1
of
26
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
TXR
No.
0054204
April
4,
2006
Memorandum
Subject:
Toxicology
Disciplinary
Chapter
for
the
Re­
Registration
Eligibility
Decision
(
RED)
Risk
Assessment
Active
Ingredient:
2­(
thiocyanomethylthio)
benzothiazole
(
TCMTB)
PC
Code
035603
DP
Barcode:
D328184
From:
Deborah
Smegal,
Toxicologist/
Risk
Assessor
Re­
Registration
Branch
1
(
RRB1)
Health
Effects
Division
(
7509C)

Through:
Whang
Phang
,
Branch
Senior
Scientist
Re­
Registration
Branch
1
(
RRB1)
Health
Effects
Division
(
7509C)

To:
Kathryn
Jakob,
Chemical
Review
Manager
Regulatory
Management
Branch
II
Antimicrobials
Division
(
7510C)
2
of
26
1.0
HAZARD
CHARACTERIZATION..................................................................................
3
2.0
REQUIREMENTS............................................................................................................
5
3.0
DATA
GAP(
S)..................................................................................................................
6
4.0
HAZARD
ASSESSMENT................................................................................................
6
4.1
Acute
Toxicity
........................................................................................................................................
6
4.2
Subchronic
Toxicity................................................................................................................................
7
4.3
Prenatal
Developmental
Toxicity.............................................................................................................
9
4.4
Reproductive
Toxicity...........................................................................................................................
10
4.5
Chronic
Toxicity...................................................................................................................................
11
4.6
Carcinogenicity.....................................................................................................................................
11
4.7
Mutagenicity.........................................................................................................................................
15
4.8
Neurotoxicity........................................................................................................................................
15
4.9
Metabolism...........................................................................................................................................
15
5.0
HAZARD
CHARACTERIZATION
FOR
2­
MERCAPTOBENZOTHIAZOLE
(
2­
MBT17
6.0
TOXICITY
ENDPOINT
SELECTION
...........................................................................
18
6.1
See
Section
9.2
for
Endpoint
Selection
Table.........................................................................................
18
6.2
Dermal
Absorption................................................................................................................................
18
6.3
Classification
of
Carcinogenic
Potential
................................................................................................
19
7.0
FQPA
CONSIDERATIONS............................................................................................
19
7.1
Special
Sensitivity
to
Infants
and
Children.............................................................................................
19
7.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
..................................................................
19
8.0
REFERENCES
...............................................................................................................
19
9.0
APPENDICES
....................................................................................................................
21
9.1
Toxicity
Profile
Summary
Tables
..........................................................................................................
22
9.2
Summary
of
Toxicological
Dose
and
Endpoints
for
2­(
Thiocyanomethylthio)
benzothiazole
(
TCMTB)
for
Use
in
Human
Risk
Assessment1
......................................................................................................................
25
3
of
26
1.0
HAZARD
CHARACTERIZATION
The
toxicology
data
base
for
TCMTB
is
considered
complete
for
a
food
use
pesticide.
No
additional
studies
are
required
at
this
time.
TCMTB
exhibits
low
acute
oral
and
dermal
toxicity
(
toxicity
category
III).
However,
it
is
highly
irritating
to
the
eyes
and
skin
(
toxicity
category
I
and
II,
respectively)
and
is
also
considered
to
be
highly
toxic
via
the
inhalation
route
of
exposure
(
toxicity
category
I).
TCMTB
is
a
dermal
sensitizer.

Following
subchronic
oral
exposures
to
rodents,
TCMTB
caused
increased
incidence
of
mild
to
severe
stomach
lesions
characterized
by
inflammation,
hyperplasia,
necrosis,
and
ulceration.
Inflammatory
cells
infiltration
and
edema
were
also
noted
at
a
low
incidence.
TCMTB
resulted
in
decreased
body
weight
gains
(
78
to
84%
of
control),
food
consumption
(
87­
95%
of
control)
and
food
efficiency.
In
a
21­
day
rat
dermal
toxicity
study,
TCMTB
produced
dose­
dependant
dermal
irritation
in
all
dose
groups
beginning
on
treatment
days
3­
4,
which
progressed
to
eschar
formation.
Rats
in
the
mid
and
high
dose
group
had
ulcers,
hemorrhages
and
chronic
dermatitis.
Decreased
body
weight
gain,
food
consumption,
and
hematological
(
changes
in
hemoglobin,
hematocrit,
and
segmented
neutrophils)
and
clinical
chemistry
changes
(
blood
urea
nitrogen,
glucose,
globulins,
and
elevated
serum
aspartate
aminotransferase
(
AST)
were
also
noted.
However,
the
clinical
chemistry
changes
did
not
correspond
to
any
treatment­
related
findings
in
the
liver
or
kidney.

Developmental
toxicity
studies
were
available
in
both
the
rat
and
rabbit
for
TCMTB.
Rabbits
appear
to
be
more
sensitive
to
the
toxicity
of
TCMTB
than
rats.
In
rabbits,
the
maternal
NOAEL
and
LOAEL
were
16
and
32
mg
ai/
kg/
day,
respectively.
In
rats,
the
maternal
NOAEL
and
LOAEL
were
21
and
64
mg
ai/
kg/
day.
No
developmental
effects
were
noted
in
the
rabbit
at
the
highest
dose
tested
(
32
mg
ai/
kg/
day).
However,
in
the
rat
adverse
developmental
effects
including
increased
fetal
and
litter
incidence
of
fused/
wavy
ribs,
rudimentary
cervical,
thoracic
and
lumbar
ribs
and
increased
incidence
of
sternebrae
and
pelvic
girdle
anomalies
were
noted
at
doses
of
105
mg
ai/
kg/
day,
which
was
maternally
toxic.

In
a
two­
generation
rat
reproduction
study,
there
were
no
treatment
related
effects
noted
at
the
highest
dose
tested
for
parental
toxicity
or
on
reproductive
parameters
examined
in
this
study.
Slight,
statistically
significant
effects
were
noted
in
mean
body
weight
in
the
high
dose
offspring
in
the
second
mating
(
F2B)
around
lactation
day
21.
This
must
be
considered
as
systemic
toxicity
as
the
litters
began
with
relatively
similar
mean
body
weights,
and
around
lactation
day
14
the
pups
began
to
consume
diet
while
continuing
to
nurse.
Mean
pup
weight
was
not
significantly
reduced
at
days
7
or
14
in
the
F2B
pups,
and
there
were
no
consistent
effects
on
pup
weight
in
the
F0
and
F1a
generation
pups.
Thus,
the
Agency
believes
this
finding
in
the
F2B
pups
on
day
21
is
of
questionable
toxicological
significance.

Dogs
appear
to
be
the
most
sensitive
species
to
TCMTB
toxicity
following
chronic
exposure.
In
the
chronic
dog
toxicity
study,
adverse
effects
were
noted
at
the
lowest
dose
tested
of
3.8
mg/
kg/
day.
Adverse
effects
included
decreased
body
weight
gain,
hematological
effects
(
changes
in
white
blood
cells,
monocytes),
alterations
in
clinical
chemistry
parameters
(
plasma
ALT)
and
decreased
uterine
weight
in
females.

In
the
chronic
rat
toxicity/
carcinogenicity
study,
no
adverse
systemic
toxicity
effects
were
noted
at
the
highest
dose
tested
of
20
mg/
kg/
day.
However,
there
was
a
statistically
significant
increase
in
4
of
26
the
incidence
of
testicular
interstitial
cell
adenomas
in
males
of
mid
(
P=
0.0155)
and
high­
dose
(
P=
0.0087)
levels,
that
had
a
highly
significant
positive
dose­
related
trend
(
P=
0.0018).

Treatment
was
also
associated
with
a
possible
increased
incidence
of
thyroid
C­
cell
adenomas
in
females
of
the
mid­
and
high­
dose
levels,
which
had
a
highly
significant
(
P=
0.0067)
positive
dose­
related
trend,
but
did
not
attain
a
statistically
significant
level
in
the
pairwise
comparison
with
concurrent
controls.
No
historical
data
were
available
for
review.

In
the
chronic
mouse
toxicity/
carcinogenicity
study,
decreased
body
weight
gain
was
noted
in
both
sexes,
while
there
was
a
statistically
increased
incidence
of
focal
and
diffuse
hyperplasia
of
duodenal
mucosa
in
males
(
10/
42
vs
1/
41
in
controls)
at
150
mg
TCMTB/
kg/
day
(
122
mg
ai/
kg/
day).
There
was
no
evidence
of
carcinogenicity.

The
available
toxicity
data
do
no
indicate
neurotoxicity
in
the
experimental
animals
exposed
to
TCMTB
by
either
oral
or
derma
routes.

TCMTB
was
negative
for
mutagenicity
in
the
gene
mutation
assay
with
bacteria,
and
did
not
cause
an
increase
in
unscheduled
DNA
synthesis
(
UDS)
in
rat
primary
hepatocytes
assay.
It
was
also
negative
for
chromosomal
aberrations
in
the
in
vivo
micronucleus
assay
in
mice.

TCMTB
has
been
classified
as
Group
C
­
possible
human
carcinogen
­
and
the
Agency
recommended
that
for
the
purpose
of
risk
characterization,
the
Reference
Dose
(
RfD)
approach
be
used
for
quantitation
of
cancer
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.
5
of
26
2.0
REQUIREMENTS
The
Toxicology
Data
Requirements
(
40CFR
158.340)
for
food
uses
of
TCMTB
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.

Technical
Test
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.................................................
870.6100
Acute
Delayed
Neurotox.
(
Hen)
................................
870.6200a
Acute
Neurotox.
Screening
Battery
(
Rat)...................
Y
Y
Y
Y
Y
Y
N
N
Y
Y
Y
Y
Y
Y
870.3100
Oral
Subchronic
(
Rodent)
.........................................
870.3150
Oral
Subchronic
(
Non­
Rodent)..................................
870.3200
21­
Day
Dermal
.........................................................
870.3250
90­
Day
Dermal
.........................................................
870.3465
90­
Day
Inhalation
.....................................................
Y
Y
N
N
Held
in
reserve
Y
(
by
chronic)
Y
(
by
chronic)
Y
870.3700a
Developmental
Toxicity
(
rodent)...............................
870.3700b
Developmental
Toxicity(
non­
rodent)........................
870.3800
Reproduction
............................................................
Y
Y
Y
Y
Y
Y
870.4100a
Chronic
Toxicity
(
Rodent)
........................................
870.4100b
Chronic
Toxicity
(
Non­
rodent)..................................
870.4200a
Oncogenicity
(
Rat)....................................................
870.4200b
Oncogenicity
(
Mouse)...............................................
870.4300
Chronic/
Oncogenicity
...............................................
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
870.5100
Mutagenicity
C
Gene
Mutation
­
bacterial...................
870.5300
Mutagenicity
C
Gene
Mutation
­
mammalian..............
870.5395
Mutagenicity
C
Mammalian
erythrocyte
micronucleus
870.5xxx
Mutagenicity
C
Other
Genotoxic
Effects.....................
Y
Y
Y
N
Y
Y
N
870.6100
90­
Day
Neurotoxicity
(
hen).......................................
870.6200b
90
Day
Neuro.
Screening
Battery
(
Rat)
.....................
870.6300
Develop.
Neuro.........................................................
N
N
N
­­
­­
­­

870.7485
General
Metabolism..................................................
870.7600
Dermal
Penetration
...................................................
Y
N
­­

870.7200
Companion
Animal
Safety
........................................
N
­­

Special
Studies
for
Ocular
Effects
...............................................
Acute
Oral
(
Rat)
.......................................................
Subchronic
Oral
(
Rat)
...............................................
Six­
month
Oral
(
Dog)
...............................................
N
­­

Y
­
Yes;
N
 
no;
­­
not
necessary
6
of
26
3.0
DATA
GAP(
S)

There
are
no
toxicology
data
gaps
for
TCMBT
at
this
time.
The
Antimicrobials
Division
Toxicology
Endpoint
Selection
Committee
(
ADTC)
recommended
that
a
repeated
dose
inhalation
toxicity
study
for
TCMTB
be
held
in
reserve,
pending
the
outcome
of
inhalation
risk
assessments
using
the
oral
toxicity
data.

4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
data
base
for
acute
toxicity:
The
data
base
for
acute
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
TCMTB
exhibits
low
acute
oral
and
dermal
toxicity
(
toxicity
category
III).
However,
it
is
highly
irritating
to
the
eyes
and
skin
(
toxicity
category
I
and
II,
respectively))
and
is
also
considered
to
be
highly
toxic
via
the
inhalation
route
of
exposure
(
toxicity
category
I).
TCMTB
is
a
dermal
sensitizer.
The
acute
toxicity
data
on
the
TCMTB
Technical
(
80%
ai),
or
Busan
72
(
containing
60%
ai)
is
summarized
below
in
Table
2.

Table
2.
Acute
Toxicity
Data
on
TCMTB
Technical
(
80%
ai)

Guideline
No./
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
oral
toxicity
41583801
LD50
=
750
mg/
kg
(
M+
F);
80%
ai
III
870.1200
Acute
dermal
toxicity
41515401
LD50
>
2000
mg/
kg
(
M+
F);
80%
ai
III
870.1300
Acute
inhalation
toxicity
41640601
LC50=
0.07
mg/
L;
80%
ai
I
870.2400
Acute
eye
irritation
Acc
No.
111991
Diluted
Busan
72
(
60
%
ai):
primary
irritation
score
(
PIS)=
2/
110
(
slight
conjunctival
redness,
no
corneal
opacity);
undiluted
Busan
72
(
60%
ai)
PIS=
34/
110
(
blanched
conjunctivae,
chemosis,
corneal
opacity
not
reversible
by
day
7)
I
870.2500
Acute
dermal
irritation
41583701
primary
irritation
index=
7.42
with
severe
erythema
and
edema
observed
at
72
hours;
80%
ai
II
870.2600
Skin
sensitization
MRID
42349201
Acc
No.
259676
Busan
74
(
80%
ai)
caused
delayed
contact
hypersensitivity
in
guinea
pigs
when
induced
and
challenged
by
a
40%
w/
v
aqueous
concentration
of
active
ingredient.
Sensitizer.
­­
7
of
26
4.2
Subchronic
Toxicity
Adequacy
of
data
base
for
subchronic
toxicity:
The
data
base
for
subchronic
toxicity
is
considered
adequate
for
risk
assessment
purposes.
Although
the
subchronic
rodent
studies
are
unacceptable,
there
are
chronic
studies
available
to
fulfill
the
guideline
requirements
Following
repeat
oral
exposures
to
rodents,
TCMTB
caused
increased
incidence
of
mild
to
severe
stomach
lesions
characterized
by
inflammation,
hyperplasia,
necrosis,
and
ulceration.
Inflammatory
cells
infiltration
and
edema
were
also
noted
at
a
low
incidence.
TCMTB
resulted
in
decreased
body
weight
gains
(
78
to
84%
of
control),
food
consumption
(
87­
95%
of
control)
and
food
efficiency.
In
a
21­
day
rat
dermal
toxicity
study,
TCMTB
produced
dose­
dependant
dermal
irritation
in
all
dose
groups
beginning
on
treatment
days
3­
4,
which
progressed
to
eschar
formation.
Rats
in
the
mid
and
high
dose
group
had
ulcers,
hemorrhages
and
chronic
dermatitis.
Decreased
body
weight
gain,
food
consumption,
and
hematological
(
changes
in
hemoglobin,
hematocrit,
and
segmented
neutrophils)
and
clinical
chemistry
changes
(
blood
urea
nitrogen,
glucose,
globulins,
and
elevated
serum
aspartate
aminotransferase
(
AST)
were
also
noted.
However,
the
clinical
chemistry
changes
did
not
correspond
to
any
treatment­
related
findings
in
the
liver
or
kidney.

870.3100
90­
Day
Oral
Toxicity
­
Rat
In
a
13
week
range
finding
study
(
MRID
43112801),
TCMTB
(
81.56%
ai,
Batch
1517
MRID
46698604,
92179001)
was
administered
to
Sprague­
Dawley
rats
(
n=
10/
sex/
dose)
in
the
diet
at
dose
levels
of
0,
10,
30,
70
or
100
mg/
kg/
day
(
actual
doses:
10.2,
31,
70
and
100
mg
TCMTB/
kg/
day
for
males
and
10.3,
31,
72
and
99
mgTCMTB/
kg/
day
for
females
using
food
consumption
data).
These
doses
are
equivalent
to
8.3/
8.4
(
M/
F),
24.5,
57/
59
(
M/
F),
80.8/
81.6
(
M/
F)
mg
ai/
kg/
day,
respectively
when
considering
the
purity
of
the
test
substance
as
81.56%
ai.
This
study
examined
limited
parameters.

Systemic
toxicity
was
noted
at
30
mg/
kg/
day
(
24.5
mg
ai/
kg/
day)
and
above
in
the
form
of
increased
incidence
of
squamous
epithelial
hyperplasia
of
the
stomach.
There
were
also
treatment
related
decreases
in
body
weight
gains
(
78
to
84%
of
control),
food
consumption
(
87­
95%
of
control)
and
food
efficiency
(
89­
94%
of
control)
in
both
sexes
of
to
70
and
100
mgTCMTB/
kg/
day
(
57/
59
(
M/
F)
and
80.8/
82.6
(
M/
F)
mg
ai/
kg/
day).
The
LOAEL
for
systemic
toxicity
is
30
mg
TCMTB/
kg/
day
(
24.5
mg
ai/
kg/
day)
and
the
NOAEL
for
systemic
toxicity
is
10
mg
TCMTB/
kg/
day
(
8.3.8.4
mg
ai/
kg/
day)
based
on
increased
incidences
of
stomach
lesions.

This
90­
day
oral
toxicity
study
in
the
rat
is
UNACCEPTABLE­
GUIDELINE
and
does
not
satisfy
the
guideline
requirement
for
a
subchronic
(
90­
day)
oral
toxicity
study
OPPTS
870.3100
in
the
rat
because
is
was
only
a
range
finding
study,
and
based
on
major
deficiencies
(
stability,
diet
concentrations
and
homogeneity
were
not
measured,
and
hematology
and
clinical
chemistry
parameters
were
not
measured).
This
study
can
not
be
upgraded.

870.3100
90­
Day
Oral
Toxicity
­
Rat
In
a
90­
day
study
(
MRID
92179026),
TCMTB
(
Lot
9­
3573;
approximately
80%
as
supplied
by
the
8
of
26
registrant
via
email
correspondence)
was
administered
to
Sprague­
Dawley
rats
(
n=
30/
sex/
dose)
in
the
diet
at
dose
levels
of
0,
333,
500
and
750
ppm
for
90
days.
Dietary
doses
were
approximately
0,
16.7,
25,
37.5
mgTCMTB/
kg/
day,
which
is
equivalent
to
0,
13.4,
20
and
30
mg
ai/
kg/
day,
respectively
based
on
a
purity
of
approximately
80%
ai.
(
as
supplied
by
the
registrant).

There
were
no
treatment­
related
effects
on
any
of
the
parameters
measured
except
histopathology.
Mild
inflammatory
changes
were
found
in
the
gastric
mucosa
of
males
in
the
high
dose
group.
Mild
to
severe
changes
in
the
stomach,
including
inflammation,
necrosis
and
ulceration,
were
found
in
the
females
in
this
group.
Females
in
the
mid­
dose
group
had
a
low
incidence
of
inflammatory
cells
infiltration
(
5%
vs.
0%
in
the
control)
and
edema
(
10%
vs.
0%
in
the
control).

The
NOAEL
is
500
ppm
(
25
mg
TCMTB/
kg/
day
or
20
mg
ai/
kg/
day).
The
LOAEL
is
750
ppm
(
37.5
mg
TCMTB/
kg/
day
or
30
mg
ai/
kg/
day).
The
Maximum
Tolerated
Dose
(
MTD)
in
males
is
slightly
higher
than
750
ppm
(
based
on
histopathology
findings);
females
is
slightly
lower
than
750
ppm
(
based
on
incidence
and
severity
of
histopathology
findings
in
the
stomach).

This
90­
day
oral
toxicity
study
in
the
rat
is
UNACCEPTABLE­
GUIDELINE
and
does
not
satisfy
the
guideline
requirement
for
a
subchronic
(
90­
day)
oral
toxicity
study
OPPTS
870.3100
in
the
rat
because
the
percent
recovery
of
TCMTB
in
the
diets
was
low
(
81,
82
and
84%
for
the
low,
mid­
and
high
dose
groups,
respectively),
and
ophthalmoscopic
examinations
were
not
done.
The
approximate
purity
of
80%
ai
was
submitted
in
late
2005
by
the
registrant.

870.3200
21­
Day
Dermal
Toxicity
­
Rat
Executive
Summary:
In
a
dermal
toxicity
study
(
MRID
41655801),
TCMTB
(
82.33%
a.
i.
Lot
OB­
8483
via
fax
submission
dated
December
8,
2005)
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).
These
doses
are
equivalent
to
0,
20.6,
82.3
and
206
mg
ai/
kg/
day.
TCMTB
produced
slight
to
moderate
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)
in
the
low
dose
group
in
all
rats
of
the
mid
and
high
dose
groups.
Blanching
occurred
in
all
rats
of
the
high
dose
group
and
in
all
females
and
3/
5
males
in
the
mid
dose
group.
Decreased
body
weight
gain
was
noted
at
the
mid
and
high
dose
groups
of
male
rats.
Statistically
significant
changes
in
hemoglobin,
hematocrit,
and
segmented
neutrophils
were
observed
in
male
and
female
rats
of
the
high
dose
level.
Several
clinical
chemistry
parameters
were
significantly
increased
in
high
dose
males
and
females
(
blood
urea
nitrogen,
glucose
and
globulins);
while
high
dose
females
also
had
elevated
serum
aspartate
aminotransferase
(
AST).
However,
the
clinical
chemistry
changes
did
not
correspond
to
any
treatment­
related
findings
in
the
liver
or
kidney.

The
Systemic
NOAEL
=
20.6
mg
ai/
kg/
day,
and
the
Systemic
LOAEL
=
82.3
mg
ai/
kg/
day,
based
on
decreased
body
weight
gain,
food
consumption,
and
hematological
and
clinical
chemistry
changes.
A
Dermal
NOAEL
was
not
identified.
The
Dermal
LOAEL
is
20.6
mg
ai/
kg/
day
based
on
dose­
dependent
irritation
which
progressed
to
eschar
formation
in
2
rats
of
the
low
dose
group
and
in
all
rats
of
the
mid­
and
high­
dose
groups.
Mid­
and
high­
dose
groups
exhibited
ulcers,
hemorrhages
and
chronic
dermatitis.
9
of
26
Based
on
the
recent
submission
of
purity
information
in
2005,
this
21­
day
dermal
toxicity
study
in
the
rat
can
be
upgraded
to
ACCEPTABLE­
GUIDELINE,
and
satisfies
the
guideline
requirement
for
a
subchronic
dermal
toxicity
study
OPPTS
870.3200
in
the
rat.

4.3
Prenatal
Developmental
Toxicity
Adequacy
of
data
base
for
Prenatal
Developmental
Toxicity:
The
data
base
for
prenatal
developmental
toxicity
is
considered
complete.
Developmental
toxicity
studies
were
available
in
both
the
rat
and
rabbit
for
TCMTB.
No
additional
studies
are
required
at
this
time.
Rabbits
appear
to
be
more
sensitive
to
the
toxicity
of
TCMTB
than
rats.
In
rabbits,
the
maternal
NOAEL
and
LOAEL
were
16
and
32
mg
ai/
kg/
day,
respectively.
In
rats,
the
maternal
NOAEL
and
LOAEL
were
21
and
64
mg
ai/
kg/
day.
No
developmental
effects
were
noted
in
the
rabbit
at
the
highest
dose
tested
(
32
mg
ai/
kg/
day).
However,
in
the
rat
adverse
developmental
effects
including
increased
fetal
and
litter
incidence
of
fused/
wavy
ribs,
rudimentary
cervical,
thoracic
and
lumbar
ribs
and
increased
incidence
of
sternebrae
and
pelvic
girdle
anomalies
were
noted
at
doses
of
105
mg
ai/
kg/
day,
which
was
maternally
toxic.
Thus,
the
Agency
concludes
that
these
studies
show
no
evidence
of
primary
developmental
toxicity
of
TCMTB,
which
is
consistent
with
the
previous
conclusion
of
the
Health
Effects
Division's
RfD
Peer
Review
committee
(
September
29,
1994;
document
#
011302).

870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
In
a
prenatal
developmental
toxicity
study
(
MRID
00154295,
accession
no.
260491);
TCMTB
(
83.6%
a.
i.
Lot
511230,
MRID
46698601),
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.
These
doses
are
equivalent
to
0,
21,
64
and
105
mg
ai/
kg/
day,
respectively.
Maternal
toxicity
was
evident
at
the
64
mg
ai/
kg/
day
(
76.5
mg
TCMTB/
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
105
mg
ai/
kg/
day
(
125.5
mg
TCMTB/
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
=
21
mg
ai/
kg/
day
(
25.1
mg
TCMTB/
kg/
day),
based
on
observations
of
clinical
toxicity
at
64
mg
ai/
kg/
day
(
76.5
mgTCMTB/
kg/
day)
(
LOAEL).
The
Developmental
NOAEL
=
64
mg
ai/
kg/
day
(
76.5
mg
TCMTB/
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.

870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
10
of
26
In
a
prenatal
developmental
toxicity
(
teratology)
study
(
MRID
40075102),
TCMTB
(
81.0
%
a.
i.,
Lot
5­
13002,
MRID
46698602)
was
orally
dosed
to
presumed
pregnant
rabbits
at
dose
levels
of
0,
10,
20
and
40
mg/
kg/
day
(
20
rabbits/
group)
during
gestation
days
6­
19
inclusive.
These
doses
are
equivalent
to
0,
8,
16,
and
32
mg
ai/
kg/
day,
which
were
verified
by
the
registrant.

Maternal
toxicity
was
evidenced
by
decreased
body
weight
gain
and
food
consumption
in
the
32
mg
ai/
kg/
day
dose
group.
Statistically
significant
(
p>
0.01)
body
weight
loss
was
noted
in
the
high
dose
group
on
gestation
days
6­
12,
6­
19
and
19­
29.
Mean
food
consumption
was
significantly
reduced
for
the
high
dose
group
during
gestation
days
6­
12
and
6­
19.
One
high
dose
and
two
mid­
dose
group
rabbits
died
during
the
study.
However,
only
the
high
dose
death,
which
occurred
on
gestation
day
18,
was
considered
treatment
related
based
on
corroded
gastric
mucosa
and
reddened
duodenal
mucosa.
There
were
no
clinical
signs
of
toxicity
in
any
dose
level
during
the
study.
Five
dams
aborted
their
litters
prior
to
scheduled
sacrifice
(
1
control,
2
in
the
low
dose
group
and
2
in
the
mid­
dose
group).
No
animals
in
the
high
dose
group
aborted,
therefore,
the
abortions
occurring
in
the
lower
dose
groups
were
considered
to
be
spontaneous,
which
is
not
uncommon
in
rabbits.
The
Maternal
Toxicity
NOAEL
is
16
mg
ai/
kg/
day
and
the
Maternal
Toxicity
LOAEL
is
32
mg
ai
/
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
deaths/
resorptions,
altered
growth,
developmental
anomalies
or
malformations.
The
Developmental
Toxicity
LOAEL
is
greater
than
32
mg
ai/
kg/
day
and
the
Developmental
Toxicity
NOAEL
is
greater
than
or
equal
to
32
mg
ai/
kg/
day.

This
study
is
classified
as
acceptable­
guideline
and
satisfies
the
guideline
requirement
(
§
870.3700)
for
a
developmental
toxicity
(
teratology)
study
in
rabbits.

4.4
Reproductive
Toxicity
Adequacy
of
data
base
for
Reproductive
Toxicity:
The
data
base
for
reproductive
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
The
available
data
showed
that
TCMTB
did
not
cause
reproductive
effects
in
rats.

In
a
2­
generation
reproduction
toxicity
study
(
MRID
41471401),
TCMTB
(
81.6%
ai,
Batch
1517;
MRID
92179011,
46698604)
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
in
the
second
mating
(
F2B)
around
lactation
day
21
(
approximately
88%
of
control
pups).
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,
and
thus
mostly
likely
received
more
than
400
ppm
TCMTB.
Mean
pup
weight
was
not
significantly
reduced
at
days
7
or
14
in
the
F2B
pups,
and
there
were
no
consistent
effects
on
pup
weight
in
the
F0
and
F1a
generation
pups.
Thus,
the
Agency
believes
this
finding
in
the
F2B
pups
11
of
26
on
day
21
is
of
questionable
toxicological
significance.

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
offspring
NOAEL
is
400
ppm
(
HDT)
and
the
offspring
LOAEL
>
400
ppm.
The
Reproductive
toxicity
NOAEL
>
400ppm
and
the
Reproductive
toxicity
LOAEL
>
400
ppm.

This
study
is
classified
as
acceptable­
guideline
and
satisfies
the
guideline
requirement
for
a
2­
generation
reproductive
study
(
§
870.3800;
OECD
416)
in
rats
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.

4.5
Chronic
Toxicity
Adequacy
of
data
base
for
chronic
toxicity:
The
data
base
for
chronic
toxicity
is
considered
complete,
and
no
additional
studies
are
required
at
this
time.

In
a
chronic
toxicity
study
(
MRID
41342201),
technical
TCMTB
(
81.6%
ai,
Batch
1517;
MRID
92179008,
46698604)
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.
Hematological
effects
include
significant
decreases
in
circulating
white
blood
cells
and
monocytes
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
for
males;
4.0
mg
/
kg/
day
for
females],
based
on
decreased
body
weight
gain,
white
blood
cells,
monocytes
and
plasma
ALT
in
males;
decreased
plasma
ALT
and
uterine
weight
in
females.

This
chronic
study
in
the
dog
is
classified
as
acceptable­
non­
guideline
and
does
not
satisfy
the
guideline
requirement
for
a
chronic
oral
study
(
OPPTS
§
870.4100,
OECD
452)
in
dogs
because
a
systemic
NOAEL
was
not
achieved.
However,
this
study
is
scientifically
sound
and
adequate
for
use
in
risk
assessment
4.6
Carcinogenicity
Adequacy
of
data
base
for
Carcinogenicity:
The
data
base
for
carcinogenicity
is
considered
complete,
and
no
additional
studies
are
required
at
this
time.
TCMTB
produced
an
increase
in
12
of
26
testicular
interstitial
adenomas
in
male
rats
and
thyroid
C­
cell
adenomas
in
female
rats.

1.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
(
MRID
No.:
42116301;
41529701;
41570301)

Executive
Summary:
In
a
combined
chronic/
carcinogenicity
study
(
MRID
42116301;
41529701;
41570301),
TCMTB
(
81.6%
ai
purity,
MRID
46698604)
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
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
13
of
26
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
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:
In
a
carcinogenicity
study
(
MRID
42383001),
TCMTB
(
81.6%
ai,
batch
1517/
Lot
number
6­
14285,
MRID
46698604)
was
administered
to
groups
of
CD­
1
mice
(
50/
sex)
in
the
diet
at
concentrations
calculated
to
give
dose
levels
of
0,
15,
50,
or
150
mg/
kg/
day
for
2
years.
These
doses
are
equivalent
to
0,
4,
41
and
122
mg
ai/
kg/
day,
respectively.
No
carcinogenic
potential
was
seen.
Body
weights
were
significantly
reduced
in
high­
dose
males
and
high
dose
females
compared
to
controls.
Weight
gains
in
high
dose
males
and
females
were
approximately
25%
lower
than
controls
at
78
weeks.
Cumulative
weight
gain
was
reduced
36%
and
28%
for
high
dose
males
and
females,
respectively
at
week
104.
There
was
no
effect
on
food
consumption
in
this
study.
None
of
the
gross
findings
were
remarkable.
An
increase
in
focal
and
diffuse
hyperplasia
of
the
duodenal
mucosa
was
seen
microscopically
in
males
receiving
150
mg/
kg/
day:
the
14
of
26
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
(
41
mg
ai/
kg/
day),
and
the
Systemic
LOAEL
is
determined
to
be
150
mg/
kg/
day
(
122
mg
ai/
kg/
day),
based
on
histologic
changes
in
the
duodenum
of
high
dose
males
and
decreased
weight
gain
in
both
sexes
at
the
high
dose.

This
carcinogenicity
study
in
the
mouse
is
acceptable
guideline
and
satisfies
the
guideline
requirement
for
a
carcinogenicity
study
(
OPPTS
870.4200;
OECD
451).

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
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
LOAEL
is
considered
to
be
150
mg/
kg/
day
(
122
mg
ai/
kg/
day)
and
the
systemic
toxicity
NOAEL
is
50
mg/
kg/
day
(
41
mg
ai/
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.
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,
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
cancer
risk.
15
of
26
4.7
Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
The
data
base
for
Mutagenicity
is
considered
adequate
based
on
pre
1991
mutagenicity
guidelines.
TCMTB
was
negative
for
mutagenicity
in
the
gene
mutation
assay
with
bacteria
(
MRID#
41386101),
and
did
not
cause
an
increase
in
unscheduled
DNA
synthesis
(
UDS)
in
rat
primary
hepatocytes
assay
(
Accession
No.
266150;
MRID#
00165518).
It
was
also
negative
for
chromosomal
aberrations
in
the
in
vivo
micronucleus
assay
in
mice
(
MRID#
00165520).

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
29).
In
the
Rat
Primary
Hepatocyte
Unscheduled
DNA
Synthesis
Assay
In
an
UDS
assay
(
Accession
No.
266150;
MRID#
00165518),
TCMTB
did
not
cause
a
significant
increase
in
the
unscheduled
DNA
synthesis
(
UDS)
in
rat
primary
hepatocytes
as
measured
in
this
study.

4.8
Neurotoxicity
Adequacy
of
data
base
for
Neurotoxicity:
These
studies
are
not
required
at
this
time.
The
available
data
do
not
indicate
neurotoxicity
in
experimental
animals
exposed
by
oral
or
dermal
administration.

4.9
Metabolism
2­
Mercaptobenzothiazole
(
2­
MBT)
is
the
main
mammalian
urinary
metabolite
of
TCMTB,
and
has
been
suggested
as
a
biological
marker
of
exposure
to
TCMTB
(
Manninen
et
al.
1996).
In
this
study,
three
doses
of
TCMTB
in
olive
oil
were
given
to
male
rats
by
gavage
for
3
weeks.
Urine
16
of
26
was
collected
daily
and
the
metabolites
were
analyzed
as
thioethers
by
derivatization
with
pentafluorobenzylbromide
by
gas
chromatography­
mass
spectrometry.
The
parent
chemical
was
not
detected
in
urine
samples,
but
two
metabolites
of
TCMTB
were
identified.

2­
Mercaptobenzothiazole
(
2­
MBT)
was
the
main
metabolite,
and
its
excretion
varied
according
to
the
dose.
The
second
metabolite
was
2­(
mercaptomethylthio)
benzothiazole.
The
amount
of
2­
MBT
excreted
in
rat
urine
was
66
±
12%
(
SD),
51
±
20%
and
44
±
9%
for
TCMTB
doses
of
15,
75,
and
150
mg/
kg,
respectively.
Two
doses,
75
and
150
mg/
kg
,
caused
diuresis
in
rats
during
the
1
week
of
dosing.
During
the
3­
week
TCMTB
treatment,
rat
liver
microsomal
CYP
enzyme
profile
was
not
significantly
changed.
Urine
samples
for
sawmill
workers
exposed
to
TCMTB
were
collected
after
their
work
shifts
for
exposure
assessment.
TCMTB
could
not
be
detected
in
the
urine
samples
of
exposed
workers.
Most
concentrations
of
2­
MBT
were
below
the
limit
of
detection,
0.12
µ
mol/
l,
the
concentrations
were
0.12­
0.15
µ
mol/
l
only
in
few
cases.
The
authors
conclude
that
the
determination
of
2­
MBT
in
urine,
when
a
sample
is
taken
immediately
after
a
work
shift,
is
a
suitable
indicator
of
workers'
exposure
to
TCMTB.

In
a
rat
metabolism
study
(
MRID
40884801)
14C­
TCMTB
as
administered
to
Sprague
Dawley
rats
(
5/
sex/
dose)
by
oral
gavage
at
single
doses
of
3
and
30
mg/
kg,
and
at
a
repeated
oral
dose
of
3
mg/
kg.
Excretion
of
TCMTB
derived
radioactivity
was
monitored,
as
well
as
measurement
of
plasma
levels
and
excretion
of
TCMTB
derived
radioactivity
in
bile.
Metabolites
of
TCMTB
in
urine,
plasma,
and
bile
were
characterized
using
thin
layer
chromatography.
Absorption
of
TCMTB
was
rapid,
with
80%
excreted
in
urine
by
24
hours
post­
dose
at
both
the
3
and
30
mg/
kg
dose
levels.
In
bile,
cannulated
rats,
there
was
a
marked
reduction
in
0­
24
hour
urinary
excretion
(
25­
35%).

Distribution
data
indicated
that
red
blood
cells
and
kidney
were
the
only
sites
of
significant
retention
of
residual
radioactivity.
However,
these
levels
were
low
(
0.02­
2.41
µ
g
equiv./
g
tissue).
Measurement
of
elimination
of
radioactivity
from
blood
showed
that
the
half­
life
in
red
cells
might
be
in
excess
of
7
days.

Excretion
of
TCMTB
derived
radioactivity
was
mainly
in
urine,
with
between
80­
85%
of
the
total
dose
excreted
in
non­
cannulated
rats.
Fecal
excretion
comprised
about
5%
of
an
administered
dose,
and
was
not
altered
in
cannulated
rats,
suggesting
reabsorption
of
radioactivity
from
the
gastrointestinal
tract
and
excretion
in
urine.
Pharmacokinetic
data
indicated
that
clearance
was
approximately
equal
at
both
the
low
and
high
dose,
and
the
AUC
was
proportional
to
the
dose,
suggesting
first
order
elimination
at
both
the
low
and
high
dose.

Metabolite
characterization
using
radio­
TLC
showed
the
presence
of
one
and
possibly
2
metabolites
of
TCMTB
in
urine
and
bile.
However,
definitive
identification
was
not
made,
other
than
to
suggest
that
at
least
one
metabolite
could
be
a
glucuronide
conjugate.

This
metabolism
study
in
the
rat
is
classified
as
unacceptable
guideline
and
does
not
satisfy
the
guideline
requirement
for
a
metabolism
study
[
OPTTS
870.7485,
OECD
417]
in
rats
because
there
are
incomplete
data
for
the
repeated
low
oral
dose
group,
incomplete
identification
of
metabolites
and
the
purity
of
TCMTB
was
not
reported.
17
of
26
5.0
HAZARD
CHARACTERIZATION
FOR
2­
MERCAPTOBENZOTHIAZOLE
(
2­
MBT)

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
conduced
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
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
18
of
26
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
2­
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,
2­
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.

2
­
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].
2­
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
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.
2­
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.

6.0
TOXICITY
ENDPOINT
SELECTION
6.1
See
Section
9.2
for
Endpoint
Selection
Table.

6.2
Dermal
Absorption
19
of
26
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).

A
dermal
absorption
study
was
submitted
by
the
registrant
as
an
unaudited
draft
report
(
MRID
NR42516601).
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.

6.3
Classification
of
Carcinogenic
Potential
See
Section
4.6.

7.0
FQPA
CONSIDERATIONS
7.1
Special
Sensitivity
to
Infants
and
Children
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,
the
ADTC
recommended
that
the
hazard­
based
FQPA
safety
factor
be
reduced
to
1x.

7.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
A
developmental
neurotoxicity
study
for
TCMTB
is
not
required
at
this
time.

8.0
REFERENCES
MRID
00154295,
92179009.
Goad
P.
T.,
et
al.
1985.
Teratogenicity
study
of
TCMTB
in
rats.
HED
Doc
no.
005769.

MRID
No.
40075101,
40075102,
92179011.
Adam,
C.
P.
1986.
TCMTB 
A
teratology
study
in
rabbits.

MRID
40884801.
Cameron,
B.
D.
Scott,
G.
1987.
The
Metabolism
of
2­(
Thiocyanomethylthio)
benzothiazole
(
TCMTB)
in
the
rat.
Buckman
Laboratories,
Inc.,
Memphis
TN.
Inveresk
Research
International
Ltd.,
Scotland.

MRID
No.
41342201,
92179008.
Goburdhun,
R.,
and
Greenough,
R.
J.
1989.
2­(
Thiocyanomethylthio)
benzothiazole
(
TCMTB):
52­
Week
dietary
toxicity
study
in
dogs.

MRID
No.
41471401,
92179011.
Hazelden,
K.,
Pl.
and
Wilson,
J.
A.
1988.
TCMTB­
Two
generation
reproduction
study
in
rats.
HED
Doc
010607
20
of
26
MRID
No.
41529701,
41570301,
421165301.
Everett,
D.
J.
et
al.
1989.
104­
Week
dietary
toxicity/
carcinogenicity
study
n
rats
with
52­
week
interim
kill.

MRID
No.
42383301.
Everett,
D.
J.,
et
al.
1990.
2­(
Thiocyanomethylthio)
benzothiazole­
104­
Week
dietary
carcinogenicity
study
in
mice.
HED
Doc.
010332.

MRID
No.
43112801.
Atkinson,
C.,
et
al.
1987.
2­(
Thiocyanomethylthio)
benzothiazole
(
TCMTB).
13­
Week
dietary
dose
range
finding
study
in
rats.

MRID
No.
92179026.
Rao,
G.,
No.
1980.
90­
Day
subchronic
oral
toxicity
study
of
TCMTB
in
rats.

Manninen,
A.,
Auriola
S,
Vartiainen
M.,
Leisivuori
J.,
Turunen,
T.,
Pasanen
M.
1996.
Determination
of
urinary
2­
mercaptobenzothiazole
(
2­
MBT),
the
main
metabolite
of
2­(
thiocyanomethylthio)
benzothiazole
(
TCMTB)
in
humans
and
rats.
21
of
26
9.0
APPENDICES
Tables
for
Use
in
Risk
Assessment
22
of
26
9.1
Toxicity
Profile
Summary
Tables
9.1.1
Acute
Toxicity
Table
­
See
Section
4.1
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
13­
week
oral
toxicity
rodents
(
Range
finding)
(
Diet)

Batch
1517
43112801
(
1987)
unacceptable/
guideline
(
range
finding
study)
0,
10,
30,
70
and
100
mgTCMTB/
kg/
day
in
diet
(
0,
8.2,
24.5,
57
and
81.6
mg
ai/
kg/
day)

M:
0,
10.2,
31,70
and
100
mg/
kg/
day
F:
0,
10.3,
31,
72,
99
mg
/
kg/
day
81.56%
ai
purity
(
46698604,
92179001)
NOAEL
=
10.2
mg/
kg/
day(
M);
10.3
mg/
kg/
day
(
F)
(
8.3
mg
ai/
kg/
day)
LOAEL
=
31
mg/
kg/
day
(
M+
F)
(
25
mg
ai/
kg/
day)
based
on
increased
incidence
of
squamous
epithelial
hyperplasia
of
the
stomach
and
decreased
in
body
weight
gains,
food
consumption
and
food
efficiency
in
both
sexes
of
the
70
and
100
mg/
kg/
day
dose
groups.

870.3100
90­
Day
oral
toxicity
rodents
(
diet)

Lot
9­
3573
92179026
(
1980)
unacceptable/
guideline
0,
333,
500,
750
ppm
in
diet
0,
16.7,
25,
37.5
mgTCMTB/
kg/
day
which
is
equivalent
to
13.4,
20
and
30
mg
ai/
kg/
day
Purity
approximately
80%
ai.
(
as
supplied
by
the
registrant
via
email)
NOAEL
=
25
mg
TCMTB/
kg/
day
(
20
mg
ai/
kg/
day)
LOAEL
=
37.5
mg
TCMTB/
kg/
day(
30
mg
ai/
kg/
day)
based
on
increased
incidence
of
histopathology
of
the
stomach,
including
inflammation,
necrosis
and
ulceration.

870.3700a
Prenatal
developmental
in
rodents
Lot
511230
00154295,
92179009
(
1985)
0,
25.1,
76.5,
125.5
mg/
kg
via
gavage
acceptable
guideline
83.6%
ai
purity
(
46698601)

Equivalent
to
21,
64
and
105
mg
ai/
kg/
day
Maternal
NOAEL
=
21
mg
ai/
kg/
day
(
25.1
mg
TCMTB/
kg/
day)
LOAEL
=
64
mg
ai/
kg/
day
(
76.5
mg
TCMTB/
kg/
day)
based
on
clinical
signs
of
ventral
alopecia,
rough
coat,
dyspnea/
wheezing,
oral
discharge,
diarrhea/
loose
stool,
urine
staining,
piloerection
and
hunched
gait
along
with
reduced
body
weight
gain.

Developmental
NOAEL
=
64
mg
ai/
kg/
day
(
76.5
mg
TCMTB/
kg/
day)
LOAEL
=
105
mg
ai/
kg/
day
(
125.5
mg
TCMTB/
kg/
day)
based
on
skeletal
anomaly
observations
consisting
of
fused/
wavy
ribs,
rudimentary
cervical
thoracic
and
lumbar
ribs,
increased
number
of
sternebrae
and
pelvic
girdle
anomalies.

870.3700b
Prenatal
developmental
in
nonrodents
Lot
5­
13002
40075101,
40075102,
92179011
(
1986)
acceptable
guideline
0,
10,
20,
40
mgTCMTB/
kg/
day
via
gavage
of
81%
ai
purity
(
MRID
46698602)

Equivalent
to
0,
8,
16
and
32
mg
ai/
kg/
day
Maternal
NOAEL
=
16
mg
ai/
kg/
day
(
20
mg
TCMTB/
kg/
day
)
LOAEL
 
=
32
mg
ai/
kg/
day
(
40
mg
TCMTB/
kg/
day)
based
on
decreased
body
weight
gain
and
food
consumption.

Developmental
NOAEL 
 
32
mg
ai/
kg/
day
(
40
mg
TCMTB
/
kg/
day)
LOAEL=.
32
mg
ai/
kg/
day
(
40
mg
TCMTB
/
kg/
day).
23
of
26
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Two
generation
reproduction
study
in
rats
Batch
1517
41471401,
92179011
(
1988)
acceptable
guideline
0,
25,
100
and
400
ppm;
M:
0,
2.4,
9.6,
38.4
mg/
kg/
day;

F:
0,
3,
11.7,
45.5
mg/
kg/
day
81.6%
ai
purity
(
MRID
46698604)
Offspring
NOAEL
(
HDT)
=
38.4
mg/
kg/
day
(
M);
45.5
mg/
kg/
day
(
F)
mg/
kg/
day
(
400
ppm)
Offspring
LOAEL
=
Not
identified
Parental/
systemic
NOAEL
=
38.4
mg/
kg/
day
(
M);
45.5
mg/
kg/
day
(
F)
(
HDT)
(
400
ppm)
Parental/
systemic
LOAEL
=
Not
identified.

Reproductive
NOAEL
=
38.4
mg/
kg/
day
(
M);
45.5
mg/
kg/
day
(
F)
(
HDT)
(
400
ppm)
LOAEL
=
Not
identified.

83­
1a
Chronic
toxicity
in
rats
Batch
1517
41529701,
41570301,
42116301
(
1989)
acceptable
guideline
0,
2,
8
and
20
mg/
kg/
day
81.6%
ai
purity(
MRID
46698604)
NOAEL=
20
mg/
kg/
day
LOAEL=
not
identified.
Statistically
significant
increase
in
the
incidence
of
testicular
interstitial
cell
adenomas
in
males
of
mid
(
P=
0.0155)
and
high­
dose
(
P=
0.0087)
levels,
that
had
a
highly
significant
positive
dose­
related
trend
(
P=
0.0018).
Treatment
was
also
associated
with
a
possible
increased
incidence
of
thyroid
C­
cell
adenomas
in
females
of
the
mid­
and
high­
dose
levels,
which
had
a
highly
significant
(
P=
0.0067)
positive
dose­
related
trend,
but
did
not
attain
a
statistically
significant
level
in
the
pairwise
comparison
with
concurrent
controls.
No
historical
data
were
available
for
review.

83­
2
Chronic
toxicity/
Carcinogenicity
in
mice
Batch
1517
42383001
(
1990)
acceptable
guideline
0,
5,
50,
150
mg/
kg/
day
which
is
equivalent
to
4,
41
and
122
mg
ai/
kg./
day
based
on
81.6%
ai
purity(
MRID
46698604)
NOAEL=
50
mg
TCMTB/
kg/
day
(
41
mg
ai/
kg/
day)
LOAEL=
150
mg
TCMTB/
kg/
day
(
122
mg
ai/
kg/
day)
based
on
decreased
body
weight
gain
in
both
sexes,
statistically
increased
incidence
of
focal
and
diffuse
hyperplasia
of
duodenal
mucosa
in
males
(
10/
42
vs
1/
41
in
controls).
No
evidence
of
carcinogenicity.

One­
year
dog
Batch
1517
41342201,
92179008
(
1989)
unacceptable
guideline
(
No
NOAEL)
0,
100,
300
and
1000
ppm;
M:
0,
3.8,
11.7
and
38.8
mg/
kg/
day
F:
0,
4,
11.2,
43.2
mg/
kg/
day
81.6%
ai
purity(
MRID
46698604)
NOAEL=
not
identified
(<
100
ppm
or
3.8
mg/
kg/
day)
LOAEL=
3.8
mg/
kg/
day
(
M)
and
4
mg/
kg/
day
(
F)
based
on
decreased
body
weight
gain,
white
cells,
monocytes
and
plasma
ALT
in
males
and
decreased
plasma
ALT
and
uterine
weight
in
females.

21­
Day
dermal
toxicity
study
Lot
OB­
8483
41655801
(
1990)

0,
25,
100
and
250
mg/
kg/
day
which
is
equivalent
to
0,
20.6,
82.3
and
206
mg
ai/
kg/
day
based
on
82.33%
ai
purity
Systemic
NOAEL=
20.6
mg
ai/
kg/
day
(
25
mgTCMTB/
kg/
day)
Systemic
LOAEL=
82.3
mg
ai/
kg/
day
(
100
mg
TCMTB/
kg/
day)
based
on
decreased
body
weight
gain
and
food
consumption
in
males,
in
addition
to
significant
hematalogical
(
increased
neutrophils,
decreased
hemoglobin,
hematocrit
and
erythrocytes)
and
clinical
chemistry
changes
(
increased
urea
nitrogen,
glucose
and
globulins)

Dermal
NOAEL=
not
identified
Dermal
LOAEL=
20.6
mg
ai/
kg/
day
(
25
mg
T
CMTB/
kg/
day)
for
dermal
effects
based
on
dose­
dependent
irritation
which
progressed
to
eschar
formation
in
2
rats
of
the
low
dose
group,
and
in
all
rats
of
mid­
and
high­
dose
group.
Mid
and
high
dose
group
exhibited
ulcers,
hemorrhages
and
chronic
dermatitis.

870.5100/
84­
2
Mutagenicity
study:
Gene
mutation
(
S.
Typhimurium)
MRID
41386101
acceptable
TCMTB
was
negative
for
inducing
reverse
gene
mutations
in
Salmonella
typhimurium
strains
TA1535,
TA1537,
TA1538,
TA
98
or
TA
100
exposed
in
the
presence
of
absence
of
S9
activation
up
to
cytotoxic
concentrations
(
 
33.3
ug/
plate
­
S9;
 
66.7
ug/
plate
+
S9).
The
results
were
confirmed
in
an
independently
performed
trial.
24
of
26
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.5395/
84­
2
Structural
Chromosomal
Aberrations:
Clastogenic
Evaluation
in
in
vivo
mouse
micronucleus
assay
MRID
00165520
Acceptable;
EPA
Accession
No.
266152
TRID
470330­
022
Purity
not
provided
In
a
structural
chromosomal
aberration
assay,
the
high
dose
of
TCMTB
(
500
mg/
kg)
exhibited
mortality
and
signs
of
clinical
toxicity.
No
evidence
of
an
increase
in
micronucleated
polychromatic
erythrocytes
(
PCE)
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.

870.5550/
84­
4
Rat
Primary
Hepatocyte
Unscheduled
DNA
Synthesis
Assay
MRID
00165518
Acceptable;

TRID
470330­
020
EPA
Accession
No.
266150
Purity
not
provided;
Lot
No.
5­
13002
TCMTB
did
not
cause
a
significant
increase
in
the
unscheduled
DNA
synthesis
(
UDS)
in
rat
primary
hepatocytes
as
measured
in
this
study.
Concentrations
used
were
0.05­
25
ug/
ml
in
DMSO.
25
of
26
9.2
Summary
of
Toxicological
Dose
and
Endpoints
for
2­(
Thiocyanomethylthio)
benzothiazole
(
TCMTB)
for
Use
in
Human
Risk
Assessment1
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=
25.1
mg/
kg/
day
83.55%
ai
purity
UF
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)

FQPA
SF
=
1x
Acute
PAD
=
0.25
mg
TCMTB/
kg/
day
Developmental
toxicity
study
in
rats
(
MRID
00154295,
92179009
(
1985))

Maternal
LOAEL
=
76.5
mg
TCMTB/
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
81.6%
ai
purity
UF
=
300
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation,
3x
for
use
of
a
LOAEL)

FQPA
SF
=
1x
Chronic
PAD
=
0.01
mg
ai/
kg/
day
Chronic
toxicity
study
in
dogs
(
MRID
41342201,
92179008
(
1989))

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

Short­
and
Intermediate­
Term
Incidental
Oral
(
1­
30
days;
30
days­
6
months)
NOAEL=
16.2
mg
ai/
kg/
day
81%
ai
purity
(
20
mg
TCMTB/
kg/
day)
MOE
=
100
Developmental
toxicity
study
in
rabbits
(
MRID
40075101,
40075102,
92179011
(
1986))

LOAEL
=
32
mg
ai/
kg/
day
(
40
mg
TCMTB/
kg/
day),
based
on
decreased
body
weight
gain
and
food
consumption
in
maternal
animals.
26
of
26
Dermal
(
all
durations)
(
1­
30
days;
30
days­
6
months;
>
6
months)
NOAEL=
25
mg/
kg/
day
82.33%
ai
purity
(
20.6
mg
ai//
kg/
day)
MOE
=
100
(
ST
and
IT)

MOE
=
300
(
LT)
21­
Day
dermal
toxicity
study
in
rats
(
MRID
41655801)

LOAEL
=
100
mg
TCMTB/
kg/
day
(
82.3
mg
ai/
kg/
day),
based
on
decreased
body
weight
gain,
food
consumption,
and
hematological
and
clinical
chemistry
changes
Inhalation
(
short­
and
intermediate­
term)
NOAEL=
16.2
mg
ai/
kg/
day
81%
ai
purity
(
20
mg
TCMTB/
kg/
day)

Absorption=
100
%
(
inhalation
and
oral
equivalent)
MOE
=
300
(
ST
and
IT)
Developmental
toxicity
study
in
rabbits
(
MRID
40075102)

LOAEL
=
=
32
mg
ai/
kg/
day
(
40
mg
TCMTB/
kg/
day),
based
on
decreased
body
weight
gain
and
food
consumption
in
maternal
animals
Inhalation
(
long­
term)
LOAEL
=
3.8
mg/
kg/
day
81.6%
ai
purity
Absorption=
100
%
(
inhalation
and
oral
equivalent)
MOE
=
1000
Chronic
toxicity
study
in
dogs
(
MRID
41342201,
92179008
(
1989))

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