Document ID: EPA-HQ-ORD-2006-0310-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-17T04:00Z

Page
1
of
19
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
April
13,
2006
MEMORANDUM
SUBJECT:
Human
Studies
Review
Board:
Weight
of
Evidence
Discussion
for
Methyl
isothiocyanate
(
MITC).

DP
Barcode
D293353
TXR
No.:
0054209
PC
Codes:
068103
FROM:
Anna
Lowit,
Ph.
D.,
Toxicologist
Toxicology
Branch
Health
Effects
Division
(
7509C)

THROUGH:
Louis
Scarano,
Branch
Chief
Toxicology
Branch
Health
Effects
Division
(
7509C)

TO:
Tina
Levine,
Ph.
D.,
Director
Health
Effects
Division
(
7509C)

This
document
describes
the
scientific
support
for
deriving
a
point
of
departure
for
methyl
isothiocyanate
(
MITC)
using
a
human
odor
threshold
and
eye
irritation
study
(
MRID
no.
44400401).
This
point
of
departure
is
applicable
for
use
in
acute
(
1­
day)
risk
assessments
to
by­
standers
and
occupational
workers
exposed
to
MITC
in
air.
Page
2
of
19
I.
Background
and
Introduction:

There
are
several
pathways
of
exposure
for
methyl
isothiocyanate
(
MITC,
see
figure
1
for
chemical
structure).
MITC
can
be
used
as
a
pesticide
directly
to
treat
wood
poles.
MITC
is
also
a
key
degradate
of
several
fumigant
pesticides
(
i.
e.,
metam
sodium,
metam
potassium
and
dazomet).
Following
application,
metam
sodium,
metam
potassium
and
dazomet
break
down
quickly
to
a
variety
of
degradates,
including
the
major
degradate,
MITC.
It
is
believed
that
MITC
that
provides
the
fumigating
properties
of
the
parent
active
ingredients.
Metam
sodium
and
metam
potassium
are
used
to
treat
sewage
systems.
Metam
sodium,
metam
potassium,
and
dazomet
are
used
as
a
soil
fumigants.
Soil
fumigants
are
pesticides
which,
when
injected
or
incorporated
into
soil,
form
a
gas
which
permeates
the
soil
and
kills
soil­
borne
pests,
such
as
insects,
microorganisms,
weeds,
and
nematodes.
After
the
fumigant
dissipates
from
the
soil
in
a
few
days
to
a
couple
of
weeks,
planting
can
take
place.
Soil
fumigants
have
the
potential
to
move
off
site
following
field
applications,
resulting
in
exposure
to
bystanders
near
treated
areas
and
to
people
far
away
from
treated
areas
through
ambient
air.
Use
of
the
soil
fumigants
also
results
in
exposure
to
those
handling
the
pesticides
or
working
in
treated
fields.
Acute
inhalation
exposures
to
bystanders
and
workers
appear
to
present
the
greatest
risk
concern.
Based
on
pounds
of
active
ingredient
applied,
metam
sodium
is
the
most
widely
used
soil
fumigant
in
the
U.
S
and
in
2001
was
the
3rd
most
commonly
used
pesticide
in
the
country.
As
such,
due
to
the
extensive
use
of
metam
sodium
as
a
soil
fumigant,
the
major
pathway
of
exposure
to
MITC
is
acute
inhalation
exposure
from
the
off­
gassing
following
metam
sodium
application.

Figure
1.
Chemical
structure
of
MITC.

The
Agency
is
currently
undertaking
a
systematic
effort
to
evaluate
the
human
health
risks
from
exposure
to
soil
fumigants.
The
public
comment
period
of
the
Agency's
preliminary
risk
assessments
for
metam
sodium
and
MITC
ended
in
October,
2005.
The
Agency's
risk
assessments
for
metam
sodium,
metam
potassium,
dazomet,
and
MITC
have
relied
on
the
MITC
eye
irritation
study
as
the
basis
for
the
point
of
departure
(
PoD)
for
acute
inhalation
exposures
to
by­
standers
and
occupational
workers
from
off­
gassing
of
MITC.
The
California
Department
of
Pesticide
Regulation
(
CDPR)
has
also
used
this
study
in
the
CDPR
human
health
risk
assessment
for
exposure
to
MITC
from
metam
sodium
applications.
In
accordance
with
the
human
studies
rule,
the
Agency
is
asking
the
Human
Studies
Review
Board
to
review
the
scientific
conduct
and
design
of
the
eye
irritation
study
and
its
potential
utility
in
assessing
human
health
risk.
Page
3
of
19
II.
Hazard
Characterization
and
Database
Summary
The
mode
of
toxic
action
for
MITC
is
not
known
at
this
time.
However,
reactivity
with
biological
nucleophiles
such
as
sulfhydryl
groups
of
glutathione
or
proteins
has
been
proposed
as
the
potential
mode
of
action
(
Valentine,
et
al.,
1995).
Consistent
with
this
proposed
mode
of
action,
MITC
is
primarily
an
irritating
compound
that
produces
non­
specific
systemic
effects
in
oral
toxicity
studies
such
as
changes
in
body
weight,
food
consumption,
and
hematological
parameters.
Following
air
exposures
to
MITC,
consistent
effects
are
observed
in
rats
and
humans.
For
example,
clinical
signs
and
pathological
changes
of
the
respiratory
tract
consistent
with
an
irritant
have
been
observed
in
laboratory
studies
in
rat.
Humans
exposed
to
MITC
complain
of
symptoms
such
as
itchy
and
burning
eyes,
rash
and
burning
skin,
nausea,
scratchy
throat,
salivation,
coughing,
and
shortness
of
breath.
In
acute
toxicity
testing
with
animals,
MITC
is
considered
Acute
Toxicity
Category
I
(
corrosive)
for
skin
and
eye
irritation.
MITC
is
also
a
skin
sensitizer
in
guinea
pigs.

A.
Animal
database
The
majority
of
animal
studies
available
for
metam
sodium/
potassium,
dazomet,
and
MITC
are
for
oral
exposure
and
are
not
considered
relevant
for
assessing
acute
inhalation
exposure
for
MITC.
At
the
present
time,
the
data
base
of
acceptable
animal
inhalation
toxicology
studies
for
MITC
is
very
limited.
A
28­
day
inhalation
study
with
MITC
in
rats
(
MRID
no.
45314802)
is
available.
There
are
several
acute
lethality
studies
available
with
MITC.
However,
one
acute
inhalation
lethality
study
(
MRID
no
45919410)
is
considered
the
most
reliable.
There
is
also
a
90­
day
inhalation
study
with
MITC
which
is
considered
unacceptable
due
a
variety
of
deficiencies
including
lack
of
nasal
pathology
and
poor
analytical
data
(
MRID
no.
41221407).
Executive
summaries
of
the
two
subchronic
studies
are
provided
in
Appendix
1.

There
are
no
studies
with
laboratory
animals
available
which
specifically
evaluate
the
dose­
response
relationship
and
the
continuum
of
potential
acute,
single­
day
respiratory
effects
(
i.
e.,
progression
to
more
serious
clinical
outcomes)
from
exposure
to
MITC.
Beginning
on
day
3
of
exposure,
observations
of
clinical
signs
of
eyelid
closure,
somnolence,
and
ruffled
fur
were
noted
in
the
28­
day
inhalation
study
in
rat.
Acute
lethality
studies
are
not
designed
to
evaluate
sub­
lethal
dose
response
effects.
At
the
lowest
exposure
concentration
of
282
mg/
m3
(
approximately
80
ppm)
in
the
acute
lethality
study,
no
mortality
or
gross
pathological
changes
were
observed
but
lung
weights
were
increased
and
rales
were
noted
on
day
one
and
reoccurred
on
day
six
post­
dosing.

B.
Human
information
Epidemiological
and
incidence
reporting
data
indicate
that
eye
and
respiratory
irritation
are
common
complaints
among
individuals
exposed
to
MITC.
Humans
exposed
to
MITC
complain
of
symptoms
such
as
itchy
and
burning
eyes,
rash
and
burning
skin,
nausea,
scratchy
throat,
salivation,
and
coughing.
According
to
California
EPA's
Risk
Characterization
Document
for
MITC
(
2003),
following
a
spill
of
metam
sodium
in
the
Sacramento
River
in
1991,
of
the
848
spill­
related
hospital
visits
(
705
separate
individuals)
in
the
month
following
the
accident,
64%
reported
headache,
49%
eye
irritation,
42%
throat
irritation,
46%
nausea,
30%
dizziness,
27%
shortness
of
breath,
Page
4
of
19
25%
diarrhea,
23%
nasal
irritation
and
22%
chest
tightness.
Measurements
of
MITC
air
levels
in
the
area
were
not
available
for
the
first
three
days
after
the
spill;
modeling
estimates
of
MITC
air
concentrations
by
CDPR
and
the
Metam
Sodium
Task
Force
range
significantly
(
3
ppm
up
to
4000
ppm)
depending
on
the
assumptions
used
in
different
modeling
simulations.
It
is,
therefore,
not
possible
to
correlate
reported
signs
and
symptoms
with
exposed
air
concentrations
based
on
these
data.
Cone
et
al.
(
1994)
performed
a
follow­
up
study
of
197
adults
referred
to
health
practitioners
for
evaluation
of
potentially
spill­
related
health
problems.
Thirty
of
these
were
considered
positive
for
persistent
effects
including
10
who
reported
persistent
exacerbation
of
asthma
and
met
the
criteria
for
reactive
airways
dysfunction
syndrome
(
RADS).
An
additional
MITC
drift
incident
occurred
in
the
town
of
Earlimart,
California
in
1999;
reported
symptoms
by
individuals
exposed
were
consistent
with
those
in
the
Sacramento
spill.
Again,
no
air
concentration
measurements
are
available;
modeling
simulations
with
EPA's
ISC
model
estimate
that
air
concentrations
of
MITC
ranged
from
0.5
to
1
ppm
(
O'Malley
et
al,
2004).

In
order
to
evaluate
human
odor
threshold
and
eye
irritation
produced
by
MITC
vapors,
human
volunteers
were
exposed
to
air
concentrations
of
MITC
in
a
laboratory
setting.
A
brief
summary
of
this
study
is
provided
below.

Summary
of
the
MITC
eye
irritation
and
odor
threshold
study
:

In
the
olfactory
threshold
study,
33
individuals
(
16
males,
17
females)
with
a
mean
age
of
25
years
(
range,
18
to
34
years)
were
tested.
They
were
exposed
to
three
positive
control
odorants,
pyridine,
acetic
acid,
and
n­
butyl
alcohol
as
well
as
to
MITC.
The
technician
chose
the
odorant
and
concentration
level.
The
odorant
was
dispensed
in
double
blind
fashion
from
one
of
three
presentation
ports.
The
subject
was
responsible
for
identifying
from
which
of
the
presentation
ports
the
odorant
was
dispersed.
A
30­
second
rest
period
between
exposures
was
permitted
in
order
to
allow
the
subject
to
recover
prior
to
the
next
exposure.
The
operator
tested
each
subject
over
the
range
of
concentrations
for
each
odorant
until
he
was
assured
that
the
threshold
had
been
adequately
ascertained.
A
standard
procedure
was
employed
in
order
to
make
this
determination.
The
observed
odor
threshold
for
MITC
ranged
from
0.2
to
8
ppm
with
a
geometric
mean
of
1.7
ppm.

In
the
eye
irritation
study,
seventy
individuals
(
38
males,
32
females)
with
a
mean
age
of
32
years
(
range,
18­
67
years;
median
age,
28
years)
were
exposed
to
air,
MITC,
and/
or
acetic
acid.
Between
9
and
16
subjects
were
examined
under
each
dose/
time
period
combination.
Some
individuals
were
tested
for
more
than
one
exposure
duration.
The
subject
identification
numbers
were
changed
with
each
session
and
thus,
the
reader
can
not
determine
which
subjects
were
included
repeatedly.
Sessions
consisting
of
three
exposure
durations
(
14
minutes,
4
hours
and
8
hours)
were
included.
A
range
of
MITC
concentrations
were
used
(
see
Table
1).
Page
5
of
19
An
olfactometer
which
permitted
the
operator
to
dispense
the
test
material
through
a
manifold
system
was
used.
The
test
material
could
thus
be
diluted
over
a
100­
fold
concentration
range.
The
olfactometer
was
modified
by
attaching
goggles
to
the
presentation
line.
This
permitted
the
test
material
to
be
directed
only
to
the
eyes.
Five
parameters
were
used
to
ascertain
an
irritation
response:

1.
the
subjects'
subjective
estimation
of
irritation
(
using
the
"
Likert"
scale).
Subjects
marked
the
level
of
perceived
irritation
from
`
no
irritation'
to
`
so
much
that
you
feel
you
should
end
the
exposure'
with
mid­
level
similar
to
that
for
cutting
up
an
onion;
2.
photographs
of
the
subjects'
eyes
prior
to
and
after
exposure;
3.
blink
rate
as
measured
by
electromyography;
4.
effect
upon
visual
acuity;
5.
tear
production.

Both
a
positive
control
(
acetic
acid)
and
a
negative
control
(
air)
were
employed.
Baseline
responses
for
each
of
the
assessment
parameters
were
determined
under
preexposure
conditions
("
zero­
time
controls")
and
upon
exposure
to
the
negative
control
("
air­
only
controls")
for
the
prescribed
period.
A
positive
irritation
response
was
based
on
three
criteria:
1.
the
average
response
must
be
quantitatively
greater
than
the
preexposure
response;
2.
the
average
response
must
be
greater
than
pre­
exposure
and
greater
than
could
be
expected
statistically
from
individual
to
individual
differences
within
the
group;
3.
the
average
treated
response
must
be
greater
than
the
air­
only
group's
response
and
greater
than
could
be
expected
from
individual
differences
observed
within
the
group.

In
the
eight
hour
test,
subjective
responses,
blink
rates
and
tearing
were
assessed
at
0,
1.5,
3,
3.5,
6
and
8
hours
(
tearing
was
not
measured
at
3.5
hours).
Two
15­
minute
rest
breaks
and
a
30­
minute
lunch
break
were
permitted
during
the
8­
hour
period.
In
the
four
hour
test,
these
same
parameters
were
assessed
at
0,
1,
2,
3
and
4
hours
(
tearing
was
not
measured
at
0,
2
and
3
hours).

In
the
14­
minute
exposure
protocol,
subjective
responses
and
blink
rates
were
measured
at
0,
1,
4
and
14
minutes
after
the
start
of
exposure.
Tearing
was
measured
at
14
minutes
only.
Visual
acuity
and
ocular
morphology
were
assessed
at
the
beginning
and
end
of
each
exposure
period.

All
analyses
were
performed
in
a
double­
blind
manner.
Table
1
below
provides
the
design
for
the
study.
Page
6
of
19
Table
1:
Study
design
for
the
eye
irritation
human
study
with
MITC.

Duration
Dates
Concentration(
s)
Tested
Number
of
subjects
Air
only
control
12
Acetic
acid
control
7
8
hour
trial
12/
8/
94
 
1/
9/
95
0.22
ppm
16
Air
only
control
12
Acetic
acid
control
14
0.23
ppm
12
4
hour
trial
3/
13/
95
 
3/
31/
95
0.8
ppm
9
Air
only
control
10
Acetic
acid
control
0
0.6
ppm
9
1.9
ppm
9
14
minute
4/
18/
95
 
4/
26/
95
3.3
ppm
9
Subjective
(
Likert
scale)
responses.
Exposure
to
0.8
ppm
(
800
ppb)
MITC
resulted
in
a
statistically
significant
positive
response
based
on
averaging
the
subjective
assessments
by
the
subjects
using
the
Likert
scale
methodology
(
Table
2).
In
that
test,
as
many
as
8
out
of
9
subjects
showed
a
positive
response
at
1
and
2
hours,
the
first
two
time
points
examined.
(
Note:
judgement
of
a
positive
response
is
itself
somewhat
subjective
in
light
of
the
variability
observed
among
control
subjects.)
Mean
responses
at
those
times,
expressed
as
the
percentage
of
the
full
Likert
scale
indicated
by
the
subject,
were
25%
±
14%
and
26%
±
14%,
respectively,
compared
to
2%
±
2%
in
zero­
time
untreated
controls
(
a
judgement
of
50%
was
stated
to
be
equivalent
to
the
irritation
one
might
expect
from
the
cutting
of
a
single
mild
onion).
One­
hour
and
2­
hour
air­
only
controls
exhibited
responses
of
6%
±
9%
and
5%
±
8%,
respectively.
By
3
and
4
hours,
all
9
subjects
at
0.8
ppm
appeared
to
respond
positively,
with
mean
responses
of
39%
±
19%
and
39%
±
26%,
respectively.
Air­
only
controls
at
the
latter
2
times
were
5%
±
6%
and
4%
±
6%,
respectively.

Exposure
to
0.22
ppm
(
220
ppb)
did
not
result
in
a
statistically
significant
mean
Likert
scale
response
when
compared
against
air­
only
controls.
Despite
the
fact
that
statistical
significance
was
achieved
at
1
hour
when
compared
against
zero­
time
controls
(
13%
±
15%
vs.
4%
±
8%
among
zero­
time
controls),
the
lack
of
statistical
significance
when
compared
against
air­
only
controls
(
which
registered
6%
±
9%)
resulted
in
a
judgement
of
no
response.
Page
7
of
19
Shorter
exposures
to
0.6
ppm
(
600
ppb)
did
not
result
in
statistically
significant
Likert
scale
changes,
though
1
of
9
individuals
appeared
to
respond
at
4
and
14
minutes.
Exposure
to
1.9
ppm
(
1900
ppb)
or
3.3
ppm
(
3300
ppb)
MITC
for
4
or
14
minutes
resulted
in
positive
subjective
responses
at
4
and
14
minutes.
At
1
minute
of
exposure,
levels
as
high
as
3.3
ppm
did
not
evoke
a
statistically
significant
positive
response.

Table
2.
Mean
perception­
of­
eye­
irritation
(
Likert
scale)
data,
human
subjects
Units:
%
of
total
line
distance
(
standard
deviation)

4­
hr
trial
Time
points,
hours
0
1
2
3
4
#
subjects
Air­
only
control
p­
value
#
1a
p­
value
#
2b
1%
(
2%)
n/
a
n/
a
6%
(
9%)
n/
a
0.08
5%
(
8%)
n/
a
0.07
5%
(
6%)
n/
a
0.02
4%
(
6%)
n/
a
0.07
12
0.22
ppm
p­
value
#
1a
p­
value
#
2b
4%
(
8%)
0.21
n/
a
13%
(
15%)
0.16
0.02
8%
(
10%)
0.43
0.05
6%
(
8%)
0.55
0.16
6%
(
7%)
0.49
0.42
12
0.8
ppm
p­
value
#
1a
p­
value
#
2b
2%
(
2%)
0.57
n/
a
25%
(
14%)*
0.00
0.00
26%
(
14%)*
0.00
0.00
39%
(
19%)*
0.00
0.00
39%
(
26%)*
0.00
0.00
9
ap­
value
#
1,
t­
test
against
air­
only
control
subjects
bp­
value
#
2,
t­
test
against
zero­
time
values
*
Judged
a
positive
irritation
response.
An
irritation
effect
is
considered
to
have
been
detected
only
if
both
statistical
tests
indicate
significant
differences
and
if
mean
is
higher
than
the
zero­
time
mean.

8­
hr
trial
Time
points
(
hours)
0
1.5
3
3.5
6
8
subjects
Air­
only
control
p­
value
#
1a
p­
value
#
2b
1%
(
1%)
n/
a
n/
a
9%
(
10%)
n/
a
0.04
12%(
15%)
n/
a
0.03
6%
(
10%)
n/
a
0.16
15%(
19%)
n/
a
0.03
8%
(
13%)
n/
a
0.09
12
0.22
ppm
p­
value
#
1a
p­
value
#
2b
2%
(
2%)
0.23
n/
a
5%
(
4%)
0.18
0.01
5%
(
4%)
0.10
0.00
4%
(
4%)
0.44
0.24
8%
(
8%)
0.18
0.01
6%
(
5%)
0.46
0.00
16
0.8
ppm
p­
value
#
1a
p­
value
#
2b
Not
done
n/
a
ap­
value
#
1,
t­
test
against
air­
only
control
subjects
bp­
value
#
2,
t­
test
against
zero­
time
values
Page
8
of
19
Eyeblink
responses.
Mean
blink
rate
determinations
at
0.8
ppm
were
statistically
significantly
increased
at
the
2­
and
3­
hour
time
points
compared
both
to
air­
only
and
zero­
time
controls
(
Table
3),
with
7
of
9
subjects
responding
positively.
Mean
blinks
per
minute
(
minus
the
zero­
time
rate)
were
16
±
11
and
14
±
13
at
those
times.
Air­
only
control
rates
at
2
and
3
hours
were
3
±
9
and
3
±
8
blinks
per
minute,
respectively.
Statistical
significance
was
not
achieved
at
1
and
4
hours,
though
a
positive
response
was
indicated
in
several
individuals.
The
blink
response
to
0.6
ppm
and
1.9
ppm
at
1,
4
and
14
minutes
did
not
indicate
positivity.
At
3.3
ppm,
statistical
significance
was
achieved
at
4
and
14
minutes.
A
strong
suggestion
of
a
response
was
also
present
at
1
minute,
though
it
was
not
statistically
significant.

Table
3.
Mean
eyeblink
data,
human
subjects
Units:
Blinks
per
minute
minus
zero­
time
rate
(
standard
deviation)

4­
hr
trial
Time
points,
hours
0
1
2
3
4
#
subjects
Air­
only
control
p­
value
#
1a
p­
value
#
2b
n/
a
3
(
6)
n/
a
0.13
3
(
9)
n/
a
0.24
3
(
8)
n/
a
0.23
3
(
8)
n/
a
0.18
12
0.22
ppm
p­
value
#
1a
p­
value
#
2b
n/
a
­
5
(
6)
0.00
0.02
­
2
(
6)
0.13
0.35
­
5
(
5)
0.01
0.01
­
3
(
4)
0.03
0.04
12
0.8
ppm
p­
value
#
1a
p­
value
#
2b
n/
a
7
(
7)
0.15
0.00
16
(
11)*
0.01
0.00
14
(
13)*
0.03
0.01
12
(
11)
0.052
0.01
9
ap­
value
#
1,
t­
test
against
air­
only
control
subjects
bp­
value
#
2,
t­
test
against
zero­
time
values
*
Judged
a
positive
irritation
response.
An
irritation
effect
is
considered
to
have
been
detected
only
if
both
statistical
tests
indicate
significant
differences
and
if
mean
is
higher
than
the
zero­
time
mean.

8­
hr
trial
Time
points
(
hours)
0
1.5
3
3.5
6
8
#
subjects
Air­
only
control
p­
value
#
1a
p­
value
#
2b
n/
a
­
2
(
7)
n/
a
0.42
­
3
(
7)
n/
a
0.15
­
1
(
5)
n/
a
0.48
­
1
(
7)
n/
a
0.54
0
(
7)
n/
a
0.97
12
0.22
ppm
p­
value
#
1a
p­
value
#
2b
n/
a
­
3
(
6)
0.62
0.07
­
2
(
5)
0.67
0.15
­
2
(
5)
0.55
0.10
­
2
(
4)
0.81
0.12
­
2
(
5)
0.48
0.19
16
0.8
ppm
p­
value
#
1a
p­
value
#
2b
Not
done
n/
a
ap­
value
#
1,
t­
test
against
air­
only
control
subjects
bp­
value
#
2,
t­
test
against
zero­
time
values
Page
9
of
19
Tearing,
ocular
morphology,
and
visual
acuity.
No
statistically
positive
tearing
responses
were
observed.
However,
2
of
9
individuals
exposed
to
3.3
ppm
MITC
showed
apparently
positive
responses
at
14
minutes
(
longer
exposures
were
not
evaluated
at
this
concentration).

With
respect
to
the
possibility
that
there
were
changes
in
ocular
morphology
or
visual
acuity,
the
following
passage
is
quoted
from
the
study
report
(
page
39):

"
Preliminary
analysis
of
the
photographs
of
test
subjects'
eyes
indicated
that
no
notable,
exposure
related
changes
were
observable
in
the
large
majority
of
tests.
In
a
few
tests
in
which
minimal
increases
in
redness
and
swelling
were
observed,
it
appeared
that
they
were
more
likely
to
occur
in
exposures
to
air
than
in
exposures
to
MITC.
A
few
individuals
evinced
a
degree
of
mild
edema
at
the
highest
level
of
MITC
exposure,
but
this
tended
to
be
canceled
out
by
other
subjects
who
evinced
some
native
edema
and
redness,
pre­
exposure
in
the
early
morning.
Changes
in
subjects'
visual
acuity
were
also
few
and
apparently
random.
Accordingly
the
results
of
the
photographic
and
acuity
tests
were
not
considered
to
provide
any
meaningful
information
on
chemical
exposure.
Results
from
these
tests
are
retained
in
study
records."

Recovery.
Rates
of
recovery
from
irritating
MITC
exposures
were
not
evaluated
directly.
The
comments
of
the
test
subjects
indicated
that
recovery
began
immediately
upon
removal
of
the
masks,
and
was
complete
within
20
minutes
at
the
highest
concentration
tested,
and
sooner
at
lower
concentrations.
Page
10
of
19
Table
4.
Summary
of
MITC
eye
irritation
effects
from
human
subjects
Exposure
time
NOAEL
(
ppm)
LOAEL
(
ppm)
Source
of
observed
Effect
1
minute
3.3
­
­

4
minutes
0.6
1.9
Subjective
eye
irritation
14
minutes
0.6
1.9
Subjective
eye
irritation
1
hour
0.23a
0.8
Subjective
eye
irritation
1.5
hours
0.22a
­
­

2
hours
0.23a
0.8
Subjective
eye
irritation
and
blink
rate
3
hours
0.23a
0.8
Subjective
eye
irritation
and
blink
rate
3.5
hours
0.22a
­
­

4
hours
0.23a
0.8
Subjective
eye
irritation
6
hours
0.22a
­
­

8
hours
0.22a
­
­

aThe
slightly
different
values
obtained
at
the
low
dose
NOAEL
level
(
0.22
and
0.23
ppm)
reflected
the
fact
that
they
were
derived
from
tests
performed
on
different
days.

Conclusions
from
the
eye
irritation
portion
of
the
study
include:

°
For
a
one­
minute
exposure,
the
NOAEL
for
eye
irritation
is
3.3
ppm
due
to
a
lack
of
response
in
any
parameter
tested.

°
For
exposures
4­
14
minutes,
the
NOAEL
for
eye
irritation
is
0.6
ppm
based
on
responses
on
the
Likert
subjective
scale
at
1.9
ppm.

°
For
exposures
of
1­
8
hours,
based
on
the
statistically
significant
subjective
(
Likert
scale)
responses
at
0.8
ppm
MITC
at
1­
4
hours
and
the
statistically
significant
eyeblink
responses
at
2
and
3
hours,
0.22
ppm
was
designated
as
the
NOAEL
for
this
study.
Page
11
of
19
C.
Point
of
Departure
and
Uncertainty
Factor(
s)

As
stated
above,
there
are
no
studies
with
laboratory
animals
available
which
specifically
evaluate
the
dose­
response
relationship
and
the
continuum
of
potential
acute,
single­
day
respiratory
effects
(
i.
e.,
progression
to
more
serious
clinical
outcomes)
from
exposure
to
MITC.
In
most
cases,
the
Agency
does
not
consider
an
acute
lethality
study
as
appropriate
for
deriving
a
PoD
for
assessing
human
health
risk
assessment.
For
purposes
of
characterization
the
Agency
has
evaluated
the
potential
that
the
acute
inhalation
lethality
study
in
rat
could
provide
a
PoD
for
acute
risk
assessment
of
MITC.
If
the
lowest
dose
in
the
acute
lethality
study
of
282
mg/
m3
is
treated
as
an
acute
lowobserved
adverse­
effect­
level
(
LOAEL)
and
a
typical
LOAEL
to
NOAEL
10X
factor
is
applied
along
with
100X
for
inter­
and
intra­
species
variation,
then
the
final
value
would
be
0.24
mg/
m3.
The
1­
8
hour
NOAEL
from
the
eye
irritation
study
is
0.66
mg/
m3
(
0.22
ppm).
Using
an
intra­
species
factor
of
10X,
the
final
regulatory
value
from
the
eye
irritation
study
is
0.066
mg/
m3.
Thus,
in
the
case
of
MITC,
use
of
the
human
eye
irritation
study
provides
a
more
sensitive
endpoint
for
assessing
acute
human
health
risk
to
MITC.

Eye
irritation
is
not
an
effect
from
inhalation
exposure
per
se.
However,
eye
irritation
can
result
from
exposures
in
the
air.
With
respect
to
respiratory
impairment,
arguably,
eye
irritation
is
less
severe
compared
to
other
possible
effects
associated
with
inhalation
exposure
to
MITC,
particularly
given
the
expected
reversible
nature
of
the
eye
irritation
effects
at
lower
concentrations.
Nonetheless,
eye
(
as
well
as
nose
and
throat)
irritation
is
uncomfortable
and
could
potentially
interfere
with
everyday
tasks
or
activities.
OPP
notes
that
the
Agency's
Reference
Concentration
(
RfC)
methodology
(
1994)
includes
eye,
nasal,
and
throat
irritation
in
the
list
of
adverse
effects­­
albeit
at
the
lower
end
of
the
hierarchal
list
which
ranks
effects
from
most
to
less
severe.
Due
to
the
limitations
in
the
existing
inhalation
toxicology
database
for
MITC,
the
degree
to
which
eye
irritation
predicts
more
serious
outcomes
is
unclear.
However,
given
that
humans
exposed
to
MITC
complain
of
symptoms
such
as
itchy
and
burning
eyes
in
addition
to
rash
and
burning
skin,
nausea,
scratchy
throat,
salivation,
coughing,
and
shortness
of
breath,
in
the
absence
of
more
robust
dose­
response
data
from
acute
exposures,
eye
irritation
can
be
considered
as
a
biomarker
and
surrogate
for
potential
respiratory
effects.

The
MITC
odor
threshold
and
eye
irritation
study
(
MRID
44400401)
evaluated
the
dose­
response
relationship
for
eye
irritation
at
exposure
durations
ranging
from
4
minutes
to
8
hours.
The
results
of
the
odor
threshold
study
indicate
that
the
eyes
are
likely
to
become
irritated
prior
to
detecting
the
odor;
thus
the
odor
threshold
study
has
not
be
used
for
PoD
derviation.
The
eye
irritation
study
with
MITC
appears
to
have
been
scientifically
well
conducted
with
sensitive
methods
similar
to
those
used
by
other
laboratories
(
Doty
et
al,
2004).
The
study
provides
a
dose
and
time­
related
response
to
MITC
for
the
subjective
scale
and
the
blinking
rate.
Thus,
the
Agency
has
selected
the
human
eye
irritation
study
as
the
basis
for
the
PoD
in
acute
risk
assessment
to
MITC
in
air.
Page
12
of
19
The
Agency
has
established
the
following
PoDs
for
varying
durations
of
exposure:

°
For
a
one­
minute
exposure,
the
NOAEL
(
no­
observed­
adverse­
effect­
level)
for
eye
irritation
is
3.3
ppm
due
to
a
lack
of
response
in
any
parameter
tested.

°
For
exposures
4­
14
minutes,
the
NOAEL
for
eye
irritation
is
0.6
ppm
based
on
responses
on
the
Likert
subjective
scale
at
1.9
ppm.

°
For
exposures
of
1­
8
hours,
based
on
the
statistically
significant
subjective
(
Likert
scale)
responses
at
0.8
ppm
MITC
at
1­
4
hours
and
the
statistically
significant
eyeblink
responses
at
2
and
3
hours,
0.22
ppm
was
designated
as
the
NOAEL.

For
acute
inhalation
exposures
to
MITC,
because
a
study
using
human
subjects
is
being
used,
an
interspecies
factor
is
not
necessary.
A
standard
10X
was
assigned
for
intraspecies
variability.

III.
Conclusions
The
general
public
may
be
exposed
to
fumigants,
like
MITC,
in
air
following
application
because
of
their
volatility
since
these
chemicals
can
off­
gas
into
ambient
air
and
can
be
transported
off­
site
by
wind
to
non­
agricultural
areas.
The
inhalation
database
for
MITC
for
acute
exposures
is
limited.
The
Agency
has
selected
the
human
eye
irritation
study
as
the
appropriate
study
for
deriving
a
PoD
for
assessing
acute
risk
to
MITC.
Page
13
of
19
References:

California
Environmental
Protection
Agency,
(
2003)
Risk
Characterization
Document
for
MITC.
Department
of
Pesticide
Regulation,
California
Environmental
Protection
Agency
July
25,
2003.

Cone,
J.
E.,
L.
Wugofski,
J.
R.
Balmes,
R.
Das,
R.
Bowler,
G.
Alexeeff
and
D.
Shusterman.
1994.
Persistent
respiratory
health
effects
after
a
metam
sodium
pesticide
spill.
Chest
106:
500­
508
Doty
RL,
Cometto­
Muniz
JE,
Jalowayski
AA,
Dalton
P,
Kendal­
Reed
M,
Hodgson
M.
(
2004)
Assessment
of
upper
respiratory
tract
and
ocular
irritative
effects
of
volatile
chemicals
in
humans.
Crit
Rev
Toxicol.
2004
Mar­
Apr;
34(
2):
85­
142.

O'Malley,
M,
Barry,
T,
Verder­
Carlos,
M,
Rubin,
A.
2004.
Modeling
of
methyl
isothiocyanate
air
concentrations
associated
with
community
illnesses
following
a
metam
sodium
sprinkler
application.
American
Journal
of
Industrial
Medicine.
46:
1­
15.

41221407
Rosskamp,
G.;
Schobel,
G.;
Bhargava,
A.;
et.
al.
(
1978)
T22
Methyl
Isothiocyanate:
ZK
3.318:
A
12_
13
Week
Inhalation
Study
in
the
Rat:
Project
ID
374/
77.
Unpublished
study
prepared
by
Schering
AG.
202
p.

44400401
Russell,
M.;
Rush,
T.
(
1996)
Methyl
Isothiocyanate:
Determination
of
Human
Olfactory
Detection
Threshold
and
Human
No
Observable
Effect
Level
for
Eye
Irritation:
Lab
Project
Number:
MITC_
UCD_
1A_
1993:
MITC_
UCD_
1B_
1994:
RR
96_
049B.
Unpublished
study
prepared
by
University
of
California
and
Western
Research
Center
(
Zeneca).
136
p.

45314802
Klimisch,
H.
(
1987)
Study
of
the
Subchronic
Inhalation
Toxicity
of
Methyl
Isothiocyanate
in
Wistar
Rats
(
4_
Week
Study):
Lab
Project
Number:
87/
0244:
40I0231/
8539.
Unpublished
study
prepared
by
BASF
Aktiengesellschaft.
272
p.

45919410
Jackson,
G.;
Clark,
G.;
Prentice,
D.;
et
al.
(
1981)
Methyl
Isothiocyanate:
Acute
Inhalation
Toxicity
in
Rats__
4
Hour
Exposure:
Lab
Project
Number:
81/
082:
378/
801109.
Unpublished
study
prepared
by
Huntingdon
Research
Center.
115
p.

US
Environmental
Protection
Agency.
1994.
Methods
for
derivation
of
inhalation
reference
concentrations
and
application
of
inhalation
dosimetry.
Office
of
Research
and
Development.
EPA/
600/
8­
90/
066F,
October
1994.

Valentine,
W.
M.,
Amarnath,
V.,
Amarnath,
K.,
and
Graham,
D.
G.
1995.
Characterization
of
protein
adducts
produced
by
N­
methyldithiocarbamate
and
N­
methyldithicarbamate
esters.
Chem.
Res.
Toxicol.
8:
254­
261.
Page
14
of
19
Appendix
1:
Executive
summaries
of
sub­
chronic
inhalation
studies
with
MITC.
Page
15
of
19
CITATION:
Klimisch,
H.
J.
(
1987).
Study
of
the
Subchronic
Inhalation
Toxicity
of
Methyl
Isothiocyanate
in
Wistar
Rats
(
4
weeks
study).
Department
of
Toxicology.
BASF
Aktiengesellschaft,
D­
W6700
Ludwigshafen,
Federal
Republic
of
Germany.
Project
No
4010231/
8539,
BASF
Reg.
Document
Number
87/
0244,
January
29,
1987.
MRID
45314802.
Unpublished.

EXECUTIVE
SUMMARY:
In
a
28
day
inhalation
toxicity
study
(
MRID
45314802),
Methyl
Isothiocyanate
[
96.9
%
a.
i.]
was
administered
to
5/
sex/
dose
of
SPF
Wistar/
Chubb:
THOM
rats
by
whole
body
exposure
at
analytical
concentrations
of
0,
5.0,
20,
or
100
mg/
m3
equivalent
to
0,
5.0,
20,
or
100
ug/
L
(
measured
concentrations
0,
5.1,
19.9
or
100
ug/
L)
and
(
equivalent
to
concentrations
of
0,
1.7,
6.8,
and
34
ppm)
for
6
hours
per
day,
5
days/
week
for
a
total
of
28
days.

All
animals
survived
to
study
termination.
Mid
and
high
dose
rats
demonstrated
clinical
signs
during
exposure
from
the
third
exposure
period
day.
No
clinical
signs
were
observed
in
the
low
dose
animals.
According
to
the
study
report,

"
During
exposure,
the
animals
of
test
group
2
showed
eyelid
closure,
somnolence,
and
ruffled
fur
from
the
third
day
of
exposure
onwards.
On
the
next
morning
before
exposure
nothing
abnormal
was
found
in
the
animals......
At
20
mg/
m3
the
animals
showed
first
indications
of
an
irritating
effect
of
the
test
substance
and
a
slightly
deteriorated
general
state
of
health."

Additional
clinical
signs
observed
at
the
high
exposure
concentration
included
reddish
nasal
discharge,
salivation,
eye
discharge,
and
difficulty
in
breathing
or
whooping
respiration,
and
stretched
posture.
In
the
high
dose
rats,
although
signs
recovered
between
exposures
at
the
beginning
of
the
study,
towards
the
end
of
the
study
ruffled
fur
and
respiratory
sounds
were
no
longer
reversible.

Body
weight
and
body
weight
gain
were
significantly
decreased
(
p<
0.05)
at
the
high
dose.
Food
consumption
and
feed
efficiency
were
not
measured.
There
were
decreases
in
plasma
urea,
glucose,
triglyceride,
and
albumin
the
high
dose
males.
In
high
dose
females,
urea
and
glucose
were
also
decreased.
In
the
males
of
mid
exposure
group,
there
was
a
decrease
in
urea
concentration
in
the
plasma.

At
the
mid
and
high
exposure
concentrations,
increase
in
neutrophilic
polymorphonuclear
granulocytes
in
the
peripheral
blood
was
observed
in
males;
this
was
also
observed
in
the
high
exposure
concentration
for
females.

There
was
increased
lung
weight
at
the
high
exposure
concentration.
Histopathology
revealed
an
increase
in
incidence
and
severity
of
rhinitis
in
the
nasal
cavity
at
the
high
exposure
concentration
in
both
sexes
(
incidence
in
males:
2/
5,
2/
5,
2/
5,
5/
5;
females:
0/
5,
3/
5,
1/
5,
5/
5).
Other
histopathologic
findings
at
the
high
exposure
concentration
included:
atrophy
of
the
olfactory
epithelium,
metaplasia
of
the
nasal
respiratory
epithelium
(
3
males
in
section
plane
1
only,
5
females
in
section
planes
1
and,
to
a
lesser
extent,
section
plane
2),
tracheal
epithelial
proliferation
and
single
cell
necrosis
(
all
high
exposure
concentration),
bronchopneumonia
and
bronchial
and
bronchiolar
epithelial
proliferation
(
5
males,
2
females),
and
emphysema
(
3
males,
2
females).
Page
16
of
19
The
systemic
LOAEL
is
19.9
mg/
m3,
(
6.8
ppm),
based
on
clinical
signs
consistent
with
irritation
in
both
sexes
and
increased
neutrophilic
polymorphonuclear
granulocytes
in
the
blood
of
males.
The
systemic
NOAEL
is
5
mg/
m3
(
1.7
ppm).

The
LOAEL
for
effects
in
the
extrathoracic
(
ET)
region
is
100
mg/
m3,
(
34ppm),
based
on
observation
of
pathological
changes
of
the
nasal
cavity
(
metaplasia
of
respiratory
epithelium
and
atrophy
of
the
olfactory
epithelium).
The
ET
NOAEL
is
19.9
mg/
m3
(
6.8
ppm).

The
LOAEL
for
effects
in
the
tracheabronchial
(
TB)
region
is
100
mg/
m3
(
34ppm),
based
on
observation
of
pathological
changes
(
tracheal
epithelial
proliferation
and
single
cell
necrosis,
bronchopneumonia
and
bronchial
and
bronchiolar
epithelial
proliferation).
The
TB
NOAEL
is
19.9
mg/
m3(
6.8
ppm).

This
subchronic
toxicity
study
is
Acceptable
but
does
not
satisfy
the
guideline
requirement
for
a
subchronic
inhalation
study
(
82­
4)
in
the
rat.
The
study
duration
was
too
short
and
the
number
of
animals
used
were
inadequate
to
satisfy
the
Guideline
requirement.
Detailed
tables
of
the
clinical
signs
were
not
provided
in
the
study
report.
Page
17
of
19
CITATION:
Rosskamp,
G.;
Schobel,
G.;
Bhargava,
A.;
et.
al.
(
1978)
T22
Methyl
Isothiocyanate:
ZK
3.318:
A
12­
13
Week
Inhalation
Study
in
the
Rat:
Project
ID
374/
77.
Prepared
by
Schering
AG.
November
26,
1975
MRID
no.
41221407.
Unpublished
Davis,
C.
(
1990)
Nor­
Am
Chemical
Company
Phase
3
Summary
of
MRID
41221407.
Methyl
Isothiocyanate:
A
12­
13
Week
Inhalation
Study
in
the
Rat
(
T22);
Lab
ID.
No.
374/
77.
Prepared
by
Schering
AG,
Berlin,
Federal
Republic.
September
26,
1978
MRID
no.
92114013.
Unpublished
EXECUTIVE
SUMMARY:
In
a
subchronic
inhalation
study
(
MRID
no.
41221407)
4
groups
of
10
Wistar
rats/
sex/
dose
received
a
nose­
only
inhalation
exposure
to
MITC
(
95.69%
a.
i.,
Batch
no.
26,300)
at
0,
3.16,
30.67,
and
137.13
ug/
L
for
4
hours/
day,
5
days/
week
over
a
12
to
13
week
period
(
By
extrapolation
from
four
to
six
hours
of
exposure,
the
dose
levels
are
0,
2.1,
20.6,
and
91.9
ug/
L).
There
were
two
control
groups
of
10
rats/
sex/
dose,
one
maintained
in
the
laboratory
without
inhalation
exposure
and
the
other
in
chamber
without
MITC.

No
effects
on
urinalysis
parameters,
gross
or
microscopic
pathology
or
organ
weights
were
noted
at
any
dose
level.
Although
no
clinical
signs
were
noted
in
the
low
or
middle
dose
groups,
clinical
signs
of
apathetic
appearance
accompanied
with
salivation
and
nasal
discharge
was
observed
throughout
the
study
in
high
dose
rats.
Six
of
20
rats
in
the
high
dose
exhibited
stimulated
vocalization
during
the
last
30
days
of
exposure.

A
treatment
related
decrease
in
body
weight
gain
was
noted
in
male
and
females
of
the
middle
(
11%
M
and
15%
F,
not
statistically
significant)
and
the
high
(
63%
M
and
47%
F,
p
<
0.01)
dose
groups.
A
treatment
related
increase
in
water
consumption
was
noted
in
males
and
females
of
the
mid
dose
group
(
14%
and
21%,
p
<
0.05)
and
males
of
the
high
dose
group
(
16%,
p<
0.05).
Food
consumption,
however,
was
decreased
(
p
<
0.05)
in
only
the
high
dose
group.

Hematological
parameters
of
leucocyte
and
neutrophil
counts
and
hematocrit
and
RBC
values
were
significantly
increased
in
the
high
dose
group
only.
A
significant
decrease
in
total
blood
protein
was
noted
in
males
and
females
of
the
mid
dose
group
(
p<
0.05)
and
females
of
the
high
dose
group.
Changes
in
fasting
glucose,
alkaline
phosphatase,
and
alanine
aminotransferase
were
also
in
the
high
dose
females.

Effects
reported
at
the
mid
dose
were
decreased
body
weight,
food
efficiency
and
blood
protein
values
accompanied
by
increased
water
intake.
At
the
high
dose
(
91.9
ug/
L)
the
animals
exhibited
apathy,
salivation,
nasal
discharge,
and
stimulated
vocalization.
These
animals
exhibited
a
decrease
in
body
weight,
food
intake,
and
food
efficiency
accompanied
by
an
increase
in
water
intake.
Alterations
in
clinical
chemistry
values
at
this
dose
included
decreased
total
protein
with
increased
alkaline
phosphatase
and
alanine
aminotransferase
values.

Overall,
the
results
of
this
study
are
questionable
for
a
variety
reasons
detailed
by
California
Department
of
Pesticide
Regulation.
The
following
text
was
extracted
from
California
Environmental
Protection
Agency,
(
2003)
RISK
CHARACTERIZATION
DOCUMENT
Methyl
Isothiocyanate
(
MITC)
Following
the
Agricultural
Use
of
Metam
Sodium,
Sacramento,
California
July,
2003.
Page
18
of
19
It
may
be
asked
why
the
12­
13­
week
rat
nose­
only
inhalation
study
of
Rosskamp
(
1978)
did
not
provide
the
critical
subchronic
NOEL.
In
this
study,
the
endpoints
used
to
establish
the
NOEL
of
1
ppm
were
decrements
in
weight
gain,
increased
water
consumption
and
decreased
serum
protein
levels,
all
occurring
at
the
LOEL
concentration
of
10
ppm.
Overt
toxicity
in
the
form
of
salivation
/
nasal
discharge,
mild
and
moderate
apathy,
vocalization
and
a
much
more
severe
weight
gain
decrement
were
detected
at
the
high
dose
of
45
ppm.
However,
there
was
massive
uncertainty
inherent
in
the
study
report,
which
made
it
very
difficult
to
rely
upon
it
for
risk
assessment
purposes,
particularly
as
another
more
adequate
study
using
the
same
strain
of
rat
was
available.
The
uncertainties
are
delineated
as
follows:

1.
The
toxicologic
significance
of
the
three
endpoints
used
to
establish
the
NOEL
was
not
clear.
Statistically
significant
decreases
in
body
weight
gain
with
respect
to
sham­
treated
controls
only
occurred
at
the
high
dose
of
45
ppm,
while
a
much
lower,
non­
statistically
significant
decrement
was
noted
at
the
mid
dose
(
10
ppm).
Interestingly,
a
much
larger
suppression
of
body
weight
gain
was
evident
in
the
sham­
treated
controls
when
compared
to
the
untreated
controls
than
occurred
when
comparing
the
sham­
treated
controls
to
the
10
ppm
animals.
This
may
indicate
the
presence
of
a
stress
effect
imposed
on
the
animals
as
they
were
fitted
into
the
nose­
only
apparatus
day
after
day.
Individual
animal
data
were
not
supplied,
making
it
impossible
to
say
with
assurance
what
the
effect
was
on
individual
animals.
In
the
case
of
water
consumption,
the
increase
that
was
observed
compared
to
sham­
treated
controls
was
statistically
significant
at
both
10
and
45
ppm
(
in
females
only
at
the
latter
dose),
though
the
values
at
45
ppm
were
not
greater
than
those
at
10
ppm.
The
significant
decrease
in
serum
protein
in
mid
and
high
dose
males
and
high
dose
females
was
conceivably
a
consequence
of
the
increased
water
consumption.
(
However,
a
similar
lowering
of
serum
protein
was
detected
in
the
chronic
mouse
drinking
water
study
in
conjunction
with
a
decrease
in
water
consumption
[
Sato,
1980],
raising
the
possibility
that
protein
levels
were
suppressed
independent
of
an
effect
on
water
consumption,
perhaps
due
to
an
effect
of
MITC
on
the
liver.)

2.
Insufficient
analytic
data
were
provided
in
the
study
report
to
validate
the
reported
chamber
concentrations.
According
to
the
report,
MITC
levels
were
determined
at
hours
1
and
3
during
each
4­
hour
exposure
by
withdrawing
the
chamber
air
for
10
minutes
and
routing
it
to
an
infra­
red
analyzer.
The
reported
levels
were
thus
mean
values
computed
from
hundreds
of
separate
determinations.
Without
a
report
of
the
daily
levels
or,
at
the
very
least,
standard
deviations
from
the
mean
values,
there
is
an
implicit
assumption
that
those
mean
values
were
in
fact
the
levels
that
the
animals
were
actually
responding
to,
and
were
not
in
reality
much
lower
or
higher
for
significant
periods.
Page
19
of
19
3.
Rosskamp
(
1978)
failed
to
provide
a
histological
examination
of
the
nasal
cavity
of
the
exposed
rats.
As
MITC
is
known
to
cause
irritation
of
mucus
membranes,
the
lack
of
nasal
examination
in
that
study
may
have
resulted
in
the
assignment
of
an
inappropriately
high
NOEL
value
or,
at
the
very
least,
an
appreciation
of
the
importance
of
irritation
to
the
overall
toxic
response.

The
LOAEL
is
30.67
ug/
L/
day
(
extrapolated
to
20.6
ug/
L/
day
for
6
hour
exposure),
based
on
decreased
body
weight,
food
efficiency
and
blood
protein
values
accompanied
by
increased
water
intake.
The
NOAEL
is
3.16
ug/
L/
day
(
extrapolated
to
2.1
ug/
L/
day
for
6
hour
exposure).

This
subchronic
inhalation
toxicity
study
in
the
rat
is
acceptable­
guideline
and
satisfies
the
guideline
requirement
for
a
subchronic
inhalation
study
OPPTS
870.3465;
OECD
413
in
the
rat.