Document ID: EPA-HQ-OPP-2006-0283-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-12T04:00Z

EPA
Registration
Division
contact:
Barbara
Madden
Interregional
Research
Project
No.
4
(
IR­
4)

PP#
2E6478
EPA
has
received
a
pesticide
petition
(
2E6478)
from
Interregional
Research
Project
No.
4
(
IR­
4),
Rutgers,
The
State
University
of
NJ,
681
US
Highway
1
South,
North
Brunswick,
NJ
08902
proposing,
pursuant
to
section
408(
d)
of
the
Federal
Food,
Drug,
and
Cosmetic
Act
(
FFDCA),
21
U.
S.
C.
346a(
d),
to
amend
40
CFR
part
180.371
by
establishing
a
tolerance
for
residues
of
thiophanate­
methyl
and
its
metabolite
MBC
in
or
on
the
raw
agricultural
commodities
corn,
sweet,
kernel
plus
cob
with
husk
removed;
corn,
sweet,
forage;
and
corn,
sweet,
stover
at
0.05
parts
per
million
(
ppm).
EPA
has
determined
that
the
petition
contains
data
or
information
regarding
the
elements
set
forth
in
section
408(
d)(
2)
of
the
FFDCA;
however,
EPA
has
not
fully
evaluated
the
sufficiency
of
the
submitted
data
at
this
time
or
whether
the
data
supports
granting
of
the
petition.
Additional
data
may
be
needed
before
EPA
rules
on
the
petition.

A.
Residue
Chemistry
1.
Plant
metabolism.
The
qualitative
nature
of
the
metabolism
of
thiophanate­
methyl
(
TM)
in
plants
is
adequately
understood
for
the
purposes
of
these
tolerances.
The
residues
of
concern
are
combined
residues
of
thiophanate­
methyl
and
its
primary
metabolite
methyl
2­
benzimidazolyl
carbamate
(
MBC).

2.
Analytical
method.
High
pressure
liquid
chromatography
/
ultraviolet
(
HPLC/
UV)
method
is
used
for
residue
analysis.

3.
Magnitude
of
residues.
Sweet
corn
was
treated
at
0.125
lbs.
of
active
ingredient
per
100
lbs.
of
seed
and
planted
at
nine
locations,
one
each
in
Region
2,
Region
10,
and
Region
11,
two
in
Region
3,
and
four
in
Region
5.
Sweet
corn
ears,
forage
and
stover
were
harvested.
Residues
found
in
sweet
corn
samples
were
all
less
than
the
lowest
level
of
method
validation
which
was
0.05
ppm.
The
proposed
tolerances
for
corn,
sweet,
kernel
plus
cob
with
husk
removed;
corn,
sweet,
forage;
and
corn,
sweet,
stover
are
all
0.05
parts
per
million.

B.
Toxicological
Profile
1.
Acute
toxicity.
Toxicity
is
summarized
in
the
EPA
"
Reregistration
Eligibility
Decision
for
Thiophanate­
methyl"
originally
approved
March
28,
2003.
Both
TM
and
MBC
have
low
acute,
oral,
dermal
and
inhalation
toxicity.
TM
is
a
skin
sensitizer,
MBC
is
not.
Eye
and
skin
irritation
are
minimal
to
slight
for
both
compounds.

2.
Genotoxicty.
TM
was
negative
in
in­
vitro
CHO
cytogenic
and
rat
liver
unscheduled
DNA
synthesis
assays.
TM
caused
abnormal
chromosome
numbers
in
mouse
bone
marrow
micronucleus
and
BALB/
c
3T3
cell
transformation
assays.
TM
was
weakly
positive
in
an
Ames
test
and
negative
in
a
bacterial
reverse
gene
mutation
assay.

3.
Reproductive
and
developmental
toxicity.
Fetuses
of
rabbits
exposed
to
40
mg/
kg/
day
TM
showed
developmental
toxicity
including
increased
number
of
ribs
and
decreased
fetal
weight.
The
dose
also
caused
maternal
toxicity
based
on
decreased
body
weight
gain
and
decreased
food
consumption.

4.
Subchronic
toxicity.
Liver
and
thyroid
are
primary
target
organs
of
TM
and
MBC
in
several
species
from
subchronic
dietary
exposure.
TM
also
appeared
to
cause
mild
anemia
at
higher
dose
levels
in
rats,
dogs
and
mice
following
subchronic
exposure.

5.
Chronic
toxicity.
Liver
and
thyroid
are
primary
target
organs
of
TM
and
MBC
in
several
species
from
chronic
dietary
exposure.
Testicular
effects
were
noted
in
rat
studies.
Testes
is
a
known
target
organ
of
MBC.
TM
also
appeared
to
cause
mild
anemia
at
higher
dose
levels
in
rats,
dogs
and
mice
from
chronic
exposure.

TM
is
classified
as
"
likely
to
be
carcinogenic
to
humans".
TM
has
a
Q1*
of
1.16
x
10­
2
(
mg/
kg/
day)­
1
based
on
liver
tumors
in
male
and
female
mice.
MBC
is
classified
in
Group
C
(
possible
human
carcinogen).
MBC
has
a
Q1*
of
2.39
x
10­
3
(
mg/
kg/
day)­
1
based
on
hepatocellular
tumors
in
female
mice.

6.
Animal
metabolism.
Metabolism
in
animals
is
understood
based
on
ruminant
and
poultry
metabolism
studies.
Metabolites
in
animal
commodities
include
TM,
MBC
and
hydroxylated
derivatives
of
MBC
(
4­
OH­
MBC,
5­
OH­
MBC,
and
5­
OH­
MBC­
S).

7.
Metabolite
toxicology.
MBC
is
a
possible
human
carcinogen.

8.
Endocrine
disruption.
The
toxicology
database
for
TM
is
incomplete
until
subchronic
neurotoxicity
is
conducted.
Studies
in
the
database
include
evaluation
of
the
potential
effects
on
reproduction
and
development
and
evaluation
of
the
pathology
of
endocrine
organs
following
short
and
long­
term
exposure.
No
primary
endocrine
effects
were
noted.

C.
Aggregate
Exposure
1.
Dietary
exposure.
Thiophanate­
methyl
is
a
systemic
fungicide
used
on
trees,
vine
and
root
crops,
canola,
wheat,
and
as
a
seed
treatment
for
peanuts
and
a
seed­
piece
treatment
for
potato.

i.
Food.
The
acute
FQPA
SF
of
0.06
mg/
kg/
day
was
used
for
sub­
population
females
aged
10
to
50.
The
acute
FQPA
SF
of
0.13
mg/
kg/
day
was
used
for
the
general
population.
The
chronic
FQPA
SF
of
0.027
mg/
kg/
day
was
used
for
the
general
population.

The
EPA
dietary
risk
analysis
reported
in
"
Reregistration
Eligibility
Decision
for
Thiophanate­
methyl"
approved
March
28,
2003,
shows
the
acute
dietary
risk
estimates
are
less
than
the
EPA's
level
of
concern
at
99.9th
percentile
of
exposure
for
all
population
subgroups
for
TM
and
MBC.
The
highest
exposed
population
subgroup
is
infants
(<
1
year)
with
dietary
risk
estimates
of
22%
for
TM
and
89%
for
MBC
of
the
acute
PAD
at
99.9th
percentile
exposure.
The
chronic
non­
cancer
dietary
risks
are
2%
chronic
PAD
for
TM
and
26%
for
MBC
for
the
highest
exposed
population
subgroup,
children
(
1
to
6
years).
The
lifetime
cancer
risk
estimates
are
6.4
x
10­
7
to
1.1
x
10­
6
for
TM
and
7.7
x
10­
8
to
9.3
x
10­
8
for
MBC,
depending
on
the
uses.
The
acute
and
chronic
dietary
risk
contribution
is
shown
in
Table
1
for
TM
and
Table
2
for
MBC.

Table
1.
Dietary
Assessment
for
thiophanate­
methyl
Population
Group/
Subgroup
Acute
99.9th
Percentile
Chronic
%
aPAD
Exposure
(
mg/
kg
bodywt
day)
%
cPAD
Exposure
(
mg/
kg
bodywt
day)
Q*

US
Population
­
Total
0.16
0.000213
0.0
0.000005
5.41
x
10­
8
All
Infants
0.14
0.000187
0.0
0.000003
­

Nursing
Infants
(<
1
yr)
0.14
0.000187
0.0
0.000002
­

Non­
nursing
Infants
(<
1
yr)
0.14
0.000187
0.0
0.000003
­

Males
(
12­
19
yrs)
0.11
0.000138
0.0
0.000004
­

Males
(+
20
yrs)
0.09
0.000114
0.0
0.000004
­

Seniors
(+
55
yrs)
0.09
0.000118
0.0
0.000003
­

Children
(
1­
2
yrs)
0.35
0.000451
0.0
0.000013
­

Children
(
3­
5
yrs)
0.30
0.000384
0.0
0.000012
­

Children
(
6­
12
yrs)
0.19
0.000251
0.0
0.000008
­

Females
(
13­
50
yrs)
0.19
0.000128
0.0
0.000004
­

Table
2.
Dietary
Assessment
for
MBC
metabolite
Population
Group/
Subgroup
Acute
99.9th
Percentile
Chronic
%
aPAD
Exposure
(
mg/
kg
bodywt
day)
%
cPAD
Exposure
(
mg/
kg
bodywt
day)
Q*

US
Population
­
Total
0.13
0.000213
0.0
0.000005
1.11
x
10­
8
All
Infants
1.1
0.000187
0.1
0.000003
­
Nursing
Infants
(<
1
yr)
1.1
0.000187
0.1
0.000002
­

Non­
nursing
Infants
(<
1
yr)
1.1
0.000187
0.1
0.000003
­

Males
(
12­
19
yrs)
­
­
0.0
0.000004
­

Males
(+
20
yrs)
­
­
0.0
0.000004
­

Seniors
(+
55
yrs)
­
­
0.0
0.000003
­

Children
(
1­
2
yrs)
2.66
0.000451
0.5
0.000013
­

Children
(
3­
5
yrs)
2.26
0.000384
0.5
0.000012
­

Children
(
6­
12
yrs)
1.48
0.000251
0.3
0.000008
­

Females
(
13­
50
yrs)
1.28
0.000128
0.1
0.000004
­

The
dietary
exposure
from
sweet
corn
will
not
exceed
the
PAD
for
any
sub­
population,
including
infants
and
children.

ii.
Drinking
water.
There
are
no
drinking
water
monitoring
data
on
TM
or
MBC.
The
estimated
environmental
concentrations
(
EEC)
from
use
on
sweet
corn
are
acute
TM
8.2
ppb,
acute
MBC
23.5
ppb,
chronic
TM
and
MBC
9.72
ppb,
and
cancer
TM
and
MBC
6.39
ppb.
The
EPA
used
modeling
to
estimate
acute
DWLOC
of
18
ppb
and
chronic
(
cancer)
DWLOC
of
2.1
ppb.
The
screening
level
model
assumes
maximum
application
rates
used
every
year
for
70
years,
which
is
a
worst
case
assumption.

2.
Non­
dietary
exposure.
TM
can
be
applied
in
residential
areas
to
lawns,
ornamentals
and
backyard
orchards
by
homeowners
and
commercially.
Post
application
exposure
can
occur
in
parks,
recreational
areas
and
golf
courses.
MBC
is
used
as
a
fungicide/
preservative
in
paints,
coatings,
plaster
and
adhesives.
MOEs
are
greater
than
100
and
cancer
risks
are
less
than
1
x
10­
6
(
mg/
kg/
day)­
1
based
on
EPA
Phase
3
risk
assessments.

D.
Cumulative
Effects
TM
is
structurally
related
to
other
benzimidazole
compounds
that
are
potential
carcinogens,
including
albendazole,
fenbendazole,
mebendazole,
oxfendazole
and
thiabendazole.
The
EPA
has
not
determined
whether
TM
shares
a
common
mechanism
of
toxicity
with
these
pesticides
to
determine
if
a
cumulative
assessment
is
necessary.

E.
Safety
Determination
1.
U.
S.
population.
Using
the
conservative
exposure
estimates
described
above
and
based
on
the
completeness
and
reliability
of
the
toxicity
data,
it
can
be
concluded
that
the
addition
of
sweet
corn
to
the
dietary
exposure
will
increase
the
acute
PAD
by
0.16%
for
the
U.
S.
population.
The
total
exposure
will
be
below
the
100%
acute
PAD
for
TM.
The
acute
PAD
from
sweet
corn
attributable
to
MBC
for
the
U.
S.
population
is
0.13%.
The
total
exposure
will
be
below
the
100%
acute
PAD
for
MBC.

The
TM
and
MBC
chronic
PADs
for
the
U.
S.
population
will
increase
less
than
0.0%.
The
TM
cancer
risk
from
sweet
corn
will
increase
5.41
x
10­
8
(
mg/
kg/
day)­
1
and
for
MBC
1.1
x
10­
8
(
mg/
kg/
day)­
1.
The
total
cancer
risk
will
be
less
than
1
x
10­
6
allowed
by
EPA.
The
DWLOC
contribution
from
sweet
corn
will
slightly
increase
the
total
DWLOC.
It
can
be
concluded
that
there
is
a
reasonable
certainty
that
no
harm
will
result
from
additional
exposure
for
the
U.
S.
general
population.
The
aggregate
MOEs
for
exposure
to
TM
and
MBC
will
not
be
increased
for
residentialtype
exposures.

2.
Infants
and
children.
The
acute
PAD
and
chronic
PAD
for
exposures
to
infants
and
children
contain
FQPA
safety
factors
of
10.
Using
the
conservative
exposure
estimates
and
based
on
completeness
and
reliability
of
the
toxicity
data,
it
can
be
concluded
that
the
addition
of
sweet
corn
to
the
dietary
exposure
will
increase
the
TM
acute
PAD
by
0.14%
for
infants
and
0.35%
for
the
highest
exposed
group,
children
(
1­
2
years).
The
MBC
acute
PAD
for
infants
is
1.1%
and
2.66%
for
the
highest
exposed
group,
children
(
1­
2
years).
The
total
exposure
will
be
below
100%
acute
PAD
for
both
TM
and
MBC.
The
TM
chronic
PAD
for
infants
from
sweet
corn
is
less
than
0.0%
and
for
MBC
the
chronic
PAD
is
0.1%.
The
TM
chronic
PAD
for
children
(
1­
2
years)
is
less
than
0.0%.
The
MBC
chronic
PAD
for
children
(
1­
2
years)
is
0.5%.
The
total
exposure
will
be
below
100%
chronic
PAD
for
both
TM
and
MBC.

The
TM
plus
MBC
acute
PAD
for
females
(
13­
50
years),
to
account
for
the
total
acute
dietary
risk
estimate
for
developmental
effects
is
0.19
+
1.28
=
1.47%
acute
PAD.
The
total
exposure
will
be
below
100%
acute
PAD.
The
TM
plus
MBC
chronic
PAD
for
female
(
13­
50
years),
is
0.0
+
0.1
=
0.1%.
The
total
exposure
will
be
below
100%
chronic
PAD.
It
can
be
concluded
that
there
is
a
reasonable
certainty
that
no
harm
will
result
from
additional
exposure
to
infants
and
children.

F.
International
Tolerances
The
Codex
Alimentarius
Commission
has
established
maximum
residue
limits
(
MRLs)
for
TM
residues
in/
on
plant
and
animal
commodities.
Codex
MRLs
for
TM
are
expressed
as
MBC.
The
Codex
definition
and
the
EPA
tolerance
definition
are
thus
different
since
the
EPA
tolerance
definition
includes
both
TM
and
MBC.