Document ID: EPA-HQ-OPP-2006-0320-0010
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-26T04:00Z

Page
1
of
21
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
MEMORANDUM
DATE:
April
19,
2006
SUBJECT:
2­(
Thiocyanomethylthio)
benzothiazole
(
TCMTB)­
Report
of
the
Antimicrobials
Division
Toxicity
Endpoint
Selection
Committee
(
ADTC).

FROM:
Timothy
F.
McMahon,
Ph.
D.;
Chair,
ADTC
Michelle
Centra,
Pharmacologist;
Executive
Secretary,
ADTC
Antimicrobials
Division
(
7510C)

TO:
Deborah
Smegal,
MPH,
Toxicologist
Re­
Registration
Branch
1
Health
Effects
Division
(
7509C)

and
Kathryn
Jakob,
Chemical
Review
Manager
Ben
Chambliss,
Team
Leader
Regulatory
Management
Branch
II
Antimicrobials
Division
(
7510C)

PC
Code:
035603
On
September
22,
2005,
the
Antimicrobials
Division's
Toxicity
Endpoint
Selection
Committee
(
ADTC)
evaluated
the
toxicology
data
base
of
TCMTB,
and
established
toxicological
endpoints
for
acute
and
chronic
dietary
as
well
as
occupational
exposure
risk
assessments.
The
ADTC
also
addressed
the
potential
enhanced
sensitivity
of
infants
and
children
from
exposure
to
TCMTB
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.
The
conclusions
of
this
meeting
are
presented
in
this
report.
Page
2
of
21
Committee
Members
in
Attendance
Members
present:
Tim
McMahon,
Ph.
D.,
John
Redden,
Stephen
Dapson,
Ph.
D.,
Roger
Gardner;
Karen
Hamernik,
Ph.
D,
Melba
Morrow,
D.
V.
M.,
Sanyvette
Williams­
Foy,
D.
V.
M,
Jonathan
Chen,
Ph.
D.;
Michelle
Centra;
Najm
Shamim,
Ph.
D.,
Timothy
Leighton,
Deborah
Smegal,
MPH.

DATA
EVALUATION/
PRESENTATION:
____________________________________
Deborah
Smegal,
MPH,
Toxicologist
DRAFT
DOCUMENT
PREPARATION:
____________________________________
Timothy
F.
McMahon,
Ph.
D.,
Chair
FINAL
DOCUMENT
PREPARATION:
____________________________________________
Michelle
Centra,
Pharmacologist,
Executive
Secretary
Page
3
of
21
COMMITTEE
MEMBERS
(
Signature
indicates
concurrence
unless
otherwise
stated)

Stephen
Dapson
___________________________

Jonathan
Chen
___________________________

Roger
Gardner
___________________________

Karen
Hamernik
___________________________

Tim
McMahon
(
Chair)
___________________________

Melba
Morrow
___________________________

John
Redden
___________________________

Sanyvette
Williams­
Foy
___________________________

Tim
Leighton
___________________________

Michelle
Centra
(
Executive
Secretary)
___________________________

Najm
Shamim
___________________________

Deborah
Smegal
___________________________
Page
4
of
21
I.
INTRODUCTION
TCMTB
is
a
pesticide
chemical
with
both
agricultural
and
antimicrobial
uses.
As
an
agricultural
pesticide,
TCMTB
is
used
as
a
contact
fungicide
for
the
following
grain
crops:
barley,
oats,
rice,
sorghum,
wheat;
for
safflower
as
an
oil
crop,
for
all
types
of
corn,
field
corn,
cotton,
sorghum,
sugar
beets;
on
the
following
flowers:
gladiolus,
iris,
narcissus,
tulips.
As
antimicrobial
pesticide,
TCMTB
is
used
as
a
wood
preservative
on
the
following
woods:
pine,
white
fur;
for
wood
protection
treatment
to
existing
buildings
or
parts
of
buildings,
unseasoned
forest
products,
finished
wood
products,
wooden
containers
for
growing
plants,
forest
products
by
pressure;
in
pulp
and
paper
mill
systems,
commercial
and
industrial
water
cooling
tower
systems,
secondary
oil
recovery
injection
water,
sewage
systems;
as
a
preservative
incorporation
in
adhesive,
coatings,
leather
products
and
hides,
leather
processing
liquors,
metalworking
cutting
fluids,
oil
recovery
drill
muds
and
packer
fluids,
latex
paints,
paper
and
paper
products,
textiles,
fibers,
cordage,
wet­
end
industrial
process
chemicals,
applied
film
paints;
as
an
additive
to
fuels,
paper
and
paper
products,
textiles,
fibers,
cordage;
also
for
paper/
paperboard
surface
treatments
and
pesticide
products
for
formulation
of
other
products.

Structure:
Page
5
of
21
Physical
Chemical
Properties
The
following
characteristics
have
been
reported
for
TCMTB:

Cas
No.
21564­
17­
0
Melting
Point
<
10
o
C
Boiling
Point:
120
oC
Vapor
pressure:
4.08
x
10­
6
mm
Hg
at
25o
C
Solubility
in
Water:
125
mg/
L
at
24o
C
Log
Kow
:
2.45
Specific
Gravity
1.4
g/
cm3
Physical
State:
Viscous
liquid
II.
HAZARD
IDENTIFICATION
A1.
Acute
Reference
Dose
(
aRfD)
[
general
population
including
infants
and
children]

Study
Selected:
Rat
Developmental
Toxicity
(
MRID
00154295,
accession
number
260491)

Executive
Summary:
In
a
prenatal
developmental
toxicity
study
(
MRID
00154295,
accession
no.
260491),
TCMTB
(
83.6%
a.
i.)
was
administered
to
5
groups
of
29
mated
female
Sprague­
Dawley
rats
per
group
by
oral
gavage
using
technical
TCMTB
dissolved
in
corn
oil/
1%
Tween
80
at
doses
of
0,
25.1,
76.5,
and
125.5
mg
/
kg/
day
from
gestation
days
6
through
15.
Maternal
toxicity
was
evident
at
the
76.5
mg/
kg/
day
dose
level
as
ventral
alopecia,
rough
coat,
dyspnea/
wheezing,
oral
discharge,
nasal
discharge,
diarrhea/
loose
stool,
urine
staining,
piloerection,
and
hunched
gait.
Developmental
toxicity
was
evident
at
the
125.5
mg
/
kg/
day
dose
level
in
the
form
of
increased
fetal
and
litter
incidence
of
fused/
wavy
ribs,
rudimentary
cervical,
thoracic,
and
lumbar
ribs,
and
increased
number
of
sternebrae
and
pelvic
girdle
anomalies.

The
Maternal
NOAEL
=
25.1
mg
/
kg/
day,
based
on
observations
of
clinical
toxicity
at
76.5
mg
/
kg/
day
(
LOAEL).
The
Developmental
NOAEL
=
76.5
mg
/
kg/
day,
based
on
increased
fetal
and
litter
incidence
of
skeletal
anomalies.

This
developmental
toxicity
study
in
the
rat
is
classified
as
acceptable/
guideline
and
satisfies
the
requirement
(
OPPTS
870.3700)
for
a
developmental
toxicity
study
in
the
rodent.

Dose
Selected
for
Risk
Assessment:
Maternal
NOAEL
of
25.1
mg
/
kg/
day.

Uncertainty
factors:
10x
for
interspecies
extrapolation,
10x
for
intraspecies
variation
Page
6
of
21
Comments
about
study
selected
and/
or
uncertainty
factors:
The
effects
observed
in
offspring
in
this
study
occurred
at
doses
higher
than
those
producing
maternal
toxicity.
The
ADTC
further
considered
that
the
developmental
effects
observed
were
not
a
primary
developmental
effect.
The
maternal
endpoint
is
appropriate
for
this
risk
assessment
as
clinical
signs
are
felt
to
be
the
result
of
a
single
dose.

A2.
Acute
Reference
Dose
(
females
13­
49)

Study
Selected:
none.

An
endpoint
for
the
female
13­
49
subpopulation
was
not
identified
in
the
available
database
for
TCMTB.

This
risk
assessment
is
not
required.

B.
Chronic
Reference
Dose
(
cPAD)

Study
Selected:
Chronic
Toxicity
Study
in
the
Dog
(
MRID
41342201)

Executive
Summary:
In
a
chronic
toxicity
study
(
MRID
41342201),
technical
TCMTB
was
administered
to
male
and
female
beagle
dogs
at
dose
levels
of
0,
100ppm
(
3.8
mg/
kg/
day
in
males;
4.0
mg/
kg/
day
in
females),
300ppm
(
11.7
mg/
kg/
day
in
males;
11.2
mg/
kg/
day
in
females),
and
1000ppm
(
38.8
mg/
kg/
day
in
males;
43.2
mg/
kg/
day
in
females).
Decreased
body
weight
and
body
weight
gain
were
observed
in
male
dogs
at
the
100
ppm
dose
level
for
weeks
0­
13
of
the
study,
and
overall
body
weight
and
weight
gain
were
decreased
greater
than
10%
in
both
male
and
female
dogs
at
the
1000
ppm
dose
level.
Significant
decreases
in
circulating
white
cells
and
monocytes
were
also
observed
in
male
dogs
at
all
dose
levels
tested,
while
effects
on
hematology
in
female
dogs
were
limited.
Plasma
ALT
was
significantly
decreased
in
both
sexes
in
a
doserelated
manner
at
all
dose
levels
in
both
male
and
female
dogs
for
the
duration
of
the
study.
Decreased
weight
of
the
lung,
thymus,
and
spleen
were
observed
in
male
dogs
at
the
1000
ppm
dose
level,
while
decreased
spleen,
thymus,
and
uterine
weight
were
observed
in
female
dogs.
Involution
of
the
thymus
was
the
main
histologic
finding,
and
the
severity
of
this
lesion
appeared
to
increase
with
increasing
dose
in
both
sexes.
The
Systemic
NOAEL
<
100
ppm
(
males
and
females).
The
Systemic
LOAEL
=
100
ppm
[
3.8
mg
/
kg/
day
males;
4.0
mg
/
kg/
day]
,
based
on
decreased
body
weight
gain,
white
cells,
monocytes
and
plasma
ALT
in
males;
decreased
plasma
ALT
and
uterine
weight
in
females.
Acute
RfD
=
25.1
mg/
kg/
day
=
0.25
mg
/
kg/
day
100
Page
7
of
21
Dose
Selected
for
Risk
Assessment:
LOAEL
of
3.8
mg
/
kg/
day
Uncertainty
factors:
10x
interspecies
extrapolation,
10x
intraspecies
variation,
3x
for
lack
of
a
NOAEL.

Comments
about
study
selected
and/
or
uncertainty
factors:
The
study
chosen
by
the
ADTC
for
the
chronic
RfD
is
consistent
with
the
previous
study
selection
by
the
HED
RfD
committee
in
1994.
However,
the
ADTC
chose
a
total
uncertainty
factor
of
300
instead
of
the
factor
of
1000
chosen
by
the
RfD
Committee
in
1994.
The
difference
was
that
the
ADTC
felt
a
factor
of
3x
for
lack
of
a
NOAEL
was
sufficient
compared
to
the
10x
factor
previously
chosen.

C.
Incidental
Oral
Exposure
1.
Short­
Term
(
1­
30
days)
AND
Intermediate­
term
(
30
days­
6
months)

Study
Selected:
Developmental
toxicity
study
in
the
rabbit
(
MRID
No.:
40075101,
40075102)
(
This
summary
is
an
update
using
re­
calculated
doses
based
on
purity
information
provided
by
the
registrant).

Executive
Summary:
In
a
prenatal
developmental
toxicity
(
teratology)
study
(
MRID
40075102),
TCMTB
was
orally
dosed
to
presumed
pregnant
rabbits
(
20
rabbits/
group)
at
dose
levels
of
0,
10,
20,
and
40
mg/
kg/
day
on
gestation
days
6­
19
inclusive.
As
confirmed
by
the
registrant,
actual
doses
were
0,
8,
16,
and
32
mg
a.
i./
kg/
day
based
on
purity
of
TCMTB
(
81.0
%
a.
i).

Maternal
toxicity
was
evidenced
by
decreased
body
weight
gain
and
food
consumption
in
the
32
mg/
kg/
day
dose
group.
The
Maternal
Toxicity
NOAEL
is
16
mg/
kg/
day
and
the
Maternal
Toxicity
LOAEL
is
32
mg/
kg/
day
based
on
decreased
body
weight
gain
and
food
consumption.

No
statistically
significant
or
treatment­
related
changes
were
noted
in
any
treatment
group
for
developmental
anomalies.
The
Developmental
Toxicity
LOAEL
is
greater
than
32
mg/
kg/
day
and
the
Developmental
Toxicity
NOAEL
is
greater
than
or
equal
to
32
mg/
kg/
day.

This
study
is
classified
as
acceptable­
guideline
and
satisfies
the
guideline
requirement
(
§
870.3700)
for
a
developmental
toxicity
(
teratology)
study
in
rabbits.
Chronic
RfD
=
3.8
mg/
kg/
day
=
0.012
mg
/
kg/
day
300
Page
8
of
21
Dose
and
Endpoint
selected
for
Risk
Assessment:
Maternal
NOAEL
of
16
mg/
kg/
day.

Uncertainty
factors:
10x
for
interspecies
extrapolation,
10x
for
intraspecies
variation
Comments
about
Study/
Endpoint:
The
maternal
effect
of
minimal
body
weight
gain
decreases
during
the
dosing
period
coupled
with
increased
body
weight
gain
after
cessation
of
dosing
is
indicative
of
maternal
toxicity
at
the
16
and
32
mg
/
kg/
day
doses.
There
was
no
evidence
of
developmental
toxicity
in
this
study.

D.
Dermal
Absorption
A
dermal
absorption
study
was
submitted
by
the
registrant
as
an
unaudited
draft
report
(
MRID
42516601).
This
study
was
reviewed
by
the
Office
of
Pesticide
Programs.
The
report
was
considered
unacceptable
for
review
based
on
the
unaudited
nature
of
the
submission
and
other
errors
noted
in
the
review.
However,
the
executive
summary
of
the
unaudited
submission
is
of
interest
in
noting
that
the
dermal
absorption
of
TCMTB
appears
to
increase
with
time
of
contact
as
well
as
dose
level.
This
study
will
require
formal
review
of
a
final
report
to
verify
these
conclusions.

For
TCMTB,
a
dermal
absorption
value
is
currently
not
needed
based
on
selection
of
dermal
endpoints
from
a
route­
specific
study
(
21­
day
dermal
toxicity
study
in
rats,
MRID
41655801).

D1.
Short­,
Intermediate,
and
Long­
Term
Dermal
(
1
­
30
days;
30
days­
6months;
6
months)

Study
Selected:
21­
Day
Dermal
Toxicity
study
in
Rats
(
MRID
No.:
41655801)

Executive
Summary:
In
a
dermal
toxicity
study
(
MRID
41655801),
TCMTB
was
applied
to
the
skin
of
Sprague­
Dawley
rats
(
5/
sex/
group)
at
dose
levels
of
0,
25,
100,
or
250
mg/
kg/
day
for
21
days
(
6
hours/
day).
TCMTB
produced
significant
dermal
irritation
in
all
dose
groups
beginning
on
treatment
days
3­
4.
Dermal
irritation
was
dose­
dependent
and
progressed
to
eschar
formation
in
2
rats
(
1
male
and
1
female)
at
25
mg/
kg/
day
and
in
all
rats
at
the
100
and
250
mg/
kg/
day
dose
groups.
Blanching
occurred
in
all
rats
at
250
mg/
kg/
day
and
in
all
females
and
3/
5
males
at
100
mg/
kg/
day.
Decreased
body
weight
gain
was
noted
at
the
100
and
250
mg/
kg/
day
dose
groups
of
male
rats.
Statistically
significant
changes
in
hemoglobin,
hematocrit,
and
segmented
neutrophils
were
observed
in
male
and
female
rats
at
the
250
mg/
kg/
day
dose
level.
Increased
AST,
BUN,
and
glucose
were
observed
in
female
rats
at
250
mg/
kg/
day;
male
rats
showed
increased
BUN
and
glucose
at
250
mg/
kg/
day.
However,
the
clinical
chemistry
changes
did
not
correspond
to
any
treatment­
related
findings
in
the
liver
or
kidney.
The
Systemic
NOAEL
=
25
mg/
kg/
day,
and
the
Systemic
LOAEL
=
100
mg/
kg/
day,
based
on
decreased
body
weight
gain,
food
consumption,
and
hematological
and
clinical
chemistry
changes.

Dose
and
Endpoint
selected
for
Risk
Assessment:
Systemic
NOAEL
=
25
mg/
kg/
day
Page
9
of
21
Uncertainty
factors:
For
short­
and
intermediate­
term
risk
assessments,
the
Margin
of
Exposure
was
determined
to
be
100
(
10x
interspecies
extrapolation,
10x
intraspecies
variation).
For
long­
term
risk
assessments,
the
Margin
of
Exposure
was
determined
to
be
300
(
includes
the
two
10x
factors
just
noted,
and
an
additional
3x
factor
for
extrapolation
from
a
subchronic
study
to
a
chronic
endpoint)

Comments
about
Study/
Endpoint:
A
dermal
irritation
study
of
product
grade
TCMTB
will
not
be
requested
because
the
committee
felt
that
the
systemic
NOAEL
for
technical
grade
TCMTB
is
protective
of
dermal
irritation
(
dermal
and
systemic
effects
occurred
at
the
same
dose
level).

E.
Inhalation
Note:
where
possible,
the
ADTC
will
employ
the
Agency's
RfC
guidance
on
calculation
of
human
equivalent
concentrations
when
there
are
animal
data
available
that
the
ADTC
considers
scientifically
acceptable.
An
example
of
this
derivation
can
be
found
within
the
ADTC
report
on
chlorine
dioxide.

For
TCMTB,
there
are
no
available
inhalation
toxicity
studies
from
which
to
select
an
endpoint.
Therefore,
oral
data
were
used
with
the
understanding
that
additional
uncertainty
factors
are
applied
for
route
extrapolation.

E1
.
Inhalation­
Short­
and
Intermediate­
term
(
1­
30
days;
30
days­
6months)

Study
selected:
Developmental
Toxicity
study
in
the
Rabbit
(
MRID
No.
0075101,
40075102)

Executive
Summary:
In
a
prenatal
developmental
toxicity
(
teratology)
study
(
MRID
40075102),
TCMTB
was
orally
dosed
to
presumed
pregnant
rabbits
(
20
rabbits/
group)
at
dose
levels
of
0,
10,
20,
and
40
mg/
kg/
day
on
gestation
days
6­
19
inclusive.
As
confirmed
by
the
registrant,
actual
doses
were
0,
8,
16,
and
32
mg
a.
i./
kg/
day
based
on
purity
of
TCMTB
(
81.0
%
a.
i).

Maternal
toxicity
was
evidenced
by
decreased
body
weight
gain
and
food
consumption
in
the
32
mg/
kg/
day
dose
group.
The
Maternal
Toxicity
LOAEL
is
32
mg/
kg/
day
and
the
Maternal
Toxicity
NOAEL
is
16
mg/
kg/
day
based
on
decreased
body
weight
gain
and
food
consumption.

No
statistically
significant
or
treatment­
related
changes
were
noted
in
any
treatment
group
for
developmental
anomalies.
The
Developmental
Toxicity
LOAEL
is
greater
than
32
mg/
kg/
day
and
the
Developmental
Toxicity
NOAEL
is
greater
than
or
equal
to
32
mg/
kg/
day.

This
study
is
classified
as
acceptable­
guideline
and
satisfies
the
requirement
(
§
870.3700)
for
a
developmental
toxicity
study
in
rabbits.
Page
10
of
21
Endpoint
for
Risk
Assessment:
Maternal
NOAEL
of
16
mg/
kg/
day
Uncertainty
Factors:
10x
interspecies
extrapolation,
10x
intraspecies
variation
Comments
about
Study/
Endpoint:
The
results
of
two
90­
day
oral
toxicity
studies
in
the
rat
(
MRIDs
92179026
and
43112801)
support
the
NOAEL
value
chosen
from
the
rabbit
developmental
toxicity
study
(
NOAELs
of
25
and
10
mg/
kg/
day
respectively).

E2:
Inhalation:
long­
term
(>
6
months)

Study
Selected:
Chronic
Toxicity
study
in
Dogs
(
MRID
No.:
41342201)

Executive
Summary:
In
a
chronic
toxicity
study
(
MRID
41342201),
technical
TCMTB
was
administered
to
male
and
female
beagle
dogs
at
dose
levels
of
0,
100ppm
(
3.8
mg/
kg/
day
in
males;
4.0
mg/
kg/
day
in
females),
300ppm
(
11.7
mg/
kg/
day
in
males;
11.2
mg/
kg/
day
in
females),
and
1000ppm
(
38.8
mg/
kg/
day
in
males;
43.2
mg/
kg/
day
in
females).
Decreased
body
weight
and
body
weight
gain
were
observed
in
male
dogs
at
the
100
ppm
dose
level
for
weeks
0­
13
of
the
study,
and
overall
body
weight
and
weight
gain
were
decreased
greater
than
10%
in
both
male
and
female
dogs
at
the
1000
ppm
dose
level.
Significant
decreases
in
circulating
white
cells
and
monocytes
were
also
observed
in
male
dogs
at
all
dose
levels
tested,
while
effects
on
hematology
in
female
dogs
were
limited.
Plasma
ALT
was
significantly
decreased
in
both
sexes
in
a
dose­
related
manner
at
all
dose
levels
in
both
male
and
female
dogs
for
the
duration
of
the
study.
Decreased
weight
of
the
lung,
thymus,
and
spleen
were
observed
in
male
dogs
at
the
1000
ppm
dose
level,
while
decreased
spleen,
thymus,
and
uterine
weight
were
observed
in
female
dogs.
Involution
of
the
thymus
was
the
main
histologic
finding,
and
the
severity
of
this
lesion
appeared
to
increase
with
increasing
dose
in
both
sexes.
The
Systemic
NOAEL
<
100
ppm
(
males
and
females).
The
Systemic
LOAEL
=
100
ppm
[
3.8
mg
/
kg/
day
males;
4.0
mg
/
kg/
day]
,
based
on
decreased
body
weight
gain,
white
cells,
monocytes
and
plasma
ALT
in
males;
decreased
plasma
ALT
and
uterine
weight
in
females.

Dose
Selected
for
Risk
Assessment:
LOAEL
of
3.8
mg
/
kg/
day
Uncertainty
factors:
10x
interspecies
extrapolation,
10x
intraspecies
variation,
3x
for
lack
of
a
NOAEL
F.
Margins
of
Exposure
for
Occupational/
Residential
Exposure
Risk
Assessments
Page
11
of
21
Route
Short­
term
(
1­
30
days)
Intermediate­
term
(
30
days­
6
months)
Long­
term
(>
6
months)

Oral
100
100
300
Dermal
100
100
300
Inhalation
100
100
300
G.
Recommendation
for
Aggregate
Risk
Assessments
Acute
dietary
exposures
can
be
aggregated
with
short­
term
and
intermediate­
term
incidental
oral
exposures
as
well
as
short­
term
and
intermediate­
term
inhalation
exposures,
as
the
study
selected
for
these
endpoints
(
developmental
toxicity
study
in
rabbits)
was
the
same.
Dermal
and
inhalation
exposures
can
be
aggregated
since
the
effect
of
concern
is
similar
(
decreased
body
weight
gain).
The
total
MOE
approach
should
be
used
since
the
target
MOEs
are
both
100
for
short­
and
intermediate
term
durations,
and
300
for
long
term
durations.

Chronic
dietary
exposure
can
be
aggregated
with
long­
term
inhalation
exposure
as
the
study
selected
for
these
endpoints
(
chronic
toxicity
study
in
the
dog)
is
the
same.
Dermal
exposures
can
also
be
aggregated
because
the
toxicological
effect
of
concern
is
similar
(
decreased
body
weight
gain).
The
total
MOE
approach
should
be
used
since
the
target
MOEs
is
300
for
long
term
oral,
dermal
and
inhalation
exposures.

III.
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
1.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
(
MRID
No.
2116301)

Executive
Summary:
TCMTB
was
administered
to
Sprague
Dawley
rats
of
both
sexes
(
50/
sex/
dose,
main
group;
and
20/
sex/
dose,
interim
kill
group)
for
a
period
of
up
to
104
weeks
in
the
diet
at
dose
levels
of
0,
2,
8,
or
20
mg/
kg/
day.
Mortality
was
variable
with
survival
rates
of
80­
100%
in
the
interim
kill
group
and
38 
82%
in
the
carcinogenicity
group.
No
treatment­
related
clinical
signs
of
toxicity
were
noted
during
the
study.
No
dose­
related
or
significant
effects
were
noted
in
the
interim
kill
group.
The
only
significant
reduction
in
body
weight
gains
occurred
in
the
20
mg/
kg/
day
males
at
week
80,
and
these
do
not
appear
to
be
treatment­
related.
No
dose­
related
or
significant
effects
were
noted
in
the
food
consumption
of
either
the
interim
kill
group
or
the
carcinogenicity
group.

A
dose­
related
decrease
in
platelets
was
noted
in
all
treated
females
at
week
104.
All
other
changes
in
hematology
parameters
were
not
considered
to
be
toxicologically
significant.
No
changes
in
the
clinical
chemistry
parameters
were
considered
to
be
biologically
significant
due
to
the
lack
of
a
dose 
response
relationship.
No
treatment­
related
changes
were
noted
in
the
organ
weights
of
the
Page
12
of
21
interim
kill
group,
but
an
increasing
trend
was
noted
in
the
female
absolute
liver
weights
in
all
treatment
groups.
Since
a
dose­
response
relationship
was
not
present,
it
was
not
considered
to
be
biologically
significant,
Terminal
organ
weights
were
not
reported.

Only
one
finding
displayed
a
dose­
response
relationship
in
the
microscopic
pathology,
interstitial
cell
tumors
in
the
testes.
The
tumor
incidences
were
control
group
4/
50,
low
dose
5/
50,
mid
dose
13/
50
and
the
high
dose
with
14/
50.
The
mid
and
high
doses
were
significantly
different
(
p<
0.05)
from
the
controls.
Additionally,
the
incidence
of
thyroid
C­
cell
adenomas
was
increased
in
female
rats
of
the
high
dose
group,
as
compared
to
controls.
The
incidence
of
this
lesion
was
6/
49,
4/
49,
7/
48
and
13/
50
for
the
control,
low,
mid
and
high
dose
groups,
respectively.
Thus,
TCMTB
appears
to
be
carcinogenic
inducing
the
formation
of
interstitial
cell
tumors
in
the
testes
and
thyroid
C­
cell
adenomas
in
female
rats.

Although
the
current
study
did
not
appear
to
test
to
high
enough
doses
to
produce
systemic
toxicity,
on
the
basis
of
results
from
other
toxicity
studies
(
noted
below)
as
cited
in
the
Cancer
Peer
Review
document,
this
study
is
classified
as
acceptable­
guideline
and
satisfies
the
OPPTS
870.4300
test
guideline.

Discussion
of
Tumor
Data
Two
findings
displayed
dose­
response
relationships
in
the
microscopic
pathology,
interstitial
cell
tumors
in
the
testes
and
thyroid
C­
cell
adenomas
in
female
rats.
Male
rats
had
a
significant
dose­
related
increasing
trend,
as
well
as
significant
differences
in
the
pair­
wise
comparisons
of
the
8
and
20
mg/
kg/
day
dose
groups
with
the
controls,
for
testicular
interstitial
cell
tumors.

Female
rats
had
significant
dose­
related
increasing
trends,
and
significant
differences
in
the
pair­
wise
comparisons
of
the
20
mg/
kg/
day
dose
group
with
the
controls
for
thyroid
C­
cell
adenomas
and
adenomas
and/
or
carcinomas
combined;
however,
only
adenomas
were
present
in
treated
groups
(
the
control
group
had
the
single
carcinoma
noted).
Although
there
were
no
significant
differences
in
the
pair­
wise
comparisons
of
the
dosed
groups
with
the
controls,
female
rats
did
have
a
significant
increasing
trend
in
thyroid
C­
cell
hyperplasia
at
p
<
0.01.

Adequacy
of
the
Dose
Levels
Tested
The
statistical
evaluation
of
mortality
indicated
no
significant
incremental
changes
with
increasing
doses
of
TCMTB
in
male
rats.
Female
rats
showed
a
significant
decreasing
trend
in
mortality
with
increasing
doses
of
TCMTB.

No
treatment­
related
clinical
signs
of
toxicity
were
noted
during
the
study.
The
only
significant
reduction
in
body
weight
gains
occurred
in
the
20
mg/
kg/
day
males
at
week
80,
and
this
did
not
appear
to
be
treatment­
related.
No
dose­
related
or
significant
effects
were
noted
in
the
food
consumption.

A
dose­
related
decrease
in
platelets
was
noted
in
all
treated
females
at
week
104.
All
other
changes
Page
13
of
21
in
hematology
parameters
were
not
considered
to
be
toxicologically
significant.
No
changes
in
the
clinical
chemistry
parameters
were
considered
to
be
biologically
significant.
An
increasing
trend
was
noted
in
the
female
absolute
liver
weights
in
all
treatment
groups;
however,
since
a
dose
response
relationship
was
not
present
it
was
not
considered
to
be
biologically
significant.

The
systemic
toxicity
observed
in
this
study
in
male
and
female
rats
was
minimal
and
there
were
no
major
differences
between
the
treated
and
control
groups.
However,
data
obtained
from
two
subchronic
feeding
studies
in
rats
(
the
13
week
range
finding
study,
MRID#
43112801
and
the
90
day
study
in
rats,
MRID#
92179026)
indicate
that
toxic
effects
(
decreased
body
weight
gain
and
increased
incidence
of
squamous
epithelial
hyperplasia
of
the
stomach)
were
observed
at
the
dose
level
of
30
mg/
kg/
day
(
a
dose
slightly
higher
than
the
HDT
in
this
study).
The
Systemic
LOEL
is
greater
than
20
mg/
kg/
day
and
the
NOEL
is
equal
to
or
greater
than
20
mg/
kg/
day.
The
study
is
considered
in
combination
with
the
13
week
range
finding
study
(
MRID#
43112801)
and
the
90
day
study
in
rats
(
MRID#
92179026).
Based
on
this
information,
the
dose
levels
used
in
the
chronic/
carcinogenicity
study
in
rats
(
MRID#'
s
42116301,
41529701,
and
41570301)
were
adequate
for
testing
for
the
carcinogenic
potential
of
TCMTB.

2.
Carcinogenicity
Study
in
Mice
(
MRID
No.:
42383001)

Executive
Summary:
Groups
of
CD­
1
mice
(
50/
sex)
were
dosed
with
TCMTB
at
dietary
concentrations
calculated
to
give
dose
levels
of
0,
15,
50,
or
150
mg/
kg/
day
for
2
years.
Body
weights
were
significantly
reduced
in
high­
dose
males
and
high
dose
females
compared
to
controls.
Weight
gain
in
high
dose
males
and
females
were
approximately
25%
lower
than
controls
at
78
weeks.
Cumulative
weight
gain
was
reduced
36%
and
28%
for
males
and
females
at
week
104
respectively.
There
was
no
effect
on
food
consumption
in
this
study.
An
increase
in
focal
and
diffuse
hyperplasia
of
the
duodenal
mucosa
was
seen
microscopically
in
males
receiving
150
mg/
kg/
day:
the
incidence
was
10/
42
compared
to
1/
41
in
controls
(
p<
0.01).
A
nonsignificant
increase
was
seen
for
mucosal
hyperplasia
of
the
duodenum
in
high­
dose
females
(
8/
45
compared
to
4/
46
in
controls).
No
other
pathologic
findings
were
considered
treatment
related.
The
Systemic
NOAEL
is
determined
to
be
50
mg/
kg/
day,
and
the
Systemic
LOAEL
is
determined
to
be
150
mg/
kg/
day,
based
on
histologic
changes
in
the
duodenum
of
high
dose
males
and
decreased
weight
gain
in
both
sexes
at
the
high
dose.

Discussion
of
Tumor
Data
There
were
no
compound­
related
tumors
observed
in
male
or
female
mice.
All
tissues
were
examined.

Adequacy
of
the
Dose
Levels
Tested
The
statistical
evaluation
of
mortality
indicated
no
significant
incremental
changes
with
increasing
doses
of
TCMTB
in
male
mice.
Female
mice
showed
a
significant
decreasing
trend
in
mortality
with
increasing
doses
of
TCMTB.

Body
weights
were
significantly
reduced
in
high­
dose
males
and
high­
dose
females
as
compared
to
controls.
Weight
gains
in
high­
dose
groups
were
about
88%
of
control
in
males
and
97%
of
control
in
females
at
13
weeks;
however
at
80
weeks
the
weight
gains
were
67%
of
control
in
the
males
and
Page
14
of
21
78%
of
control
in
the
females
and
cumulative
mean
gains
for
the
entire
treatment
period
(
weeks
0­
104)
were
64%
and
72%
of
the
controls
for
the
high­
dose
males
and
females,
respectively.
No
marked
effects
on
food
consumption
were
observed.
None
of
the
gross
findings
were
remarkable.
Based
on
the
histologic
changes
in
the
duodenum
in
high­
dose
males
and
the
decreased
weight
gain
in
both
sexes
at
the
high­
dose,
the
systemic
toxicity
LOEL
is
considered
to
be
150
mg/
kg/
day
and
the
systemic
toxicity
NOEL
is
50
mg/
kg/
day.

The
high
dose
tested
(
150
mg/
kg/
day)
is
considered
to
be
an
adequate
dose
for
assessing
the
carcinogenic
potential
of
TCMTB
in
male
and
female
CD­
1
mice.

3.
Classification
of
Carcinogenic
Potential
The
Health
Effects
Division
Carcinogenicity
Peer
Review
Committee
(
CPRC)
met
on
June
28,
1995
to
discuss
and
evaluate
the
weight­
of­
the­
evidence
on
2­(
Thiocyanomethylthio)
benzothiazole
(
TCMTB)
with
particular
reference
to
its
carcinogenic
potential.
The
CPRC
concluded
that
TCMTB
should
be
classified
as
Group
C
­
possible
human
carcinogen
­
and
recommended
that
for
the
purpose
of
risk
characterization,
the
Reference
Dose
(
RfD)
approach
should
be
used
for
quantitation
of
human
risk.
This
was
based
on
statistically
significant
increases
in
tumors
in
both
sexes
of
the
Sprague­
Dawley
rat:
testicular
interstitial
cell
adenomas
in
males
and
thyroid
c­
cell
adenomas
in
females.

IV.
MUTAGENICITY
Study
Type:
Mutagenicity
Test
on
TCMTB
in
the
Salmonella/
Mammalian­
Microsome
Reverse
Mutation
(
Ames
Test)
with
Confirmatory
Assay
I
n
an
Ames
assay
(
MRID#
41386101)
TCMTB
was
negative
for
inducing
reverse
gene
mutations
in
Salmonella
typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98,
or
TA100
exposed
in
the
presence
or
absence
of
S9
activation
up
to
cytotoxic
doses
($
33.3
Fg/
plate
­
S9;
$
66.7
Fg/
plate
+
S9).
The
results
were
confirmed
in
an
independently
performed
trial.

Study
Type:
Evaluation
for
Structural
Chromosomal
Aberration
of
TCMTB
(
EPA
Reg.
No.
1448­
29):
Clastogenic
Evaluation
in
the
In
Vivo
Mouse
Micronucleus
Assay
In
a
structural
chromosomal
aberration
assay
(
MRID#
00165520),
the
high
dose
of
TCMTB
(
500
mg/
kg)
exhibited
mortality
and
signs
of
clinical
toxicity.
No
evidence
of
an
increase
in
micronucleated
polychromatic
erythrocytes
was
noted
at
the
dose
levels
tested
in
this
study
(
50,
167
and
500
mg/
kg).
There
was
evidence
of
some
PCE
depression
at
the
high
dose
in
the
48
and
72
hour
animals.

Study
Type:
Evaluation
of
Other
Genotoxic
Effects
of
TCMTB
(
EPA
Reg.
No.:
1448­
290:
In
the
Rat
Primary
Hepatocyte
Unscheduled
DNA
Synthesis
Assay
In
an
UDS
assay
(
MRID#
00165518),
TCMTB
did
not
cause
a
significant
increase
in
the
Page
15
of
21
unscheduled
DNA
synthesis
(
UDS)
in
rat
primary
hepatocytes
as
measured
in
this
study.

V.
FQPA
CONSIDERATIONS
1.
Neurotoxicity
There
are
no
studies
that
specifically
examined
neurotoxicity
of
TCMTB
in
the
available
database.
From
examination
of
the
available
data,
however,
the
ADTC
concluded
that
there
was
no
evidence
of
neurotoxicity
of
TCMTB
and
that
neurotoxicity
studies
would
not
be
required.

2.
Developmental
Toxicity
Developmental
toxicity
studies
were
available
in
both
the
rat
and
rabbit
for
TCMTB.
The
results
of
both
of
these
studies
(
noted
in
this
document
under
the
endpoint
selection
section)
show
no
evidence
of
primary
developmental
toxicity
of
TCMTB.
This
conclusion
is
consistent
with
the
previous
conclusion
of
the
Health
Effects
Division's
RfD
Peer
Review
committee
(
September
29,
1994;
document
#
011302)

3.
Reproductive
Toxicity
Executive
Summary:
(
note:
this
summary
is
an
update
of
the
original,
based
on
discussions
by
the
ADTC;
the
parental
NOAEL
and
LOAEL
values
are
changed)

In
a
2­
generation
reproduction
toxicity
study
(
MRID
41471401),
TCMTB
was
administered
to
Sprague
Dawley
CD
outbred
albino
rats
from
Charles
River
UK
Ltd.
in
the
diet
at
dose
levels
of
0,
25,
100,
or
400
ppm
(
2.4,
9.6,
and
38.4
mg/
kg/
day
for
males
and
3.0,
11.7,
and
45.5
mg/
kg/
day
for
females
for
the
25,
100,
and
400
ppm
groups,
respectively)
for
2
generations
with
1
litter
in
the
first
generation
and
2
litters
in
the
second
generation.
No
treatment
related
effects
were
noted
on
reproductive
parameters
examined
in
this
study.
Slight,
statistically
significant
effects
were
noted
in
mean
body
weight
in
the
high
dose
offspring
around
lactation
day
24.
This
must
be
considered
as
systemic
toxicity
as
the
litters
began
with
relatively
equal
mean
body
weights
and
around
lactation
day
14,
the
pups
began
to
consume
diet
while
continuing
to
nurse.
The
parental/
systemic
NOAEL
=
400
ppm
(
38.4/
45.5
mg
/
kg/
day
[
males/
females])
and
the
parental/
systemic
LOAEL
>
400
ppm
(>
38.4/
45.5
mg
/
kg/
day
[
males/
females]).
The
Reproductive
toxicity
NOAEL
>
400ppm
and
the
Reproductive
toxicity
LOAEL
>
400
ppm.

Consistent
with
both
the
RfD
Peer
Review's
conclusion
and
that
of
the
California
Environmental
Protection
Agency's
summary
of
TCMTB
(
February
22,
2001),
there
was
no
evidence
of
reproductive
toxicity
of
TCMTB.

4.
Recommendation
for
Developmental
Neurotoxicity
Study
A
developmental
neurotoxicity
study
for
TCMTB
is
not
required
at
this
time.
Page
16
of
21
5.
Hazard­
based
Recommendation
for
the
FQPA
safety
factor
On
the
basis
of
the
results
of
developmental
and
reproductive
toxicity
testing
as
well
as
consideration
of
the
conclusions
of
the
RfD
Peer
Review
committee
and
CAL
EPA's
findings,
the
ADTC
recommended
that
the
hazard­
based
FQPA
safety
factor
be
reduced
to
1x.

VI.
DATA
GAPS
/
REQUIREMENTS
A
repeated
dose
inhalation
toxicity
study
with
TCMTB
is
held
in
reserve
at
this
time,
pending
the
outcome
of
inhalation
risk
assessments
using
the
oral
toxicity
data.

VII.
OTHER
ISSUES
2­
mercaptobenzothiazole
(
2­
MBT)
is
the
main
mammalian
metabolite
of
TCMTB
(
Manninen
et
al.,
Arch.
Toxicol.
70:
579­
584,
1996).
Although
the
current
uses
of
2­
MBT
have
been
cancelled,
it
is
instructive
to
summarize
the
hazard
of
2­
MBT
relative
to
that
of
TCMTB,
as
this
will
be
the
main
metabolite
that
mammalian
organisms
are
exposed
to
when
exposed
to
TCMTB.

2­
MBT
shows
low
acute
toxicity
by
the
oral
route
(
Toxicity
Category
IV,
MRID
41571901)
and
dermal
route
(
LC50
>
2000
mg/
kg,
Toxicity
Category
III,
MRID
41571902).
2­
MBT
was
minimally
irritating
to
the
eyes
(
Toxicity
Category
III,
MRID
41571903)
and
slightly
irritating
to
the
skin
(
Toxicity
Category
IV,
MRID
41571904).
A
dermal
sensitization
study
submitted
for
the
zinc
salt
of
2­
MBT
showed
no
evidence
of
hypersensitivity
when
tested
using
the
modified
Buehler
test
method
(
MRID
41571905).

A
90­
day
oral
toxicity
study
conducted
with
2­
MBT
(
96.3%
a.
i.)
by
the
National
Toxicology
Program
at
doses
of
187.5,
375,
750,
and
1500
mg/
kg/
day
(
technical
report
no.
332)
in
rats
showed
decreased
body
weight
gain
at
1500
mg/
kg/
day
in
both
sexes
compared
to
control,
and
increased
liver
weight
at
1500
mg/
kg/
day.
A
90­
day
toxicity
study
by
the
NTP
with
2­
MBT
in
mice
at
doses
of
0,
94,
188,
375,
750,
and
1500
mg/
kg/
day
showed
mortality
at
the
high
dose
(
5/
10
males
and
7/
10
females),
clonic
seizures,
lacrimation,
and
salivation
at
750
and
1500
mg/
kg/
day,
and
lethargy
and
rough
coat
at
375
and
750
mg/
kg/
day.
There
were
no
gross
or
microscopic
pathological
effects
noted
in
mice.

In
a
13­
week
dermal
toxicity
study
with
2­
MBT
(
98.22%),
administration
of
2­
MBT
at
doses
of
0,
200,
1000,
and
2000
mg/
kg/
day
resulted
in
increased
relative
liver
weight
at
1000
and
2000
mg/
kg/
day,
the
only
effect
noted
in
this
study
(
MRID
42146301).

In
a
developmental
toxicity
study
in
rats
(
MRID
41422202),
2­
MBT
(
98.5%
a.
i.)
was
administered
to
mated
female
SD
Crl:
COBS
CD
BR
VAF
rats
(
26/
dose)
at
doses
of
0,
300,
1200,
and
1800
mg/
kg/
day
on
gestation
days
6
through
15
inclusive.
At
1200
mg/
kg/
day,
maternal
toxicity
was
observed
in
the
form
of
salivation
and
urine
staining.
There
was
no
evidence
of
developmental
toxicity
related
to
Page
17
of
21
administration
of
2­
MBT
in
this
study.
The
Maternal
NOAEL
=
300
mg/
kg/
day
and
the
Maternal
LOAEL
=
1200
mg/
kg/
day,
based
on
increased
salivation
and
urine
staining.
The
Developmental
NOAEL
>
1800
mg/
kg/
day
and
the
Developmental
LOAEL
>
1800
mg/
kg/
day.

In
a
2­
generation
reproduction
toxicity
study
(
MRID
41912501),
2­
MBT(
98.0­
98.5%
a.
i.)
was
administered
in
the
diet
to
groups
of
COBS
BR
rats
at
doses
of
0,
194,
695,
and
1195
mg/
kg/
day
[
males]
and
0,
218,
783,
and
1327
mg/
kg/
day
[
females]).
At
the
high
dose,
decreased
body
weight
and
weight
gain
were
observed
as
well
as
increased
incidence
of
microscopic
changes
in
the
kidney.
Fertility,
length
of
gestation,
and
pup
viability
were
unaffected
by
2­
MBT
treatment.
Pup
growth
(
in
the
form
of
decreased
body
weight)
was
decreased
at
the
695/
783
and
1195/
1327
mg/
kg/
day
dose
levels
by
9%
and
15%
respectively
on
day
14
and
by
13%
and
21%
on
day
21
in
the
first
generation,
and
was
decreased
significantly
(
9­
13%)
at
all
dose
levels
in
the
second
generation
on
days
14
and
21.
The
systemic/
reproductive
toxicity
NOAEL
=
194
mg/
kg/
day
and
the
systemic/
reproductive
toxicity
LOAEL
=
695
mg/
kg/
day
based
on
decreases
in
body
weight
in
parental
animals
and
in
offspring
at
this
dose.

In
carcinogenicity
studies
conducted
by
the
NTP,
there
was
some
evidence
of
carcinogenicity
for
MBT
in
male
and
female
rats.
The
evidence
included
increased
incidences
of
pituitary
adenomas/
adeno­
carcinomas
and
adrenal
gland
pheochromocytomas
in
both
female
dosed
groups
and
increased
incidences
of
adrenal
gland
pheochromocytomas/
malignant
pheochromocytomas
and
preputial
gland
adenomas/
carcinomas
in
both
male
dosed
groups
along
with
an
increased
incidence
of
mononuclear
cell
leukemia
and
pancreatic
acinar
cell
adenomas
in
the
low
dose
males.
For
both
male
dosed
groups,
however,
the
treatment
levels
appeared
to
be
excessive.

Based
on
the
available
data
from
the
NTP
report,
MBT
appears
to
be
carcinogenic
in
female
mice
based
on
increased
incidences
of
hepatocellular
adenomas
or
carcinomas
(
combined)
in
the
low
dose
females.
The
high
dose
tested
in
this
study
was
excessive
based
on
the
increased
mortality
noted
in
high
dose
females.

MBT
was
negative
in
a
salmonella
(
Ames)
assay,
a
rat
dominant
lethal
test,
a
CHO/
HGPRT
test
[
gene
mutation],
and
a
mouse
micronucleus
test
[
chromosomal
aberration].
MBT
was
positive
both
with
and
without
metabolic
activation
in
a
mouse
lymphoma
test
[
gene
mutation].
MBT­
sodium
salt
was
negative
in
a
rat
hepatocyte
unscheduled
DNA
synthesis
assay.

The
HED
RfD/
Peer
Review
committee
met
in
April
of
1994
to
establish
a
Reference
Dose
for
2­
MBT.
The
committee
recommended
that
the
RfD
be
established
on
the
basis
of
the
2­
generation
reproduction
toxicity
study
using
the
NOAEL
value
of
194
mg/
kg/
day.
Using
a
total
uncertainty
factor
of
300
(
10x
interspecies
extrapolation,
10x
intraspecies
variation,
3x
for
lack
of
a
chronic
toxicity
study
in
non­
rodents
[
per
the
RfD
peer
review
committee
memo]),
the
RfD
committee
calculated
a
Reference
Dose
for
2­
MBT
of
0.6
mg/
kg/
day.
Note
that
this
chronic
RfD
value
is
considerably
higher
than
that
for
the
parent
TCMTB,
consistent
with
the
toxicity
database
which
shows
lower
toxicity
for
2­
MBT
than
TCMTB.

The
HED
Carcinogenicity
Peer
Review
Committee
decided
that
2­
MBT
should
be
classified
as
Group­
C
possible
human
carcinogen
and
recommended
that
for
the
purpose
of
risk
characterization
the
Reference
Dose
(
RfD)
approach
should
be
used
for
quantification
of
human
risk.
This
decision
Page
18
of
21
to
use
the
RfD
approach
was
based
on
some
evidence
of
adrenal
gland
tumors
in
male
and
female
rats
and
some
evidence
of
preputial
gland
tumors
in
male
rats.
There
is
equivocal
evidence
for
pituitary
gland
tumors
in
male
rats.
The
evidence
for
hepatocellular
tumors
in
mice
was
also
equivocal.
MBT
was
also
considered
to
have
genotoxic
activity.
The
q1*
approach
to
risk
assessment
was
not
used
since
the
tumors
were
found
in
only
1
species
and
there
was
no
clear
evidence
of
carcinogenicity
from
any
of
the
tumor
types.
Page
19
of
21
Table
1.
Acute
Toxicity
of
TCMTB
Guideline
No.
Study
Type
MRID
#(
s)
Results
Toxicity
Category
81­
1
Acute
Oral
41583801
LD50
=
750
mg/
kg
III
81­
2
Acute
Dermal
41515401
LD50
>
2000
mg/
kg
III
81­
3
Acute
Inhalation
41640601
LC50
=
0.07
mg/
L
I
81­
4
Primary
Eye
Irritation
No
acceptable
studies;
all
show
corrosivity
I
81­
5
Primary
Skin
Irritation
41583701
Severe
erythema
at
72
hrs.
II
81­
6
Dermal
Sensitization
111991
Positive
Sensitizer
Page
20
of
21
Table
2.
Summary
of
Toxicity
Endpoints
Selected
for
TCMTB
Exposure
Scenario
Dose
Used
in
Risk
Assessment
(
mg/
kg/
day)
Target
MOEs/
UFs
FQPA
safety
factor
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
general
population
including
infants
and
children)
NOAEL(
maternal)
=
25.1
mg/
kg/
day
Target
MOE
=
100
UF
=
100
(
10x
interspecies
extrapolation,
10x
intra­
species
variation)

FQPA
SF
=
1x
Acute
PAD
=
0.25
mg/
kg/
day
DevelopmentalToxicity
Study
in
Rats
(
accession
no.
260491)

LOAEL(
maternal)
=
76.5
mg
/
kg/
day,
based
on
clinical
signs
of
toxicity
(
ventral
alopecia,
rough
coat,
dyspnea/
wheezing,
oral
discharge,
diarrhea/
loose
stool,
urine
staining,
piloerection,
and
hunched
gait).

Acute
Dietary
(
females
13­
49)
An
endpoint
for
females
13­
49
was
not
identified
in
the
available
database
for
TCMTB.
This
risk
assessment
is
not
required.

Chronic
Dietary
(
all
populations)
LOAEL
=
3.8
mg/
kg/
day
Target
MOE
=
300
UF
=
100
(
10x
interspecies
extrapolation,
10x
intra­
species
variation)
DB
UF
=
3
(
3x
for
use
of
a
LOAEL)

FQPA
SF
=
1x
Chronic
PAD
=
0.013
mg/
kg/
day
Chronic
Toxicity
Study
in
Dogs
(
MRID
41342201)

LOAEL
=
3.8
mg/
kg/
day
(
males),
based
on
decreased
body
weight
gain,
decreased
white
cells,
monocytes,
and
plasma
ALT
in
males;
decreased
plasma
ALT
and
uterine
weight
in
females.

Incidental
Oral
Short­
and
Intermediate­
Term
(
1­
30
days;
30
days­
6
months)
NOAEL=
16
mg/
kg/
day
Target
MOE
=
100
UF
=
100
(
10x
interspecies
extrapolation,
10x
intra­
species
variation)

FQPA
SF
=
1x
Developmental
Toxicity
Study
in
Rabbits
(
MRID
40075102)

LOAEL
=
32
mg/
kg/
day,
based
on
decreased
body
weight
gain
and
food
consumption
in
maternal
animals.

Dermal
All
Durations
(
1­
30
days;
1­
6
months;
>
6
months)
NOAEL=
25
mg/
kg/
day
Target
MOE
=
100
(
ST
and
IT)

Target
MOE
=
300
(
LT)

UF
=
100
(
10x
interspecies
extrapolation,
10x
intra­
species
variation)

DB
UF
=
3
(
3x
for
use
of
a
subchronic
endpoint)
21­
Day
Dermal
Toxicity
Study
in
Rats
(
MRID
41655801)

LOAEL
=
100
mg/
kg/
day,
based
on
decreased
body
weight
gain,
food
consumption,
and
hematological
and
clinical
chemistry
changes.
Page
21
of
21
FQPA
SF
=
1x
Inhalation
Short­
and
Intermediate­
Term
(
1­
30
days;
1­
6
months)
NOAEL
=
16
mg/
kg/
day
Target
MOE
=
100
(
ST
and
IT)
UF
=
100
(
10x
interspecies
extrapolation,
10x
intra­
species
variation)

Note:
an
additional
10x
is
necessary
for
route
extrapolation.
If
results
are
below
a
MOE
of
1,000,
a
confirmatory
inhalation
study
may
be
required
Developmental
Toxicity
Study
in
Rabbits
(
MRID
40075102)

LOAEL
=
32
mg/
kg/
day,
based
on
decreased
body
weight
gain
and
food
consumption
in
maternal
animals
Inhalation
Long­
Term
(>
6
months)
LOAEL
=
3.8
mg/
kg/
day
Target
MOE
=
300
(
LT)

UF
=
100
(
10x
interspecies
extrapolation,
10x
intra­
species
variation)

Note:
an
additional
10x
is
necessary
for
route
extrapolation.
If
results
are
below
a
MOE
of
1,000,
a
confirmatory
inhalation
study
may
be
required
Chronic
Toxicity
Study
in
Dogs
(
MRID
41342201)

LOAEL
=
3.8
mg/
kg/
day
(
males),
based
on
decreased
body
weight
gain,
decreased
white
cells,
monocytes,
and
plasma
ALT
in
males;
decreased
plasma
ALT
and
uterine
weight
in
females.

Carcinogenicity
The
CPRC
concluded
that
TCMTB
should
be
classified
as
Group
C
­
possible
human
carcinogen
­
and
recommended
that
for
the
purpose
of
risk
characterization,
the
Reference
Dose
(
RfD)
approach
should
be
used
for
quantitation
of
human
risk.
This
was
based
on
statistically
significant
increases
in
tumors
in
both
sexes
of
the
Sprague­
Dawley
rat:
testicular
interstitial
cell
adenomas
in
males
and
thyroid
c­
cell
adenomas
in
females.