
kg/
day
NEUROTOX
=
M:
1434
mg/
kg/
day;
F:
2314
mg/
kg/
day
LOAEL
=
SYSTEMIC=
M:
342
mg/
kg/
day
based
on
decreased
body
wt
F
=
2314
mg/
kg/
day
based
on
decreased
body
wt
and
increased
food
consumption
NEUROTOXICITY
=
M
&
F:
not
attained.
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
21
870.7485
Metabolism
and
pharmacokinetics
[
biokinetic
behaviour
and
metabolism]
(
Rat)
98­
99.0%
44865733
(
1997)

2.0
mg/
kg/
day
(
Low
dose,
single
dose
&
15
repeated
doses)

150.0
mg/
kg/
day
(
high
dose;
single
dose)

1
mg/
kg:
bile
canulation
experiment
4.0
mg/
kg
(
single
oral
dose):
whole­
body
autoradiography
Following
oral
administration,
rapid
absorption
of
radioactivity,
wide
distribution
with
minimal
tissue
residence
time,
extensive
metabolism,
followed
by
fast
elimination
which
was
independent
of
sex,
rate
or
frequency
of
dosing.
Peak
plasma
levels
after
20­
90
minutes
in
low
dose,
or
within
8
hours
at
high
dose.
In
intraduodenally
dosed
animals,
>
91%
absorbed
from
the
GIT
within
48
hours.
Different
absorption
profile
for
individual
diastereomers:
S,
S
absorbed
more
rapidly
and
reached
plasma
level
4x
as
high
as
S,
R
isomer.
One
hour
post
administration,
liver
and
kidney
contained
significantly
higher
radioactivity
than
blood,
indicating
rapid
elimination.
Little
tissue
bioaccumulation.
Material
metabolized
extensively;
small
percent
of
parent
passed
through
rat
unchanged.
Twelve
metabolites
identified.
The
main
metabolite
pair
was
the
diastereomers
of
iprovalicarb­
carboxylic
acid
(
M03).
This
metabolite
pair
accounted
for
more
than
58%
of
administered
dose
(
AD).
Small
amounts
of
8
other
metabolites
were
found
in
the
urine.
These
minor
metabolites
accounted
for
less
than
2%
each
or
7%
AD
when
combined.
In
the
bile­
fistulation
experiment,
the
main
radioactive
components
identified
in
the
bile
were
iprovalicarb­
carboxylic
acid
(
MO3)
and
two
conjugates
thereof
(
iprovalicarb­
carbonylglycine
(
MO5)
and
iprovalicarb­
carbonyltaurine
(
MO6).
These
three
metabolites
accounted
for
about
87%
of
the
radioactivity
in
the
bile
and
about
73%
of
the
administered
dose.
Main
metabolite
pair:
iprovalicarb­
carboxylic
acid
(
M03),
>
58%
of
administered
dose.
Proposed
biotransformation
pathway
via
oxidation
of
methyl
group
on
aromatic
ring,
leading
to
carboxylic
acid
metabolite
via
hydroxylmethyl­
derivative.

870.7485
Metabolism
and
pharmacokinetics
[
biokinetic
behavior
and
metabolism
following
subchronic
feeding]
(
Rat)
44865734
(
1997)

500
and
20000
ppm
(
unlabelled
in
diet)
mg/
kg
=
2.0
(
labelled,
single
dose)
mg/
kg
=
4.0
(
labelled,
single
dose,
whole
body
autoradiography)
Absorption
and
excretion
similar
to
standard
metabolism
study
(
44865733).
Females
had
less
radioactivity
in
plasma
than
males
after
20000
ppm.
Whole
body
autoradiography
4
h
post­
administration
confirmed
rapid
absorption
and
distribution
(
found
mainly
in
liver,
stomach,
kidney
and
small
intestine).
Up
to
99%
excreted
via
urine
and
feces
within
72
hours.
Feces
major
route
of
excretion
for
males
(
70%).
Females,
equally
feces
and
urine.
Little
activity
outside
GIT.
Metabolites
noted
in
standard
study
not
affected
by
long­
term
feeding.
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
22
Special
studies
Liver
Foci
Test
For
Initiating
Effect
­
(
Rat)
99.7%
44908616
(
1993)

mg/
kg
=
0
or
1000
(
28
days)
[
males
only]
Males
dosed
for
28
days
followed
by
8
weeks
of
promotion
treatment
(
0.05%
phenobarbital).
Foci
of
altered
hepatocytes
(
FAH)
microscopically
assessed
by
4
marker
reactions
(
glycogen
storage,
glucose­
6­
phosphatase,
gamma­
glutamyl
transpeptidase
and
glycerin­
3­
phosphate
dehydrogenase).
Detectable
(
not
statis.
sig.)
FAH
more
frequent
in
promotion
control
group.
NOAEL
for
FAH
in
males
was
1000
mg/
kg/
day.

4.2
FQPA
Hazard
Considerations
4.2.1
Adequacy
of
the
Toxicity
Data
Base
The
toxicological
database
for
iprovalicarb
is
complete
and
adequate
for
FQPA
assessment.
There
are
developmental
toxicity
studies
in
two
species,
the
rat
and
the
rabbit,
a
multi­
generation
study
in
the
rat
as
well
as
acute
and
subchronic
neurotoxicity
studies.
There
is
no
evidence
of
neurotoxicity
or
neuropathology
in
the
hazard
database.
The
HIARC
(
March
1,
2002)
determined
that
a
developmental
neurotoxicity
study
was
not
required
for
this
chemical
and
no
additional
uncertainty
factors
are
needed
to
account
for
data
deficiencies.

4.2.2
Evidence
of
Neurotoxicity
There
is
no
evidence
of
neurotoxicity
or
neuropathology
in
the
hazard
database.
The
HIARC
determined
that
a
developmental
neurotoxicity
study
was
not
required
for
this
chemical
and
no
additional
safety
factors
are
needed
to
account
for
data
deficiencies.

4.2.2.1
Acute
Neurotoxicity
­
Rats
OPPTS
870.6200
[
§
81­
8];.
(
1997):

EXECUTIVE
SUMMARY:
In
an
acute
neurotoxicity
study
(
MRID
44865731),
groups
of
fasted,
young
adult,
Wistar
rats
(
12/
sex/
dose)
were
given
a
single
oral
gavage
dose
(
20
ml/
kg)
of
Technical
grade
SZX
0722
(
97.7
%
a.
i
)
in
Tylose
®
­
demineralized
water
(
0.5
%
w/
v),
at
a
dose
levels
of
0,
200,
800,
and
2000
mg/
kg
bw,
and
observed
for
14
days.
Behavioural
testing,
Functional
Observational
Battery
(
FOB)
and
motor
activity
testing
were
started
approximately
one
hour
after
dosing
and
on
days
7
and
14.
There
were
no
treatment­
related
clinical
signs
and
no
mortality
in
any
dose
group.
Body
weight
was
not
affected
by
treatment
either
in
males
or
in
females.
Results
from
the
FOB
revealed
no
treatment­
related
effects
on
the
day
of
treatment,
or
later
during
the
study.
There
were
no
treatment­
related
effects
on
motor,
and
locomotor
activity,
nor
on
habituation,
throughout
the
study.
Treatment­
related
gross
lesions
were
not
evident
at
necropsy
for
males
or
females
at
any
dose
level,
and
brain
weight
was
not
affected
by
treatment
in
either
sex.
There
were
no
treatment­
related
microscopic
lesions
in
skeletal
muscle
or
neural
tissues.

The
LOAEL
for
systemic
toxicity
and
neurotoxicity
was
>
2000
mg/
kg
bw
for
males
and
23
females,
based
on
absence
of
signs
of
systemic
toxicity
and
neurotoxicity
at
the
highest
dose
tested.
The
NOAEL
for
systemic
toxicity
and
neurotoxicity
was
2000
mg/
kg
bw
for
males
and
females.
The
results
of
the
study
demonstrate
the
absence
of
acute
systemic
toxicity
and
neurotoxicity
at
dose
levels
up
to
and
including
2000
mg/
kg
bw.

4.2.2.2
Sub­
chronic
Oral
Toxicity
OPPTS
870.6200
(
thirteenweek
administration
in
the
diet).

EXECUTIVE
SUMMARY:
In
a
sub­
chronic
neurotoxicity
screening
study
(
MRID
44865732),
SZX
0722
technical
(
97.3%
­
97.7%
a.
i.)
was
administered
in
the
diet
to
youngadult
male
and
female
Wistar
rats
(
12/
sex/
dose)
at
dose
levels
of
0,
1250,
5000,
or
20000
ppm
(
equal
to
0,
86,
342,
and
1434
mg/
kg
bw/
day
in
males
or
0,
131,
476,
and
2314
mg/
kg
bw/
day
in
females),
for
13
weeks.
All
rats
were
examined
for
neurobehavioural
changes
and
one
half
of
the
total
were
examined
for
neuropathology.
There
were
no
treatment­
related
clinical
signs
or
deaths
in
males
or
females
at
any
dose
level.
There
were
treatment­
related
reductions
in
body
weights
of
males
at
5000
ppm,
and
in
both
sexes
at
20000
ppm,
and
increased
food
consumption
in
males
(
10%)
and
females
(
12%)
at
20000
ppm.
Feed
intake
relative
to
body
weight
gain
(
g/
kg
bw)
was
also
increased
in
males
(
10%)
and
females
(
12%)
at
20000
ppm.
Results
of
the
functional
observational
battery
(
FOB)
revealed
no
treatment­
related
effects
in
males
or
females
at
all
dose
levels,
except
for
decreased
body
weights
in
5000
and
20000
ppm
males
and
20000
ppm
females.
A
marginal
decrease
in
measures
of
motor
activity
occurred
in
high
dose
females
at
week­
8
only.
A
decrease
in
motor
activity
was
not
observed
at
13
weeks,
indicating
the
absence
of
a
cumulative
effect
beyond
8
weeks
of
exposure.
This
finding
was
ascribed
to
the
general
nonspecific
toxicity,
associated
with
decreased
body
weight
at
the
high
dose,
and
was
not
considered
a
neurotoxic
effect
per
se.
In
addition,
habituation
was
not
affected.
There
were
no
treatment­
related
effects
on
gross
morphology,
microscopic
findings
in
skeletal
muscle
and
the
nervous
system,
or
brain
weights
at
any
dose
level.
The
LOAEL
for
systemic
toxicity
in
males
was
5000
ppm,
based
on
reduction
of
body
weight
in
males
at
that
dose.
The
NOAEL
for
general
toxicity
in
males,
was
1250
ppm
(
86
mg/
kg
bw).
The
LOAEL
for
general
systemic
toxicity
in
females
was
20000
ppm
(
2314
mg/
kg
bw/
day),
based
on
reduced
body
weights
and
increased
food
consumption
at
this
dose.
The
NOAEL
for
general
systemic
toxicity
in
females
was
5000
ppm
476
(
mg/
kg
bw/
day).
The
NOAEL
for
neurotoxicity
in
both
sexes
was
 
20000
ppm
(
1434
or
2314
mg/
kg
bw/
day
in
males
and
females
respectively),
based
on
absence
of
specific
neurotoxicity
at
the
highest
dose
tested.

4.2.3
Developmental
Toxicity
Studies
There
are
developmental
toxicity
studies
in
two
species,
the
rat
and
the
rabbit,
In
the
rat
and
rabbit
studies,
NOAELs
for
developmental
and
maternal
toxicity
are
1000
mg/
kg/
day.
There
were
no
apparent
maternal
or
developmental
effects
at
the
limit
dose.

4.2.3.1
Executive
Summary
for
Developmental
Toxicity
Study
in
Rats
24
In
a
developmental
toxicity
study
(
MRID
44865716),
iprovalicarb
was
administered
by
gavage
to
inseminated
Wistar
(
Hsd/
Cpb:
WU)
rats,
28­
29/
dose,
at
dose
levels
of
0,
100,
300,
and
1000
mg/
kg
bw/
day,
from
gestation
day­
6
through
day­
15.
The
animals
were
observed
daily
for
clinical
signs
and
mortality.
Fetuses
were
delivered
by
caesarian
section
on
the
20th
day
of
gestation
and
the
dams
were
subjected
to
gross
pathological
evaluation.
All
fetuses
were
assessed
for
external
gross
anomalies.
One
half
of
the
fetuses
was
examined
for
visceral
anomalies
and
the
other
half
was
processed
and
evaluated
for
skeletal
abnormalities.
There
were
no
treatment
related
clinical
signs,
mortalities
nor
effects
on
body
weight
or
food
consumption,
throughout
the
gestation
period,
at
all
dose
levels.
There
were
no
treatment­
related
effects
on
developmental
parameters;
including
incidences
of
malformations,
skeletal
deviations
(
delayed
ossification
or
variation)
or
on
general
reproductive
parameters
(
gestation
rate,
number
of
dams
with
viable
fetuses,
number
of
corpora
lutea,
placental
weight,
embryo­
fetal
resorption
rates,
number
and
sex
ratio
of
live
fetuses),
up
to
the
highest
dose
tested
1000
mg/
kg
bw.

The
LOAEL
for
both
maternal
and
developmental
toxicity
in
the
rat
was
>
1000
mg/
kg
bw,
based
on
the
absence
of
treatment
related
toxicity
in
the
dams
or
in
the
fetuses
at
the
highest
dose
tested
(
1000
mg
/
kg
bw/
day).
The
NOAEL
for
maternal
and
developmental
toxicity
was
1000
mg
/
kg
bw/
day.
Under
conditions
of
this
study,
iprovalicarb
did
not
show
developmental
toxicity
in
rats.

4.2.3.2
Executive
Summary
for
Developmental
Toxicity
Study
in
Rabbits
In
a
developmental
toxicity
study
(
MRID
44865718),
iprovalicarb
in
0.5
%
Tylose
suspension)
was
administered
daily
to
16
mated
female
Russian
rabbits
(
16/
dose),
by
gavage,
at
dose
levels
of
0,100,
300,
or
1000
mg/
kg
bw/
day
from
day­
6
through
day­
16
of
gestation.
There
was
no
treatment­
related
maternal
systemic
toxicity
nor
reproductive/
developmental
toxicity.
The
maternal
LOAEL
was
>
1000
mg/
kg
bw/
day,
based
on
absence
of
treatment
related
toxicity
at
the
highest
dose
tested.
The
maternal
NOAEL
was
1000
mg/
kg
bw/
day.
There
were
no
treatment­
related
effects
in
developmental
parameters.
The
developmental
LOAEL
was
>
1000
mg/
kg
bw/
day,
based
on
absence
of
treatment
related
developmental
toxicity
at
the
highest
dose.
The
developmental
NOAEL
is
1000
mg/
kg
bw/
day.
Under
conditions
of
this
study,
iprovalicarb
did
not
show
teratogenic
effects
in
rabbits
up
to
the
dose
level
of
1000
mg/
kg
bw/
day.

4.2.4
Reproductive
Toxicity
Study
In
the
2­
generation
reproduction
study,
limit
doses
resulted
in
a
decrease
in
body
weight
gain
in
males
and
an
increase
in
liver
weights
in
both
sexes.
No
effects
on
reproductive
parameters
were
reported
at
any
dose.
Regarding
offspring,
at
the
highest
dose
tested
(>
limit
dose),
there
was
a
decrease
in
mean
litter
weight
on
day
28
(
F
1
and
F
2),
reduced
body
weight
in
F
1
and
F
2
during
lactation
and
increased
pup
relative
liver
weights
as
well
as
reduced
lactation
index
in
F
1
pups.
The
laction
index
was
low
in
all
groups
(
including
control)
in
the
F
2
pups.
25
4.2.4.1
Executive
Summary
for
2­
Generation
Reproduction
Study
in
Rats
In
a
2­
generation
reproduction
study
(
MRID
44865720),
iprovalicarb
was
administered
to
28­
30
Wistar
(
ICO:
WU
(
IOPS
Cpb)
rats/
sex/
dose
in
the
diet,
at
dose
levels
of
0,
100,
2000
or
20000
(
equal
to
pre­
mating
doses:
0,
7.3,
146.3
or
1514.3
mg/
kg
bw/
day
in
males
and
0,
9.6,
190.4
or
2074.0
mg/
kg
bw/
day
in
females
of
F
0
generation
and
0,
7.7,
155.3,
1838.0
mg/
kg
bw/
day
in
males
or
0,
10.8,
239.5,
2944.1
mg/
kg
bw/
day
in
females
of
F
1
generation),
over
2
generations
with
one
litter
per
generation
[
mean
0,
7.5,
150.8,
1676.2
or
0,
10.1,
214.95,
2509.1
mg/
kg
bw/
day
in
males
and
females
respectively].

There
were
no
treatment­
related
clinical
signs,
or
mortality
in
F
0
or
F
1
parental
animals
of
either
sex
at
all
dose
levels.
At
20000
ppm,
parental
F
0
and
F
1
females
consumed
more
feed
(
14.7%
and
23%
respectively)
than
the
controls
during
the
pre­
mating
period,
and
F
1
males
had
significantly
decreased
(
10%)
terminal
body
weight.
In
addition,
at
20000
ppm,
F
1
male
and
female
parents
had
significantly
increased
relative
liver
weights
(
11.4%
and
28.3%,
respectively)
compared
to
controls.
There
was
also
a
treatment­
related
increase
in
the
incidence
of
bile
duct
proliferation
in
F
1
parental
males
at
20000
ppm.
There
were
no
treatment­
related
effects
on
reproductive
parameters
in
F
0
and
F
1
parental
animals
of
either
sex
(
sperm
parameters
in
males
and
estrus
cycles,
pre
or
post­
implantation
losses
in
females),
at
all
dose
levels.

Among
the
offspring,
there
were
no
treatment­
related
effects
on
the
number
of
pups
born,
live
birth
index,
pups
sex
ratio,
mean
litter
size
at
birth
in
F
1
or
in
F
2
pups
at
all
dose
levels.
At
20000
ppm,
slightly
reduced
litter
weights
were
observed
at
weaning
in
both
generations,
and
were
considered
toxicologically
significant.
In
addition,
F
1
pups
at
20000
ppm
group
had
a
significantly
lower
mean
lactation
index
than
the
controls.
Among
F
2
pups,
there
was
no
treatment
related
change
in
the
lactation
indices
at
all
dose
levels.
There
were
no
treatmentrelated
malformations,
skeletal
deviations,
maturation
of
external
sexual
organs,
or
gross
pathological
findings
in
any
of
the
F
1
or
F
2
pups
at
all
dose
levels.
The
relative
liver
weights
of
weanling
F
2
males
and
females
at
20000
ppm
were
significantly
higher
(
13
to
15%
)
than
the
controls.
The
mean
weights
of
other
organ
systems
of
treated
animals
did
not
differ
from
the
controls.

The
LOAEL
for
parental
systemic
toxicity
was
20000
ppm
(
2509
mg/
kg
bw),
based
on
decreased
body
weights
(
F1
males),
increased
relative
liver
weights
in
both
sexes
and
bile
duct
proliferation
in
F0
and
F1
parental
males.
The
NOAEL
for
parental
systemic
toxicity
was
2000
ppm
(
214.9
mg/
kg
bw/
day
in
females).
There
were
no
effects
on
fertility
or
reproductive
performance
at
all
dose
levels.

The
LOAEL
for
reproductive/
developmental
toxicity
was
20000
ppm
(
2509
mg/
kg
bw),
based
on
deceased
mean
litter
weight
at
day
28
(
F1
and
F2),
reduced
body
weight
development
in
F1
and
F2
pups
during
lactation,
increased
pup
relative
liver
weights
and
reduced
lactation
index
in
F1
pups
at
20000
ppm.
The
NOAEL
for
reproductive/
developmental
toxicity
was
2000
ppm
(
214.9
mg/
kg
bw/
day
in
females).
26
4.2.5
Additional
Information
from
Literature
Sources
A
literature
search
was
conducted,
but
no
additional
toxicity
information
was
found.

4.2.6
Pre­
and/
or
Postnatal
Toxicity
HED
has
concluded
there
is
no
concern
for
pre­
and/
or
postnatal
toxicity
resulting
from
exposure
to
iprovalicarb.

4.2.6.1
Determination
of
Susceptibility
There
was
no
evidence
for
increased
susceptibility
of
fetuses
to
in
utero
exposure
of
iprovalicarb
in
either
the
rat
developmental
or
rabbit
developmental
studies.
In
both
studies,
the
NOAELs
for
both
maternal
and
developmental
toxicity
were
the
highest
dose
tested,
1000
mg/
kg/
day
(
Limit
Dose).

Based
on
the
results
in
the
2­
generation
reproduction
study
in
rats,
a
qualitative
increased
susceptibility
of
the
neonates
(
as
compared
with
adults)
was
demonstrated
for
iprovalicarb.
The
parental
systemic
NOAELs
were
146.3/
155.3
mg/
kg/
day
for
F
0/
F
1
males
with
the
LOAELs
being
1514.3/
1838.0
mg/
kg/
day
based
on
decreased
body
weights
and
increased
liver
weights
as
well
as
bile
duct
proliferation;
for
females,
the
parental
systemic
NOAELs
were
190.4/
239.5
mg/
kg/
day
and
the
LOAELs
were
2074.0/
2944.1
mg/
kg/
day
based
on
increased
relative
liver
weights.
Reproductive
LOAELs
were
not
attained
(>
HDT,
LIMIT
DOSE).
In
offspring,
the
NOAELs
were
190.4/
239.5
mg/
kg/
day
(
F
1/
F
2)
and
the
LOAELs
were
2074.0/
2944.1
mg/
kg/
day
based
on
decreased
mean
litter
weight
on
day
28,
reduced
body
weight
during
lactation,
and
increased
pup
relative
liver
weights
as
well
as
reduced
lactation
index
in
F
1.
There
was
considered
to
be
an
increase
in
sensitivity
of
the
neonates
(
as
compared
with
adults)
because
of
the
lower
lactation
index
(
decreased
pup
survival)
and
decreased
pup
body
weights.

4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
Although
there
is
evidence
for
increased
qualitative
susceptibility
in
the
2­
generation
reproduction
study,
the
Iprovalicarb
Risk
Assessment
Team
concluded
that
there
is
a
low
level
of
concern
(
and
no
residual
uncertainty)
because:
1)
the
increased
susceptibility
(
decrease
in
pup
survival)
was
seen
only
at
the
highest
dose
tested
(
2074
mg/
kg/
day)
which
is
twice
the
limit
dose;
2)
the
decrease
in
pup
survival
was
seen
only
in
one
generation
(
F
1,
not
replicated
in
F
2);
3)
there
are
clearly
defined
NOAELs/
LOAELs
for
parental
and
offspring
toxicity;
and
4)
the
effects
seen
in
the
offspring
occurred
at
a
much
higher
dose
(
192
mg/
kg/
day)
than
that
used
to
establish
the
Chronic
RfD
(
NOAEL
of
2.62
mg/
kg/
day).

The
Iprovalicarb
Risk
Assessment
Team
concluded
that
the
data
indicate
there
are
no
(
residual)
concerns
for
pre­
and/
or
postnatal
toxicity
following
exposure
to
iprovalicarb
and
therefore,
no
additional
safety
factors
are
necessary
to
protect
the
safety
of
infants
and
children.

4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
27
4.3.1
Evidence
that
supports
not
requiring
a
Developmental
Neurotoxicity
study
Treatment­
related
toxicologically
significant
signs
of
neurotoxicity
were
not
observed
in
any
of
the
available
studies
on
iprovalicarb.
No
signs
of
neurotoxicity
were
observed
in
either
the
acute
or
chronic
neurotoxicity
studies.
In
the
developmental
toxicity
studies
on
rats
and
rabbits,
treatment­
related
increased
incidences
of
malformations
of
nervous
system
tissues
were
not
observed
and
treatment­
related
increased
susceptibility
of
fetuses,
as
compared
with
adults,
to
in
utero
exposure
to
iprovalicarb
was
not
demonstrated.
In
the
2­
generation
reproduction
study
on
rats,
no
increased
quantitative
sensitivity
of
the
neonates,
as
compared
with
adults,
was
demonstrated
for
iprovalicarb.

4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49
The
developmental
toxicity
rat
and
rabbit
studies
and
the
2­
generation
rat
reproduction
study
did
not
demonstrate
developmental,
reproductive,
or
offspring
acute
toxicity.
Therefore,
there
is
not
a
concern
for
prenatal
exposure
to
iprovalicarb
following
a
single
dose.
A
separate
aRfD
for
women
of
childbearing
age
is
not
required.

4.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
An
appropriate
endpoint
attributable
to
a
single
dose
was
not
identified
in
the
database,
including
the
rat
and
rabbit
developmental
studies,
where
no
toxicity
was
seen
at
the
limit
dose.
An
acute
RfD
is
not
established.

4.4.3
Chronic
Reference
Dose
(
cRfD)
One­
year
feeding
study
in
dogs
Guideline
#
870.4100
EXECUTIVE
SUMMARY:
In
a
1­
year
dog
study
(
MRID
44865721),
iprovalicarb
technical
was
administered
to
beagle
dogs
(
4/
sex/
group),
in
the
diet
at
doses
of
0,
80,
800,
or
8000
ppm
(
0,
2.62/
2.68,
24.69/
28.10,
256.21/
261.70
mg/
kg
bw/
day,
males/
females),
for
53
weeks.
There
were
no
treatment
related
clinical
signs
of
toxicity.
At
8000
ppm,
incomplete
food
uptake
was
observed
in
one
animal
of
each
sex,
and
body
weight
gain
was
reduced
in
males.
A
slight
increase
in
poikilocytosis
(
free
radical
change
to
red
blood
cells)
occurred
in
females
at
800
and
above,
and
in
males
at
8000
ppm,
and
there
was
a
marginal
increase
in
the
number
of
normoblasts
in
females
at
8000
ppm.
Serum
liver
enzyme
activities
(
ALT
and
ALP)
were
increased
at
>
800
ppm
in
both
sexes,
while
aspartate
transaminase
(
AST),
glutamate
dehydrogenase
(
GLDH)
and
gamma
glutamyl
transpeptidase
(
GGT)
activities
were
increased
in
both
sexes
at
8000
ppm.
Plasma
albumin
was
decreased
at
8000
ppm
in
both
sexes.
One
male
at
8000
ppm
had
decreased
plasma
cholesterol
and
T4
levels,
and
increased
total
bilirubin,
which
were
attributed
to
marked
liver
injury
and
severe
emaciation.
At
necropsy,
one
female
at
800
ppm
and
one
male
at
8000
ppm,
were
judged
to
be
skinny.
At
>
800
ppm,
there
were
increases
in
the
relative
and
absolute
liver
weights
in
both
sexes,
as
well
as
swelling,
enlargement,
distinct
28
lobulation
and
discolouration
of
the
liver,
which
correlated
with
histopathological
changes.
Microscopically,
there
was
hypertrophy,
fatty
change
and
increased
intracellular
iron
storage
in
livers
of
both
sexes
at
800
ppm
and
above,
and
focal
hepatic
necrosis,
single
cell
necrosis,
multi
lamellar
inclusions,
and
binucleated
hepatocytes
at
8000
ppm.
Two
males,
and
one
female
at
8000
ppm
had
liver
fibrosis,
which
in
one
animal
was
accompanied
by
marked
nodular
hyperplasia.
The
gall
bladders
of
animals
of
both
sexes
contained
large
quantities
of
adhesive
mucous
at
800
ppm
and
above,
and
at
8000
ppm,
there
was
pseudo
gland
formation,
and
increased
lymphoid
tissue
in
the
gall
bladder
walls.
Two
males
at
8000
ppm
had
inactive
prostate
glands,
and
one
of
these
animals
showed
decreased
spermatogenesis
in
the
testes.
Liver
triglyceride
content
was
increased
at
800
ppm
and
above,
which
may
be
indirectly
attributable
to
other
toxic
events
occurring
in
the
liver
at
these
dose
levels.
There
was
a
dose­
dependent
increase
in
the
levels
of
liver
microsomal
enzymes;
N­
demethylase,
O­
demethylase
and
cytochrome
P­
450­
content,
at
80
ppm
and
above
in
both
sexes.
The
microsomal
enzyme
induction
was
considered
an
adaptive
response
rather
than
an
adverse
effect.
The
LOAEL
in
dogs
was
800
ppm
(
24.69
and
28.10
mg/
kg
bw/
day
in
males
and
females,
respectively),
based
on
the
biochemical
and
morphological
liver
effects
(
e.
g.
swelling,
enlargement,
distinct
lobulation
and
discolouration,
increases
in
absolute
and
relative
liver
weights,
and
activities
of
ALT
and
ALP,
hepatocellular
hypertrophy
and
periportal
fatty
change)
at
this
dose.
The
NOAEL
was
80
ppm
(
2.62
and
2.68
mg/
kg
bw/
day
in
males
and
females,
respectively).

Dose
and
Endpoint
for
Establishing
RfD:
NOAEL
of
2.62
mg/
kg/
day
based
on
biochemical
and
morphological
liver
effects
(
swelling,
enlargement,
distinct
lobulation
and
discoloration,
increases
in
absolute
and
relative
liver
weights,
increases
in
ALT
and
ALP
activities
and
hepatocellular
hypertrophy
as
well
as
periportal
fatty
change)
at
24.69
mg/
kg/
day
(
LOAEL).

Uncertainty
Factor(
s):
100,
based
on
10
for
intraspecies
variation
and
10
for
interspecies
extrapolation.

Chronic
RfD
=
2.62
mg/
kg/
day
(
NOAEL)
=
0.0262
mg/
kg/
day
100
(
UF)

Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
The
dose
selected
is
supported
by
the
subchronic
studies
presented
below,
all
of
which
was
conducted
in
the
dog.

1.
90­
Day
Dietary
(
MRID
44865714):
Doses
were
0,
9.1,
62.5
or
1250
mg/
kg/
day
for
both
sexes.
The
NOAEL
was
9.1
mg/
kg/
day.
The
LOAEL
was
62.5
mg/
kg/
day
based
on
increased
absolute
and
relative
liver
weight,
hepatocellular
hypertrophy,
increased
serum
activity
of
alkaline
phosphatase
and
decreased
plasma
protein
levels.

2.
28­
Day
Dietary
(
MRID
44865712):
Doses
were
(
mg/
kg/
day)
for
males
=
0,
3.0,
31.5,
280
or
1322;
for
females
=
0,
3.4,
35.0,
169.5
or
1164.5.
The
NOAEL
was
3.0
mg/
kg/
day
for
males
and
3.4
mg/
kg/
day
for
females.
The
LOAEL
was
31.5
mg/
kg/
day
for
males
and
35.0
mg/
kg/
day
for
females
based
on
hepatocellular
hypertrophy,
vacuolated
hepatocytes
and
increased
alkaline
phosphatase.
29
3.
28­
Day
Dietary
+
28­
Day
Recovery
(
MRID
44865713):
Doses
were
0,
0.41,
0.77,
1.61,
2.93­
3.01
or
0
+
2.93­
3.01
recovery
for
both
sexes.
The
systemic
NOAEL
was
2.93­
3.01
mg/
kg/
day
(
the
highest
dose
tested).
Liver
microsomal
enzymes
were
determined
(
N­
Demethylase,
ODemethylase
and
Cytochrome
P­
450):
The
LOAEL
for
N­
Demethylase
was
(
mg/
kg/
day)
1.61,
for
Cytochrome
P­
450
was
1.61
and
O­
Demethylase
was
3.01.
After
28
days
of
recovery,
all
microsomal
enzymes
were
normal.
Levels
of
AST,
ALT
and
ALK
levels
of
treated
dogs
did
not
differ
from
controls
during
either
treatment
or
recovery.

In
addition,
similar
liver
effects
(
increased
weights
and/
or
hepatocellular
hypertrophy
and/
or
increased
enzyme
activity)
were
reported
(
at
doses
at
or
higher
than
263
mg/
kg/
day)
in
the
following
rat
studies:
2­
year
dietary
toxicity/
carcinogenicity
study
(
MRID
44865723),
2­
generation
dietary
reproduction
study
(
MRID
44835720),
90­
day
dietary
study
(
MRID
44865710)
and
28­
day
dietary
study
(
MRID
44865709).

4.4.4
Incidental
Oral
Exposure,
Dermal
and
Inhalation
Exposure
Since
this
action
is
for
an
import
tolerance
on
tomatoes,
no
proposed
uses
would
result
in
either
occupational
and
residential
exposure
in
the
U.
S.
and,
therefore,
no
oral,
dermal
or
inhalation
risk
assessments
are
required.
Such
endpoints
were
not
selected.

4.4.5
Recommendation
for
Aggregate
Exposure
Risk
Assessments
Since
iprovalicarb
is
not
registered
in
the
United
States
there
are
no
residential
uses
or
drinking
water
levels
to
aggregate
and
therefore,
no
reason
to
perform
an
aggregate
exposure
assessment.

4.4.6
Classification
of
Carcinogenic
Potential
In
accordance
with
the
EPA
Draft
Guidelines
for
Carcinogen
Risk
Assessment
(
July,
1999),
the
Cancer
Assessment
Review
Committee
(
CARC)
classified
iprovalicarb
as
"
Likely
to
be
carcinogenic
to
humans".
The
CARC
further
recommended
using
a
linear
low­
dose
extrapolation
(
Q
1*)
approach
for
estimating
the
human
cancer
risk
based
on
most
potent
tumor
in
rats.
The
most
potent
unit
risk,
Q
1*
(
mg/
kg/
day)­
1,
for
iprovalicarb
was
determined
to
be
4.47
x
10­
4
in
human
equivalents,
based
on
combined
follicular
cell
adenomas
and
carcinomas
in
the
thyroid
gland
of
female
rats.

4.4.6.1
Two­
Year
Dietary
Toxicity/
Carcinogenicity
Study
in
Rats
EXECUTIVE
SUMMARY:
In
a
combined
chronic/
carcinogenicity
study
(
MRID
44865723),
iprovalicarb
(
95.8%
­
98.5%)
was
administered
to
50
rats
(
Bor:
WISW[
SPF­
Cpb)/
sex/
dose
in
the
diet
(
admixed
with
1%
peanut
oil),
at
concentrations
of
0,
500,
5000,
and
20000
ppm
(
0,
26.0,
262.5,
or
1109.6
and
0,
31.7,
326.3,
and
1379.7
mg
mg/
kg
bw/
day
in
males
and
females
respectively)
for
24
months.
Ten
additional
rats/
sex/
dose
were
treated
similarly
and
included
in
the
study
for
the
12
months
interim
sacrifice.

There
were
no
treatment
related
mortalities
in
either
sex.
At
20000
ppm
there
was
an
increase
in
30
the
incidence
of
vaginal
bleeding
among
females,
and
the
males
had
an
increase
in
the
incidence
of
cataracts,
and
turbidity
of
the
vitreous
body
after
one
year
of
treatment.
Treatment
related
decreases
in
body
weight
gain
occurred
in
females
at
20000
ppm
Plasma
cholesterol
levels
were
increased
in
females
at
5000
ppm
and
above,
and
alkaline
phosphatase
activity
was
significantly
increased
in
males
at
20000
ppm.
At
interim
sacrifice,
the
relative
liver
weight
(
compared
to
body
mass)
of
females
at
20000
ppm
was
increased
(
22%),
and
some
females
at
5000
ppm
(
2/
10)
and
at
20000
ppm
(
3/
10)
had
slight
hypertrophy
of
hepatocytes.
At
study
termination,
there
were
increases
in
relative
liver
weights
of
females
at
5000
(
9%)
and
20000
ppm
(
19%),
and
increased
absolute
liver
weights
of
males
at
20000
ppm
(
22%).
There
was
also
increased
incidence
of
hepatocellular
hypertrophy
in
females,
and
bile
duct
hyperplasia
affecting
both
sexes
at
5000
ppm
and
above.
Furthermore,
females
had
slightly
increased
incidence
of
thyroid
follicular
cell
adenomas
and
thyroid
follicular
cell
carcinoma
at
5000
ppm
and
above,
with
a
positive
trend
evident
for
follicular
adenomas.
Benign
transitional
cell
papillomas
of
the
urinary
bladder
occurred
in
females
at
20000
ppm
(
4%),
and
mixed
Muellerian
tumours
of
the
uterus
occurred
at
5000
ppm
(
2%)
and
at
20000
ppm
(
4%).
The
increased
incidence
of
these
tumours
was
considered
treatment
related
as
it
exceeded
historical
control
range,
or
showed
a
positive
trend.
In
addition,
females
at
20000
ppm
had
a
slight
increase
in
the
incidence
of
uterine
adenocarcinomas
(
6/
50;
12%)
compared
to
4%
(
2/
50)
in
the
control
group,
and
clitoral
gland
carcinomas
were
observed
in
4%
of
females
(
2/
50)
at
that
dose,
compared
to
0%
in
the
control
group.
Although
both
these
tumour
types
were
within
the
historical
control
incidence,
they
may
add
to
the
number
of
tumours
involving
the
uterus
(
Muellerian
tumours)
to
achieve
statistical
and
toxicological
significance.
In
males
at
20000
ppm,
osteosarcomas
occurred
in
three
animals
(
two
in
the
femur,
one
in
the
lower
jaw)
and
chondrosarcoma
of
the
nasal
cavity
was
observed
in
one
animal.
These
tumours
(
chondrosarcoma
and
osteosarcomas)
were
considered
treatment
related
as
both
were
unusual
in
the
rat
strain
and
outside
the
historical
control
range
for
the
conducting
laboratory.

The
LOAEL
in
females
was
5000
ppm
(
326.3
mg/
kg
bw/
day),
based
on
increases
in
plasma
cholesterol
levels,
relative
liver
weights,
hepatocellular
hypertrophy
and
bile
duct
hyperplasia,
as
well
occurrence
of
uterine
Muellerian
tumour
and
a
positive
trend
for
thyroid
adenomas
at
that
dose.
The
NOAEL
in
females
was
500
ppm
(
31.7
mg/
kg
bw/
day).

The
LOAEL
in
males
was
5000
ppm
(
262.5
mg/
kg
bw/
day),
based
on
histopathological
changes
in
the
liver
(
bile
duct
hyperplasia)
at
that
dose
and
above.
The
NOAEL
in
males
was
500
ppm
(
26.0
mg/
kg
bw/
d).

The
NOAEL
for
carcinogenic
effects
was
500
ppm,
(
26.0
mg/
kg
bw/
d).

Dosing
was
considered
adequate.
It
exceeded
the
limit
dose
and
there
were
observations
at
the
highest
dose
of
clinical
signs,
organ
and
body
weight,
clinical
chemistry,
and
histological
changes
in
the
liver,
as
well
as
a
slight
increase
in
the
incidence
of
neoplasms
in
a
variety
of
tissues
(
bones,
thyroid,
urinary
bladder,
and
uterus).

This
chronic/
carcinogenicity
study
in
the
rat
is
acceptable,
and
satisfies
the
guideline
requirement
for
a
carcinogenicity
study
(
83­
2);
OECD
453
in
the
rat.
31
4.4.6.2
Two­
Year
Dietary
Carcinogenicity
Study
in
Mice
EXECUTIVE
SUMMARY:
In
a
carcinogenicity
study
(
MRID
44865722),
iprovalicarb
technical
(
95.8
­
98.5
%)
was
administered
to
groups
of
50
male
and
50
female
B6C3F
1
mice,
in
the
diet
at
concentrations
of
0,
280,
1400,
and
7000
ppm
(
equal
to
0,
58.5,
283.4,
and
1566.8
mg/
kg
bw/
day
for
males
and
0,
97.4,
503.1,
and
2544.0
mg/
kg
bw/
day
for
females)
for
up
to
105
weeks.
An
additional
10
animals/
sex/
dose
were
similarly
treated
to
serve
as
interim
sacrifices
at
52
weeks.
There
were
no
treatment
related
effects
on
clinical
signs,
mortality,
body
weight,
absolute
food
consumption
and
water
intake.
However,
relative
to
body
weight
gain,
food
and
water
intakes
of
males
at
7000
ppm
were
marginally
(
5­
9%)
increased.
Absolute
body
weights
of
males
at
7000
ppm
were
slightly
lower
(
4.1%)
compared
to
controls,
throughout
the
study.
Blood
urea
concentrations
were
increased
in
both
sexes
at
1400
and
7000
ppm,
suggestive
of
restricted
kidney
function
at
these
dose
levels.
Triglyceride
concentration
was
significantly
higher
in
males
at
7000
ppm
at
52
weeks,
but
not
at
the
end
of
the
treatment
period.
At
the
interim
and
the
final
necropsy,
male
mice
at
1400
and
7000
ppm
showed
lower
absolute
and
relative
kidney
weights
compared
to
controls.
Both
absolute
and
relative
liver
weights
were
increased
in
males
at
280
ppm
and
above,
but
the
increase
was
not
dose­
related.
The
increased
absolute
and
relative
liver
weights
in
males
at
280
ppm
were
attributed
to
the
higher
incidence
of
hepatocellular
neoplasms
at
this
dose,
and
not
considered
treatment­
related,
because
of
the
lack
of
a
dose
relationship.
The
increase
in
liver
weights
in
both
sexes
at
7000
ppm
was
accompanied
by
histological
changes
in
the
tissue
and
considered
toxicologically
significant.
Increases
in
the
incidences
of
fatty
changes
in
the
liver
were
observed
in
male
and
female
mice
at
7000
ppm,
and
were
considered
treatment­
related.
At
terminal
necropsy,
the
incidence
of
tubular
vacuolization
of
the
kidney
was
markedly
decreased
in
males
at
1400
ppm
and
above.
As
the
kidney
histological
changes
correlated
with
decreased
kidney
weights
and
increased
blood
urea
concentration
at
these
dose
levels,
they
were
deemed
to
indicate
an
impairment
of
kidney
function.
There
was
no
evidence
of
treatment­
related
tumours
in
either
sex
at
all
dose
levels.

The
LOAEL
in
both
sexes
was
1400
ppm
(
283.4
mg/
kg
bw/
day
in
males
and
503.1
mg/
kg
bw/
day
in
females),
based
on
increased
blood
urea
concentrations
(
both
sexes)
and
decreased
kidney
weights
(
males),
as
well
as
histological
kidney
changes
in
males
1400
ppm
and
above.
The
NOAEL
in
both
sexes
was
280
ppm
(
58.5
mg/
kg
bw/
day).

Iprovalicarb
technical
was
not
carcinogenic
in
mice
under
the
conditions
of
this
study.

This
carcinogenicity
study
in
the
mouse
is
acceptable,
and
satisfies
the
guideline
requirements
for
a
carcinogenicity
study
(
83­
2);
OECD
451
in
mice.

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)
No
toxicological
endpoint
attributable
to
a
single
exposure
was
identified
in
the
available
toxicity
studies
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
32
Acute
Dietary
(
general
population)

Chronic
Dietary
(
all
populations)
NOAEL
=
2.6
mg/
kg/
day
UF
=
100X
(
inter
&
intraspecies)

Total
UF
=
100X
Chronic
RfD
=
0.026
mg/
kg/
day
FQPA
SF
=
1X
cPAD
=
Chronic
RfD
FQPA
SF
cPAD
=
0.026
mg/
kg/
day
1­
Year
Dog
Study
Effects
on
liver
(
increased
weight,
increased
enzyme
levels
and
hepatocellular
hyperplasia)

Incidental
Oral
(
All
durations)
Endpoints
were
not
selected
for
occupational/
residential
exposure
risk
assessments
since
this
petition
is
for
an
import
tolerance.

Dermal
(
All
durations)

Inhalation
(
All
durations)

Cancer
(
oral,
dermal,
inhalation)
Classification:
"
Likely
to
be
carcinogenic
to
humans".
The
most
potent
unit
risk,
Q1
*(
mg/
kg/
day)­
1,
for
Iprovalicarb
is
4.47
x
10­
4
in
human
equivalents
based
on
female
rat
thyroid
gland
follicular
cell
adenoma
and/
or
carcinoma
combined
tumor
rates.

UF
=
uncertainty
factor,
FQPA
SF
=
Special
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
NA
=
Not
Applicable
*
Refer
to
Section
4.5
4.5
Special
FQPA
Safety
Factor
Based
on
the
review
of
the
toxicology
data
base
and
the
FQPA
SFC
recommendations
(
April
2,
2002),
the
Iprovalicarb
Risk
Assessment
Team
recommends
that
no
Special
FQPA
Safety
Factor
needs
to
be
retained
to
protect
the
safety
of
infants
and
children
in
assessing
iprovalicarb
exposure
and
risks.
This
recommendation
is
applicable
to
all
population
subgroups
for
all
exposure
routes
and
durations.

The
FQPA
SFC
concluded
that
the
Special
FQPA
safety
factor
can
be
removed
because:
there
is
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
of
fetuses
in
pre­
natal
exposure
in
the
rat
or
rabbit
developmental
toxicity
study;
although
there
is
qualitative
evidence
of
susceptibility
in
the
multi­
generation
reproduction
study
in
the
rat,
it
was
concluded
that
there
is
a
low
degree
of
concern
(
and
no
residual
uncertainty)
for
the
effects
seen
because:
1)
the
increased
susceptibility
(
decrease
in
pup
survival)
was
seen
only
at
the
highest
dose
tested
(
2074
mg/
kg/
day)
which
is
twice
the
limit
dose;
2)
the
decrease
in
pup
survival
was
seen
only
in
one
generation
(
F
1,
not
replicated
in
F
2);
3)
there
are
clearly
defined
NOAELs/
LOAELs
for
parental
33
and
offspring
toxicity;
and
4)
the
effects
seen
in
the
offspring
occurred
at
a
much
higher
dose
(
192
mg/
kg/
day)
than
that
used
to
establish
the
Chronic
RfD
(
NOAEL
of
2.62
mg/
kg/
day).
Furthermore,
the
HIARC
concluded
that
a
developmental
neurotoxicity
study
is
not
required,
and
there
are
no
data
deficiencies
or
residual
uncertainties
identified
in
the
hazard
or
dietary
food
exposure
data
bases
for
this
import­
tolerance
only
assessment
of
iprovalicarb
(
no
drinking
water
or
residential
exposures
are
anticipated).

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
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).

5.0
Public
Health
Data
(
Review
of
Iprovailcarb
Incident
Reports,
Monica
Hawkins,
DP
Barcode
D317046,
6/
15/
05)

5.1
Incident
Reports
There
were
no
reports
of
ill
effects
from
exposure
to
iprovalicarb
in
the
available
data
bases.
No
reports
for
iprovalicarb
were
found
in
the
Incident
Data
System,
the
Poison
Control
Center
Data
(
1993
through
2001).
No
reports
of
iprovalicarb
poisoning
were
reported
in
California
from
1982
through
2002.
On
the
list
of
the
top
200
chemicals
for
which
National
Pesticide
Information
Center
(
NPIC)
received
calls
from
1984­
1991
inclusively,
iprovalicarb
was
not
reported
to
be
involved
in
human
incidents.
No
scientific
literature
was
found
concerning
human
poisoning
or
other
adverse
effects
from
exposure
to
iprovalicarb.

6.0
Exposure
Characterization/
Assessment
6.1
Dietary
Exposure/
Risk
Pathway
6.1.1
Residue
Profile
(
Tolerance
Petition
Requesting
Food
Use
of
Iprovalicarb
on
Imported
Tomatoes.
Summary
of
Analytical
Chemistry
and
Residue
Data.
Petition
No
3E6578.
William
Drew,
DP
Barcode
D307042,
Draft)

The
number
and
geographic
representation
of
the
submitted
tomato
field
trials
are
adequate
to
support
a
tolerance
for
residues
of
iprovalicarb
in/
on
imported
tomatoes.
Based
on
the
34
formulations
being
supported
by
Bayer,
iprovalicarb­
treated
tomatoes
and
processed
tomato
products
would
be
imported
from
Mexico,
Chile,
Italy,
Portugal,
and
Greece
into
the
US.
Tomato
samples
from
the
field
trials
were
analyzed
using
an
adequate
analytical
method,
and
the
sample
storage
durations
are
supported
by
the
available
storage
stability
data.
In
the
trials
conducted
at
1X
the
maximum
labeled
rates,
residues
of
iprovalicarb
were
<
0.020
to
0.25
ppm
in/
on
tomatoes
harvested
at
0
to
20
days
after
the
last
application.
In
the
3
trials
conducted
in
the
US
at
a
1.5X
rate,
residues
were
0.22
to
0.50
ppm
in/
on
tomatoes
harvested
on
the
day
of
treatment.
The
minimum
PHI
specified
on
any
label
is
4
days
in
Mexico.

The
tomato
processing
study
indicates
that
iprovalicarb
residues
concentrate
on
average
by
1.6X
in
tomato
paste.
Based
on
the
highest
average
field
trial
(
HAFT)
residue
of
0.25
ppm
from
the
field
trials
conducted
at
1X,
maximum
anticipated
residues
in
paste
would
be
0.40
ppm.
Since
the
recommended
tolerance
in/
on
tomato
fruit
is
1.0
ppm
to
harmonize
with
the
European
Union
MRL,
a
separate
tolerance
for
tomato
paste
will
not
be
required.

Adequate
residue
analytical
methods
are
available
for
the
enforcement
of
established
and
proposed
tolerances.
The
enforcement
method
(
Bayer
Method
00442)
has
successfully
passed
independent
laboratory
validation
(
ILV)
and
petition
method
validation
(
PMV)
trials,
and
is
available
from
the
Analytical
Chemistry
Laboratory
of
the
Biological
and
Economic
Analysis
Division
(
ACL/
BEAD).
Residues
in
the
current
tomato
field
trials
were
determined
using
an
HPLC/
MS
method
(
Bayer
Method
00442,
the
tolerance
enforcement
method
for
grape
and
proposed
for
enforcement
of
tolerances
on
tomato)
or
one
of
two
adequate
HPLC/
MS/
MS
methods
(
Bayer
Method
00562
or
Bayer
Method
00442/
M003)
which
are
similar
to
the
enforcement
method.
Adequate
method
validation
data
were
provided
for
Bayer
Method
00562
using
numerous
plant
matrices.
The
limit
of
quantitation
(
LOQ)
for
residues
of
iprovalicarb
in/
on
tomatoes
is
0.050
ppm
for
Bayer
Methods
00442,
00442/
M003
and
00562.
All
methods
were
adequately
validated
in
conjunction
with
the
field
trial
analyses.

6.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk
(
Iprovalicarb:
Chronic
Dietary
Exposure
Assessment
to
Support
Proposed
Section
3
Registration
Import
Tolerance
on
Tomatoes.
William
Drew,
DP
Barcode
D317314;
06/
22/
05)

An
acute
dietary
exposure
analysis
was
not
performed
for
iprovalicarb
since
no
appropriate
dose
or
endpoint
could
be
identified
for
acute
dietary
exposure
in
the
general
population
or
any
of
the
population
subgroups.

A
chronic
dietary
risk
assessment
was
conducted
for
iprovalicarb
using
the
Dietary
Exposure
Evaluation
Model
(
DEEM­
FCID
 
,
Version
2.03)
and
the
LifeLine
 
Model
(
Version
2.0),
both
of
which
use
the
most
recent
food
consumption
data
from
USDA
(
CSFII,
1994­
1996
and
1998).

Both
the
Dietary
Exposure
Evaluation
Model
(
DEEM­
FCID
 
)
and
the
LifeLine
 
assessments
were
based
on
tolerance­
level
residues
in/
on
grape
commodities,
anticipated
residue
(
AR)
values
for
tomato
commodities,
DEEM
default
processing
factors,
and
100%
crop
treated
(
100%
CT)
assumptions.
The
AR
used
for
tomatoes
was
0.5
ppm,
or
half
the
proposed
tolerance
level
of
1.0
ppm
for
harmonization
purposes.
ARs
were
utilized
for
tomato
commodities
because
use
of
tolerance­
level
residues
in
the
chronic
dietary
analysis
resulted
in
a
cancer
risk
slightly
above
HED's
level
of
concern.
35
These
assumptions
result
in
highly
conservative
estimates
of
dietary
exposure
and
risk.
In
calculating
dietary
risk
estimates,
HED
has
compared
the
estimated
dietary
exposure
from
both
models
to
the
chronic
population­
adjusted
dose
(
cPAD).
Typically,
HED
has
concerns
regarding
dietary
risk
when
the
exposure
estimates
exceed
100%
of
the
cPAD.
Even
with
the
conservative
assumptions
noted
above,
risk
estimates
associated
with
dietary
exposure
to
iprovalicarb
are
significantly
below
HED's
level
of
concern.

The
DEEM­
FCID
 
and
LifeLine
 
models
provided
similar
estimates
of
chronic
dietary
exposure
and
risk.
The
most
highly
exposed
population
subgroup
was
children
1­
2
years
old.
The
chronic
exposure
estimate
of
approximately
0.00972
mg/
kg/
day
corresponds
to
37
%
cPAD.
Risks
for
the
general
US
population
and
all
other
population
subgroups
were
lower.

Table
6.1.
Result
of
Chronic
Dietary
Exposure
and
Risk
Estimates
for
Iprovalicarb.

Population
Subgroup
cPAD,
mg/
kg/
day
DEEM­
FCID
Lifeline
Exposure,
mg/
kg/
day
%
cPAD
Exposure,
mg/
kg/
day
%
cPAD
Chronic
Dietary
Estimates
U.
S.
Population
0.026
0.002189
8.4
0.00203
7.8
All
infants
(<
1
yr)
0.026
0.00258
9.9
0.00256
9.8
Children
1­
2
yrs
0.026
0.00972
37
0.00898
35
Children
3­
5
yrs
0.026
0.00651
25
0.00651
25
Children
6­
12
yrs
0.026
0.00303
12
0.00279
11
Youth
13­
19
yrs
0.026
0.00153
5.9
0.00146
5.6
Adults
20­
49
yrs
0.026
0.00151
5.8
0.00157
6.1
Adults
50+
yrs
0.026
0.00151
5.8
0.00161
6.2
Females
13­
49
yrs
0.026
0.00154
5.9
0.00171
6.6
Note:
The
values
for
the
population
with
the
highest
risk
for
each
type
of
risk
assessment
are
bolded.

The
cancer
dietary
exposure
analysis
was
based
on
the
same
assumptions
as
the
chronic
analysis.
The
esitmated
lifetime
cancer
risk
for
the
general
US
population
is
9.74
x
10­
7,
which
is
below
HED's
level
of
concern.

Table
6.1.2
Result
of
Cancer
Dietary
Exposure
Analysis
for
Iprovalicarb.

Population
Subgroup
Chronic
PAD
(
mg/
kg/
day)
Exposure
(
mg/
kg/
day)
%
cPAD
Cancer
Risk
Chronic
Chronic
(
Cancer)

U.
S.
Population
0.026
0.002189
0.002189
8.4
9.74
x
10­
7
Note:
Q*
=
0.000447
mg/
kg/
day
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
(
Water
Exposure/
Residential
(
Non­
Occupational/
Risk
Pathways)

Iprovalicarb
is
proposed
for
use
only
on
imported
tomatoes.
Since
there
are
no
registered
36
(
agricultural,
occupational
nor
residential)
uses
associated
with
iprovalicarb
in
the
U.
S.,
the
only
route
of
exposure
is
dietary
(
food
only).
Dietary
exposure
will
be
limited
to
residues
from
imported
tomatoes.
With
no
proposed
US
registrations,
there
is
no
expectation
that
iprovalicarb
residues
would
occur
via
water
consumption
or
residential
use.
Therefore,
neither
a
residential,
water
or
aggregate
exposure
is
expected
and
no
aggregate
risk
assessment
was
required.

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
iprovalicarb
and
any
other
substances
and
iprovalicarb
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
iprovalicarb
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
There
are
no
proposed
occupational
uses
associated
with
iprovalicarb.
Therefore,
an
occupational
exposure
and
risk
assessment
is
not
required.

10.0
Data
Needs
and
Label
Requirements
10.1
Toxicology
None
10.2
Residue
Chemistry
There
are
no
residue
chemistry
deficiencies
in
this
petition
that
would
preclude
establishing
a
tolerance
for
iprovalicarb
on
imported
tomatoes.
The
available
tomato
field
trial
data
are
adequate
and
would
support
a
tolerance
of
0.50
ppm
for
iprovalicarb
residues
in/
on
imported
tomatoes;
however,
HED
is
recommending
a
1.0
ppm
tolerance
on
tomatoes
in
order
to
harmonize
with
the
existing
1.0
mg/
kg
provisional
MRL
for
iprovalicarb
on
tomatoes
in
the
European
Union
(
scheduled
to
be
permanently
established
in
July
2007).
37
TABLE
10.2
Tolerance
Summary
for
Iprovalicarb.

Commodity
Proposed
Tolerance
(
ppm)
Recommended
Tolerance
(
ppm)
Comments
Tomato
1.0
1.0
The
available
residue
data
would
support
a
tolerance
of
0.50
ppm
on
tomatoes.
However,
a
tolerance
of
1.0
ppm
is
being
recommended
in
order
to
harmonize
with
the
existing
provisional
1.0
mg/
kg
MRL
in
Europe.

10.3
Occupational
and
Residential
Exposure
None
References:

Iprovalicarb
­
Report
of
the
Hazard
Indentification
Assessment
Review
Committee,
Alan
Levy,
Ph.
D.,
TXR
No.
0050515,
March
1,
2002
Iprovalicarb
­
Report
of
the
FQPA
Safety
Factor
Committee,
Carol
Christensen
and
Brenda
Tarplee,
TXR
No.
0050633,
April
2,
2002
Iprovalicarb
­
Report
of
the
Cancer
Assessment
Review
Committee,
Sanjivani
Diwan,
TXR
No.
0050652,
April
11,
2002
Iprovalicarb
Revised
Quantitative
Risk
Assessment
(
Q*)
Based
on
Hsd/
WIN:
WU
(
SPF)
Rat
Chronic
Dietary
Study
with
3/
4'
s
Interspecies
Scaling
Factor,
Virginia
Fornillo,
TXR
No.
0050483,
February
21,
2002
Iprovalicarb.
Tolerance
Petition
Requesting
Food
Use
of
Iprovalicarb
on
Imported
Tomatoes.
Summary
of
Analytical
Chemistry
and
Residue
Data.
Petition
No
3E6578.
William
Drew,
DP
Barcode
307042,
06/
22/
05
Iprovalicarb.
Chronic
and
Cancer
Dietary
Exposure
Assessment
for
Tolerances
on
Imported
Tomatoes
and
Tomato
Commodities.
William
Drew,
DP
Barcode
D317314,
06/
22/
05
Iprovalicarb
Incident
Report.
Monica
Hawkins,
DB
Barcode
06/
15/
05
38
Appendices
A­
1.0
TOXICOLOGY
DATA
REQUIREMENTS
The
requirements
(
40
CFR
158.340)
for
food
use
(
tolerances
on
imported
commodities
only)
of
iprovalicarb
are
in
Appendix
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.

APPENDIX
TABLE
1
Toxicology
Data
Requirements.

Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1200
Acute
Dermal
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1300
Acute
Inhalation
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2400
Primary
Eye
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2500
Primary
Dermal
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2600
Dermal
Sensitization
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100
Oral
Subchronic
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3150
Oral
Subchronic
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3200
21­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3250
90­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3465
90­
Day
Inhalation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
no
no
no
yes
yes
no
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
yes
yes
yes
yes
870.5100
Mutagenicity
 
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
.
.
870.5300
Mutagenicity
 
Gene
Mutation
­
mammalian
.
.
.
.
.
.
.
.
870.5375
Mutagenicity
 
Structural
Chromosomal
Aberrations
.
.
870.5xxx
Mutagenicity
 
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
870.6100a
Acute
Delayed
Neurotox.
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6100b
90­
Day
Neurotoxicity
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
.
.
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6300
Develop.
Neuro
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
no
no
no
no
yes*
yes*
no
870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
no
yes
no
*
Acute
and
90
day
neurotoxicity
studies
were
not
required
but
were
submitted
39
A­
2.0
NON­
CRITICAL
TOXICOLOGY
STUDIES
Executive
summaries
of
the
toxicolgocial
studies
not
used
for
toxicity
endpoint
selection
or
FQPA
Assessment
are
as
follows.

2.1
Sub­
chronic
Oral
Toxicity;
OPPTS
870.3100
(
rodent),
[
§
82­
1];
OECD
408.
(
1996):
SZX
0722
­
Sub­
chronic
Toxicological
investigations
in
Wistar
Rats
(
Administration
in
feed
over
13
weeks
followed
by
a
4­
week
recovery
period.)

EXECUTIVE
SUMMARY:
In
a
sub­
chronic
toxicity
study
(
MRID
44865710),
iprovalicarb
technical
(
98.1
­
98.7
%)
was
administered
to
Wistar
rats
(
10/
sex/
group),
in
the
diet
at
dose
levels
of
0,
1250,
5000,
20000
ppm
(
0,
87.4/
133.9,
372.7/
561.4,
1524.0/
2585
mg/
kg
bw/
day,
males/
females),
for
13
weeks.
Recovery
groups
of
10
rats/
sex
were
treated
at
levels
of
0
or
20000
ppm
for
13
weeks,
and
observed
for
an
additional
four
weeks
after
termination
of
treatment,
for
evidence
of
recovery.
There
were
no
treatment­
related
clinical
signs,
nor
mortalities
in
any
dose
group.
At
20000
ppm,
there
was
increased
food
intake
(
17
%)
and
decreased
food
efficiency
(
food
intake
increased
(
23
%)
relative
to
body
weight
gained)
among
females,
which
persisted
during
the
recovery
period.
There
was
also
a
slight
reduction
in
body
weight
gain
in
both
sexes
(
males;
6
%,
females:
9
%,
compared
to
controls)
which
persisted
throughout
the
recovery
periods.
In
addition,
there
was
a
slight
increase
in
leukocyte
counts
in
males,
but
was
absent
following
the
recovery
period.
Terminal
plasma
cholesterol
levels
were
increased
in
females,
alkaline
phosphatase
activity
was
slightly
elevated,
and
plasma
triglycerides
were
decreased
in
males,
at
20000
ppm.
Six
of
8
males
of
the
20000
ppm
dose
group
had
pale
livers.
Absolute
liver
weights
were
increased
in
females
at
20000
ppm
but
relative
liver
weights
were
increased
in
both
sexes
at
that
dose.
There
were
no
treatment­
related
histopathological
changes
in
any
of
the
tissues
examined.
Liver
N­
demethylase
activity
was
increased
in
females
at
20000
ppm
whereas
O­
demethylase
activity
was
increased
in
both
sexes
at
5000
ppm
and
above.
Liver
cytochrome
P­
450
levels
were
elevated
in
males
at
20000
ppm
and
in
females
at
1250
ppm
and
above.
These
liver
microsomal
enzyme
changes
were
interpreted
as
indicators
of
enzyme
induction,
and
not
necessarily
as
indicators
of
overt
toxicity.

The
LOAEL
for
both
sexes
was
20000
ppm
(
1524.0
or
2585.9
mg/
kg
bw/
d
in
males
and
females
respectively),
based
on
treatment
related
increased
food
intake
with
decrease
in
body
weight
gain
and
food
efficiency,
and
increased
plasma
cholesterol
levels
in
females,
decrease
in
plasma
triglycerides
and
increases
in
leukocyte
counts,
alkaline
phosphatase
levels
and
incidence
of
pale
livers
in
males,
as
well
as
increased
relative
liver
weights,
in
both
sexes.
The
NOAEL
was
5000
ppm
(
372.7/
561.4
mg/
kg
bw/
day
in
males/
females).

This
sub­
chronic
toxicity
study
is
classified
acceptable
and
satisfies
the
guideline
requirement
for
a
sub­
chronic
oral
study
(
OPPTS
870.3100;
OECD
408)
in
the
rat.
40
2.2
Repeat­
Dose
Oral
Toxicity];
OPPTS
870.3100
(
rodent),
[
§
82­
1];
OECD
408.
:
SZX
0722
­
Subacute
oral
toxicity
study
in
Wistar
rats
(
28­
day
feeding
study).
(
November
20,
1995)

EXECUTIVE
SUMMARY:
In
a
subchronic
toxicity
study
(
MRID
44865709),
iprovalicarb
technical
(
99.4
%)
was
administered
to
10
SPF­
bred
Wistar
rats
(
Bor:
WISW[
SPFCpb
sex/
dose,
in
the
diet
at
dose
levels
of
0,
2000,
6000
and
20000
ppm
(
equal
to
0,
195.8,
579.3,
or
1973.9
and
0,
198.7,
572.8,
or
1934.4
mg/
kg
bw/
day
in
males
and
females
respectively),
for
28
days.
There
were
no
treatment
related
clinical
signs,
nor
mortalities
in
any
dose
group.
A
slight
reduction
in
food
intake
was
observed
in
females
at
20000
ppm
in
the
first
week
but
was
later
fully
compensated
and
had
no
effect
on
body
weight
development.
A
slight
reduction
in
body
weight
development
occured
in
males
at
20000
ppm
in
the
first
week,
but
subsequent
body
weight
gain
measurements
of
that
group
did
not
differ
from
controls.
These
transient
small
reductions
in
body
weight
gain
were
not
considered
biologically
significant.
There
were
significant
and
dose
related
increases
in
cholesterol
and
triglyceride
levels
and
elevation
of
the
absolute
and
relative
liver
weights
of
females
at
6000
ppm
and
above,
and
increases
in
alkaline
phosphatase
activity,
plasma
cholesterol
levels
and
relative
(
compared
to
body
mass)
liver
weights
of
the
males
at
20000
ppm.
The
liver
weight
changes
were
considered
toxicologically
significant
because
of
the
associated
cholesterol,
triglyceride
or
alkaline
phosphataes
changes.
There
were
no
treatment
related
histological
lesions
in
any
of
the
tissues
examined.

The
LOAEL
in
females
was
6000
ppm,
based
increases
in
cholesterol
and
triglyceride
levels
and
elevation
of
the
absolute
and
relative
liver
weights
at
that
dose.
The
NOAEL
in
females
was
2000
ppm
(
195.8
mg/
kg
bw/
d
).
The
LOAEL
in
males
was
20000
ppm,
based
on
increases
in
alkaline
phosphatase
activity,
plasma
cholesterol
levels
and
relative
liver
weights
at
that
dose.
The
NOAEL
in
males
was
6000
ppm
(
579.3
mg/
kg
bw/
d
)

This
28­
day
feeding
study
is
classified
satisfactory
and
satisfies
the
guideline
requirement
(
OECD
407)
for
a
repeat­
dose
oral
study
in
the
rat.

2.3
Sub­
chronic
oral
Toxicity
;
OPPTS
870.3100
[
§
82­
1];
OECD
408.
(
1996):
Iprovalicarb
­
Dose­
Range­
Finding
Study
in
B6C3F1
mice
(
administration
in
food
over
13
weeks).

EXECUTIVE
SUMMARY:
In
a
dose­
range
finding
sub­
chronic
toxicity
study
(
MRID
44865711),
iprovalicarb
technical
(
98.1
­
98.7
%)
was
administered
to
B6C3F1
mice
(
6
or
10/
sex/
group)
in
the
diet
at
dose
levels
of
0,
280,
1400,
7000,
1400
ppm
(
0,
63.9,
325.0,
1724.6,
and
3473.1
or
0,
125.2,
696.5,
3599.5,
and
6869.0
mg/
kg
bw/
day
for
males
and
females,
respectively)
for
13
weeks.

There
were
no
treatment
related
clinical
signs,
nor
effects
on
body
weight
development,
or
food
intake.
Water
intake
per
animal
and
water
intake
relative
to
the
body
weight
gain
were
elevated
in
males
at
7000
ppm
and
above,
and
in
females
at
14000
ppm.

Haematological
investigations
revealed
a
slight
increases
in
the
mean
corpuscular
volume
in
41
males
beginning
at
7000
ppm,
and
slight
decreases
in
the
erythrocyte
count
(
in
both
sexes),
haematocrit
(
females
only),
and
as
well
as
the
mean
corpuscular
haemoglobin
(
both
sexes),
and
mean
corpuscular
haemoglobin
concentration
(
females
only)
at
14000
ppm.
Plasma
cholesterol
levels
were
increased
in
females
at
7000
ppm
and
above.
Slight
increases
in
absolute
liver
weights
were
observed
in
both
sexes
at
14000
ppm.
Relative
liver
weights
were
increased
in
females
beginning
at
7000
ppm,
and
in
males
at
14000
ppm.
The
changes
in
liver
weights
of
females
were
accompanied
by
alterations
in
plasma
cholesterol
and
was
assessed
as
indicative
of
early
liver
effects.
There
were
decreases
in
absolute
and
relative
kidney
weights
in
males
at
14000
ppm,
but
there
was
no
accompanying
histopathology
in
the
kidneys
and
therefore
considered
incidental.
Histopathological
investigations
did
not
provide
any
evidence
of
changes
in
any
tissue
related
to
treatment
with
SZX
0722.

The
LOAEL
in
males
was
7000
ppm,
based
on
elevated
water
intake
and
changes
in
haematological
parameters
(
erythrocyte
count,
MCV).
The
NOAEL
in
males
was
1400
ppm
(
325.0
mg/
kg
bw/
day).
The
LOAEL
in
females
was
7000
ppm,
based
on
increases
in
liver
weights,
and
plasma
cholesterol
levels.
The
NOAEL
in
females
was
1400
ppm
(
696.5
mg/
kg
bw/
day).

Dose
levels
for
the
long
term
study
selected
based
on
the
findings
from
this
study
were
appropriate.

This
short
term
toxicity
study
is
classifiable
as
acceptable
supplementary
study
because
it
was
a
dose­
range
finding
study
for
a
long­
term
toxicity
study
in
mice.

2.4
Sub­
chronic
Oral
Toxicity;
OPPTS
870.3150
(
non­
rodent)
[
§
82­
1];
(
1995):
iprovalicarb
­
Sub­
chronic
toxicity
in
dogs
(
13­
week
study
by
oral
administration).

EXECUTIVE
SUMMARY:
In
a
sub­
chronic
toxicity
study
(
MRID
44865714),
beagle
dogs
(
4/
sex/
group)
were
fed
diets
containing
technical
iprovalicarb
(
95.8
%)
at
doses
of
0,
250,
2500,
or
50000
ppm
(
9.1,
62.5
or
1250
mg/
kg
bw/
day
for
both
sexes),
for
13
weeks.
Four
dogs
in
the
50000
ppm
dose
group
were
described
as
being
skinny.
One
female
of
the
50000
ppm
group
was
killed
in
extremis
four
weeks
prior
to
study
termination.
Decreases
in
food
consumption
and
body
weight
gain
occurred
in
both
sexes
at
50000
ppm.
Plasma
protein,
especially
albumin
was
decreased
in
both
sexes
at
2500
ppm
and
markedly
decreased
in
50000
ppm
dose
group.
Alkaline
phosphatase
(
ALP)
activity
was
slightly,
and
markedly
elevated
at
2500,
and
50000
ppm
respectively.
The
activities
of
AST,
ALT
and
GLDH
were
distinctly
increased
at
50000
ppm.
Serum
LDH
activity
was
slightly
increased
at
the
end
of
the
study,
at
50000
ppm.
A
decrease
in
cholesterol
level
was
seen
at
50000
ppm.
The
absolute
and
relative
liver
weights
were
increased
in
all
dogs
at
2500
ppm
and
above.
The
absolute
prostate
weight
was
deceased
in
2/
4
dogs
at
2500
ppm
and
in
4/
4
males
at
50000
ppm.
Absolute
testes
weights
were
decreased
in
4/
4
males
at
50000
ppm,
and
absolute
thymus
weights
were
decreased
in
2/
3
females
and
3/
4
males
at
50000
ppm.
Treatment­
related
discolouration
and
distinct
lobulation
of
the
liver
occurred
most
frequently
in
males
at
>
2500
and
50000
ppm,
and
in
one
female
at
50000
ppm.
Abnormal
contents
of
the
gall
bladder
were
observed
at
50000
ppm.
42
Hepatocellular
hypertrophy,
multi
lamellar
bodies,
and
granulocytic
infiltration
were
observed
in
one
or
more
animals
of
either
sex
at
2500
ppm
and
above.
In
addition,
dogs
at
Hepatocyte
cytoplasmic
vacuolation,
focal
hepatic
necrosis,
and
iron
containing
pigments
(
hemosiderin)
within
peri­
portal
hepatocytes
and
Kupffer
cells
were
noted
in
dogs
at
50000
ppm.
The
presence
of
a
generalised
atrophy
of
fatty
tissues
with
dilatation
and
edema
of
the
lymphatic
vessels,
and
serous
atrophy
of
femoral
and
sternum
bone
marrow,
and
decreased
absolute
testes
and
prostate
weights
at
50000
ppm
were
attributed
to
the
very
poor
physical
condition
of
the
dogs
rather
than
a
specific
organ/
tissue
toxicity
response.
The
microsomal
enzymes
N­
Demethylase
(
N­
DEM)
and
O­
Demethylase
(
O­
DEM)
and
cytochrome
P­
450
were
increased
at
>
250
ppm.
The
elevation
of
liver
microsomal
enzyme
at
250
ppm
was
considered
and
adaptive
response
resulting
from
enzyme
induction
rather
than
an
adverse
effect.
The
LOAEL
was
2500
pmm
(
62.5
mg/
kg
bw/
d),
based
on
increased
absolute
and
relative
weight,
hepatocellular
hypertrophy,
increased
serum
activity
of
alkaline
phosphatase,
decreased
plasma
protein
levels).
The
NOAEL
in
both
sexes
was
250
ppm
(
9.1
mg/
kg
bw/
day).

This
sub­
chronic
toxicity
study
is
classified
acceptable
and
satisifies
guideline
requirements
(
409)
for
a
short
term
toxicity
study
in
dogs.

2.5
Repeat­
Dose
Oral
Toxicity;
OPPTS
870.3150
(
nonrodent)
[
§
82­
1];
OECD
407.
(
1993):
Safety
evaluation
of
iprovalicarb:
Four­
Week
Dietary
Toxicity
Study
in
Dogs.

EXECUTIVE
SUMMARY:
In
a
repeat­
dose
oral
toxicity
study
(
MRID
44865712),
iprovalicarb
technical,
(
97.9
%
a.
i.)
was
administered
to
beagle
dogs
(
2/
sex/
group)
in
the
diet
at
dose
levels
of
0,
100,
1000,
10000,
50000
ppm
(
0,
3.0/
3.4,
31.5/
35.0,
280/
269.5,1322/
1164.5
mg/
kg
bw/
day,
males/
females)
for
4
weeks.
Survival
rates
were
unaffected
at
all
dose
levels.
Hepatocyte
hypertrophy
with
vacuolated
cytoplasmic
appearance
and
elevated
serum
alkaline
phosphatase
activity
were
seen
at
>
1000
ppm,
in
both
sexes.
Food
consumption
was
reduced
in
both
sexes
at
10000
ppm
and
above.
The
females
at
10000
ppm,
and
both
sexes
at
50000
ppm
lost
weight
during
the
4­
week
study
period.
Cholesterol
levels
were
decreased
in
males
at
10000
ppm,
and
in
both
sexes
at
50000
ppm.
Activated
partial
thromboplastin
time
(
APTT)
was
significantly
decreased
in
males
at
50000
ppm
by
week­
2,
and
at
10000
ppm
by
week­
4,
and
was
attributable
to
impaired
ability
of
the
liver
to
clear
activated
coagulation
proteins,
hence
considered
toxicologically
significant.
Serum
alkaline
phosphatase
activity
(
ALP)
was
markedly
elevated
in
both
sexes
at
>
10,000
ppm.
Serum
GGT,
GLDH,
ALT,
and
AST
activities
were
elevated
in
males
at
50000
ppm.
Absolute
and
relative
liver
weights
were
increased
in
both
sexes
at
10000
ppm
and
above.
The
LOAEL
in
both
sexes
was
1000
ppm
(
31.5
­
35.0
mg/
kg
bw/
day,
based
on
hepatocellular
hypertrophy,
a
vacuolated
appearance
of
hepatocytes
and
elevated
serum
alkaline
phophatase
activity.
The
NOAEL
in
both
sexes
was
100
ppm
(
3.0/
3.4
mg/
kg
bw/
day
in
males/
females).

This
repeat­
dose
oral
toxicity
study
in
dogs
is
classified
acceptable
and
satisfies
the
guideline
requirements
for
a
repeat­
dose
(
28
day)
oral
study
(
82­
1)
;
OECD
407
in
the
dog.
43
2.6
Special
Sub­
chronic
Oral
Toxicity;
OPPTS
870.3150
(
non­
rodent)
[
§
82­
1];
OECD
409
(
1997):
Iprovalicarb:
Sub­
acute
Toxicity
Study
in
Beagle
Dogs
(
4
Week
Study
by
Diet
admixture
with
a
4
week
recovery
period).

EXECUTIVE
SUMMARY:
In
a
special
sub­
chronic
toxicity
study
(
MRID
44865713),
iprovalicarb
technical,
(
97.9
%
a.
i.)
was
administered
to
beagle
dogs
(
3/
sex/
group0,
in
the
diet,
at
doses
of
0,
10,
20,
40,
or
80
ppm
(
equal
to
0,
0.41,
0.77,
1.61,
2.93­
3.01
mg/
kg
bw/
d)
for
4
weeks.
Additional
two
groups
of
3
animals/
sex/
group
were
administered
the
test
compound
at
0,
and
80
ppm
for
four
weeks,
then
removed
from
the
treatment
and
observed
for
a
four­
week
recovery
period.
The
objective
of
this
study
was
to
determine
the
no
observable
adverse
effect
level
(
NOAEL)
for
liver
microsomal
enzyme
induction.
There
were
no
treatment
related
clinical
signs,
mortality,
or
effects
on
food
consumption,
nutritional
status,
or
body
weight
gain.
Levels
of
the
serum
enzymes;
AST,
ALT,
ALP
and
GLDH
were
unaffected
at
all
doses.
There
were
no
treatment
gross
or
microscopic
necropsy
findings,
and
no
effects
on
organ
weights
at
any
of
the
dose
levels.
At
40
ppm,
levels
of
liver
microsomal
enzymes
(
N­
demethylase
and
cytochrome
P­
450)
were
significantly
increased,
but,
O­
demethylase
was
not
changed.
At
80
ppm,
all
three
microsomal
enzymes
(
N­
demethylase,
O­
demethylase,
cytochrome
P­
450
)
were
increased.
No
overt
toxicity
was
manifested
in
dogs
at
80
ppm.
The
LOAEL
for
liver
microsomal
enzyme
induction
in
both
sexes
was
40
ppm,
based
on
elevated
levels
of
the
microsomal
enzymes
Ndemethylase
levels
and
cytochrome
P­
450
at
that
dose.
The
NOAEL
for
microsomal
liver
enzyme
induction
in
both
sexes
was
20
ppm
(
0.77
mg/
kg
bw/
day).
The
induction
of
all
three
microsomal
enzymes
was
completely
reversible
by
the
end
of
the
4­
week
recovery
period
This
special
non­
guideline
sub­
chronic
toxicity
study
is
classified
as
supplementary
to
the
subchronic
oral
toxicity
guideline
studies
in
the
dog.
The
study
is
a
non­
guideline
study
designed
to
investigate
the
effect
of
the
test
substance
on
liver
microsomal
enzyme
induction,
which
is
not
a
guideline
requirement.

MUTAGENICITY
Studies
on
Technical
Grade
Iprovalicarb
Technical
grade
Iprovalicarb
did
not
demonstrate
mutagenic
potential
in
the
five
studies
submitted
by
the
registrant.
In
addition,
there
was
one
reverse
gene
mutation
study
with
the
metabolite
methyl­
phenethylamine
and
one
with
32P­
postlabelling
to
investigate
possible
DNA
adduct
formation
in
the
uterus,
urinary
bladder
epithelium
and
whole
urinary
bladder.

2.7
Reverse
gene
mutation
assay
(
Salmonella
typhimurium
plate
test)
MRID
No.
44865724
Guideline
No.:
870.5100
EXECUTIVE
SUMMARY:
In
a
reverse
gene
mutation
assay
in
bacteria,
Salmonella
typhimurium
strains
(
TA
98,
TA
100,
TA
1535
and
TA
1537)
were
exposed
to
iprovalicarb
(
purity:
98.1%)
in
dimethyl
sulfoxide
(
DMSO)
at
concentrations
of
0,
8,
40,
200,
1,000
or
5,000

g/
plate
in
the
presence
and
absence
of
S9
mammalian
metabolic
activation
using
the
standard
plate
method.
In
an
independent
confirmatory
trial
the
concentrations
were
0,
125,
250,
500,
1,000,
2,000
or
4,000

g/
plate
in
the
presence
and
absence
of
S9
mammalian
metabolic
activation.
The
S9
fraction
was
derived
from
Aroclor
1254­
induced
rat
livers.
44
The
test
substance
was
tested
up
to
the
highest
concentration
recommended
for
microbial
assays
(
5,000

g/
plate),
although
the
test
substance
started
to
precipitate
at
4,000

g/
plate
such
that
evaluation
was
not
possible
at
5,000

g/
plate.
A
weak
strain­
specific
(
TA100)
bacteriotoxic
effect
was
possibly
observed
at
doses
of
4,000

g/
plate
and
above.
Evaluation
of
individual
dose
groups
with
respect
to
relevant
assessment
parameters
(
dose
effect
and
reproducibility)
indicate
that
the
test
substance
did
not
induce
a
mutagenic
response
in
the
two
independently
performed
trials.
The
positive
controls
induced
the
appropriate
responses
in
the
corresponding
strains.
There
was
no
evidence
of
induced
mutant
colonies
over
background.

This
study
is
classified
as
acceptable
/
guideline
and
satisfies
the
requirement
for
FIFRA
Test
Guideline
84­
2;
OECD
471
/
472
for
in
vitro
mutagenicity
(
bacterial
reverse
gene
mutation)
data.

2.8
In
vitro
Chinese
hamster
lung
fibroblast
MRID
No.
44865727
Guideline
No.
870.5375
EXECUTIVE
SUMMARY:
In
a
mammalian
cell
gene
mutation
assay
at
the
poxanthineguanine
phosphoribosyl
transferase
locus,
V79
cells
(
Chinese
hamster
lung
fibroblasts)
cultured
in
vitro
were
exposed
to
iprovalicarb
(
purity:
98.1%)
at
concentrations
of
0,
12.5,
25,
50,
75,
100
or
125

g/
mL
in
the
presence
S9
metabolic
activation
and
at
concentrations
of
0,
7.8,
15.6,
31.3,
62.5,
125
or
250

g/
mL
in
the
absence
of
S9
metabolic
activation.

Iprovalicarb
was
tested
up
to
its
limit
of
solubility
under
culture
conditions.
No
treatmentrelated
effect
on
cloning
efficiency
or
relative
population
growth
was
observed
in
either
the
presence
or
absence
of
S9
metabolic
activation.
The
test
substance
did
not
induce
a
significant,
dose­
related,
reproducible
increase
in
mutation
frequency
compared
to
the
solvent
controls
in
the
presence
or
absence
of
S9
metabolic
activation.
The
positive
controls,
ethyl
methanesulfonate
(
without
S9
mix)
and
dimethylbenzanthracene
(
with
S9
mix),
induced
the
appropriate
responses.
There
was
no
evidence
of
induced
mutant
colonies
over
background;
therefore,
under
the
conditions
of
this
in
vitro
mammalian
cell
gene
mutation
assay,
iprovalicarb
was
considered
to
be
non­
mutagenic.

This
study
is
classified
as
acceptable
/
guideline.
This
study
satisfies
the
requirement
for
Test
Guideline
OPPTS
870.5300,
OECD
476
for
in
vitro
mutagenicity
(
mammalian
forward
gene
mutation)
data.

2.9
Cytogenetics
assay
(
chromosomal
aberrations
in
Chinese
hamster
ovary
cells)
MRID
No.
44865726
Guideline
No.
870.5375
EXECUTIVE
SUMMARY:
In
a
mammalian
cell
cytogenetics
assay
(
Chromosomal
aberration),
Chinese
Hamster
Ovary
(
CHO)
cultures
were
exposed
to
iprovalicarb
(
purity
­
98.7%)
in
ethanol
at
concentrations
of
0,
6,
30
or
150

g/
mL
in
both
the
presence
and
absence
of
S9
mammalian
metabolic
activation
(
S9
fraction
derived
from
Aroclor
1254­
induced
rat
45
livers).
The
positive
controls
were
mitomycin
C
(
without
S9
metabolic
activation;
final
concentration
­
1.0

g/
mL)
and
cyclophosphamide
(
with
S9
metabolic
activation;
final
concentration
­
10

g/
mL).

The
highest
dose
tested,
150

g/
mL,
was
based
on
the
insolubility
of
the
stock
concentration
at
higher
doses
in
the
treatment
medium.
In
the
presence
of
S9
metabolic
activation
no
cytotoxicity
was
observed.
In
the
absence
of
S9
metabolic
activation
cytotoxicity
was
observed
at
150

g/
mL
at
the
24
hour
harvest
time.
When
compared
to
controls,
there
were
no
biologically
relevant
or
statistically
significant
increases
in
the
number
of
metaphases
with
aberrations
at
any
dose
level
at
the
8,
24
or
30
hour
harvest
time
in
either
the
presence
or
absence
of
S9
metabolic
activation.
Positive
controls
induced
the
appropriate
response.
Under
the
conditions
of
this
study,
there
was
no
evidence
of
chromosomal
aberrations
induced
over
background.

This
study
is
classified
as
acceptable
/
guideline.
This
study
satisfies
the
requirement
for
Test
Guideline:
In
vitro
mammalian
cytogenetics
[
chromosomal
aberration]
OPPTS
870.5375;
OECD
473
for
in
vitro
cytogenetic
mutagenicity
data.

2.10
Mouse
bone
marrow
micronucleus
assay
MRID
No.
44865728
Guideline
No.:
870.5375
EXECUTIVE
SUMMARY:
In
a
HsDd/
Win:
NMRI
mouse
bone
marrow
micronucleus
assay,
5
animals/
sex/
dose/
sampling
time
were
treated,
by
intraperitoneal
injection
(
single
dose),
with
iprovalicarb
(
purity
­
96.7%)
at
doses
of
0
or
2,000
mg/
kg
bw.
Bone
marrow
cells,
isolated
from
the
femur,
were
harvested
at
16,
24
and
48
hours
post­
treatment.
The
vehicle
and
negative
control
was
0.5%
aqueous
Cremophor
emulsion
(
20
mL/
kg
bw).
The
positive
control
was
cyclophosphamide
(
20
mg/
kg
bw).
The
treated
animals
exhibited
the
following
treatment­
related
symptoms
until
sacrifice:
apathy,
roughened
fur,
spasm,
difficulty
in
breathing
and
diarrhea.
Their
feeding
behaviour
appeared
normal
and
there
were
no
mortalities.
The
ratio
of
normochromatic
erythrocytes
(
NCE)
per
1,000
polychromatic
erythrocytes
(
PCE)
was
increased
in
the
treated
group
over
time.
This
was
statistically
significant
at
48
hours.
There
was
no
biologically
relevant
or
statistically
significant
difference
between
the
negative
control
group
and
the
treated
group
with
respect
to
the
incidence
of
micronucleated
polychromatic
erythrocytes
or
micronucleated
normochromatic
erythrocytes
at
any
sacrifice
time
for
both
sexes.
Iprovalicarb
was
tested
at
an
adequate
dose
based
on
the
maximum
tolerated
dose
(
MTD)
as
indicated
in
OECD
Guideline
474
or
based
on
the
limit
dose
(
2,000
mg/
kg
bw)
as
indicated
in
OPPTS
870.5395
[
§
84­
2].
The
positive
control,
cyclophosphamide
(
20
mg/
kg
bw),
induced
the
appropriate
response.
There
was
not
a
significant
increase
in
the
frequency
of
micronucleated
polychromatic
erythrocytes
in
bone
marrow
after
any
treatment
time.

This
study
is
classified
as
acceptable
/
guideline.
This
study
satisfies
the
requirement
for
Test
Guideline
OPPTS
870.5395;
OECD
474
for
in
vivo
cytogenetic
mutagenicity
data.
46
2.11
Unscheduled
DNA
synthesis,
primary
rat
hepatocyte
cultures
MRID
No.
44865729
Guideline
No.:
870.5375
EXECUTIVE
SUMMARY:
In
an
unscheduled
DNA
synthesis
assay,
primary
rat
hepatocyte
cultures
were
exposed
to
iprovalicarb
(
purity:
98.7%)
in
dimethylsulfoxide
(
DMSO;
final
concentration

1%
v/
v)
at
concentrations
of
0,
50,
150,
200,
250,
300,
400
or
500

g/
mL
for
16­
24
hours.
The
positive
control
substance
was
2­
acetylaminofluorene
in
DMSO
(
2­
AAF;
final
concentration
­
0.25
and
0.50

g/
mL).

Iprovalicarb
was
tested
up
to
cytotoxic
(
250
and
300

g/
mL)
and
precipitating
concentrations
(
400
and
500

g/
mL).
The
initial
trial
was
considered
invalid
since
the
mean
nuclear
net
grain
value
of
the
vehicle
control
was
outside
the
range
of
the
historical
control
data
and
the
positive
control
(
0.25

g/
mL
2­
AAF)
did
not
induce
an
effect
which
was
strong
enough
according
to
acceptable
assay
criteria.
In
the
second
trial
hepatocyte
viability
was
84.7
and
75.8%
after
isolation
and
attachment,
respectively,
demonstrating
that
the
hepatocyte
cultures
were
in
good
condition
for
the
UDS
assay.
Precipitation
of
the
test
substance
was
observed
at
400
and
500

g/
mL.
The
test
substance
exhibited
clear
cytotoxic
effects
at
250
and
300

g/
mL
(
19.3
and
52.6%
relative
survival,
respectively)
and
probable
cytotoxic
effects
at
200

g/
mL
(
71.4%
relative
survival).
There
were
no
biologically
relevant
or
statistically
significant
differences
in
nuclear
labelling
or
in
the
percentage
of
cells
in
repair
between
the
treatment
groups
and
the
vehicle
control.
The
positive
control
(
0.5

g/
mL
2­
AAF)
induced
the
appropriate
response.
There
was
no
evidence
that
unscheduled
DNA
synthesis,
as
determined
by
radioactive
tracer
procedures
[
nuclear
silver
grain
counts]
was
induced.

This
study
is
classified
as
acceptable
/
guideline.
This
study
satisfies
the
requirement
for
Test
Guideline
OPPTS
870.5550;
OECD
482
for
other
genotoxic
mutagenicity
data.

Mutagenicity
Study
on
the
Metabolite
of
Iprovalicarb
2.12
Reverse
gene
mutation
assay
(
Salmonella
typhimurium
plate
test)
MRID
No.
44865725
Guideline
No.:
870.5100
EXECUTIVE
SUMMARY:
In
a
reverse
gene
mutation
assay
in
bacteria,
histidine­
auxotrophic
strains
of
Salmonella
typhimurium
(
TA
1535,
TA
100,
TA
1537,
TA
98
and
TA
102)
were
exposed
to
P­
Methyl­
phenethylamine
(
98.8%)
disolved
in
DMSO,
at
concentrations
of
0,
16,
50,
158,
500,
1581
or
5,000

g/
plate,
in
the
presence
and
absence
of
S9
mammalian
metabolic
activation
using
the
standard
plate
method,
in
two
independent
trials.
The
S9
fraction
was
derived
from
Aroclor
1254­
induced
rat
livers.
The
test
substance
was
tested
up
to
the
highest
concentration
recommended
for
microbial
assays
(
5,000

g/
plate).
Doses
greater
than
50

g/
plate
caused
some
strain
specific
cytotoxic
effects.
Evaluation
of
individual
dose
groups
with
respect
to
relevant
assessment
parameters
indicate
that
the
test
substance
did
not
induce
a
mutagenic
response
(
biologically
relevant
increase
in
mutant
counts,
in
comparison
to
controls)
in
the
two
trials.
There
was
no
evidence
of
induced
mutant
colonies
above
background.
The
positive
controls
(
sodium
azide,
nitrofurantoin,
4­
nitrophenylene
diamine,
cumene
hydroperoxide,
and
2­
amino­
anthracene)
induced
the
appropriate
responses
in
the
corresponding
strains.
Therefore,
P­
Methyl­
phenethylamine
was
non­
mutagenic
in
the
Ames
assay,
using
47
Salmonella
typhimurium
strains,
in
the
presence
and
absence
of
S­
9
metabolic
activation.

This
study
is
classified
as
acceptable
/
guideline
and
satisfies
the
requirement
for
FIFRA
Test
Guideline
84­
2;
OECD
471
/
472
for
in
vitro
mutagenicity
(
bacterial
reverse
gene
mutation)
data.

2.13
In
vivo
32P­
postlabelling
assay,
possible
DNA
adduct
formation
(
uterus,
urinary
bladder
epithelium
and
whole
urinary
bladder.
MRID
No.
44865730
Guideline
No.:
none
EXECUTIVE
SUMMARY:
The
32P­
postlabelling
assay
was
employed
to
investigate
iprovalicarb
(
purity
96.4%)
in
vivo
in
female
Wistar
rats
for
possible
DNA
adduct
formation
in
the
uterus,
urinary
bladder
epithelium
and
whole
urinary
bladder.
The
test
substance
was
administered
to
9
female
rats/
dose
in
the
diet
(
ad
libitum)
at
dose
levels
of
0,
10,000
or
20,000
ppm
for
7
days.
Approximately
17
hours
prior
to
sacrifice,
the
positive
control
animals
(
4
animals/
group)
received
a
single
dose
of
2­
acetylaminofluorene
(
2­
AAF;
final
concentration
=
120
mg/
kg
bw)
or
7,12­
dimethylbenzanthracene
(
DMBA;
final
concentration
=
150
mg/
kg
bw)
by
oral
gavage.

There
were
no
treatment­
related
effects
on
mortality,
clinical
signs,
food
consumption
or
water
consumption.
Body
weight
development
was
retarded
at
10,000
and
20,000
ppm.
Based
on
the
data
presented
in
the
study
report,
no
iprovalicarb­
induced
DNA
adducts
could
be
detected
in
the
uterus,
urinary
bladder
epithelium
or
in
the
whole
urinary
bladder.
The
positive
control
substance,
DMBA,
induced
the
appropriate
response
(
DNA
adducts)
in
the
uterus,
urinary
bladder
and
in
the
whole
urinary
bladder.
In
the
urinary
bladder
epithelium
2­
AAF
induced
the
appropriate
response
only
after
butanol
extraction.
After
nuclease
P1
enrichment
no
DNA
adducts
could
be
detected.
The
study
author
concluded
that
the
lack
of
effect
was
not
due
to
the
inappropriateness
of
the
test
performance
but
due
to
the
fact
that
nuclease
P1
enrichment
is
not
suitable
for
the
detection
of
2­
AAF
specific
adducts
in
urinary
bladder
epithelium.
Based
on
the
study
findings,
SZX
0722
was
assessed
as
negative
in
the
32P­
postlabelling
assay
in
vivo
in
uterus,
urinary
bladder
epithelium
and
whole
urinary
bladder.

Study
Deficiencies:
Currently,
there
are
no
DACO
requirements
and
no
accepted
guidelines
available
for
the
32P­
post­
labelling
in
vivo
assay.
This
study
was
a
non­
guideline
study
to
assess
whether
iprovalicarb,
or
its
metabolites,
are
able
to
form
DNA
adducts
in
the
female
rat
uterus
and
urinary
bladder
epithelium
in
vivo
after
application
in
the
diet
for
7
days.
Measurement
of
covalently
formed
DNA
adducts
is
considered
to
be
a
tool
to
assess
the
ability
of
a
chemical
to
reach
and
alter
the
DNA.
Stable
DNA
adducts
can
be
detected
by
the
32P­
postlabelling
method
by
incorporation
of
32P
into
non­
radioactive
nuclei
acid
constituents
by
enzyme­
catalysed
derivatization
followed
by
a
chromatographic
separation
of
radioactive
products.
The
32Ppostlabelling
assay
is
considered
to
be
particularly
valuable
in
assessing
genotoxicity
and
the
carcinogenicity
potential
of
chemicals
and
their
metabolites.
The
methods
used
in
this
study
were
considered
to
represent
further
developments
of
the
techniques
originally
described
by
Randerath
et
al
(
1981;
Proc.
Natl.
Acad.
Sci.
USA.,
78,
6126­
6129),
Reddy
and
Randerath
(
1986;
Carcinogenesis,
7,
1543­
1551)
and
Gallagher
et
al(
1989;
Cancer
Letters,
45,
7­
12).
48
This
study
appears
to
be
acceptable
for
the
purpose
for
which
it
was
intended.
However,
this
study
is
not
a
required
guideline
study
and
in
the
absence
of
any
accepted
guidelines
the
reviewer
cannot
attest
to
the
significance
of
the
study
author's
conclusions
or
to
the
validity
of
the
study.
This
study
should
not
impact
on
the
determination
of
the
genotoxicity
potential
of
SZX
0722
since
it
is
not
a
required
guideline
study
and
the
genotoxicity
potential
of
SZX
0722
has
been
adequately
addressed
in
DACO's
4.5.4,
4.5.5,
4.5.6,
4.5.7
and
4.5.8.

A­
3.0
METABOLISM
CONSIDERATIONS
1.0
Nature
of
the
Residue
Studies
in
Plants
The
terminal
residue
of
concern
in
plants
is
parent
iprovalicarb
(
PMRA
Monograph,
September
2001).

2.0
Nature
of
the
Residue
in
Livestock
There
are
no
significant
livestock
feed
items
associated
with
this
petition;
therefore,
the
nature
of
the
residue
in
livestock
does
not
need
to
be
addressed.

3.0
Confined
Rotational
Crop
Studies
Per
the
NAFTA
Guidance
Document
on
Data
Requirements
for
Tolerances
on
Imported
Commodities
(
dated
April
2003),
rotational
crop
data
are
not
required
to
support
the
proposed
tolerances
on
imported
tomatoes.

4.0
Summary
of
Magnitude
of
Residue
(
MOR)
Studies
For
Fruiting
Vegetables
(
Crop
Group
8)

Crop
field
trials
are
conducted
to
determine
the
maximum
residue
which
may
be
expected
in/
on
a
raw
agricultural
commodity
as
a
result
of
the
legal
use
of
the
pesticide.
The
trials
must
reflect
label
directions
which
would
be
expected
to
result
in
the
maximum
residue
levels;
ergo,
the
trials
should
employ
maximum
label
rates,
maximum
number
of
applications,
minimum
retreatment
interval(
s),
and
minimum
pre­
harvest
interval.

Data
generated
in
the
US
or
countries
other
than
those
where
the
petitioner
has
existing
or
proposed
uses
may
be
substituted
for
up
to
half
of
the
required
number
of
foreign
trials,
but
a
minimum
of
three
trials
must
be
from
the
countries
in
which
the
pesticide
is
marketed.
The
petitioner
should
demonstrate
that
crop
cultural
practices,
climatological
conditions,
and
use
patterns
are
substantially
similar
between
the
subject
foreign
regions
and
regions
represented
by
the
US
(
or
other)
data.

In
the
case
of
tolerances
to
cover
treated
commodities
imported
from
Canada
or
Mexico
only,
it
may
be
acceptable
for
more
than
50%
of
the
trials
to
be
conducted
in
the
United
States.
As
part
of
the
harmonization
process
under
the
NAFTA,
the
crop
field
trial
regions
in
the
US
guidelines
have
been
extended
into
Canada
and
efforts
are
in
progress
to
do
the
same
into
Mexico.
This
49
would
allow
trials
in
the
US
to
support
registration
and
tolerances
in
Canada
and
Mexico
or
vice
versa.
As
a
result,
among
these
three
countries,
for
certain
crops
most
or
all
the
field
trials
could
be
in
a
different
country
than
the
one
in
which
the
tolerance
is
to
be
established.
For
example,
if
a
tolerance
is
desired
to
cover
the
export
of
cranberries
from
Canada
to
the
US,
most
of
the
trials
could
be
conducted
in
the
northern
regions
of
the
US
even
though
the
pesticide
is
to
be
registered
in
Canada.
Similarly,
for
certain
crops
being
imported
from
Mexico,
many
of
the
trials
could
be
done
in
the
southwestern
US
In
the
future,
if
other
countries
develop
zone
maps
employing
similar
concepts
as
were
used
for
the
NAFTA
countries,
and
the
regions
and
cultural
practices
are
demonstrated
to
be
substantially
similar
to
US
regions,
then
the
Agency
may
consider
substitution
of
US
data
for
those
countries
as
well.

APPENDIX
TABLE
5.0.1
Summary
of
Residue
Data
from
Tomato
Field
Trials
with
Iprovalicarb
in
the
US,
Mexico,
and
Chile
(
MRID
#
45899605).

Commodity
EUP
Total
Rate
(
kg
ai/
ha)
PHI
(
Days)
Residue
Levels
(
ppm)
1
n
Min.
Max.
HAFT
2
Mean
Std.
Dev.

Tomato
(
Fruit)
6%
WP
1.00­
1.06
4
­
5
14
<
0.020
0.133
0.119
0.059
0.035
9%
WP
0.544
5
2
0.055
0.062
0.059
0.059
0.005
1.
The
LOQ
is
0.020
ppm;
the
LOD
is
0.005
ppm.
Residues
<
0.020
ppm
(
less
than
the
LOQ)
were
estimated
to
be
0.020
ppm
for
calculation
of
the
mean
and
standard
deviation.
2.
HAFT
=
Highest
Average
Field
Trial.

APPENDIX
TABLE
5.0.2
Summary
of
Residue
Data
from
Tomato
Field
Trials
with
Iprovalicarb
in
the
US
(
MRID
#
45899606).

Commodity
EUP
Total
Rate
(
kg
ai/
ha)
PHI
(
Days)
Residue
Levels
(
ppm)
1
n
Min.
Max.
HAFT
Mean
Std.
Dev.

Tomato
(
Fruit)
50%
WDG
1.05­
1.06
0
4
0.07
0.25
0.25
0.18
0.08
1.54­
1.56
0
6
0.22
0.5
0.47
0.35
0.11
1.05­
1.56
0
10
0.07
0.5
0.47
0.28
0.13
1.
The
LOQ
is
0.050
ppm;
the
LOD
was
not
reported.

APPENDIX
TABLE
5.0.3
Summary
of
Residue
Data
from
Tomato
Field
Trials
with
Iprovalicarb
in
Italy,
France,
and
Portugal
(
MRID
#
45899607).

Commodity
EUP
Total
Rate
(
kg
ai/
ha)
PHI
(
Days)
1
Residue
Levels
(
ppm)
2
n
Min.
Max.
HAFT
3
Mean
Std.
Dev.

Tomato
(
Fruit)
4.2%
WP
0.84
0
5
0.115
0.183
 
0.136
0.028
20
5
<
0.050
<
0.050
 
0.05
0
1.
In
Italy,
minimum
pre­
harvest
intervals
(
PHIs)
are
7
days
for
fresh
tomatoes
and
20
days
for
processing
tomatoes
.
2.
The
LOQ
is
0.050
ppm;
the
LOD
was
not
reported.
Residues
<
0.050
ppm
(
less
than
the
LOQ)
were
estimated
to
be
0.050
ppm
for
calculation
of
the
mean
and
standard
deviation.
3.
HAFT
=
Highest
Average
Field
Trial;
with
only
one
sample
collected
from
each
trial,
a
HAFT
was
not
calculated.
50
APPENDIX
TABLE
5.0.4
Summary
of
Residue
Data
from
Tomato
Field
Trials
with
Iprovalicarb
in
Italy,
France,
and
Greece
(
MRID
#
45899608).

Commodity
EUP
Total
Rate
(
kg
ai/
ha)
PHI
(
Days)
1
Residue
Levels
(
ppm)
2
n
Min.
Max.
HAFT
3
Mean
Std.
Dev.

Tomato
(
Fruit)
4.2%
WP
0.84
0
4
0.076
0.247
 
0.171
0.071
7
4
<
0.050
0.142
 
0.114
0.043
14
4
<
0.050
0.095
 
0.061
0.023
20
4
<
0.050
0.086
 
0.059
0.018
25
4
<
0.050
0.05
 
0.05
0
1.
In
Italy
and
Greece,
minimum
PHIs
are
7
days
for
fresh
tomatoes
and
20
days
for
processing
tomatoes.
2.
The
LOQ
is
0.050
ppm;
the
LOD
was
not
reported.
Residues
<
0.050
ppm
(
less
than
the
LOQ)
were
estimated
to
be
0.050
ppm
for
calculation
of
the
mean
and
standard
deviation.
3.
HAFT
=
Highest
Average
Field
Trial;
with
only
one
sample
collected
from
each
trial,
a
HAFT
was
not
calculated.

5.0
International
Considerations
INTERNATIONAL
RESIDUE
LIMIT
STATUS
Chemical
Name:
1­
methylethyl
[(
1S)­
2­
methyl­
1­[[[
1­(
4­
methylphenyl)
ethyl]
amino]
carbonyl]
propyl]
carbamate
Common
Name:
Iprovalicarb
X
Proposed
tolerance

Reevaluated
tolerance

Other
Date:
1/
04/
2005
Codex
Status
(
Maximum
Residue
Limits)
US
Tolerances
X
No
Codex
proposal
step
6
or
above

No
Codex
proposal
step
6
or
above
for
the
crops
requested
Petition
Numbers:
PP#
3E6578
DP
Barcode
D317045
Other
Identifier:
PC
Code
098359
Residue
definition
(
Step
8/
CXL):
Reviewer/
Branch:
Margarita
Collantes/
RAB2
Crop(
s)
MRL
(
mg/
kg)
Crop
Tolerance
(
ppm)

N/
A
Tomato
(
proposed)
0.5
Limits
for
Canada
Limits
for
Mexico

No
Limits
X
No
Limits
for
the
crops
requested
X
No
Limits

No
Limits
for
the
crops
requested
Residue
definition:
Iprovalicarb,
[
2­
methyl­
1­[[[(
1S)­(
4­
methylphenyl)
ethyl]
amino]
carbonyl]
propyl]
carbamic
acid
methylethylester.
Residue
definition:

Crop
MRL
(
mg/
kg)
Crop(
s)
MRL
(
mg/
kg)

Grape
2
NOTE:
Per
Steven
Funk,
1/
4/
2005.
The
2.0
ppm
MRL
for
grapes
in
Canada
was
established
on
9/
25/
2004.
51
6.0
Environmental
Degradation
Since
iprovalicarb
is
proposed
for
use
only
on
imported
tomato
commodities,
with
neither
existing
nor
proposed
US
registration,
there
is
no
expectation
that
iprovalicarb
residues
would
occur
in
surface
or
ground
water.
