1
This
report
supersedes
the
previous
HIARC
report
dated
March
4,
2002
(
TXR
No.
0050586).
It
differs
from
the
previous
report
in
that
it
reflects
the
most
recent
formatting,
and
it
delineates
the
selection
of
the
FQPA
factor.
No
decision
regarding
the
FQPA
factor
was
made
previously.

TXR
NO.
0051692
DATE:
April
9,
2003
MEMORANDUM
SUBJECT:
PCNB
­
Report
of
the
Hazard
Identification
Assessment
Review
Committee.

FROM:
Elizabeth
A.
Doyle,
Chief
Toxicology
Branch
Health
Effects
Division
(
7509C)

THROUGH:
Jess
Rowland,
Co­
Chair
and
Elizabeth
Doyle,
Co­
Chair
Hazard
Identification
Assessment
Review
Committee
Health
Effects
Division
(
7509C)

TO:
Diana
Locke,
Risk
Assessor
Toxicology
Branch
Health
Effects
Division
(
7509C)

PC
Code:
056502
On
December
10,
2002,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
PCNB
with
regard
to
the
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
PCNB
was
also
evaluated
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996
in
accordance
with
the
2002
OPP
10X
Guidance
Document.
The
conclusions
drawn
at
this
meeting
are
presented
in
this
report.

Committee
Members
in
Attendance
2
Members
present
were:
Ayaad
Assaad,
William
Burnam,
Jonathan
Chen,
Elizabeth
Doyle,
John
Liccione,
Susan
Makris,
Elizabeth
Mendez,
David
Nixon,
Jess
Rowland,
and
Brenda
Tarplee
Member(
s)
in
absentia:
Steve
Knizner
(
RARC
Rep.)
and
Pamela
Hurley
Data
evaluation
prepared
by:
Elizabeth
Doyle,
Toxicology
Branch
Also
in
attendance
were:
Paula
Deschamp
and
Mark
Dow
Data
Evaluation
/
Report
Presentation
Elizabeth
A.
Doyle
Chief,
Toxicology
Branch
3
INTRODUCTION
On
December
10,
2002,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reconvened
to
evaluate
the
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
PCNB
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996
in
accordance
with
the
2002
OPP
10X
Guidance
Document,
and
discussed
the
magnitude
and
rationale
for
required
uncertainty
factors.
The
conclusions
drawn
at
both
meetings
are
presented
in
this
report.

I.
FQPA
HAZARD
CONSIDERATIONS
1.
Adequacy
of
the
Toxicity
Data
Base
Acceptable
developmental
toxicity
studies
in
rats
(
MRID#
40588601
and41361201)
and
rabbits
(
MRID
#
41361301
and
40717102)
and
reproduction
studies
(
MRID#
43469301,
43469302,
43469303
and
41918701)
are
available
and
adequate
for
FQPA
considerations.
Data
gaps
were
identified
in
data
on
thyroid
hormone
levels,
significance
of
ALT/
AST
enzyme
levels,
pharmacokinetics,
and
in
cytogenetic
toxicity.
The
data
base
is
not
complete.

2.
Evidence
of
Neurotoxicity
Acute
delayed
neurotoxicity,
acute
and
subchronic
neurotoxicity
studies
and
a
developmental
neurotoxicity
studies
are
not
required
at
this
time
since
there
is
no
evidence
that
the
compound
is
a
neurotoxicant.

3.
Developmental
Toxicity
Study
Conclusions
a.
Developmental
Toxicity
Study
in
the
Rat
(
gavage)
OPPTS
870.3700
Executive
Summary:
In
an
oral
developmental
toxicity
study
(
MRID
40588601),
25
(
presumed)
pregnant
Sprague­
Dawley
COBS
CD
rats/
dose
group
were
administered
pentachloronitrobenzene
(
PCNB
tech.,
96.0%
a.
i.;
0.025%
hexachlorobenzene
contaminant)
by
gavage
in
0.2%
high
viscosity
carboxymethylcellulose
(
10
ml/
kg
body
wt.)
at
dose
levels
of
0,
30,
600
or
1200
mg/
kg/
day
from
gestation
days
6
through
15,
inclusive.

There
were
no
treatment­
related
maternal
or
developmental
effects
observed
at
any
dose
level
tested.
The
highest
dose
tested
(
1200
mg/
kg/
day)
exceeded
the
limit
dose
requirement.
The
maternal
toxicity
LOAEL
is
>
1200
mg/
kg/
day
(
HDT)
and
the
NOAEL
is

1200
mg/
kg/
day.
The
developmental
toxicity
LOAEL
is
>
1200
mg/
kg/
day
and
the
NOAEL
is

1200
mg/
kg/
day.

This
study
is
classified
Acceptable/
Guideline
(
§
83­
3a;
OPPTS
870.3700)
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
in
the
rat.
4
b.
Developmental
Toxicity
Study
in
the
rat
(
gavage)
OPPTS
870.3700
Executive
Summary:
In
an
oral
developmental
toxicity
study
(
MRID
41361201),
25
(
presumed)
pregnant
CRL:
CD
®
(
SD)
BR
rats/
dose
group
were
administered
pentachloronitrobenzene
(
PCNB
tech.,
98.5%
a.
i.;
hexachlorobenzene
contamination
0.09%)
at
doses
of
0,
250,
750
or
1500
mg/
kg/
day
from
days
6
through
15
of
gestation,
inclusive.
Doses
were
given
by
gavage
in
1%
aqueous
carboxymethyl
cellulose
vehicle
(
10
ml/
kg
body
weight).

Maternal
toxicity:
No
treatment­
related
effects
were
observed.
The
highest
dose
level
tested
(
1500
mg/
kg/
day)
exceeded
the
limit
dose.
The
maternal
toxicity
LOAEL
is
>
1500
mg/
kg/
day
and
the
NOAEL
is

1500
mg/
kg/
day.

Developmental
toxicity:
At
750
and
1500
mg/
kg/
day,
small
but
statistically
significant
increases
in
the
average
number
of
thoracic
vertebrae/
fetus
(
13.05,
13.16,
13.23
and
13.21,
control
to
high
dose;
historical
control
range
13.00
to
13.13),
average
pairs
of
thoracic
ribs/
fetus
(
13.03,
13.13,
13.17
and
13.15;
historical
control
range
13.00
to
13.09),
and
decreases
in
the
average
number
of
lumbar
vertebrae/
fetus
(
5.94,
5.84,
5.77
and
5.79;
historical
control
range
5.85
to
6.00)
were
reported
(
all
historical
data
from
4852
fetuses
in
573
litters,
26
studies).
The
biological
significance
of
these
findings
is
uncertain
due
to
relatively
small
magnitude
of
the
changes
and
lack
of
a
clear
dose­
response.
No
treatment­
related
fetal
malformations
were
observed.
The
HIARC
concluded
that
these
small
differences
observed
in
thoracic
vertebrae
were
very
marginal
effects
and
not
biologically
significant.
Decreases
in
number
of
lumbar
vertebra/
fetus
suggest
that
increases
in
thoracic
vertebra
per
fetus
may
not
be
adverse
and
similar
effects
were
not
seen
in
the
Uniroyal
rat
study
(
MRID
40588601).
Hence,
the
developmental
toxicity
LOAEL
is
>
1500
mg/
kg/
day
and
the
NOAEL
is
>
1500
mg/
kg/
day
(
HDT).

This
study
is
classified
Acceptable/
Guideline
(
§
83­
3a;
OPPTS
870.3700)
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
in
the
rat.

c.
Developmental
Toxicity
Study
in
the
Rabbit
(
Gavage)
OPPTS
87.3700
Executive
Summary:
In
an
oral
developmental
toxicity
study
(
MRID
41361301),
20
(
presumed)
pregnant
New
Zealand
White
rabbits/
dose
group
were
administered
pentachloronitrobenzene
(
PCNB
tech.,
98.5%
a.
i.;
0.09%
hexachlorobenzene
contaminant)
by
gavage
at
0,
100,
300
or
900
mg/
kg/
day
in
10
ml
aqueous
1%
carboxymethylcellulose
vehicle/
kg
body
weight
from
gestation
days
6
through
18,
inclusive.

Maternal
toxicity:
At
900
mg/
kg/
day,
abnormal
feces
(
soft,
liquid
or
dried;
total
incidence
45
in
11
does
vs.
15
in
4
does,
controls),
decreased
weight
gain
during
dosing
(­
75%
less
than
controls;
not
statistically
significant),
slightly
decreased
food
consumption
(­
16%
less
than
controls;
not
statistically
significant)
were
observed.
Abortions
(
days
24
and
25,
2/
20
vs.
0/
20,
controls)
and
premature
delivery
(
day
25,
1/
20
vs.
0/
20,
controls)
were
observed
and
these
3
does
also
had
associated
abnormal
feces,
weight
loss
and
decreased
food
consumption.
The
doe
with
premature
delivery
also
had
decreased
motor
activity
and
a
fluid­
filled
cecum,
one
abortive
female
had
gastric
ulceration
and
the
other
had
a
litter
with
4
late
resorptions
out
of
6
conceptuses.
No
mortality
was
observed.
The
maternal
toxicity
LOAEL
is
900
mg/
kg/
day,
based
on
clinical
signs
of
toxicity,
decreased
body
weight
gain
and
food
consumption
during
dosing,
5
abortions
and
premature
delivery.
The
maternal
toxicity
NOAEL
is
300
mg/
kg/
day.

Developmental
toxicity:
There
were
no
treatment­
related
developmental
effects
reported
in
this
study
with
the
exception
of
a
slightly
increased
incidence
of
abortions
at
the
900
mg/
kg
dose
level
considered
by
HIARC
as
developmental
toxicity
due
to
the
associated
fetal
mortality.
The
developmental
toxicity
LOAEL
is
900
mg/
kg/
day
and
the
developmental
toxicity
NOAEL
is
300
mg/
kg/
day.

This
study
is
classified
Acceptable/
Guideline
(
§
83­
3b;
OPPTS
870.3700)
and
satisfies
the
Guideline
requirement
for
a
developmental
toxicity
study
in
the
rabbit.

d.
Developmental
Toxicity
Study
in
the
Rabbit
(
gavage)
OPPTS
870.3700
Executive
Summary:
In
an
oral
developmental
toxicity
study
(
MRID
#
40717102)
groups
of
16
pregnant
New
Zealand
White
rabbits
were
given
daily
doses
of
0
(
two
groups)
s,
6.25,
12.5,
125
(
two
groups)
and
250
mg/
kg/
day
PCNB
(
96%)
by
gavage
on
days
7
through
19
of
gestation.

Maternal
Toxicity:
At
the
highest
dose
tested
there
was
mortality,
abortions,
weight
loss
during
gestation
and
decreased
food
consumption.
The
only
effects
observed
in
the
125
mg/
kg/
day
dose
groups
were
decreased
body
weight
and
weight
gain.
Group
mean
maternal
body
weight
was
statistically
significantly
less
than
control
values
only
during
the
second
of
the
two
trials
that
were
conducted
at
that
dose
level.
Based
on
these
results,
a
LOAEL
for
maternal
toxicity
was
established
at
125
mg/
kg/
day
and
NOAEL
was
established
at
12.5
mg/
kg/
day.

Developmental
Toxicity:
Based
on
statistically
significant
decreased
fetal
weights
reported
in
the
highest
dose
group,
the
LOAEL
for
developmental
toxicity
was
established
at
250
mg/
kg/
day
and
the
NOAEL
was
determined
to
be
125
mg/
kg/
day
in
rabbits.

This
study
is
classified
Acceptable
(
§
83­
3b;
OPPTS
870.3700)
and
satisfies
the
Guideline
requirement
for
a
developmental
toxicity
study
in
the
rabbit.

4.
Reproductive
Toxicity
Study
Conclusions
Two
Generation
Reproduction
Study
in
Rats
(
dietary)
OPPTS
870.3800
Executive
Summary:
In
a
2­
generation
reproductive
toxicity
study
(
MRID
41918701),
26
Sprague­
Dawley
COBS
®
CD
rats/
sex/
dose
group
were
administered
pentachloronitrobenzene
(
PCNB
tech.,
>
99%
a.
i.;
<
0.1%
hexachlorobenzene
contaminant)
in
their
diet
at
concentrations
of
0,
20,
3000
or
6000
ppm
(
equivalent
to
1.2/
1.4,
169/
213
or
344/
468
mg/
kg/
day,
males
and
1.5/
1.7,
218/
255
or
455/
640
mg/
kg/
day,
females,
based
on
mean
F0/
F1
premating
compound
consumption
values),
beginning
in
55­
day
old
F0
animals
at
81
days
prior
to
mating
or
in
weanling
F1
animals
for
at
least
90
days
prior
to
mating.
Each
parental
generation
was
mated
twice
to
produce
F1/
F2
a
and
b
litters.
Dosing
of
the
F0
and
F1
parental
animals
was
continued
throughout
the
study
period
until
termination
of
the
animals
after
day
21
of
the
second
lactation
period
(
females)
or
after
the
second
mating
period
(
males).

Parental
toxicity:
At
3000
ppm,
statistically
significantly
decreased
mean
premating
body
weights
6
were
observed
in
F0
males
prior
to
both
matings
(­
7%
less
than
controls)
and
in
F1
females
prior
to
the
first
mating
(­
5.7%
to
­
10%;
due
to
decreased
initial
weights
of
the
F1
weanlings
assigned
to
be
parental
animals).
At
6000
ppm,
significantly
decreased
mean
premating
body
weights
(
F0
males
­
9
to
­
10%
less
than
controls
and
females
­
7%;
F1
males,
initial
weights
­
35%;
thereafter
­
16%;
females
initial
weights
­
37%;
thereafter
­
14%
to
­
16%).
The
small
size
of
almost
all
F1
animals
at
6000
ppm
and
emaciation
in
4
females
was
related
to
these
decreases.
Food
consumption
was
decreased,
primarily
during
the
first
weeks
of
each
premating
period.
Increased
incidence
of
pulmonary
foci
was
also
observed
in
F0
females
(
4/
26)
and
in
F1
males
(
5/
26)
and
females
(
8/
26)
(
no
controls
affected
in
either
sex).
The
parental
systemic
toxicity
LOAEL
is
3000
ppm
(
169
mg/
kg/
day,
males
and
218
mg/
kg/
day,
females),
based
on
decreased
body
weight/
weight
gain.
The
NOAEL
is
20
ppm
(
1.2
mg/
kg/
day,
males
and
1.5
mg/
kg/
day,
females).

Reproductive/
developmental
toxicity:
At
3000
ppm,
decreased
mean
pup
weight
(­
6.8%
to
­
8.7%
less
than
controls
at
lactation
day
21,
both
sexes;
statistically
significant)
was
observed
in
F1a,
F1b
and
F2b
pups.
At
6000
ppm,
decreases
in
male
and
female
pup
weights
in
all
4
litters
were
pronounced
(­
30%
to
­
41%
at
lactation
day
21).
The
reproductive/
developmental
LOAEL
is
3000
ppm
(
169
mg/
kg/
day),
based
on
decreased
mean
pup
weight
in
most
generations.
The
NOAEL
is
20
ppm
(
1.2
mg/
kg/
day).

The
Offspring
NOAEL:
Based
on
decreases
in
mean
pup
weights
of
F1a,
F1b,
and
F2b
animals,
the
offspring
NOAEL
is
1.2
mg/
kg/
day
and
the
LOAEL
is
169
mg/
kg/
day.

This
study
is
classified
Acceptable/
Guideline
(
§
83­
4;
OPPTS
870.3800)
and
satisfies
the
Guideline
requirement
for
a
multigeneration
reproductive
toxicity
study
in
the
rat.

5.
Additional
Information
from
Literature
Sources
1.
A
number
of
older
studies
have
been
identified
in
the
data
base
but
most
of
these
studies
are
associated
with
testing
of
the
older
manufactured
technical
(
high
in
HCB
and
other
contaminants)
and
therefore
these
data
cannot
be
used
as
part
of
the
present
assessment
on
the
currently
marketed
technical.

2.
A
kinetic
study
was
identified
in
the
literature
[
W.
Kogel
et
al,
(
1979)
Uptake,
Body
Distribution,
Storage
and
Excretion
of
Pentachloronitrobenzene
14­
C
in
Rhesus
Monkeys,
Chemosphere
No.
2,
pp
89­
95l.
Pergamon
Press
Ltd]
which
despite,
study
deficiencies,
demonstrated
some
ability
of
PCNB
to
accumulate
over
time.
The
half­
life
of
PCNB
(
in
monkeys)
was
1.5­
1.7
days
at
a
low
dose
of
2
mg/
kg
,
with
only
81­
85%
of
the
dose
recovered
in
excreta
after
15
days.
At
the
higher
dose
of
91
mg/
kg
only
59.5%
of
the
dose
had
been
recovered
in
excreta
after
20
days.
Feeding
studies
at
2
ppm,
indicated
that
a
plateau
was
reached
after
30­
40
days.
Because
of
concerns
about
the
uncertainties
of
the
half­
life
and
thus
for
the
accumulation
potential
of
the
chemical,
the
HIARC
recommended
that
a
study
to
determine
the
biological
half
life
on
PCNB
be
requested
(
See
7.
Data
Gaps).

3.
PCNB
studies
consistently
show
decreases
in
serum
enzyme
activities.
AST/
ALT
activities
decrease
in
a
dose
dependent
manner
by
as
much
as
30­
80%.
It
is
known
that
penicillamine,
cycloserine,
hydralazine,
and
in
particular
the
anti­
tuberculin
drug
isoniazid
can
decrease
the
7
activities
of
AST
and
ALT
at
therapeutic
doses.
The
mechanism
by
which
this
occurs
is
through
a
biochemical
interaction
between
the
drug
and
Vitamin
B6.
With
isoniazid
[
Balazs
et
al.
Arch.
Toxicol,
Suppl.
1,
159­
163
(
1978)]
this
is
thought
to
occur
through
combination
with
pyridoxal
or
pyridoxal
phosphate
to
form
a
hydrazone.

Vitamin
B6
compromises
a
group
of
closely
related
compounds,
pyridoxine,
pyridoxal
and
pyridoxamine,
that
are
phosphorylated
in
vivo
by
pyridoxal
kinase
to
form
pyridoxal
phosphate.
Pyridoxal
phosphate
serves
as
a
cofactor
in
many
reactions,
including
decarboxylation
and
transamination
of
amino
acids,
deamination
of
hydroxy
amino
acids
and
cysteine,
conversion
of
tryptophan
to
niacin,
metabolism
of
fatty
acids,
protein
metabolism,
and
the
transport
of
certain
amino
acids
across
cell
membranes.
The
inhibition
of
pyridoxal
kinase
by
the
isoniazid­
pyridoxal
complex
occurs
at
concentrations
1000
times
less
than
those
required
to
inhibit
the
enzyme
containing
the
cofactor.

The
dose­
dependent
decreases
of
AST/
ALT
activities
found
consistently
in
subchronic
and
chronic
studies
suggest
that
PCNB
disrupts
transferase
and
other
enzyme
activities
that
require
pyridoxal
phosphate,
perhaps
by
affecting
Vitamin
B6
homeostasis.
Whether
the
mechanism
is
similar
to
that
of
the
isoniazid
is
not
known
and
cannot
be
determined
from
the
subchronic
or
chronic
studies.
However,
the
clinical
data
suggests
a
disturbance
of
protein
and
amino
acid
metabolism.
This
is
supported
not
only
by
the
decreased
activities
of
AST/
ALT
but
also
by
the
dose
dependent
excretion
of
triple
phosphate
crystals
in
the
urine.
The
excretion
of
triple
phosphate
and
calcium
phosphate,
which
are
urine
buffering
systems,
suggests
a
disturbance
of
systemic
acid­
base
balance.
It
is
also
of
interest
to
note
at
terminal
sacrifice
the
presence
of
tyrosine
phosphate
crystals
in
urine.
Typically
these
crystals
suggest
severe
hepatic
toxicity.
However,
the
clinical
pathology
of
the
liver
did
not
suggest
toxicity
sufficient
to
disrupt
hepatic
function.
All
that
was
typically
found
was
hepatocellular
hypertrophy.
Although
tyrosine
phosphate
crystals
may
have
originated
from
impaired
hepatic
function,
they
could
have
also
arisen
from
tyrosine
overload.
Excess
tyrosine
could
have
resulted
from
the
chronic
and
cumulative
inhibition
of
various
transaminases,
particularly
tyrosine
transaminase,
that
are
essential
for
protein
and
amino
acid
metabolism.

Therefore,
in
the
PCNB
studies
submitted,
it
might
be
reasonable
(
in
the
absence
of
other
relevant
kinetic
data)
to
consider
the
decreases
of
AST/
ALT
as
adverse
effects.
This
would
generally
reduce
NOAEL's
and
LOAEL's
by
at
least
an
order
of
magnitude.
PCNB
appears
to
induce
a
chronic
and
progressive
inhibition
of
transferase
activity
and
to
confirm
this
would
require
additional
study.

4.
Hepatocellular
hypertrophy
occurs
following
the
administration
of
chlorinated
benzenes,
polyhalogenated
biphenyls,
TCDD,
and
other
polyhalogenated
hydrocarbons.
These
compounds
induce
hepatic
microsomal
enzymes
that
ultrastructurally
result
in
cellular
changes
consistent
with
those
reported
in
the
chronic
and
subchronic
PCNB
studies.
Likewise,
the
induction
of
thyroid
follicular
hyperplasia
and
hypertrophy
in
animals
is
a
well
documented
effect
of
many
polyhalogenated
aromatic
hydrocarbons.
Current
evidence
suggests
that
the
induction
of
certain
hepatocellular
microsomes
increases
metabolism
of
thyroxine,
thereby
inducing
a
hypothyroid
state
(
and
it
seems
likely
that
PCNB
induces
primary
hypothyroidism
in
both
male
and
female
rats).
However,
without
analysis
of
TSH,
this
cannot
be
firmly
established
nor
can
the
severity
of
the
hypothyroidism
be
determined.
Further,
what
effects
might
be
superimposed,
or
whether
the
8
effects
would
be
potentiated,
additive,
synergistic,
or
antagonistic
is
unclear
at
this
time.
For
this
and
other
reasons,
adequate
kinetic
data
should
be
available
for
use
in
the
risk
assessment
process.

6.
Pre­
and/
or
Postnatal
Toxicity
The
HIARC
concluded
that
there
is
not
a
concern
for
pre­
and/
or
postnatal
toxicity
resulting
from
exposure
to
PCNB.

A.
Determination
of
Susceptibility
There
was
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
of
rat
or
rabbit
fetuses
after
in
utero
exposure,
or
after
pre­
or
postnatal
exposure
to
rats
in
multigeneration
reproduction
studies.

B.
Degree
of
Concern
Analysis
and
Residual
Uncertainties
This
analysis
was
not
conducted
because
there
was
no
evidence
of
qualitative
or
quantitative
susceptibility.

C.
Special
FQPA
Safety
Factor(
s)

The
special
FQPA
factor
can
be
reduced
to
1x
because
there
are
no
residual
uncertainties
for
pre­
and/
or
postnatal
toxicity.

The
Special
FQPA
Safety
Factor
recommended
by
the
HIARC
assumes
that
the
exposure
databases
(
dietary
food,
drinking
water,
and
residential)
are
complete
and
that
the
risk
assessment
for
each
potential
exposure
scenario
includes
all
metabolites
and/
or
degradates
of
concern
and
does
not
underestimate
the
potential
risk
for
infants
and
children.

7.
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
HIARC
concluded
that
there
is
not
a
concern
for
developmental
neurotoxicity
resulting
from
exposure
to
PCNB.

A.
Evidence
that
suggest
requiring
a
Developmental
Neurotoxicity
study:

There
is
no
evidence
supporting
the
requirement
for
a
DNT.

B.
Evidence
that
do
not
support
a
need
for
a
Developmental
Neurotoxicity
study:

There
was
no
evidence
of
neurotoxicity
in
the
toxicity
data
base
for
PCNB.

Based
on
the
weight
of
evidence
presented,
the
HIARC
concluded
that
a
developmental
neurotoxicity
study
is
not
required
for
PCNB.

The
HIARC,
however,
did
require
a
comparative
thyroid
assay
in
young
and
adult
rats
which
9
included
hormonal
measurements
for
thyroid
function,
since
thyroid
weights
were
increased
in
a
number
of
chronic
and
subchronic
studies
in
rats,
and
TSH,
T3,
and
T4
levels
were
affected
in
a
90­
day
special
oral
study
in
male
rats.

The
absence
of
the
comparative
thyroid
study
resulted
in
a
database
uncertainty
factor
of
10x
(
UF
DB
of
10x)
which
was
applied
to
the
dietary
(
acute
and
chronic)
as
well
as
all
residential
exposure
(
incidental
oral,
dermal
and
inhalation)
scenarios.
The
HIARC
determined
that
the
10X
UF
DB
is
required
since
the
available
data
provide
no
basis
to
support
reduction
or
removal
of
the
default
10X
factor.

II.
HAZARD
IDENTIFICATION
1.
Acute
Reference
Dose
(
aRfD)
­
An
endpoint
attributable
to
a
single
dose
(
exposure)
was
not
available
in
the
database.

2.
Chronic
Reference
Dose
(
cRfD)

Study
Selected:
Combined
chronic
toxicity/
carcinogenicity
­
rat
§
OPPTS
870.4300
MRID
No.:
41987301
Executive
Summary:
In
an
oral
chronic
toxicity/
carcinogenicity
study
(
MRID
41987301),
50
Charles
River
CD
®
rats/
sex/
dose
group
were
administered
pentachloronitrobenzene
(
PCNB
tech.,
99.4%
a.
i.)
in
the
diet
at
concentrations
of
0,
20,
3000
or
6000
ppm
(
equivalent
to
estimated
average
daily
intakes
of
0,
1,
150
or
300
mg/
kg/
day;
estimated
based
on
a
standard
conversion
factor
of
0.05)
for
24
months.
An
additional
10
animals/
sex/
dose
group
were
included
for
interim
sacrifice
at
12
months.

At
3000
ppm,
statistically
significantly
increased
relative
liver
weight
in
males
(+
20%
above
controls),
absolute
thyroid/
parathyroid
weight
in
males
(+
26%),
relative
thyroid/
parathyroid
weight
(+
35%,
males
and
+
24%,
females),
and
significantly
increased
incidence
of
microscopic
lesions
including
mild
hepatocellular
hypertrophy
(
27%,
males
and
38%,
females
vs.
0%,
controls),
mild
thyroid
hyperplasia
(
15%,
males
vs.
4%,
controls
and
16%,
females
vs.
0%,
controls)
and
thyroid
hypertrophy
(
42%,
males
vs.
0%,
controls
and
36%,
females
vs.
2%,
controls)
were
observed.
Sporadic
significantly
decreased
mean
body
weights
in
both
sexes
were
not
considered
biologically
significant.
At
6000
ppm,
these
effects
showed
a
dose­
response
and
in
addition,
statistically
significantly
decreased
mean
body
weight/
weight
gain
throughout
treatment
(
at
termination,
­
11%/­
15%
less
than
controls
in
males
and
­
12%/­
18%
in
females),
decreased
food
consumption
during
the
first
6
months,
increased
serum
cholesterol
(
females),
significantly
increased
relative
liver
weight
in
both
sexes
(+
25%,
males
and
+
20%,
females)
and
increased
incidence
of
thyroid
colloid
cysts
in
males
(
16%
vs.
4.1%,
controls)
were
observed.
At
the
12­
month
interim
sacrifice,
both
sexes
showed
slight
(
not
statistically
significant)
increases
in
liver
and
thyroid
weights
at
mid
and
high
dose
and
in
high
dose
females,
there
was
a
slightly
increased
incidence
of
visible
tan
foci
in
the
lungs.
There
were
no
treatment­
related
clinical
or
10
ophthalmologic
observations
and
no
effects
on
mortality,
hematology
or
urinalysis
parameters.

The
systemic
toxicity
LOAEL
is
3000
ppm
(
150
mg/
kg/
day),
based
on
hepatocellular
hypertrophy,
hepatocellular
hyperplasia
(
females)
and
thyroid
hypertrophy
and
hyperplasia.
The
systemic
toxicity
NOAEL
is
20
ppm
(
1
mg/
kg/
day).

PCNB
caused
an
increased
incidence
of
thyroid
follicular
cell
adenomas
in
males
(
0%,
0%,
12.5%
and
10.2%,
control
to
high
dose;
p<
0.05
at
3000
ppm)
and
a
significantly
increasing
trend
(
p<
0.01).
Incidence
in
females
was
2.0%,
0%,
4.0%
and
8.7%
(
control
to
high
dose;
not
significant);
however,
a
significantly
increasing
trend
(
p<
0.05)
was
observed.
The
incidence
of
thyroid
follicular
cell
carcinoma
was
increased
at
6000
ppm
only
in
males
(
males
0%,
2.0%,
0%
and
4.1%;
females
2.0%,
0%,
0%
and
2.2%).
The
combined
incidence
of
thyroid
follicular
cell
adenomas
and
carcinomas
was
significantly
increased
in
males
at
3000
and
6000
ppm
(
control
to
high
dose,
0%,
2.0%,
12.5%,
14.3%;
p<
0.05)
but
not
females
(
4.0%,
0%,
4.0%
and
10.9%),
with
a
significant
trend
in
both
sexes
(
females
p<
0.05
and
males
p<
0.01).
The
incidence
of
follicular
cell
adenoma
in
historical
control
data
from
this
laboratory
did
not
exceed
11.1%
in
males
or
3.2%
in
females.
The
incidence
of
carcinoma
did
not
exceed
9.4%
in
males
or
3.2%
in
females.

This
study
is
classified
Acceptable/
Guideline
(
§
83­
5;
OPPTS
870.4300)
and
satisfies
the
Guideline
requirement
for
a
chronic
toxicity/
carcinogenicity
study
in
the
rodent.

Dose
and
Endpoint
for
Establishing
cRfD:
NOAEL
=
1
mg/
kg/
day
based
on
hepatocellular
hypertrophy,
hepatocellular
hyperplasia
(
females)
and
thyroid
hypertrophy
and
hyperplasia
at
The
LOAEL
=
150
mg/
kg/
day.

Uncertainty
Factor(
s):
1000
(
10x
for
interspecies
extrapolation,
10x
for
interspecies
differences,
and
UF
DB
for
lack
of
comparative
thyroid
assay).

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
This
study
is
appropriate
for
the
population
and
duration
considered
in
a
chronic
risk
assessment.

4.
Incidental
Oral
Exposure:
Short­
Term
(
1­
30
days)

Study
Selected:
Subchronic
Oral
Toxicity
in
male
rats
§
Nonguideline
MRID
No.:
42630801
Executive
Summary:
In
a
special
(
nonguideline)
subchronic
oral
toxicity
study
(
MRID
42630801),
75
male
Charles
River
CD
®
rats/
dose
were
administered
pentachloronitrobenzene
(
PCNB
tech.,
99.09%
a.
i.)
in
their
diet
at
levels
of
0,
20
or
6000
ppm
(
equivalent
to
average
daily
intakes
of
0,
1.0
or
333
mg/
kg/
day).
Groups
of
15
animals/
dose
were
sacrificed
at
7,
14,
30
or
90
days.
The
remaining
15
animals/
dose
group
at
day
90
were
fed
only
basal
diet
for
a
recovery
Chronic
RfD
=
(
NOAEL)
1
mg/
kg/
day
=
0.001
mg/
kg/
day
(
UF)
1000
11
period
of
at
least
90
days
(
sacrificed
on
day
180
or
183).
Levels
of
circulating
thyroid
hormones
(
TSH,
T3
and
T4)
and
thyroid/
liver
weights
and
pathology
were
evaluated
at
each
sacrifice
time.

At
20
ppm,
hypertrophy
of
the
liver
(
trace)
and
thyroid
(
mild)
were
observed
in
14/
15
and
15/
15
animals,
respectively
(
0/
15,
controls).
At
6000
ppm,
statistically
significantly
decreased
mean
body
weight
throughout
most
of
treatment
(
at
termination,
­
6.1%
less
than
controls)
and
decreased
body
weight
gain
(
at
termination,
­
20%,
due
largely
to
a
pronounced
decrease
during
Week
1),
decreased
food
consumption
during
Week
1
only
(­
23%
below
controls),
increased
TSH
(+
31%
to
+
132%
above
controls;
significant
at
most
time
points),
decreased
T3
(­
9
to
­
26%
less
than
controls;
significant
at
most
time
points),
decreased
T4
(­
48
to
­
54%
less
than
controls,
significant
at
all
time
points),
decreased
rT3
(­
28%
at
day
90;
significant),
increased
relative
liver
weight
(+
12
to
+
18%
above
controls),
decreased
absolute
thyroid/
parathyroid
weights
(­
14%,
day
30)
and
increased
follicular
epithelial
hypertrophy
of
the
thyroid
(
trace
to
mild,
all
animals
at
all
sacrifice
times
vs.
0/
15
controls)
and
hepatocellular
hypertrophy
(
moderate,
all
animals
at
90
days,
vs.
0/
15,
controls).
There
were
no
treatment­
related
deaths
or
clinical
signs
observed.
Animals
maintained
on
basal
diet
for
an
additional
90
days
showed
complete
recovery.
The
following
were
not
evaluated:
hematology,
urinalysis,
organ
weights
and
gross/
microscopic
pathology,
with
the
exception
of
liver,
thyroid/
parathyroids.
The
study
LOAEL
is
20
ppm
(
1.0
mg/
kg/
day),
based
on
liver
and
thyroid
histopathology.
The
study
NOAEL
was
not
determined.

This
study
is
classified
Acceptable/
nonguideline
(
§
82­
1a).
It
does
not
satisfy
the
guideline
requirement
for
a
subchronic
oral
toxicity
study
in
the
rodent
because
it
is
not
a
complete
Guideline
subchronic
study.
This
was
a
special
non­
guideline
study
designed
only
to
assess
effects
of
PCNB
on
the
thyroid
hormone
levels,
rather
than
a
complete
Guideline
subchronic
study,
and
was
adequately
conducted
to
provide
this
information.
However,
only
males
were
tested,
only
two
doses
were
utilized
and
hematology,
urinalysis,
organ
weights,
and
gross
and
microscopic
pathology
(
with
the
exception
of
thyroid/
parathyroids
and
liver)
were
not
assessed.

Dose
and
Endpoint
for
Risk
Assessment:
1
mg/
kg/
day.
Although
a
NOAEL
was
not
identified
in
the
above
non­
guideline
male
study
at
90
days,
no
effects
were
observed
at
the
1
mg/
kg/
day
dose
level
at
interim
sacrifice/
hormone
assessment
intervals
conducted
at
7,
14,
and
30
days.
This
finding
was
considered
an
appropriate
endpoint
for
risk
assessment
by
HIARC
for
periods
up
to
30
days.

Comments
about
Study/
Endpoint:
Although
no
effects
were
observed
in
this
special
study
at
the
1
mg/
kg/
day
dose
level
during
interim
assessments
up
to
30
days,
it
must
be
recognized
that
this
is
not
a
guideline
study
and
was
intended
only
for
a
limited
assessment
of
the
thyroid
and
liver
function.
In
addition,
it
included
no
assessment
for
potential
effects
on
females
(
since
none
were
utilized
in
the
study),
it
only
utilized
two
dose
levels,
and
did
not
include
routine
assessments
in
males
for
hematology,
urinalysis,
organ
weights
and
gross
and
microscopic
pathology
(
with
the
exception
of
liver
and
thyroid/
parathyroids)
and
other
endpoints.
HIARC
concluded
that
the
effects
observed
in
this
study
are
appropriate
for
the
population
(
infants
and
children)
and
duration
of
concern
(
1­
30
days).

5.
Incidental
Oral
Exposure:
Intermediate­
Term
(
1
­
6
Months)
12
Study
Selected:
Subchronic
Oral
Toxicity
in
male
rats
§
Nonguideline
MRID
No.:
42630801
Executive
Summary:
See
Short
Term
(
1
day
to
1
month)
Incidental
Oral
Exposure
section.

Dose
and
Endpoint
for
Risk
Assessment:
1
mg/
kg/
day.
A
NOAEL
was
not
identified
in
this
study.
As
noted
above
under
the
short­
term
incidental
oral
exposure,
no
adverse
effects
were
seen
up
to
30
days.
The
HIARC
determined
that
the
effects
seen
at
the
1
mg/
kg/
day
at
termination
were
minimal
and
therefore
this
dose
is
appropriate
for
this
exposure
risk
assessment.

Comments
about
Study/
Endpoint:
Although
no
effects
were
observed
in
this
special
study
at
the
1
mg/
kg/
day
dose
level
during
interim
assessments
up
to
30
days,
it
must
be
recognized
that
this
is
not
a
guideline
study
and
was
intended
only
for
a
limited
assessment
of
the
thyroid
and
liver
function.
In
addition,
it
included
no
assessment
for
potential
effects
on
females
(
since
none
were
utilized
in
the
study),
it
only
utilized
two
dose
levels,
and
did
not
include
routine
assessments
in
males
for
hematology,
urinalysis,
organ
weights
and
gross
and
microscopic
pathology
(
with
the
exception
of
liver
and
thyroid/
parathyroids)
and
other
endpoints.
In
consideration
of
these
issues,
HIARC
considered
the
observed
effects
to
be
appropriate
for
the
population
(
infants
and
children
and
duration
of
concern
(
1­
6
months).

6.
Dermal
Absorption
Dermal
Absorption
Factor:
33%

A
dermal
penetration
study
(
MRID
no.
250698
and
255226)
was
available;
two
formulations
(
20%
dust
and
75%
wettable
powder)
were
tested
in
rats
for
four
hours
or
5
days.
After
4
hours,
recovery/
dermal
penetration
was
1.3%
for
the
wettable
powder
and
3.1%
for
the
dust.
After
5
days,
the
recovery
was
32.3%
for
the
wettable
powder
and
33.8%
for
the
dust.

The
HIARC
did
not
use
this
study
since
this
study:
(
1)
did
not
follow
current
guidelines;
(
2)
test
materials
are
significantly
different
from
the
technical
product
currently
marketed:
(
3)
the
lot
number
of
the
test
materials
was
not
reported;
and
(
4)
the
report
did
not
account
for
all
radioactivity.

The
HIARC
extrapolated
a
dermal
absorption
factor
of
33%
based
on
the
ratio
of
333
mg/
kg/
day
(
based
on
the
presence
of
thyroid
hormone
changes
observed
at
7,
14,
and
30
days
at
the
333
mg/
kg/
day
dose
level
observed
in
the
male
90­
day
rat
feeding
study)
and
the
LOAEL
of
1000
mg/
kg/
day
in
the
21­
day
dermal
toxicity
study.
In
rats,
it
was
noted
that
thyroid
toxicity
was
the
common
toxicity
seen
via
both
routes
in
the
same
species
7.
Dermal
Exposure:
Short­
Term
(
1­
30
days)
Exposure
Study
Selected:
21­
Day
Dermal
Toxicity
Study
§
OPPTS
870.3200
13
MRID
No.:
42416002
Executive
Summary:
In
a
21­
day
dermal
toxicity
study
(
MRID#
42416002),
Charles
River
rats
were
exposed
dermally
to
PCNB
(
98%
a.
i)
by
application
of
the
moistened
solid
(
distilled
water
vehicle)
to
the
shaved
dorsal
skin
at
doses
of
0,
100,
300
and
1000
mg/
kg
for
6
hours
per
day,
five
days
per
week.

In
the
high
dose
males,
dilatation
of
the
thyroid
follicles
was
observed
in
3/
5
animals
and
hypertrophy
of
the
thyroid
follicular
epithelium
was
observed
in
4/
5
animals.
These
changes
were
not
observed
in
any
of
the
other
dose
groups,
including
controls
or
in
any
females.
No
other
treatment­
related
effects
were
observed
in
either
males
or
females.
Based
on
these
findings,
the
NOAEL
is
300
mg/
kg/
day
and
the
LOAEL
is
1000
mg/
kg/
day
based
on
thyroid
effects.

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
=
300
mg/
kg/
day
based
on
hypertrophy
of
the
thyroid
follicular
epithelium
and
dilation
of
the
thyroid
follicles
in
males
only
at
the
LOAEL
=
1000
mg/
kg.

Comments
about
Study/
Endpoint:
This
study
is
appropriate
for
the
route
and
duration
of
exposure
concerns.

8.
Dermal
Exposure:
Intermediate­
Term
(
1
­
6
Months)

Study
Selected:
21­
Day
Dermal
Toxicity
Study
§
OPPTS
870.3200
MRID
No.:
42416002
Executive
Summary:
See
Short­
term
Dermal
(
1
day
to
1
month)
Exposure
Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
=
300
mg/
kg/
day
based
on
hypertrophy
of
the
thyroid
follicular
epithelium
and
dilation
of
the
thyroid
follicles
in
males
at
the
LOAEL
=
1000
mg/
kg/
day.

Comments
about
Study/
Endpoint:
This
study
is
appropriate
for
the
route
and
duration
of
exposure
concerns.

9.
Dermal
Exposure
Long­
Term
(>
6
Months)

Study
Selected:
Combined
Chronic
Toxicity/
Carcinogenicity
Study
­
Rat
§
OPPTS
870.4300
MRID
No.:
41987301
Executive
Summary:
See
Chronic
Reference
Dose
(
RfD)

Dose
and
Endpoint
for
Risk
Assessment:
1
mg/
kg/
day
based
on
hepatocellular
hypertrophy,
hepatocellular
hyperplasia
(
females)
and
thyroid
hypertrophy
and
hyperplasia
at
150
mg/
kg/
day.
14
Comments
about
Study/
Endpoint:
This
dose/
end
point
study
was
also
used
to
establish
the
chronic
RFD.
Since
an
oral
dose
was
identified,
33%
dermal
absorption
should
be
used
in
routeto
route
extrapolation.

10.
Inhalation
Exposure:
Short
­
Term
(
1­
30
days)

Study
Selected:
Subchronic
Oral
Toxicity
Study
in
Male
Rats
§
Nonguideline
MRID
No.:
42630801
Executive
Summary:
See
Short
Term
(
1
day
to
1
month)
Incidental
Oral
Exposure
Dose/
Endpoint
for
Risk
Assessment:
1
mg/
kg/
day.
Although
a
NOAEL
was
not
identified
in
the
non­
guideline
male
study
at
90
days,
no
effects
were
observed
at
the
1
mg/
kg/
day
dose
level
at
interim
sacrifice/
hormone
assessment
intervals
conducted
at
7,
14,
and
30
days.
This
finding
was
considered
an
appropriate
endpoint
for
risk
assessment
by
HIARC
for
periods
up
to
30
days.

Comments
about
Study/
Endpoint:
In
the
absence
of
an
inhalation
study,
an
oral
study
was
selected.
Absorption
by
the
inhalation
route
should
be
considered
to
be
equivalent
to
absorption
by
the
oral
route.

11.
Inhalation
Exposure:
Intermediate­
Term
(
1­
6
Months)

Study
Selected:
Subchronic
Oral
Toxicity
Study
in
Male
Rats
§
Nonguideline
MRID
No.:
42630801
Executive
Summary:
See
Short
Term
(
1
day
to
1
month)
Incidental
Oral
Exposure
Dose/
Endpoint
for
Risk
Assessment:
1
mg/
kg/
day.
Although
a
NOAEL
was
not
identified
in
the
non­
guideline
male
study
at
90
days,
no
effects
were
observed
at
the
1
mg/
kg/
day
dose
level
at
interim
sacrifice/
hormone
assessment
intervals
conducted
at
7,
14,
and
30
days.
This
finding
was
considered
an
appropriate
endpoint
for
risk
assessment
by
HIARC
for
periods
up
to
30
days.

Comments
about
Study/
Endpoint:
In
the
absence
of
an
inhalation
study,
an
oral
study
was
selected.
Absorption
by
the
inhalation
route
should
be
considered
to
be
equivalent
to
absorption
by
the
oral
route.

12.
Inhalation
Exposure:
Long­
Term
(>
6
Months)

Study
Selected:
Combined
Chronic
Toxicity/
Carcinogenicity
Study
­
Rat
§
OPPTS
870.4300
MRID
No.:
41987301
Executive
Summary:
See
Chronic
Reference
Dose
(
RfD)
15
Dose/
Endpoint
for
Risk
Assessment:
1
mg/
kg/
day
based
on
hepatocellular
hypertrophy,
hepatocellular
hyperplasia
(
females)
and
thyroid
hypertrophy
and
hyperplasia
at
150
mg/
kg/
day.

Comments
about
Study/
Endpoint:
In
the
absence
of
an
inhalation
study,
an
oral
study
was
selected.
Absorption
by
the
inhalation
route
should
be
considered
to
be
equivalent
to
absorption
by
the
oral
route.

13.
Margins
of
Exposure
Summary
of
target
Margins
of
Exposure
(
MOEs)
for
risk
assessment.

Route
Duration
Short­
Term
(
1­
30
Days)
Intermediate­
Term
(
1
­
6
Months)
Long­
Term
(>
6
Months)

Occupational
(
Worker)
Exposure
Dermal
100
100
100
Inhalation
100
100
100
Residential
(
Non­
Dietary)
Exposure
Oral
1000
1000
N/
A
Dermal
1000
1000
1000
Inhalation
1000
1000
1000
For
Occupational
exposure:
This
is
based
on
the
conventional
uncertainty
factor
of
100X
(
10X
for
intraspecies
extrapolation
and
10X
for
interspecies
variation)

For
Residential
exposure:
This
is
based
on
the
conventional
uncertainty
factor
of
100X
(
10X
for
intraspecies
extrapolation
and
10X
for
interspecies
variation)
in
addition
to
a
10X
UF
DB
due
to
the
lack
of
a
comparative
thyroid
study.

14.
Recommendation
for
Aggregate
Exposure
Risk
Assessments
As
per
FQPA,
1996,
when
there
are
potential
residential
exposures
to
the
pesticide,
aggregate
risk
assessment
must
consider
exposures
from
three
major
sources:
oral,
dermal
and
inhalation
exposures.
The
toxicity
endpoints
selected
for
these
routes
of
exposure
may
be
aggregated
as
follows:

A
common
toxicological
endpoint
of
concern
(
thyroid
toxicity)
was
identified
for
the
oral,
dermal,
and
inhalation
(
oral
equivalent)
routes
of
exposure.
Therefore,
for
short,
intermediate
and
long
term
exposure
aggregate
risk
assessments,
these
routes/
durations
can
be
aggregated
for
the
appropriate
populations.
16
III.
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
1.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
OPPTS
870.4300
MRID
No.:
41987301
Executive
Summary:
In
an
oral
chronic
toxicity/
carcinogenicity
study
(
MRID
41987301),
50
Charles
River
CD
®
rats/
sex/
dose
group
were
administered
pentachloronitrobenzene
(
PCNB
tech.,
99.4%
a.
i.)
in
the
diet
at
concentrations
of
0,
20,
3000
or
6000
ppm
(
equivalent
to
estimated
average
daily
intakes
of
0,
1,
150
or
300
mg/
kg/
day;
estimated
based
on
a
standard
conversion
factor
of
0.05)
for
24
months.
An
additional
10
animals/
sex/
dose
group
were
included
for
interim
sacrifice
at
12
months.

At
3000
ppm,
statistically
significantly
increased
relative
liver
weight
in
males
(+
20%
above
controls),
absolute
thyroid/
parathyroid
weight
in
males
(+
26%),
relative
thyroid/
parathyroid
weight
(+
35%,
males
and
+
24%,
females),
and
significantly
increased
incidence
of
microscopic
lesions
including
mild
hepatocellular
hypertrophy
(
27%,
males
and
38%,
females
vs.
0%,
controls),
mild
thyroid
hyperplasia
(
15%,
males
vs.
4%,
controls
and
16%,
females
vs.
0%,
controls)
and
thyroid
hypertrophy
(
42%,
males
vs.
0%,
controls
and
36%,
females
vs.
2%,
controls)
were
observed.
Sporadic
significantly
decreased
mean
body
weights
in
both
sexes
were
not
considered
biologically
significant.
At
6000
ppm,
these
effects
showed
a
dose­
response
and
in
addition,
statistically
significantly
decreased
mean
body
weight/
weight
gain
throughout
treatment
(
at
termination,
­
11%/­
15%
less
than
controls
in
males
and
­
12%/­
18%
in
females),
decreased
food
consumption
during
the
first
6
months,
increased
serum
cholesterol
(
females),
significantly
increased
relative
liver
weight
in
both
sexes
(+
25%,
males
and
+
20%,
females)
and
increased
incidence
of
thyroid
colloid
cysts
in
males
(
16%
vs.
4.1%,
controls)
were
observed.
At
the
12­
month
interim
sacrifice,
both
sexes
showed
slight
(
not
statistically
significant)
increases
in
liver
and
thyroid
weights
at
mid
and
high
dose
and
in
high
dose
females,
there
was
a
slightly
increased
incidence
of
visible
tan
foci
in
the
lungs.
There
were
no
treatment­
related
clinical
or
ophthalmologic
observations
and
no
effects
on
mortality,
hematology
or
urinalysis
parameters.
The
systemic
toxicity
LOAEL
is
3000
ppm
(
150
mg/
kg/
day),
based
on
hepatocellular
hypertrophy,
hepatocellular
hyperplasia
(
females)
and
thyroid
hypertrophy
and
hyperplasia.
The
systemic
toxicity
NOAEL
is
20
ppm
(
1
mg/
kg/
day).

This
study
is
classified
Acceptable/
Guideline
(
§
83­
5;
OPPTS
870.4300)
and
satisfies
the
Guideline
requirement
for
a
chronic
toxicity/
carcinogenicity
study
in
the
rodent.

Discussion
of
Tumor
Data:
PCNB
caused
an
increased
incidence
of
thyroid
follicular
cell
adenomas
in
males
(
0%,
0%,
12.5%
and
10.2%,
control
to
high
dose;
p<
0.05
at
3000
ppm)
and
a
significantly
increasing
trend
(
p<
0.01).
Incidence
in
females
was
2.0%,
0%,
4.0%
and
8.7%
(
control
to
high
dose;
not
significant);
however,
a
significantly
increasing
trend
(
p<
0.05)
was
observed.
The
incidence
of
thyroid
follicular
cell
carcinoma
was
increased
at
6000
ppm
only
in
males
(
males
0%,
2.0%,
0%
and
4.1%;
females
2.0%,
0%,
0%
and
2.2%).
The
combined
incidence
of
thyroid
follicular
cell
adenomas
and
carcinomas
was
significantly
increased
in
males
17
at
3000
and
6000
ppm
(
control
to
high
dose,
0%,
2.0%,
12.5%,
14.3%;
p<
0.05)
but
not
females
(
4.0%,
0%,
4.0%
and
10.9%),
with
a
significant
trend
in
both
sexes
(
females
p<
0.05
and
males
p<
0.01).
The
incidence
of
follicular
cell
adenoma
in
historical
control
data
from
this
laboratory
did
not
exceed
11.1%
in
males
or
3.2%
in
females.
The
incidence
of
carcinoma
did
not
exceed
9.4%
in
males
or
3.2%
in
females.

Adequacy
of
the
Dose
Levels
Tested:
The
dose
levels
are
considered
adequate.
Systemic
toxicity
was
seen
at
the
mid
and
high
dose
levels
tested.

B.
Executive
Summary:
In
a
Chronic
Toxicity/
Oncogenicity
study
(
MRID
43015801),
groups
of
60
male
and
60
female
Crl:
CDBR
Sprague­
Dawley
rats
were
given
0,
5,
50,
500,
or
1000
mg/
kg
bodyweight
pentachloronitrobenzene
(
Technical
98%)
by
gavage
five
days
per
week
for
up
to
two
years.
When
adjusted
for
continuous
exposure,
these
dose
levels
were
equivalent
to
0,
3.6,
36,
357
or
714
mg/
kg/
day.
T
3,
T
4
and
TSH
parameters
were
not
examined.

No
apparent
effects
on
body
weight,
food
intake,
clinical
observations,
or
survival
were
found.
At
all
dose
levels
and
at
all
measured
time
points
(
6,
12,
and
18
months
and
study
termination),
dose­
dependent
decreases
in
serum
AST
and
ALT
activities
and
the
excretion
of
triple
phosphate
crystals
in
the
urine
were
found
in
both
sexes.
At
36
mg/
kg/
day
and
above,
increases
in
minimal
to
slight
hepatocellular
hypertrophy
were
observed
in
males
(
ranging
from
9/
60
to
26/
60
versus
2/
60
in
controls;
p
<
0.05
at
36
mg/
kg/
day;
p
<
0.01
at
357
mg/
kg/
day
and
above).
At
357
mg/
kg/
day
and
above,
increases
in
minimal
to
slight
hepatocellular
hypertrophy
were
observed
in
females
(
ranging
from
10/
60
to
22/
60
versus
1/
60
in
controls;
p
<
0.01).
Increases
in
thyroid
follicular
cell
hypertrophy/
hyperplasia
were
observed
in
both
sexes
(
6/
60
versus
2/
60
in
males
and
5/
59
versus
1/
59
in
females)
however,
the
increases
were
not
statistically
significant.
High
dose
male
rats
had
an
approximate
30%
increase
of
absolute
and
relative
liver
weight
and
an
approximate
22%
increase
in
absolute
thyroid/
parathyroid
weight
at
necropsy.
Microscopically,
increases
in
thyroid
follicular
cell
hypertrophy/
hyperplasia
(
mostly
minimal
to
slight;
12/
60
versus
2/
60
for
males
and
10/
60
versus
1/
59
for
females;
p
<
0.01)
were
found.
Based
on
the
hepatocellular
hypertrophy
and
the
thyroid
follicular
cell
hypertrophy/
hyperplasia,
the
NOAEL
was
3.6
mg/
kg/
day
for
males
and
36
mg/
kg/
day
for
females.
The
corresponding
LOAELS
would
be
36
mg/
kg/
day
for
males
and
357
mg/
kg/
day
for
females.
No
treatment
related
increase
in
neoplasia
was
found.

The
study
is
classified
as
core
guideline
and
satisfies
the
requirements
for
an
§
83­
5
Oral
Chronic/
oncogenicity
Study.

Discussion
of
Tumor
Data:
No
treatment
related
increase
in
neoplasia
was
noted.

Adequacy
of
Dosing:
Previous
concerns
for
PCNB
carcinogenicity
were
linked
to
the
high
HCB
concentrations
in
earlier
studies.
However,
in
the
Uniroyal
feeding
study
(
MRID
No.
41987301),
only
0.04%
HCB
was
reported
in
the
test
material
and
this
study
demonstrated
a
positive
carcinogenic
potential.
On
the
other
hand,
the
Amvac
study
(
MRID
No.
41987301)
was
negative
for
carcinogenicity.
This
is
a
gavage
study
with
administration
of
the
test
material
(
98%
PCNB)
only
5
days
per
week.
The
interruption
in
dosing
may
tend
to
allow
some
time
for
test
material
body
burden
to
decrease
and
for
for
recovery,
as
compared
to
a
dietary
feeding
study.
This
18
difference
in
dosing
regimen
might
tend
to
explain
the
negative
carcinogenicity
results,
although
other
similar
thyroid
findings
were
noted.
HIARC
concluded
that
the
dose
levels
tested
were
judged
to
be
adequate
based
on
thyroid
toxicity
observed
at
the
mid
and
high
dose
levels.

2.
Carcinogenicity
Study
in
Mice
MRID
No.:
45609101
Citation:
National
Toxicology
Program.
March,
1986.
NTP
Technical
Report
on
the
Toxicology
and
Carcinogenesis
Studies
of
Pentachloronitrobenzene
in
B6C3
F1
Mice.
(
Pre­
publication
draft
report
no.
NIH
86­
2581)

Executive
Summary:
In
an
oral
carcinogenicity
study,
(
MRID
No.
45609101)
50
B6C3F1
mice
per
sex
per
dose
group
were
administered
PCNB
(
purity
not
reported)
in
the
diet
at
concentrations
of
0,
2500,
or
5000
ppm
for
103
weeks.
At
the
end
of
the
feeding
period,
test
diets
were
withdrawn
and
the
animals
were
fed
control
diets
during
a
one­
week
observation
period
before
termination
of
the
study.

No
increase
in
the
incidence
of
neoplastic
lesions
was
observed
in
the
treated
mice,
but
the
test
substance
may
have
predisposed
the
female
mice
of
the
high
dose
group
to
a
bacterial
infection
which
significantly
decreased
their
survival
after
86
weeks.
PCNB
did
not
exhibit
carcinogenic
potential
under
the
conditions
of
the
experiment.

Due
to
the
decreased
survival
rate,
since
the
lot
and
concentration
of
the
test
material
used
in
the
study
are
not
indicated,
and
the
suggestion
that
study
interpretation
may
have
been
confounded
due
to
infection,
this
study
is
classified
as
unacceptable
and
does
not
satisfy
the
requirement
for
a
mouse
carcinogenicity
study.

Discussion
of
Tumor
Data:
No
carcinogenic
effects
were
noted.

Adequacy
of
Dosing:
Dosing
may
have
been
adequate,
but
survival
was
reduced
associated
with
a
bacterial
infection.

3.
Classification
of
Carcinogenic
Potential
The
carcinogenicity
of
PCNB
was
assessed
in
reviews
of
1977
(
special
review)
and
in
1986
and
1992.
In
1992,
HED's
Carcinogenicity
Peer
Review
Committee
(
CARC)
classified
PCNB
as
a
Group
C
­
possible
human
carcinogen
and
recommended
that
for
the
purpose
of
risk
characterization,
the
Reference
Dose
approach
should
be
used
for
quantification
of
human
risk.

IV.
MUTAGENICITY
The
HIARC
concluded
that
there
is
not
a
concern
for
mutagenicity
resulting
from
exposure
to
PCNB.
19
Pentachloronitrobenzene
was
selected
for
genetic
toxicology
screening
by
the
National
Toxicology
Program
(
NTP).
Testing
included:
the
Salmonella/
mammalian
microsome
test,
induction
of
forward
gene
mutations
in
L5178Y
mouse
lymphoma
cells
and
induction
of
chromosome
aberrations
and
sister
chromatid
exchanges
(
SCEs)
in
Chinese
hamster
ovary
(
CHO)
cells.
Although
formal
DERs
do
not
exist
for
these
assays,
they
are
considered
acceptable
by
HED.

GENE
MUTATIONS
1.
Salmonella
typhimurium/
mammalian
microsome
reverse
gene
mutation
assay:
Using
the
preincubation
procedure,
PCNB
(
95%)
was
negative
in
S.
typhimurium
strains
TA1535,
TA1537,
TA198
and
TA
100
up
to
high
doses
of
6666.7
to
10,000
ug/
plate
without
S(
activation
and
with
S9
activation
derived
from
rat
and
hamster
livers
induced
with
Aroclor
1254.
Compound
precipitation
was
seen
at
>
1000ug/
plate.
The
study
is
acceptable
and
satisfies
the
guideline
requirement
for
a
bacterial
gene
mutation
assay.

2.
L5178Y
mouse
lymphoma
cell
forward
gene
mutation
assay:
Independent
trial
were
negative
up
to
the
highest
doses
tested
(
15
or
30

g/
mL
­
S9;
15

/
mL
+
S9).
The
study
is
acceptable
and
satisfies
the
guideline
requirement
for
a
mammalian
cell
gene
mutation
assay.

CHROMOSOMAL
ABERRATIONS
3.
In
vitro
cytogenetics
assay
in
Chinese
hamster
ovary
(
CHO)
cells:
the
test
was
positive
in
the
absence
of
S(
activation
with
a
significant
(
p<
0.05)
increase
in
chromosome
aberrations
over
a
concentration
range
of
7.5­
75

g/
mL.
With
S9
activation,
results
were
equivocal
at
the
highest
dose
tested
(
75

g/
mL).
The
study
is
acceptable
and
satisfies
the
guideline
requirement
for
an
in
vitro
cytogenetic
assay.

OTHER
MUTAGENIC
MECHANISMS
4.
In
vitro
SCE
assay
in
CHO
cells:
The
test
was
negative
up
to
the
highest
concentration
tested
(
7.5

g/
mL
­
S9;
75

g/
mL+
S9).
The
study
is
acceptable
and
satisfies
the
guideline
requirement
for
an
in
vitro
SCE
assay.

Results
from
the
NTP
genetic
toxicology
testing
indicate
that
PCNB
(
lot
and
%
a.
i.
not
specified)
is
not
mutagenic
in
bacteria
or
in
cultured
mammalian
cells.
There
is,
however,
evidence
showing
that
PCNB
is
clastogenic
in
the
absence
of
S9
activation
and
equivocal
in
the
presence
of
S9
activation.
PCNB
was
also
negative
for
the
induction
of
SCEs
in
vitro.
Based
on
these
data,
it
is
recommended
that
the
in
vitro
test
results
of
clastogenicity
be
examined
in
an
in
vivo
cytogenetic
assay.

CITATIONS
Haworth,
S.,
Lawlor,
T.,
Mortelmans,
K.,
Speck,
W.,
and
Zeiger,
E.
(
1983).
Salmonella
mutagenicity
test
results
for
250
chemicals.
Environ
Mutagen
5(
Suppl
1):
3­
142
20
Galloway,
S.
M.,
Armstrong,
M.
A.,
Reuben,
C.,
Colman,
S.,
Brown,
B.,
Cannon,
C.
et
al
(
1987).
Chromosome
aberration
and
sister
chromatid
exchange
in
Chinese
ovary
cells:
Evaluation
of
108
chemicals.
Environ
Molec
Mutagen
10(
Suppl
10):
1­
176.

Helsley,
D
(
2000).
Personal
communication
between
d.
Helsley,
cellular
and
Genetic
toxicology
Branch,
NTP
and
N.
E.
McCarroll,
OPP/
HED/
Tox
1
 
mouse
lymphoma
data.

V.
HAZARD
CHARACTERIZATION
The
Metabolism
Assessment
Review
Committee
(
MARC)
convened
on
October
14,
2001
to
consider
the
Uniroyal
and
Amvac
PCNB
data
bases.
They
concluded
that
they
could
find
no
evidence
that
the
chemical
composition
(
i.
e.
impurity
levels)
differences
among
the
formulations
tested
in
the
toxicity
studies
affected
the
NOAELS/
LOAELS
and
endpoints
found.
This
is
interpreted
as
indicating
that
the
data
bases
for
the
two
technicals
should
be
combined
for
purposes
of
risk
assessment
PCNB
is
used
as
a
non­
systemic
soil
treatment
fungicide
for
vegetables,
field
crops,
turf,
ornamentals
and
as
a
post­
harvest
treatment
on
banana
stems
and
rose
bushes.
It
is
also
a
seed
dressing
agent.
It
is
primarily
applied
as
a
spray,
through
sprinkler
irrigation
systems
or
granular
preparations
to
soil
and
is
formulated
as
an
emulsifiable
concentrate,
granules
or
wettable
powder.
Acute
toxicities
are
low
,
with
most
study
results
in
Toxicity
Categories
III
or
IV,
although
(
Uniroyal)
PCNB
has
been
identified
as
a
weak
sensitizer.

Data
from
several
1970'
s
monkey
studies
suggest
that
PCNB
bioaccumulates,
to
some
degree,
in
mammals.
In
these
studies,
only
a
few
animals
are
utilized
but
data
suggest
that
the
half­
live
might
be
as
long
as
4
or
more
days.
These
investigators
also
noted
that
after
20
days
only
59%
of
a
given
dose
was
eliminated.
It
was
also
suggested
that
from
day
30
to
40,
the
excretion
curve
paralleled
the
dose
which
means
that
an
equilibrium
between
uptake
and
excretion
was
reached,
resulting
in
a
plateau
of
the
storage
curve.
These
data
clearly
raise
an
uncertainty
as
to
the
biological
half­
life
for
PCNB
and
therefore
as
to
its
potential
for
bioaccumulation.
Additional
data
are
necessary
before
finalization
of
the
risk
assessment
process.

Subchronic
and
chronic
studies
indicate
that
the
thyroid
and
the
liver
are
target
organs
for
PCNB.
Limited
evidence
suggest
that
the
thyroid
effects
might
be
due,
at
least
in
part,
to
disturbance
of
thyroid
homeosthasis.
(
Also
see
discussion
in
Section
5.5,
Additional
Information
from
Literature
Sources)

Aminotransferase
activities
(
AST/
ALT,
particularly
ALT)
decrease
in
dose­
dependent
manner
by
as
much
as
30­
80%
in
rats
and
dogs.
However,
data
are
inadequate
to
evaluate
the
toxicological
significance
of
these
findings.
(
Also
see
discussion
in
Section
5.5,
Additional
Information
from
Literature
Sources).
The
Registrant
has
been
requested
to
address
these
issues
of
thyroid
activity
and
transaminase
enzymatic
activity.

Results
from
the
NTP
genetic
toxicology
testing
indicate
that
PCNB
(
lot
and
%
a.
i.
not
specified)
is
not
mutagenic
in
bacteria
or
in
cultured
mammalian
cells.
There
is,
however,
evidence
showing
that
PCNB
is
clastogenic
in
the
absence
of
S9
activation
and
equivocal
in
the
presence
of
S9
activation.
PCNB
was
21
also
negative
for
the
induction
of
SCEs
in
vitro.
The
HIARC
recommended
that
the
in
vitro
test
results
of
clastogenicity
be
examined
in
an
in
vivo
cytogenetic
assay.

The
carcinogenicity
of
PCNB
was
assessed
in
reviews
of
1977
(
special
review)
and
in
1986
and
1992.
In
1992,
the
CPRC
classified
PCNB
as
a
Group
C­
possible
human
carcinogen
and
recommended
that
for
the
purpose
of
risk
characterization,
the
Reference
Dose
approach
should
be
used
for
quantification
of
human
risk.

No
findings
of
significant
toxicological
concern
have
been
identified
in
developmental
toxicity
or
reproduction
study
data.
No
neurotoxicity
studies
have
been
identified
and
no
neurobehavioral
alterations
nor
evidence
of
neuropathological
effects
have
been
observed
in
available
data.

VI.
DATA
GAPS
/
REQUIREMENTS
1.
Although
the
thyroid
is
a
target
organ
for
PCNB,
thyroid
hormone
and
TSH
determinations
have
been
performed
only
in
one
nonguideline
study
(
90­
day
study
in
male
rats)
using
inappropriate
dosing
(
0,
1,
&
333
mg/
kg/
day)
which
precludes
a
meaningful
assessment
of
doseresponse
and
time­
course
features
of
the
effect.
The
HIARC
requests
that
the
Registrant
conduct
a
study
to
assess
thyroid
toxicity
in
adults
vs.
offspring
development.
The
study
should
include:
(
a)
Assays
of
appropriate
hormones
(
b)
Organ
Weights
(
c)
Histopathology.
The
study
should
be
conducted
utilizing
an
adequate
dosing
regimen
allowing
for
meaningful
toxicological
assessment
of
dose
response
and
comparison
to
other
submitted
toxicological
studies.
In
addition,
it
should
be
integrated
with
appropriate
kinetic
data.
The
registrant
is
requested
to
consult
the
Agency
in
the
design
of
this
study.

2.
Aminotransferase
activities
(
AST/
ALT,
particularly
ALT)
decrease
in
dose­
dependent
manner
by
as
much
as
30­
80%
in
rats
and
dogs.
Although
the
literature
indicates
that
Aminotransferase
inhibition,
may
result
in
increases
in
GABA,
hepatocellular
tyrosine,
and
other
aminoacid­
related
compounds,
there
are
no
data
to
evaluate
the
toxicological
significance
of
the
inhibition
data
for
PCNB.
The
Registrant
is
requested
to
address
the
toxicological
significance
of
these
alterations
in
AST/
ALT
activities
on
the
risk
assessment
of
the
subject
chemical.
(
Also
see
Section
5.5,
Additional
Information
from
Literature
Sources)

3.
Limited
kinetic
data
have
been
identified
in
the
literature
which
suggest
that
PCNB
will
likely
accumulate
within
mammalian
tissues
potentially
impacting
upon
the
risk
assessment
process.
Because
of
concerns
about
the
uncertainties
of
the
half­
life
and
thus
for
the
accumulation
potential
of
the
chemical,
the
HIARC
recommended
that
a
study
to
determine
the
biological
half
life
on
PCNB
be
requested.
It
is
therefore
requested
that
the
Registrant
perform
a
guideline
metabolism
study
of
PCNB
(
including
a
mass
balance
of
radioactivity
in
excreta,
tissues,
and
carcass)
including
a
Tier
II
study
of
blood
kinetics,
to
determine
a
half
life
of
PCNB.
The
Registrant
should
consult
the
Agency
as
to
the
details
of
the
protocol.

4.
There
is
evidence
showing
that
PCNB
is
clastogenic
in
the
absence
of
S9
activation
and
equivocal
in
the
presence
of
S9
activation.
PCNB
was
also
negative
for
the
induction
of
SCEs
in
vitro.
The
HIARC
requests
that
the
in
vitro
test
results
of
clastogenicity
be
examined
in
an
in
22
vivo
cytogenetic
assay.

5.
There
are
no
subchronic
inhalation
toxicity
data
on
PCNB.
Due
to
the
greenhouse
use
of
PCNB
the
HIARC
requests
that
a
90­
day
inhalation
toxicity
study
of
PCNB
be
conducted.
It
is
recommended
that
interim
thyroid
hormone
analyses
be
made
at
7,
14,
30
and
90
days.
23
VII.
ACUTE
TOXICITY
Acute
Toxicity
of
PCNB
(
Uniroyal)

Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
81­
1
Acute
Oral
43198201
LD
50
=
>
5000
mg/
kg
IV
81­
2
Acute
Dermal
43198202
LD
50
=
>
5000
mg/
kg
IV
81­
3
Acute
Inhalation
43118201
LC
50
=
>
1.7
mg/
L
III
81­
4
Primary
Eye
Irritation
43198203
Slight
irritant
III
81­
5
Primary
Skin
Irritation
43198204
Non
irritant
IV
81­
6
Dermal
Sensitization
4060901
Weak
sensitizer
81­
8
Acute
Neurotoxicity
Acute
Toxicity
of
PCNB
(
Amvac)

Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
81­
1
Acute
Oral
41443101
LD
50
=
>
5050
mg/
kg
IV
81­
2
Acute
Dermal
41443102
LD
50
=
>
2020
mg/
kg
III
81­
3
Acute
Inhalation
41443103
LC
50
=
>
6.49
mg/
L
III
81­
4
Primary
Eye
Irritation
41443109
Slight
irritant
III
81­
5
Primary
Skin
Irritation
41443105
PII
=
0.0175
IV
81­
6
Dermal
Sensitization
40734001
Non
sensitizer
81­
8
Acute
Neurotoxicity
24
VIII.
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION
Summary
of
Toxicological
Dose
and
Endpoints
for
PCNB
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
All
populations)
N/
A
N/
A
None
selected
Chronic
Dietary
(
All
populations)
NOAEL=
1.0
mg/
kg/
day
UF
=
1000
Chronic
RfD
=
0.001
mg/
kg/
day
FQPA
SF
=
1X
cPAD
=
chronic
RfD
FQPA
SF
=
0.001
mg/
kg/
day
Chronic/
Oncogenicity
Study
­
rat
LOAEL
=
150
mg/
kg/
day
based
on
hepatocellular
hypertrophy,
hepatocellular
hyperplasia,
and
thyroid
hypertrophy
Short­
Term
Incidental
Oral
(
1­
30
days)
NOAEL=
1.0
mg/
kg/
day
Residential
LOC
for
MOE
=
1000
Occupational
=
NA
90­
Day
Subchronic
­
Rat
LOAEL
=
1.0
mg/
kg/
day
based
on
no
toxicity
at
30
days
Intermediate­
Term
Incidental
Oral
(
1­
6
months)
NOAEL=
1.0
mg/
kg/
day
Residential
LOC
for
MOE
=
1000
Occupational
=
NA
90­
Day
Subchronic
­
Rat
LOAEL
=
1.0
mg/
kg/
day
based
on
threshold
effects
(
liver
and
thyroid
lesions)
seen
at
the
lowest
dose
tested
Short­
(
1
to
30
days)
and
Intermediate­
Term
Dermal
(
1
to
6
months)
Dermal
NOAEL=
300
mg/
kg/
day
Residential
LOC
for
MOE
=
1000
Occupational
LOC
for
MOE
=
100
21­
Day
Dermal
­
Rat
LOAEL
=
mg/
kg/
day
based
on
hypertrophy
of
the
thyroid
follicular
epithelium
and
dilation
of
the
thyroid
follicles
in
males
at
1000
mg/
kg/
day
Long­
Term
Dermal
(>
6
months)
Oral
NOAEL=
1.0
mg/
kg/
day
(
dermal
absorption
rate
=
33%
of
oral)
Residential
LOC
for
MOE
=
1000
Occupational
LOC
for
MOE
=
100
Chronic/
Oncogenicity
Study
­
rat
LOAEL
=
150
mg/
kg/
day
based
on
hepatocellular
hypertrophy,
hepatocellular
hyperplasia,
and
thyroid
hypertrophy
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
25
Short­
Term
Inhalation
(
1
to
30
days)
Oral
NOAEL=
1.0
mg/
kg/
day
(
inhalation
absorption
=
100%
of
oral)
Residential
LOC
for
MOE
=
1000
Occupational
LOC
for
MOE
=
100
90­
Day
Subchronic
­
Rat
LOAEL
=
1.0
mg/
kg/
day
based
on
no
toxicity
at
30
days
Intermediate­
Term
Inhalation
(
1
to
6
months)
Oral
NOAEL
=
1.0
mg/
kg/
day
(
inhalation
absorption
rate
=
100%
of
oral)
Residential
LOC
for
MOE
=
1000
Occupational
LOC
for
MOE
=
100
90­
Day
Subchronic
­
Rat
LOAEL
=
1.0
mg/
kg/
day
based
on
threshold
effects
(
liver
and
thyroid
lesions)
seen
at
the
lowest
dose
tested
Long­
Term
Inhalation
(>
6
months)
Oral
NOAEL=
1.0
mg/
kg/
day
(
inhalation
absorption
rate
=
100%
of
oral)
Residential
LOC
for
MOE
=
1000
Occupational
LOC
for
MOE
=
100
Chronic/
Oncogenicity
Study
­
rat
LOAEL
=
150
mg/
kg/
day
based
on
hepatocellular
hypertrophy,
hepatocellular
hyperplasia,
and
thyroid
hypertrophy
Cancer
(
oral,
dermal,
inhalation)
HED's
Carcinogenicity
Peer
Review
Committee
(
CARC)
classified
PCNB
as
a
Group
C
­
possible
human
carcinogen
and
recommended
that
for
the
purpose
of
risk
characterization,
the
Reference
Dose
approach
should
be
used
for
quantification
of
human
risk.

UF
=
uncertainty
factor,
FQPA
SF
=
Special
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
NA
=
Not
Applicable
NOTE:
The
Special
FQPA
Safety
Factor
recommended
by
the
HIARC
assumes
that
the
exposure
databases
(
dietary
food,
drinking
water,
and
residential)
are
complete
and
that
the
risk
assessment
for
each
potential
exposure
scenario
includes
all
metabolites
and/
or
degradates
of
concern
and
does
not
underestimate
the
potential
risk
for
infants
and
children.
26
REVIEWER
NOTES:

Subsequent
to
the
HIARC
meeting
of
November
27,
2001,
the
presenting
reviewer,
Laurence
Chitlik,
added
the
following
additional
comments:

1.
It
does
not
appear
appropriate
for
the
HIARC
to
select
the
use
of
a
non­
guideline
study
conducted
only
in
male
rats
for
use
as
part
of
a
risk
assessment
process
to
protect
females.
In
addition
even
for
males,
this
study
only
evaluated
a
very
few
parameters
far
short
of
what
would
be
included
in
a
typical
90­
day
study.
For
example,
the
study
did
not
include
hematology
or
even
gross
and
histopathology
for
tissues
other
than
the
thyroid,
parathyroids,
pituitary,
and
liver.

Certainly,
the
risk
assessment
process
must
include
low
dose
hazards
identified
in
this
study.
However,
consideration
of
the
lack
of
toxicity
observed
at
certain
interim
time
points
does
not
constitute
an
appropriate
endpoint
for
safety
assessment
especially
since
so
little
was
assessed
in
this
study
and
only
in
one
sex.

2.
The
second
comment
relates
to
the
need
for
a
new
mouse
oncogenicity
study
since
previous
reviews
had
identified
a
number
of
shortcomings
(
including
bacterial
infection)
in
the
study
which
appear
to
confound
interpretation
of
study
data.
Although
this
issue
was
presented
to
the
HIARC,
it
did
not
appear
to
the
reviewer
that
a
consensus
was
reached
by
the
committee
not
to
require
a
new
study.
Some
committee
members
did
suggest
continued
use
of
the
mouse
oncogenicity
study,
but
clearly
there
was
no
actual
vote
by
the
committee
and
relative
to
such
a
critical
issue.

Since
PCNB
was
originally
registered
in
the
1950'
s,
the
contaminants
present
in
the
technical
have
changed
dramatically.
The
NTP
mouse
oncogenicity
study
listed
in
this
review
was
completed
in
1987
and
a
number
of
significant
deficiencies
have
been
identified
in
this
study.
Previous
reviews
of
the
study
indicated
that
nonneoplastic
lesions
observed
in
female
mice
were
secondary
to
bacterial
infection.
The
investigators
attempted
to
explain
the
high
levels
of
infection
observed
in
this
study
by
suggesting
that
the
test
material
might
have
predisposed
the
female
mice
(
but
curiously
not
the
males)
to
the
infection.
The
infection
was
identified
as
Klebsiella.
The
mouse
onco
study
appears
compromised
due
to
infection
confounding
interpretation
of
the
study
results
as
well
as
affecting
the
longevity
of
the
animals
on
test.
In
addition,
the
lot
#
of
the
test
material
is
not
identified
and
there
is
no
indication
in
the
report
that
the
test
diets
were
analyzed.
Lack
of
diet
analysis
by
itself
is
often
considered
adequate
for
invalidation
of
a
carcinogenicity
study.
Also,
a
review
by
R.
Gardner,
2/
2/
89,
states
that
it
is
"
prudent
to
use
the
mouse
study
in
the
absence
of
better
data"
but
at
this
time
I
do
not
find
this
a
reason
to
continue
to
use
this
study
as
was
done
in
the
1993
Cancer
review.
There
is
also
a
review
by
the
California
Department
of
Food
and
Agriculture
which
states
that
the
study
is
unacceptable
because
among
other
things,
only
two
doses
were
used,
many
missing
tissues
in
histopathology
examination,
a
questionable
MTD
was
utilized,
and
effects
of
an
infectious
agent
compromised
the
study.

3.
Due
to
the
significance
of
current
data
gaps,
conduct
of
a
meaningful
risk
assessment
especially
as
it
might
relate
to
FQPA
is
questionable
at
this
time.
The
HIARC
concurred
that
significant
additional
data
will
be
required
from
the
registrants
to
assist
in
the
risk
assessment
process.
Until
these
basic
data
are
available,
it
is
the
opinion
of
this
reviewer
that
a
meaningful
risk
assessment
cannot
be
performed
for
PCNB.
Certainly,
without
adequate
kinetic
data
demonstrating
the
potential
for
bioaccumulation
and
determination
of
steady
state
levels,
even
a
meaningful
MOE
assessment
cannot
be
performed.
