UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION
PESTICIDES
AND
TOXIC
SUBSTANCES
DATE:
December
15,
2003
MEMORANDUM
SUBJECT:
PCNB
(
PC
Code
056502)­
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
(
RED)

From:
Laurence
D.
Chitlik
,
D.
A.
B.
T.,
Senior
Toxicologist
Toxicology
Branch
Health
Effects
Division
(
7509C)

THROUGH:
Alberto
Protzel,
Ph.
D.
,
Senior
Scientist
Toxicology
Branch
Health
Effects
Division
(
7509C)

TO:
Diana
Locke
Reregistration
Branch
2
Health
Effects
Division
(
7509C)

PC
Code:
056502
TXR
No.:
056502
DP
Barcode:
296860
ACTION
REQUESTED:
Prepare
a
toxicology
chapter
for
the
RED
for
PCNB
RESPONSE:
The
toxicology
database
for
PCNB
has
been
reviewed
by
Toxicology
Branch,
the
Health
Effects
Division
Hazard
Identification
Assessment
Review
Committee
(
HIARC),
Cancer
Peer
Review
Committee
(
CPRC),
the
HED
FQPA
Safety
Factor
Committee,
and
the
Metabolism
Assessment
Review
Committee
(
MARC).
Although
a
complete
data
base
is
not
currently
available
to
support
a
risk
assessment
for
PCNB
(
since
key
kinetic,
metabolism
and
target
organ
toxicity
are
unavailable
and
need
to
be
submitted
by
the
Registrants),
available
data
for
PCNB
are
presented
in
this
document
in
support
of
a
Reregistration
Eligibility
Decision.
Page
2
PCNB
(
Pentachloronitrobenzene)

PC
Code:
056502
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
August
13,
2003
Prepared
by:
Laurence
D.
Chitlik,
DABT
Senior
Toxicologist
Toxicology
Branch
Health
Effects
Division
Mail
Code
7509C
Peer
Reviewed
by
:
Alberto
Protzel
Senior
Scientist
Toxicology
Branch
Health
Effects
Division
Mail
Code
7509C
_______________________________________
Laurence
D.
Chitlik,
DABT,
Senior
Toxicologist
_______________________________________
Alberto
Protzel,,
Senior
Scientist
Page
3
EPA
Reviewer:
Laurence
D.
Chitlik____________________________
Date___________
Toxicology
Branch
(
7509C)
EPA
Secondary
Reviewer:
Alberto
Protzel_______________________
Date___________
Toxicology
Branch
(
7509C)

TABLE
OF
CONTENTS
1.0
HAZARD
CHARACTERIZATION
4
2.0
REQUIREMENTS
6
3.0
DATA
GAPS(
S)
8
4.0
HAZARD
ASSESSMENT
9
4.1
Acute
Toxicity
9
4.2
Subchronic
Toxicity
10
4.3
Prenatal
Developmental
Toxicity
13
4.4
Reproductive
Toxicity
16
4.5
Chronic
Toxicity
18
4.6
Carcinogenicity
21
4.7
Mutagenicity
24
4.8
Neurotoxicity
25
4.9
Metabolism
26
4.10
Special
Studies
29
5.0
TOXICITY
ENDPOINT
SELECTION
(
HIARC)
30
5.1
Dietary
Exposure
5.1.1
Acute
Reference
Dose
(
aRfD)
30
5.1.2
Chronic
Reference
Dose
(
cRfD)
31
5.2
Incidental
Oral
Exposure
32
5.3
Dermal
Absorption
33
5.4
Short­
Term
Dermal
((
1­
30
days)
Exposure
34
5.5
Intermediate­
Term
Dermal
(
6
months)
Exposure
34
5.6
Long­
Term
Dermal
(>
6
months)
Exposure
35
5.7
Inhalation
Exposure:
Short­
Term
(
1­
30
days)
35
5.8
Inhalation
Exposure:
Intermediate­
Term
(
1­
6
Months)
35
5.9
Inhalation
Exposure:
Long­
Term
(>
6
Months)
36
5.10
Margins
of
Exposure
36
5.11
Recommendation
for
Aggregate
Exposure
Risk
Assessments
37
6.0
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
37
6.1
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
37
6.2
Carcinogenicity
Study
in
Mice
39
6.3
Classification
of
Carcinogenic
Potential
40
7.0
MUTAGENICITY
40
8.0
FQPA
CONSIDERATIONS
8.1
Developmental
Neurotoxicity
Recommendation
42
8.2
Other
Issues
43
9.0
REFERENCES
45
10.0
APPENDICES
48
10.1.2
Subchronic
,
Chronic
and
Other
Toxicity
Tables
49
10.1.3
Summary
of
Toxicology
Endpoint
Selection
Tables
51
Page
4
1.0
HAZARD
CHARACTERIZATION
Pentachloronitrobenzene
is
an
older
organochlorine
pesticide
and
very
few
of
these
are
still
marketed
today
due
to
cancer,
environmental
and
bioaccumulation
issues
which
plagued
them.
Until
this
reregistration
review
of
the
toxicology
data
base,
PCNB
data
was
separated
into
two
distinct
data
bases
since
it
was
concluded
that
the
toxicity
of
the
two
technicals
of
both
Amvac
and
Uniroyal
were
uniquely
distinct
and
not
comparable.
For
example,
recent
cancer
studies
had
found
one
registrant's
technical
to
produce
cancer,
while
findings
were
negative
for
the
other
registrant's
technical.

These
companies
were
directed
to
develop
separate
data
bases
in
support
of
their
registrations
and
tolerances.
In
the
1970'
s
HCB
concentrations
were
in
excess
of
10%
of
the
technical.
However,
by
1992,
the
level
of
HCB
was
much
lower
than
this
in
both
registrant
formulations
and
some
level
of
concern
was
apparently
raised
relative
to
other
impurities
in
PCNB
(
although
they
were
not
defined).
In
toxicology
reviews
conducted
during
the
mid
1990'
s
it
still
appeared
that
the
primary
concerns
were
focused
on
the
HCB
levels
which
had
by
this
time
been
dramatically
reduced
often
less
than
0.1%.
By
1992,
levels
of
impurities
including,
but
not
limited
to
hexachlorobenzene
(
HCB)
concentration,
were
still
thought
to
be
so
different
as
to
necessitate
clear
separation
of
the
data
bases
for
Uniroyal
and
Amvac
PCNB.
As
a
result,
the
Agency
required
separate
toxicology
studies
supporting
tolerances
and
registrations
for
each
company.

This
approach
to
the
data
bases
changed
on
October
14,
2001,
when
the
Metabolism
Assessment
Review
Committee
convened
to
consider
the
Uniroyal
and
Amvac
PCNB
data
bases.
Upon
examination
of
the
database,
in
particular
considering
the
more
recent
studies,
the
MARC
concluded
no
evidence
could
be
found
that
the
chemical
composition
(
i.
e.
impurity
levels)
differences
among
the
formulations
tested
in
the
toxicity
studies
affected
the
NOAELS/
LOAELS
and
endpoints
found.
Other
unspecified
factors
likely
were
considered
greater
contributors
to
the
differences
in
the
side­
by­
side
toxicity
studies
submitted
by
the
two
registrants.
As
a
consequence,
it
was
recommended
that
the
two
data
bases
be
combined.
However,
in
contradiction
to
this,
since
PCNB
was
first
registered
over
40
years
ago,
PCNB
impurities
have
changed
dramatically
as
the
manifestations
of
toxicity
have
changed.
This
is
of
key
importance
in
the
hazard
characterization
of
PCNB
since
the
toxicity,
tumorigenicity
and
even
basic
toxicological
effects
like
sensitization
still
differ
and
persist
in
the
two
data
bases.
As
well,
and
complicating
the
public
safety
issues
further,
it
seems
that
as
the
source
of
technical
material
has
changed
(
including
Mexican,
Japanese
and
US
sources)
there
has
been
a
significant
impact
on
the
levels
of
impurities
in
the
technical
material
as
compared
to
what
had
originally
been
tested
in
available
toxicology
studies.

Many
chronic,
oncogenicity
and
other
toxicity
studies
had
been
submitted
to
the
Agency
in
previous
years
in
support
of
PNCB
use
and
many
of
these
are
now
excluded
from
the
toxicity
data
base.
A
number
of
these
studies
are
excluded
since
the
technical
material
tested
years
ago
is
so
dissimilar
to
what
is
currently
marketed.
The
Cancer
Peer
Review
of
1992,
determined
that
many
of
these
studies
were
inappropriate
and
found
to
be
Page
5
unacceptable
due
to
study
conduct
issues
and
also
due
to
the
dramatic
reductions
in
HCB
which
was
expected
to
reduce
or
eliminate
the
carcinogenic
risks
previously
observed.
High
HCB
contamination
had
been
associated
with
increases
in
papillomas
in
a
skin
painting
study
and
in
hepaocellular
carcinomas
in
mouse
carcinogenicity
studies.

The
current
review
of
these
data
demonstrate
that
this
conclusion
may
no
longer
be
supportable.
The
differences
in
results
observed
in
the
Uniroyal
chronic/
oncogenicity
study
(
MRID#
41987301,
(
utilizing
a
more
purified
technical
with
less
HCB
than
the
Amvac
technical
)
resulted
in
an
increase
in
thyroid
follicular
cell
adenomas
and
carcinomas
while
the
Amvac
chronic/
oncogenicity
toxicity
(
gavage)
(
MRID#
43015801,
was
negative
for
neoplasia.
These
data
might
raise
a
flag
suggesting
significant
differences
in
toxicity
risk
potential
of
the
two
technical
materials
even
though
in
both
studies
the
HCB
concentrations
and
other
impurities
have
been
reduced
to
very
low
levels.
Conversely,
this
might
suggest
that
it
is
PCNB
itself
(
or
possibly
a
metabolite)
is
responsible
for
the
carcinogenicity
findings
and
not
the
HCB
as
thought
prevously.

Acute
toxicity
categories
are
low
with
most
study
results
in
Toxicity
Categories
III
or
IV.
A
Uniroyal
study
found
PCNB
to
be
a
sensitizer
while
the
Amvac
study
did
not.

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
the
uncertainty
as
to
the
biological
half­
life
for
PCNB
and
therefore
as
to
its
potential
for
bioaccumulation.
Additional
kinetic
and
other
data
have
been
required
by
the
HED
HIARC
and
should
eventually
be
available
to
facilitate
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.
In
addition,
aminotransferase
activities
(
AST/
ALT,
particularly
ALT)
consistently
decrease
in
a
dose­
dependent
manner
by
30­
80%
in
rats
and
dogs.
The
toxicological
significance
of
these
findings
needs
to
be
further
assessed
and
the
current
data
base
is
inadequate
to
define
this
pattern
of
PCNB
associated
toxicity.

Results
from
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.
The
HIARC
recommended
that
the
in
vitro
test
results
of
clastogenicity
be
examined
in
an
in
vivo
cytogenetic
assay.
Since
this
HIARC
review,
an
in
vivo
mammalian
cytogenetics
study
(
Erythrocyte
Micronucleus
assay
in
the
Mouse,
MRID
#
45539601)
has
been
submitted
and
reviewed.
Review
of
the
study
indicated
that
there
was
no
reproducible
significant
increase
in
the
frequency
of
micronucleated
polychromatic
erythrocytes
in
bone
marrow
after
any
treatment
time.
Page
6
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.

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.
No
findings
of
significant
toxicological
concern
have
been
identified
in
developmental
toxicity
or
reproduction
study
data.
Data
gaps
were
identified
and
special
studies
are
required
for
thyroid
assessment
(
including
hormone
levels
and
histopathology),
assessment
of
the
significance
of
ALT/
AST
enzyme
level
reductions,
metabolism
and
pharmacokinetics.
The
data
base
is
not
complete
for
adequate
FQPA
assessment.

No
neurotoxicity
studies
have
been
identified
in
the
data
base
but
no
neurobehavioral
alterations
nor
evidence
of
neuropathological
effects
have
been
observed
in
available
data.

2.0
REQUIREMENTS
The
testing
requirements
(
CFR
158.340)
for
Food
and
Non­
Food
Use
for
PCNB
are
listed
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
revised
guidelines
of
1998
were
used.
Special
studies
as
required
by
the
HIARC
are
also
included
in
this
table.
Page
7
Table
1.
Toxicology
Data
Requirements
Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
870.1200
Acute
Dermal
Toxicity
870.1300
Acute
Inhalation
Toxicity
870.2400
Primary
Eye
Irritation
870.2500
Primary
Dermal
Irritation
870.2600
Dermal
Sensitization
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100
Oral
Subchronic
(
rodent)
870.3150
Oral
Subchronic
(
nonrodent)
870.3200
21­
Day
Dermal
870.3250
90­
Day
Dermal
870.3465
90­
Day
Inhalation
yes
yes
yes
yes
yes
yes
yes
yes
yes
no
870.3700a
Developmental
Toxicity
(
rodent)
870.3700b
Developmental
Toxicity
(
nonrodent)
870.3800
Reproduction
yes
yes
yes
yes
yes
yes
870.4100a
Chronic
Toxicity
(
rodent)
870.4100b
Chronic
Toxicity
(
nonrodent)
870.4200a
Oncogenicity
(
rat)
870.4200b
Oncogenicity
(
mouse)
870.4300
Chronic/
Oncogenicity
(
satisfies
requirements
of
870.4100a
and
870.4200a)
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.5100
Mutagenicity
 
Gene
Mutation
­
bacterial
870.5300
Mutagenicity
 
Gene
Mutation
­
mammalian
870.5375
Mutagenicity
 
Strucural
Chromosomal
Aberrations
870.5395
Mutagenicity
 
in
vivo
Mammalian
Cytogenetics
870.5550
Mutagenicity
 
Other
Genotoxic
Effects
yes
yes
yes
yes
yes
yes
yes
yes
870.6100a
Acute
Delayed
Neurotoxicity
(
hen)
870.6100b
90­
Day
Neurotoxicity
(
Hen)
870.6200a
Acute
Neurotoxicity
Screening
Battery
(
Rat)
870.6300
Developmental
Neurotoxicity
no
no
no
no
n/
a
n/
a
n/
a
n/
a
870.7485
General
Metabolism
870.7600
Dermal
Penetration
yes
yes
no
no
Special
Studies:
A
special
study
to
assess
the
potential
for
bioaccumulation
a
A
special
study
to
assess
thyroid
toxicity
b
The
Registrant
must
satisfactorily
address
the
significance
of
dose
related
decreases
in
AST/
ALT
or
submit
a
special
study
to
assess
the
toxicological
significance
of
these
findings
c
yes
yes
yes
no
no
no
a
The
HIARC
has
required
that
a
special
study
be
performed
in
order
to
adequately
assess
the
potential
of
PCNB
to
bioaccumulate.
If
bioaccumulation
is
observed
in
this
study,
data
must
be
provided
to
assist
in
the
risk
assessment
process
(
eg­
circulating
blood
levels
at
various
dose
levels
over
time).
The
registrant
will
need
to
submit
a
protocol
for
review
by
the
Agency.

b
The
HIARC
has
required
that
the
potential
for
thyroid
toxicity
be
thoroughly
assessed
in
a
special
study.
The
registrant
will
need
to
submit
a
protocol
for
review
by
the
Agency.
Page
8
C
The
HIARC
has
required
that
the
registrant
adequately
address
the
toxicological
significance
of
decreases
in
AST/
ALT.
This
might
necessitate
a
special
study
be
performed
to
assess
the
toxicological
significance
of
consistent
dose
related
decreases
in
AST/
ALT
observed
in
a
multiple
test
species
in
a
dose
related
manner
at
statistically
significant
levels.
The
registrant
will
need
to
submit
a
protocol
for
review
by
the
Agency.

3.0
DATA
GAPS
A.
Although
the
thyroid
is
a
significant
target
organ
for
PCNB
toxicity,
effects
on
the
thyroid
have
been
inadequately
assessed
in
nearly
all
available
toxicity
studies.
Thyroid
weights
were
increased
in
a
number
of
chronic
and
subchronic
studies
in
rats.
In
addition,
TSH,
T3,
and
T4
levels
were
affected
in
the
only
non­
guideline
oral
study
and
only
measured
in
male
rats
using
inappropriate
dosing
(
0,
1,
&
333
mg/
kg/
day)
which
precludes
a
meaningful
assessment
of
dose­
response
and
time­
course
features
of
the
effect.
The
HIARC
requested
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
submit
a
protocol
for
review
by
the
Agency.
In
addition,
several
special
thyroid
metabolism
studies
(
MRIDs
44096601
and
44096602)
have
deficiencies
that
need
to
be
addressed
by
the
registrants.

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.

B.
Aminotransferase
activities
(
AST/
ALT,
particularly
ALT)
decrease
in
a
dosedependent
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
and
determine
the
toxicological
significance
of
these
findings.

C.
Limited
kinetic
data
have
been
identified
in
the
literature
which
suggest
that
PCNB
could
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.
If
bioaccumulation
is
observed,
additional
kinetic
data
will
also
be
necessary
to
relate
to
endpoints
observed
in
other
toxicity
studies
which
should
assist
in
meaningful
risk
assessment.
The
Registrant
should
consult
the
Agency
as
Page
9
to
the
details
of
the
protocol.

D.
There
are
no
subchronic
inhalation
toxicity
data
for
PCNB.
Due
to
the
greenhouse
use
of
PCNB,
the
HIARC
requests
that
a
90­
day
inhalation
toxicity
study
of
PCNB
be
conducted.
In
addition
to
the
guideline
requirements
of
(
870.3465)
it
is
recommended
that
interim
thyroid
hormone
analyses
be
made
at
7,
14,
30
and
90
days
and
that
histopathology
assessment
include
the
thyroid.

E.
A
dermal
penetration
study
(
870.7600)
is
conditionally
required
since
HIARC
determined
that
the
available
study
is
not
acceptable.

4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
the
data
base
for
acute
toxicity
:
The
data
base
for
acute
toxicity
of
the
technical
`
s
are
considered
complete
and
no
additional
studies
are
required
at
this
time.
PCNB
has
a
relatively
low
order
of
acute
toxicity
in
test
animals.
Both
Uniroyal
and
Amvac
data
are
presented
below.
Note
that
the
technical
materials
of
the
registrants
differ
somewhat
and
that
the
Uniroyal
technical
is
a
sensitizer
while
the
Amvac
technical
is
not.
However,
for
both
sets
of
data,
acute
toxicity
remains
relatively
low
in
Categories
III
and
IV.

Table
2.
Acute
Toxicity
of
PCNB
(
Uniroyal)

Guideline
No.
Study
Type
MRIDs
#
Results
Tox
Category
81­
1
870.1100
Acute
Oral
43198201
LD50
=
>
5000
mg/
kg
IV
81­
2
8701200
Acute
Dermal
43198202
LD50
=
>
5000
mg/
kg
IV
81­
3
870.1300
Acute
Inhalation
43118201
LC50
=
>
1.7
mg/
L
III
81­
4
870.2400
Primary
Eye
Irritation
43198203
Slight
irritant
III
81­
5
870.2500
Primary
Skin
Irritation
43198204
Non
irritant
IV
81­
6
870.2600
Dermal
Sensitization
4060901
Weak
sensitizer
n/
a
81­
8
Acute
Neurotoxicity
n/
aa
n/
a
n/
a
a
n/
a
=
not
applicable
Page
10
Table
2
con't
Acute
Toxicity
of
PCNB
(
Amvac)

Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
81­
1
870.1100
Acute
Oral
41443101
LD50
=
>
5050
mg/
kg
IV
81­
2
870.1200
Acute
Dermal
41443102
LD50
=
>
2020
mg/
kg
III
81­
3
870.1300
Acute
Inhalation
41443103
LC50
=
>
6.49
mg/
L
III
81­
4
870.2400
Primary
Eye
Irritation
41443109
Slight
irritant
III
81­
5
870.2500
Primary
Skin
Irritation
41443105
PII
=
0.0175
IV
81­
6
870.2600
Dermal
Sensitization
40734001
Non
sensitizer
n/
a
81­
8
Acute
Neurotoxicity
n/
aa
n/
a
n/
a
a
n/
a
=
not
applicable
4.2
Subchronic
Toxicity
Adequacy
of
the
data
base
for
subchronic
toxicity:
The
data
base
for
subchronic
toxicity
is
partially
complete.
Despite
the
fact
that
90­
day
studies
have
been
submitted,
reviewed
and
found
to
be
acceptable,
special
studies
are
required
to
satisfy
Agency
concerns
relative
to
thyroid
toxicity
and
AST/
ALT
findings.
In
addition,
no
subchronic
inhalation
study
was
available
in
the
data
base
although
exposure
would
be
expected.
The
HED
HIARC
has
requested
that
a
90­
day
inhalation
toxicity
study
be
conducted
(
HIARC,
4/
9/
03).
Page
11
870.3100
90­
Day
Oral
Toxicity
­
Rat
A.
Subchronic
Oral
Toxicity
rats
OPPTS
Guideline
870.3100
SPONSOR:
Amvac
Chemical
Corporation
In
a
subchronic
oral
study
(
MRID
42416001),
pentachloronitrobenzene
(
PCNB;
98%
a.
i.;
Lot/
Batch
#
05318­
7D,
batch
II)
was
administered
via
gavage
to
10
Crl:
CDBR
rats/
sex/
group
at
nominal
doses
of
0,
5,
10,
100,
or
1000
(
limit
dose)
mg/
kg/
day
for
13
weeks.

No
treatment
related
deaths
occurred.
Clinical
signs,
body
weights,
body
weight
gains,
food
consumption,
ophthalmoscopic
observations,
hematological
parameters,
and
gross
pathology
were
unaffected
by
the
test
substance.
At
1000
mg/
kg/
day,
relative
(
to
body
weight)
liver
weights
were
increased
in
the
females
(

15%,
p

0.05).
In
addition,
centrilobular
hepatocellular
hypertrophy
was
observed
(
males­
6/
10,
females
2/
10
vs.
0/
20
controls).
In
the
thyroid,
follicular
epithelium
hypertrophy/
hyperplasia
was
noted
in
both
sexes
(
males­
6/
10,
females
­
5/
10
vs.
2/
20
controls).
Colloid
vacuolation
of
the
thyroid
was
noted
in
the
females
only
(
3/
10
vs.
0/
10
controls).

The
LOAEL
for
this
study
is
1000
mg/
kg/
day
(
limit
dose)
based
on
increased
relative
(
to
body)
liver
weight
and
histopathological
changes
in
the
liver
and
thyroid.
The
NOAEL
for
this
study
is
100
mg/
kg/
day.

The
submitted
study
is
classified
as
acceptable/
guideline
(
82­
1a)
and
satisfies
the
requirements
for
a
subchronic
oral
toxicity
study
in
the
rat.

Proposed
Dose
and
Endpoint:
The
NOAEL
for
this
study
is
100
mg/
kg/
day.
The
LOAEL
for
this
study
is
1000
mg/
kg/
day
(
limit
dose)
based
on
increased
relative
liver
weight
and
histopathological
changes
in
the
liver
and
thyroid.

B.
Subchronic
Oral
Toxicity
in
male
rats
(
a
non­
guideline
study)

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
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.

In
the
thyroid,
follicular
epithelial
hypertrophy
was
observed
at
days
14
and
30
(
trace
and
Page
12
mild
severity,
respectively
at
6000
ppm)
and
at
day
90
(
mild
at
20
ppm
and
moderate
at
6000
ppm).
These
changes
had
reversed
after
the
recovery
period.
In
addition,
TSH
levels
were
statistically
significantly
greater
than
controls
starting
14
days
after
initiation
of
the
study.
After
90
days
of
dosing,
no
NOAEL
was
determined
in
this
study.
At
the
high
dose
level
of
6000
ppm,
toxicity
was
observed
after
only
7
days
of
dosing.
Although
this
is
a
non­
guideline
study,
since
it
has
sacrifices
at
7,
14,
30
or
90
days,
it
may
be
especially
useful
for
short
term
risk
assessment.

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,
LDT),
based
on
mild
liver
and
thyroid
microscopic
hypertrophy.
The
study
NOAEL
is
<
20
ppm
(
1.0
mg/
kg/
day).

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.
It
was
intended
as
a
special
study
to
evaluate
the
effects
of
PCNB
on
thyroid
hormone
levels,
rather
than
a
complete
Guideline
subchronic
study,
and
was
adequately
conducted
to
provide
this
information.

870.3100
90­
Day
Oral
Toxicity
­
Mouse
An
NTP
mouse
3­
month
study
was
conducted
as
a
rangefinding
study
for
establishing
dose
levels
for
the
mouse
oncogenicity
study.
No
MRID
number
was
ever
assigned
to
this
study.
The
study
was
conducted
in
1986
in
order
to
establish
dose
levels
in
their
oncogenicity
study.
Males
alone
received
a
dose
level
of
1250
ppm
while
both
males
and
females
received
dose
levels
of
2500,
5000,
10,000
and
20,000
ppm
.
In
addition,
females
were
also
tested
at
40,000
ppm.
A
NOAEL
was
determined
to
be
1250
in
males
and
2500
ppm
in
females.
The
LOAEL
was
determined
to
be
2500
ppm
in
males
and
5000
ppm
in
females
based
on
increased
liver
weight
and
liver­
to­
bodyweight
ratio.
There
was
no
histopathology.
This
study
doses
not
constitute
a
subchronic
feeding
study
and
is
considered
as
acceptable
only
as
a
rangefinding
study.
Page
13
870.3150
90­
Day
Oral
Toxicity
­
Dog
Not
available
in
the
data
base.
However,
this
study
is
not
required
since
there
is
an
acceptable
1­
year
chronic
dog
study.

870.3200
21/
28­
Day
Dermal
Toxicity
B
Rat
SPONSOR:
Amvac
Chemical
Corporation
In
a
21­
day
dermal
toxicity
study
(
MRID#
42416002),
male
and
female
Crl:
CDBR
rats
received
dermal
dosages
of
PCNB
(
Lot
#
05318­
7D,
98
%
a.
i.)
at
levels
of
0,
100,
300,
and
1000
mg/
kg/
day
for
5
days
per
week
for
a
minimum
of
3
weeks.
The
residual
material
was
removed
by
gently
washing
the
exposure
site
with
water
and
wiping
with
a
paper
towel.

The
NOAEL
was
determined
to
be
300
mg/
kg/
day
and
the
LOAEL
was
determined
to
be
1000
mg/
kg/
day
based
on
the
increased
incidences
of
dilatation
of
the
thyroid
follicles
and
hypertrophy
of
the
thyroid
follicular
epithelium
in
the
high
dose
males.
There
were
no
reported
treatment
related
effects
in
females.

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
repeated
dose
(
21­
day)
dermal
toxicity
study
(
OPPTS
870.3200;
§
82.2).

870.3465
90­
Day
Inhalation
B
Rat
Considered
a
data
gap
and
required
by
HIARC
(
HIARC
,
4/
9/
03).

4.3
Prenatal
Developmental
Toxicity
Adequacy
of
data
base
for
Prenatal
Developmental
Toxicity:
Acceptable
developmental
toxicity
studies
in
rats
(
MRID
40588601
and
41361201)
and
rabbits
(
MRID
41361301
and
40717102)
and
reproduction
studies
(
MRID
43469301,
43469302,
43469303
and
41918701)
are
available
and
adequate
for
FQPA
considerations.
However,
special
studies
are
required
on
the
thyroid
(
including
hormone
levels
with
histopathological
assessment),
on
the
toxicological
significance
of
ALT/
AST
enzyme
level
reductions,
metabolism
and
pharmacokinetics.
Therefore,
the
data
base
is
not
complete
although
developmental
and
reproduction
study
data
are
adequate.

870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
A.
Developmental
Toxicity
Study
in
the
Rat
(
gavage)
Guideline
#
870.3700;
83­
3
SPONSOR:
Uniroyal
Chemical
Co.,
Inc.,
Bethany,
CT
In
an
oral
developmental
toxicity
study
(
MRID
40588601),
25
(
presumed)
pregnant
Page
14
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.

B.
Developmental
Toxicity
Study
in
the
rat
(
gavage)
Guideline
#
870.3700;
83­
3
SPONSOR:
Amvac
Chemical
Corporation,
Los
Angeles,
CA
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
carboxymethylcellulose
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
doseresponse
No
treatment­
related
fetal
malformations
were
observed.
The
developmental
toxicity
LOAEL
is
750
mg/
kg/
day
and
the
NOAEL
is
250
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.

A
number
of
older
developmental
and
reproductive
studies
have
been
identified
in
the
data
base
but
most
of
these
studies
are
associated
with
testing
of
the
older
manufactured
Page
15
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.

870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
A.
Developmental
Toxicity
Study
in
the
Rabbit
(
Gavage)
Guideline
#
870.3700;
83­
3
SPONSOR:
Amvac
Chemical
Corp.,
Los
Angeles,
CA
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,
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.
The
developmental
toxicity
LOAEL
is
>
900
mg/
kg/
day
(
HDT)
and
the
developmental
toxicity
NOAEL
is

900
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.
Page
16
B.
Developmental
Toxicity
Study
in
the
Rabbit
(
gavage)
Guideline
#
870.3700;
83­
3
SPONSOR:
Uniroyal
Chemical
Co.

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
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.

4.4
Reproductive
Toxicity
Adequacy
of
data
base
for
Reproductive
Toxicity:
The
data
base
for
reproductive
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.

870.3800
Reproduction
and
Fertility
Effects
­
Rat
Two
Generation
Reproduction
Study
in
Rats
(
dietary)
OPPTS
870.3800
In
a
2­
generation
reproductive
toxicity
study
(
MRID
41918701,
Uniroyal),
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.
Page
17
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
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%
l
ess
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.

In
another
2­
generation
reproduction
study
(
MRIDs
43469301,
43469302
and
43469303,
Amvac)
PCNB,(
98%
a.
i.)
was
administered
to
35
Crl:
CD
BR
(
Sprague
Dawley)
VAF/
Plus
rats/
sex/
dose
by
gavage
at
dose
levels
of
0,
10,
100
or
1000
mg/
kg/
day.
A
dose
volume
of
10
ml/
kg
was
administered
to
all
groups.
P
1
males
and
females
received
the
test
material
for
10
weeks
prior
to
mating
and
the
females
continued
to
be
dosed
through
weaning
of
the
F
1
generation.
P
2
males
and
females
were
dosed
with
the
test
material
starting
at
weaning
for
at
least
10
weeks
prior
to
mating
and
through
the
mating
period
for
the
F
2
litters.
The
females
continued
to
be
dosed
until
the
weaning
of
the
F
2
generation.
One
litter/
generation
was
produced
and
tested.

There
were
no
compound­
related
effects
in
parental
bodyweight,
food
consumption
or
Page
18
reproductive
performance.
In
addition,
there
were
no
clinical
signs
of
toxicity
in
the
parental
animals.
In
the
P
1
generation,
hepatocellular
hypertrophy
was
observed
at
1000
mg/
kg
in
both
sexes
and
thyroid
follicular
cell
hypertrophy/
hyperplasia
was
observed
at
100
and
1000
mg/
kg
in
males
and
at
1000
mg/
kg
in
females.
There
were
no
changes
observed
in
the
reproductive
organs.
In
the
P
2
generation,
the
effects
were
the
same
except
that
the
liver
effects
were
only
observed
in
high
dose
males.
No
treatment­
related
effects
were
observed
in
litter
size,
pup
viability,
pup
bodyweight
or
pup
macroscopic
examinations.
No
microscopic
examinations
were
conducted
on
pups.

The
LOAEL
is
100
mg/
kg/
day
in
males
and
1000
mg/
kg/
day
in
females
based
on
increases
in
hepatocellular
hypertrophy
and
thyroid
follicular
cell
hypertrophy/
hyperplasia.
The
NOAEL
is
10
mg/
kg/
day
in
males
and
100
mg/
kg/
day
in
females.

The
reproductive
study
in
the
rat
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
for
a
2­
generation
reproductive
study
(
OPPTS
870.3800,
§
83­
4)
in
the
rat.

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

870.4100a
(
870.4300)
Chronic
Toxicity
B
Rat
Chronic
Oral/
Carcinogenicity
Study
in
rats
Guideline
#:
83­
2(
a)

Sponsor:
Uniroyal
A.
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
Page
19
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).

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.

COMPLIANCE:
Signed
and
dated
GLP,
Quality
Assurance
and
Flagging
Statements
were
provided.

Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):.
An
acceptable
Uniroyal
One
Year
Dog
feeding
study
was
available
in
the
data
base,
(
See
870.4100b,
Chronic
Toxicity
­
nonrodent
(
Dog).

B.
In
a
Chronic
Toxicity/
Oncogenicity
study
(
MRID
43015801)
sponsored
by
Amvac,
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
Page
20
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
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
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
difference
in
dosing
regimen
might
possibly
explain
the
negative
carcinogenicity
results
(
if
the
positive
oncogenic
effects
are
primarily
due
to
the
technical
PCNB
or
metabolites
and
NOT
due
to
impurities,
since
apparently
the
Amvac
technical
contained
a
slightly
higher
level
of
impurities),
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.

Comments
on
other
Rat
Studies:
Several
rat
chronic/
carcinogenicity
studies
were
also
conducted
and
reviewed
in
the
Carcinogenicity
Peer
Review
of
12/
18/
92
and
not
found
adequate
for
risk
assessment
purposes.
One
study
was
conducted
in
1974
by
the
Central
Institut
voor
Voedingsonderzoek
TNO
(
Netherlands)
but
the
study
was
performed
on
a
technical
containing
2.7%
HCB
and
due
to
numerous
study
deficiencies,
the
study
was
not
Page
21
considered
useful
for
risk
assessment
purposes
(
MRID
00114223).
A
second
study
was
conducted
in
1978
by
Hazleton
Laboratories
and
Tracor
Jitco
(
MRID
00114226)
utilizing
a
technical
contaminated
with
approximately
3%
HCB.
This
study
resulted
in
increases
in
pituitary
chromophobe
adenomas
in
males
but
numerous
study
deficiencies
were
identified
and
the
study
was
not
considered
acceptable/
useful
to
characterize
the
carcinogenic
potential
of
PCNB.

870.4100b
Chronic
Toxicity
­
Dog
In
a
chronic
oral
toxicity
study
(
MRIDs
41718600,
41718601)
6
beagle
dogs/
sex/
dose
were
administered
pentachloronitrobenzene
(
PCNB
tech.,
99.4%
a.
i.;
0.04%
hexachlorobenzene
contaminant)
in
their
diet
for
1
year
at
concentrations
of
0,
15,
150
or
1500
ppm
(
equivalent
to
estimated
average
daily
intakes
of
0,
0.375,
3.75
or
37.5
mg/
kg/
day;
estimated
using
standard
conversion
factor
for
dogs
of
0.025).

At
1500
ppm,
increased
serum
alkaline
phosphatase
(+
34%
to
+
56%
above
controls;
both
sexes
at
6
and
12
months),
decreased
ALT
(­
84%
to
­
93%
less
than
controls,
both
sexes
at
6
and
12
months)
increased
cholesterol
(+
37%
to
+
41%,
males
only
at
6
and
12
months),
increased
liver
weight
(
relative
+
26%
above
controls,
males;
abs./
rel
+
39%/+
30%,
females)
and
increased
incidence
of
hepatocellular
hypertrophy
(
trace,
6/
6
males;
trace
to
mild,
6/
6
females
vs.
0/
6
controls)
were
observed.
Increased
relative
kidney
weight
was
also
reported
in
females
(+
17%).
There
were
no
treatment
related
clinical,
ophthalmological
or
gross
anatomical
findings
nor
changes
in
body
weight,
food
consumption,
hematology
or
urinalysis
parameters.
The
LOAEL
is
1500
ppm
(
37.5
mg/
kg/
day),
based
on
increased
serum
ALP
and
cholesterol,
increased
liver
weight
and
hepatocellular
hypertrophy.
The
NOAEL
is
150
ppm
(
3.75
mg/
kg/
day).

This
study
is
classified
Acceptable/
Guideline
(
§
83­
1b)
and
satisfies
the
Guideline
requirement
for
a
chronic
oral
toxicity
study
in
the
dog.

4.6
Carcinogenicity
Adequacy
of
data
base
for
Carcinogenicity:
The
data
base
for
carcinogenicity
is
considered
complete
by
the
HIARC
despite
numerous
study
deficiencies
noted
in
the
Mouse
Oncogenicity
Study
conducted
by
NTP
(
NTP,
1987).
No
additional
studies
are
required
at
this
time.

870.4200a
Carcinogenicity
Study
­
rat
Note
that
the
study
addressing
this
test
requirement
is
a
combined
oncogenicity/
chronic
toxicity
study.
Page
22
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
OPPTS
870.4300
A.
In
an
oral
chronic
toxicity/
carcinogenicity
study
(
MRID
41987301,
Uniroyal),
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
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
Page
23
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
(
MRID
41987301).

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.
In
a
second
Chronic
Toxicity/
Oncogenicity
study
(
MRID
43015801)
sponsored
by
Amvac,
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
Page
24
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
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.

870.4200b
Carcinogenicity
(
feeding)
­
Mouse
In
an
oral
carcinogenicity
study
conducted
by
NTP
(
1987),
(
No
assigned
MRID
number)
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.

The
HIARC
recommended
that
this
study
be
considered
as
Acceptable.
This
NTP
mouse
oncogenicity
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
may
be
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
number
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.

4.7
Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
The
data
base
for
Mutagenicity
is
considered
adequate
based
on
the
HIARC
determination
that
there
is
no
concern
for
mutagenicity
Page
25
resulting
from
exposure
to
PCNB.
Pentachloronitrobenzene
was
selected
for
genetic
toxicology
screening
by
the
National
Toxicology
Program
(
NTP,
1987).
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
Mutation
Guideline
#
870.5100,
Gene
Mutaton­
Bacterial
MRID:
n/
a
Acceptable
NTP
(
1987)

Guideline#
870.5300,
Gene
Mutation­
Mammalian
MRID:
n/
a
Acceptable
(
NTP(
1987)
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.

L5178Y
mouse
lymphoma
cell
forward
gene
mutation
assay:
Independent
trials
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.

Cytogenetics
Guideline
#,
870.5375,
Structural
Chromosomal
Aberrations
(
CHO)
MRID:
n/
a
Acceptable
NTP
(
1987)

Guideline
#
870.5395,
in
vivo
cytogenetics
(
Mouse
Micronucleus
Test)
MRID#
45539601
Acceptable
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.

In
independently
conducted
ICR
mouse
bone
marrow
micronucleus
assays,
groups
of
five
male
and
five
female
mice
were
administered
Pentachloronitrobenzene
as
Terraclor
Technical
(
99%,
lot
#
88101)
once
via
single
intrapertioneal
(
ip)
injections
of
0,
230,
460
or
920
mg/
kg
bw.
Comparable
doses
were
administered
in
the
repeat
trial.
Bone
marrow
cells
were
harvested
at
24
and
48
hours
post­
treatment.
The
vehicle
was
corn
oil.
Based
on
preliminary
toxicity
testing,
the
highest
dose
tested
(
HDT)
was
80%
of
the
LD
50/
3.

Clinical
signs
included
lethargy
and
piloerection
at
460
and
920
mg/
kg;
a
sight
to
moderate
(
up
to
25%)
reduction
in
the
ratio
of
polychromatic
erythrocytes
to
total
erythrocytes
(
PCE:
NCE)
was
recorded
following
exposure
to
the
HDT.
Terraclor
technical
was,
therefore,
tested
up
to
an
adequate
dose
(
based
on
overt
toxicity
in
the
animals
and
cytotoxicity
in
the
target
cells).
The
positive
control
induced
the
appropriate
response.
There
was
no
reproducible
significant
increase
in
the
frequency
of
micronucleated
polychromatic
erythrocytes
in
bone
marrow
after
any
treatment
time.
Page
26
Other
Genotoxicity
Guideline
#
870.5xxx,
Other
Genotoxic
Effects
(
SCE)
MRID:
n/
a
acceptable
NTP(
1987)
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.

4.8
Neurotoxicity
Adequacy
of
data
base
for
Neurotoxicity:
No
data
suggesting
that
PCNB
is
a
neurotoxicant
were
apparent
in
the
data
base.

870.6100
Delayed
Neurotoxicity
Study
­
Hen
No
data
are
available.

870.6200
Acute
Neurotoxicity
Screening
Battery
No
data
are
available.

870.6200
Subchronic
Neurotoxicity
Screening
Battery
No
data
are
available.

870.6300
Developmental
Neurotoxicity
Study
Not
required
as
per
HIARC's
FQPA
assessment.

4.9
Metabolism
Adequacy
of
data
base
for
metabolism:
The
data
base
for
metabolism
is
considered
to
be
inadeqate.
Guideline
and
special
bioaccumulation
studies
are
required
and
are
considered
data
gaps.

870.7485
Metabolism
­
Rat
Although
the
HIARC
has
identified
the
rat
metabolism
study
as
a
significant
data
gap,
available
data
in
the
literature
suggest
that
PCNB
bioaccumlates
to
some
degree
and
requires
a
more
complete
assessment
and
a
new
special
study
has
been
required
to
resolve
outstanding
issues.
Several
special
non­
guideline
and
unacceptable
(
but
potentially
Page
27
upgradable)
rat
metabolism
studies
have
been
submitted
to
the
Agency
and
data
from
these
are
presented
below
under
"
Special
Studies".
The
HIARC
has
required
that
a
new
rat
metabolism
study
be
submitted.

Data
from
a
number
of
literature
studies
have
been
reviewed
and
data
from
these
are
presented
below.
Data
from
several
rhesus
monkey
studies
are
presented
and
these
involve
the
use
of
only
a
few
animals.
In
addition,
it
should
be
noted
that
available
literature
data
are
very
old
using
older
methodologies
with
all
identified
and
referenced
studies
conducted
more
than
24
years
ago
and
in
one
case
about
35
years
ago.
Hence,
the
determination
of
residues
of
greatest
toxicological
concern
prior
to
having
an
acceptable
and
complete
assessment
of
the
PCNB
metabolism
and
a
full
understanding
of
the
potential
for
bioaccumulation
of
PCNB
and/
or
its
metabolites
is
seriously
handicapped
at
this
time.
However,
we
do
know
that
PCNB
does
bioaccumulate
within
animal
tissues
as
do
most
other
organochlorine
pesticides,
but
the
extent
of
this
accumulation
within
tissues
is
not
adequately
quantitated
at
this
time.
On
the
other
hand,
it
is
unlikely
that
PCNB
bioaccumulates
at
the
same
levels
of
some
of
the
other
organochlorine
pestidices
including
DDT.

PCNB
Metabolism
Data
Available
in
the
Literature
In
a
study
by
Kogel
et
al
(
1979a)
the
metabolism
of
PCNB
in
the
Rhesus
monkey
was
evaluated
after
a
single
low
dose
of
2mg/
kg,
after
a
single
high
dose
of
91
mg/
kg
and
after
feeding
of
2
ppm
for
71
days.
The
major
metabolites
were
determined
to
be
pentachloroaniline
(
55.4%
of
urinary
extract
and
70.6%
of
fecal
extract
after
71
days),
pentachlorobenzene
(
11.8%
of
urinary
extract
and
0.5%
of
fecal
extract
after
71
days),
pentachlorophenol
12.2%
of
urinary
extract
after
71
days),
pentachlorothioanisole
(
9.8%
of
urinary
extract
and
6%
of
fecal
extract
after
71
days),
and
bis­
methylmercaptotetrachlorobenzene
(
9.7%
of
urinary
extract
and
9.3%
of
fecal
extract
after
71
days).
After
the
single
high
dose,
the
metabolites
2,3,5,6­
tetrachlorophenol
methylated,
tetrachlorothioanisole,
tetrachloroaminothioanisole,
tetrachloroaminophenylmethylsulfoxide
tetrachlorophenylmethyl
sulfoxide,
and
bis­
methylmercaptoaminotrichlorobenzene
and
five
other
unidentified
metabolites
were
also
noted
which
had
not
been
detected
after
the
single
low
dose
exposure.

After
the
single
low
dose,
16.3%
of
the
fecal
extract
was
parent
PCNB,
after
the
single
high
dose
12.9%
of
the
fecal
extract
was
parent
and
after
71
days,
13.4
%
of
the
fecal
extract
was
parent
while
no
parent
was
reported
in
the
urine
during
any
of
the
dosing
periods.
The
authors
concluded
that
the
two
main
pathways
of
metabolism
of
PCNB
in
the
Rhesus
monkey
were
(
1)
the
reduction
of
the
nitro­
moiety
to
the
corresponding
aniline,
and
(
2)
the
cleavage
of
the
C­
N
bond,
presumably
via
conjugation
with
sulfurcontaining
amino
acids,
e.
g.
glutathione,
with
subsequent
breakdown
of
these
conjugates.
They
also
noted
that
the
pathways
of
biotransformation
were
similar
to
those
observed
in
the
rat.
It
should
be
noted
that
no
attempt
was
made
in
this
study
to
assess
accumulation
within
tissues
and
that
the
percent
of
extract
was
assessed
rather
than
the
%
of
dosed
PCNB.
Page
28
In
another
study
by
Kogel
et
al
(
1979b)
purified
PCNB
was
administered
to
Rhesus
monkeys
as
single
oral
doses
of
0.5,
2,
or
91
mg/
kg
and
in
a
70
day
feeding
study
at
a
level
of
2
ppm
in
the
diet.
The
authors
concluded
that
PCNB
was
readily
absorbed
from
the
gastrointestinal
tract
primarily
by
the
portal
venous
route
and
is
fairly
rapidly
converted
to
pentachloroaniline
and
numerous
other
metabolites.
The
authors
noted
that
the
half­
life
of
the
PCNB
was
1.5
to
1.7
days
only
after
very
low
doses
of
2ppm
but
they
failed
to
characterize
the
half­
life
after
the
higher
dose
level.
However,
the
investigators
noted
that
"
pentachlorophenol,
which
is
comparable
to
pentachloroaniline
in
its
polarity,
has
a
much
longer
half­
life
of
15­
20
days
in
rhesus
monkeys
after
only
a
single
dose
(
Ballhorn,
1978).
The
investigators
noted
that
only
a
small
portion
of
the
parent
PCNB
(
4.3%)
was
excreted
unmetabolized
after
a
single
91
mg/
kg
dose.
In
addition,
they
noted
that
after
a
single
dose
of
91
mg/
kg
that
after
24
hours
only
15.1%
of
the
dose
was
excreted
(
11.8%
in
urine
and
3.3%
in
feces)
and
after
20
days,
the
total
excretion
was
59.5%
(
25.8%
in
urine
and
33.7%
in
feces).
These
findings
might
suggest
that
the
possibility
of
greater
accumulation
of
metabolites
of
PCNB
dependent
upon
the
level
of
exposure/
dose
levels.

These
investigators
also
noted
that
after
a
low
dose
of
2ppm
for
70
days,
that
a
plateau
level
of
storage
of
the
labeled
PCNB
was
reached
after
30­
40
days
and
that
by
day
71,
males
had
retained
7.7%
and
females
10.3%
of
the
total
dose
administered
with
highest
amounts
(
7.73
ppm
in
bile
of
males
and
3.72
ppm
reported
in
bile
of
females).
PCNB
and/
or
metabolites
were
also
noted
in
numerous
other
tissues
including
liver,
thymus
and
fat
at
0.19
ppm.

It
is
important
to
note
that
these
investigators
also
performed
a
very
limited
examination
of
hematology,
clinical
chemistry
and
several
hormones.
Hematology
of
a
single
rhesus
monkey
given
91
mg/
kg
of
PCNB
was
reported
as
normal
with
the
exception
of
an
increase
in
methemogolobin
which
was
elevated
on
the
day
after
dosing
and
returned
to
normal
the
following
day.
During
the
70
day
feeding
at
a
dose
level
of
2ppm,
hematology
and
clinical
chemistry
data
were
reported
to
be
within
normal
limits
but
data
were
based
on
only
two
animals.
The
authors
also
reported
that
radioimmunoassays
for
luteinizing
hormone,
follicle
stimulating
hormone
and
progesterone
did
not
show
any
gross
effects
in
circulating
blood.
However,
they
pointed
out
that
their
experiment
was
not
designed
as
an
endocrinology
study
and
that
more
subtle
interferences
of
PCNB
with
hormone
patterns
may
have
remained
undetected.

In
a
still
older
study
by
Kuchar
et
al(
1969),
PCNB
manufactured
by
Olin
Corporation
was
incorporated
in
feed
and
fed
daily
to
beagle
dogs
and
rats
in
a
two­
year
chronic
study.
Note
that
the
test
material
differs
from
that
currently
marketed
and
contained
impurities
including
HCB
at
1.8%,
PCB
at
<
0.1%
and
and
2,3,4,5­
tetrachloronitrobenzene
at
0.4%.
Data
obtained
from
the
fat
tissues
of
dogs
and
rats
are
indicative
of
fat
storage
of
the
chlorinated
impurities
such
as
PCB
and
HCB
as
well
as
other
chlorinated
metabolites
containing
groups
reported
to
be
­
NH2
and
­
SCH2
but
the
parent
PCNB
was
not
identified.
Other
tissues
were
analyzed
in
this
study
but
only
after
animals
were
placed
on
a
two
month
recovery
period
(
control
diet)
and
these
analyses
do
not
appear
especially
Page
29
appropriate.
The
authors
concluded
that
the
metabolic
products
of
PCNB
are
PCA
and
methyl
pentachloro­
phenyl
sulfide.
The
authors
also
concluded
that
extracts
of
rat
tissues
from
rats
fed
PCNB
and
from
plants
grown
in
PCNB
soil
are
indicative
of
an
identical
metabolism.

In
another
study
by
O'Grodnick
et
al
(
1981)
it
was
reported
that
S­(
pentachloro­
phenyl)­
N­
acetylcysteine
as
the
predominant
urinary
metabolite
from
rats
after
a
single
oral
dose
of
5
mg/
kg
labeled
PCNB.
PCA
was
the
predominant
metabolite
in
feces
and
also
a
major
urinary
metabolite
with
small
amounts
of
Pentachloro­
thioanisole
also
recovered
from
urine
and
feces.
PCNB
itself
was
only
found
in
feces.

The
investigators
concluded
that
pentachloronitrobenzene
is
metabolized
(
1)
to
sulfurcontaining
metabolites
produced
by
reaction
with
glutathione,
catalyzed
by
glutathione
Stransferase
(
2)
to
non
sulfur
containing
metabolites
by
denitration
to
pentachlorpphenol,
and
(
3)
by
reduction
to
pentachloroaniline.

The
limited
data
that
are
available
suggest
that
generally
it
is
the
metabolites
that
are
accumulated
within
tissues
to
a
greater
extent
than
parent
PCNB
itself.
In
addition,
it
must
be
recognized
that
the
determination
of
metabolites
of
concern
is
generally
carried
out
utilizing
sound
and
complete
metabolism
data
which
is
not
the
current
situation
since
an
acceptable
rat
metabolism
study
has
not
been
provided
by
the
registrant.
Hence,
it
is
possible
that
the
toxicological
significance
of
a
particular
metabolite(
s)
might
be
overlooked
at
this
time.
Hence,
for
the
above
listed
reasons,
it
is
not
possible
to
consider
/
confirm
inclusion
of
all
metabolites
of
toxicological
concern
at
this
time.

870.7600
Dermal
Absorption
­
Rat
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.
Page
30
4.10
Special/
Other
Studies
Special
Non­
Guideline
Rat
Metabolism
Data
Submitted
to
the
Agency
In
a
special
(
non­
guideline)
mechanistic
metabolism
study
(
MRID
44096602),
thyroid
uptake
of
125Iodine
and
biliary
excretion
of
[
125I]­
thyroxine
were
evaluated
in
10
male
CD
rats/
dose
treated
with
pentachloronitrobenzene
for
10
days
in
the
diet
at
0,
20,
or
6000
ppm.
An
additional
10
animals/
group
were
administered
Arochlor
1254
as
a
positive
control.
Half
of
the
animals
per
group
(
5)
received
[
125I]
by
iv
injection
8.5
hours
prior
to
sacrifice
at
which
time
thyroid
glands
were
weighed
and
[
125I
]
measured.
The
other
half
were
given
[
125I]­
thyroxine
by
iv
injection
and
bile
was
collected
at
15
minute
intervals
for
45
minutes,
then
at
30
minute
intervals
until
135
minutes
post­
dosing.
Blood
was
collected
at
the
midpoints
of
these
intervals
and
body
temperature
was
measured
at
15
minute
intervals
during
bile
collection.

At
6000
ppm,
statistically
significant
increases
in
cumulative
biliary
excretion
and
mean
clearance
of
[
125I]­
thyroxine
(+
28%
and
+
63%
above
basal
diet
controls
for
0­
135
minutes
post
dosing,
respectively),
significantly
decreased
mean
serum
thyroxine
concentration
(­
47%,
0­
135
minutes),
slightly
increased
mean
bile
flow
rate
throughout
the
sampling
and
significantly
decreased
cumulative
uptake
of
[
125I]
(­
53%,
0­
135
minutes)
were
observed.
There
were
no
treatment
related
deaths,
clinical
signs,
body
weight
changes
or
thyroid
weight
changes.
At
20
ppm
of
PCNB,
no
effects
were
observed.
However,
the
reviewer
determined
that
a
NOAELand
LOAEL
for
effects
of
thyroid
uptake
of
[
125I]
and
of
biliary
excretion
of
[
125I]­
thyroxine
could
not
be
determined
at
that
time
pending
submission
of
additional
required
data.
This
study
was
classified
as
unacceptable
since
raw
data
were
reported
to
be
missing
by
the
testing
laboratory
itself
and
information
on
the
purity
and
lots
of
labeled
thyroxine
were
not
provided.

In
another
special
(
non­
guideline)
mechanistic
metabolism
study
(
MRID
44096601),
the
effect
of
pentachloronitrobenzene
on
thyroid
uptake
of
[
125
]
Iodine
and
biliary
excretion
of
[
125I]­
thyroxine
was
evaluated.
PCNB
was
administered
in
the
diet
to
a
total
of
18
male
SD
rats/
dose
at
concentrations
of
0,
20,
or
6000
ppm
for
one
week
prior
to
administration
of
the
radiolabel.
Positive
controls
were
administered
either
Aroclor
1254
or
benzo(
a)
pyrene.
From
the
test
groups,
6
animals/
dose
were
injected
ip
with
10

g
[
125I]
kg
body
weight
in
1
ml/
kg
0.9%
saline
(
thyroid
uptake
studies)
and
6/
dose
were
injected
iv
with
1

g
[
125I]­
thyroxine/
kg
body
weight
in
2.0
ml/
kg
50%
aqueous
ethanol
(
biliary
studies).
In
the
negative
and
positive
groups
for
the
biliary
excretion
studies,
only
4
and
5
animals
were
evaluated,
respectively,
due
to
mortality
of
animals
associated
with
the
bile
cannulation
procedure.
For
the
thyroid
uptake
studies,
animals
were
sacrificed
at
3
hours
following
administration
of
[
125I],
retroorbital
blood
samples
were
withdrawn
at
1.5
hours
and
thyroids
were
weighed
and
evaluated
for
[
125I]
activity.
For
the
biliary
excretion
studies,
bile
was
collected
at
15
and
30
minutes
after
administration
of
[
125I]­
thyroxine,
then
at
30
minute
intervals
up
to
4
hours
post­
dosing.
Blood
was
collected
at
the
Page
31
midpoint
between
these
intervals.

At
6000
ppm,
biliary
excretion
of
[
125I]­
thyroxine
equivalents
was
increased
(+
23%
above
negative
controls,
not
statistically
significant),
bile:
blood
ratio
and
biliary
clearance
of
[
125I]­
thyroxine
equivalents
were
increased
and
thyroid
uptake
of
[
125I]
was
decreased
(­
43%
less
than
negative
controls;
p<
0.05).
Rats
treated
with
benzo(
a)
pyrene
showed
a
marked
increase
in
biliary
excretion
of
[
125I]­
thyroxine
(+
266%,
p<
0.01).
No
changes
in
the
uptake
of
[
125I]
by
the
thyroid
were
observed
in
the
rats
treated
with
Aroclor
1254
and
thyroid
weights
were
comparable
for
all
groups.
There
were
not
treatment
related
differences
in
rats
treated
with
20
ppm
PCNB.
A
NOAEL/
LOAEL
for
effects
on
thyroid
uptake
of
[
125I]
and
biliary
excretion
of
[
125I]­
thyroxine
were
not
determined
at
this
time,
pending
receipt
of
additional
information
to
potentially
upgrade
this
study.
This
study
was
classified
as
unacceptable
and
can
only
be
upgraded
if
acceptable
data
on
(
1)
the
fate
of
individual
animals
and
verification
of
the
number
of
treated
animals
that
died
prior
to
assignment
to
the
experimental
groups
and
(
20
the
different
compound
consumption
values
given
in
the
study
report
and
(
3)
verification
that
the
test
diets
were
prepared
and
used
within
the
time
of
demonstrated
stability.

5.0
TOXICITY
ENDPOINT
SELECTION
(
HIARC)

5.1
See
Appendix
for
Endpoint
Selection
Table
5.11
Acute
Reference
Dose
(
aRfD)­
General
Population
Acute
Reference
Dose
(
aRfD)
­
An
endpoint
attributable
to
a
single
dose
(
exposure)
was
not
available
in
the
database.

5.12
Chronic
Reference
Dose
(
cRfD)

Study
Selected:
Combined
chronic
toxicity/
carcinogenicity
­
rat
§
OPPTS
870.4300
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
Page
32
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).

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.
Page
33
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.

Chronic
RfD
=
(
NOAEL)
1
mg/
kg/
day
=
0.001
mg/
kg/
day
(
UF)
1000
5.2
Incidental
Oral
Exposure:
Short­
Term
(
1­
30
days)

Study
Selected:
Subchronic
Oral
Toxicity
in
male
rats
§
Nonguideline
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
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
Page
34
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).

5.3
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
Page
35
5.4
Short­
term
Dermal
:
(
1­
30days)
Exposure
Study
Selected:
21­
Day
Dermal
Toxicity
Study
§
OPPTS
870.3200
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.

5.5
Intermediate­
term
Dermal:
(
1­
6
months)
Exposure
Study
Selected:
21­
Day
Dermal
Toxicity
Study
§
OPPTS
870.3200
MRID
No.:
42416002
Executive
Summary:
See
Short­
Term
Dermal
(
1­
30
Days)
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.
Page
36
5.6
Long­
Term
Dermal
:
(>
6
months)
Exposure
Study
Selected:
Combined
Chronic
Toxicity/
Carcinogenicity
StudyRat
§
OPPTS
870.4300
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.

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
route­
to­
route
extrapolation.

5.7
Inhalation
Exposure:
Short­
Term
(
1­
30
days)

Study
Selected:
Subchronic
Oral
Toxicity
Study
in
Male
Rats
§
Nonguideline
See
Short
Term
(
1­
30
Days)
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.

5.8
Inhalation
Exposure:
Intermediate­
Term
(
1­
6
months)

Study
Selected:
Subchronic
Oral
Toxicity
Study
in
Male
Rats,
MRID#
42630801
§
Nonguideline
See
Short
Term
(
1­
30
Days
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.
Page
37
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.

5.9
Inhalation
Exposure:
Long­
Term
(>
6
months)

Study
Selected:
Combined
Chronic
Toxicity/
Carcinogenicity
Study
­
Rat
§
OPPTS
870.4300
(
MRID#
41987301)

See
Chronic
Reference
Dose
(
RfD)

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.

5.10
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.
Page
38
5.11
Recommendationfor
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.

6.0
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
6.1
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
OPPTS
870.4300
A.
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
Page
39
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
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.
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
Page
40
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
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
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
difference
in
dosing
regimen
might
possibly
explain
the
negative
carcinogenicity
results,
although
other
similar
thyroid
effects
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.

6.2
Carcinogenicity
Study
in
Mice
In
an
oral
carcinogenicity
study,
(
MRID
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.
Page
41
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.

6.3
Classification
of
Carcinogenic
Potential
The
carcinogenicity
of
PCNB
was
assessed
in
reviews
of
1977
(
special
review)
and
in
1986
and
1992.
In
the
most
recent
carcinogenicity
peer
review
of
PCNB
(
held
on
8/
26/
92,
memo
of
12/
18/
92)
the
peer
review
committee
agreed
that
PCNB
should
be
classified
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.
This
review
considered
the
new
chronic/
oncogenicity
study
in
the
rat
(
MRID
41987301)
by
Uniroyal
to
be
the
only
appropriate
study
to
use.
The
report
also
indicated
that
a
second
rat
study
was
being
conducted
by
Amvac
and
that
it
was
expected
at
the
Agency
by
December1993.
This
Amvac
study
(
MRID
43015801)
was
later
reviewed
by
P.
Hurley,
6/
27/
95,
and
found
to
be
negative
for
carcinogenicity..

7.0
MUTAGENICITY
The
HIARC
concluded
that
there
is
not
a
concern
for
mutagenicity
resulting
from
exposure
to
PCNB.

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.

In
independently
conducted
ICR
mouse
bone
marrow
micronucleus
assays
(
MRID
No.
45539601),
groups
of
five
male
and
five
female
mice
were
administered
Pentachloronitrobenzene
as
Terraclor
Technical
(
99%,
lot
#
88101)
once
via
single
intrapertioneal
(
ip)
injections
of
0,
230,
460
or
920
mg/
kg
bw.
Comparable
doses
were
administered
in
the
repeat
trial.
Bone
marrow
cells
were
harvested
at
24
and
48
hours
Page
42
post­
treatment.
The
vehicle
was
corn
oil.
Based
on
preliminary
toxicity
testing,
the
highest
dose
tested
(
HDT)
was
80%
of
the
LD
50/
3.

Clinical
signs
included
lethargy
and
piloerection
at
460
and
920
mg/
kg;
a
sight
to
moderate
(
up
to
25%)
reduction
in
the
ratio
of
polychromatic
erythrocytes
to
total
erythrocytes
(
PCE:
NCE)
was
recorded
following
exposure
to
the
HDT.
Terraclor
technical
was,
therefore,
tested
up
to
an
adequate
dose
(
based
on
overt
toxicity
in
the
animals
and
cytotoxicity
in
the
target
cells).
The
positive
control
induced
the
appropriate
response.
There
was
no
reproducible
significant
increase
in
the
frequency
of
micronucleated
polychromatic
erythrocytes
in
bone
marrow
after
any
treatment
time.

This
study
is
classified
as
acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
Test
Guideline
OPPTS
870.5395;
OECD
474
for
in
vivo
cytogenetic
mutagenicity
data.

8.0
FQPA
CONSIDERATIONS
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.

The
HIARC,
however,
did
require
a
comparative
thyroid
assay
in
young
and
adult
rats
which
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.

8.1
Recommendation
for
a
Developmental
Neurotoxicity
Study
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.
Page
43
8.2
OTHER
ISSUES
Generally,
decreases
in
serum
enzyme
activities
are
considered
unrelated
to
treatment
with
the
test
material
and
not
adverse
toxicological
effects.
However,
PCNB
studies
consistently
show
these
effects
in
both
subchronic
and
chronic
studies.
AST/
ALT
activities
decrease
in
a
dose
dependent
manner
by
as
much
ast
30­
80
%.
This
shows
much
more
than
a
general
association
between
decreased
AST/
ALT
activities
and
test
material
treatment.

It
is
known
that
penicillamine,
cycloserine,
hydralazine,
and
in
particular
the
antituberculin
drug
isoniazid
can
decrease
the
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
this
is
thought
to
occur
through
combination
with
pyridoxal
or
pyridoxal
phosphate
to
form
hydrazone,
a
potent
inhibitor
of
pridoxal
kinase.

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
animo
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.
PCNB
Page
44
induces
a
chronic
and
progressive
inhibition
of
transferase
activity.
The
exact
mechanism
for
the
inhibition
is
speculative,
but
likely
involves
the
cofactor
pyridoxal
phosphate.
The
requirement
by
HIARC
that
the
Registrant
submit
new
studies
to
assess
AST/
ALT
findings
as
adverse
effects
of
PCNB
will
eventually
resolve
these
issues.

It
seems
likely
that
PCNB
induces
primary
hypothyroidism
in
both
male
and
female
rats.
However,
the
study
investigators
did
not
include
the
assessment
of
thyroid
hormones
in
any
of
the
submitted
studies
except
one
non­
guideline
study
(
a
90­
day
study
in
male
rats).
In
this
study,
thyroid
hormones
were
affected
after
only
a
7­
day
exposure
at
the
high
dose
level
(
6000
ppm).
However,
the
dose
selection
in
this
study
did
not
allow
for
meaningful
assessment
of
these
effects
since
the
next
lowest
dose
level
was
20
ppm.
At
this
level
the
hormones
were
apparently
not
affected
although,
both
thyroid
and
liver
hypertrophy
were
observed
in
nearly
all
animals
of
the
20
ppm
dose
group
after
90
days
(
with
increased
severity
observed
at
the
high
dose
level
in
all
animals).
Since
this
study
was
only
performed
in
males
and
since
the
spread
of
dose
levels
is
unreasonable
(
and
there
are
only
two
levels
at
that)
it
appears
that
only
a
new
study
(
as
required
by
HIARC)
will
more
accurately
define
PCNB
toxicity
for
the
risk
assessment
process.

Hepatocellular
hypertrophy
has
been
well
documented
to
occur
following
the
administration
of
chlorinated
benzenes,
polyhalogenated
biphenyls,
TCDD,
and
other
polyhalogenated
hydrocarbons.
These
compound
induced
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
the
metabolism
of
throxine,
thereby
inducing
a
hypothyroid
state.
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
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.

Note
that
in
cases
where
bioaccumulation
takes
place,
MOE
and
safety
factor
approaches
to
risk
assessment
do
not
usually
apply
especially
for
short
duration
exposure
scenarios.
In
such
cases,
blood
levels
at
steady
state
and
other
time
points
for
short
duration
exposure
assessment
might
need
to
be
determined
and
compared
to
those
of
guideline
required
studies.
Such
data
would
then
allow
for
supportable
risk
assessments
for
pesticides
with
longer
half­
lives
(
resulting
in
accumulation
within
tissues)
which
likely
will
have
higher
risk
scenarios.
Few
of
the
newer
classes
of
pesticides
bioaccumulate.
However,
PCNB
was
developed
nearly
40
years
ago
(
an
organochlorine
pesticide)
and
it
appears
to
be
one
of
those
that
does.
Clearly,
MOE
and
safety
factor
approaches
to
risk
assessment
by
themselves
do
not
take
this
type
of
situation
into
account.
Page
45
9.0
REFERENCES
in
MRID
order
(
when
available)

114223.
Sinkeldam,
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Van
der
Heijden,
C.,
de
Groot,
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et
al
(
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Prepared
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TNO.
The
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Olin
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Stamford
,
CT:
CDL
248285­
H.
Unpublished
114226.
Weisburger,
J.,
Weisburger,
E.,
Powers,
M.
et
al
(
1978)
Bioassay
of
Pentachloronitrobenzene
for
Possible
Carcinogenicity.
DHEW
Publication
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(
NIH)
78­
1311.
Hazelton
Laboratories
and
Tracor
Jitco.
U.
S.
National
Institutes
of
Health,
NCI,
Submitted
by
Olin
Corp.,
Stamford,
CT:
CDL:
24825­
L
250698
and
255226.
Mitoma,
C.
T.,
Steeger,
S.
E.,
Jackson,
and
Wheeler
K.,
(
1983)
Skin
Penetration
Study
of
Olin's
terrachlor
Formulations
in
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Report
No.
LSC­
4675­
4
prepared
by
Stanford
Research
Institute.
January
6,
1983.
Unpublished
40588601.
Keller,
K.
A.
(
1988)
Developmental
Toxicity
Study
in
Rats.
International
Research
and
Development
Corporation,
Mattawan,
MI.
Laboratory
Project
ID
399­
068.
April
11,
1988.
Unpublished.

40717102.
Keller,
K.
A.
(
1988)
Developmental
Toxicity
Study
in
New
Zealand
White
Rabbits,
International
Research
and
Development
Corporation,
Study
Number
399­
070,
Unpublished
41361201.
Hoberman,
Alan
M.
(
1989)
Developmental
Toxicity
(
Embryo­
Fetal
Toxicity
and
Teratogenic
Potential)
Study
of
Pentachloronitrobenzene
(
PCNB)
Administered
Orally
Via
Gavage
to
Crl:
CD
®
(
SD)
BR
Presumed
Pregnant
Rats.
Argus
Research
Laboratories,
Inc.,
Horsham,
PA,
Argus
Research
Laboratories
Protocol
310­
005.
Unpublished.

41361301,
Hoberman,
Alan
M.
(
1989)
Developmental
Toxicity
(
Embryo­
Fetal
Toxicity
and
Teratogenic
Potential)
Study
of
Pentachloronitrobenzene
(
PCNB)
Administered
Orally
(
Stomach
Tube)
to
New
Zealand
White
Rabbits.
Argus
Research
Laboratories,
Inc.,
Horsham,
PA.
Argus
Research
Laboratories
Protocol
310­
006.
December
21,
1989.
Unpublished.

41718600
and
01.
Goldenthal,
Edwin
I.
(
1993)
One
Year
Chronic
Dietary
Study
in
Dogs.
International
Research
and
Development
Corp.,
Mattawan,
MI.
Study
No.
399­
087.
November
16,
1990.
Unpublished
41918701.
Schardein,
J.
(
1991)
Two­
Generation
Reproduction
Study
in
Rats.
International
Research
and
Development
Corporation
(
IRDC),
Mattawan,
MI.
Study
No.
IRDC
399­
086.
February
1,
1991.
Unpublished.

41987301.
Goldenthal,
E.
I.
(
1993)
Two
Year
Dietary
Toxicity
and
Oncogenicity
Study
in
Rats.
Internaional
research
and
Development
corp.,
Mattawan,
MI.
Study
Report
No.
399­
072.
August
1,
1991.
Unpublished
Page
46
42413901,
42713401,
42713402.
(
1992)
Twenty­
one
Day
Dermal
Toxicity
Study
in
the
Rat
42416001.
Keefe,
R.
T.
(
1992)
90­
Day
Subchronic
Oral
Toxicity
Study
in
Rats
with
Pentachloronitrobenzene(
89­
505).
Exxon
Biomedical
Sciences,
Study
Number
MRD­
89­
505
Lab
Project
ID
250570A,
Unpublished
42416002.
Trimmer,
G.
W.
(
1992)
21­
Day
Repeated
Dose
Dermal
toxicity
Study
in
Rats
with
Pentachloronitrobenzene
.
Exxon
Biomedical
Sciences,
Inc.,
Study
#
150509,
June
22,
1992.

42630801.
Goldenthal,
Edwin
I.
(
1993)
90­
Day
Dietary
Toxicity
Study
in
(
Male)
Rats.
International
research
and
Development
Corp.,
Mattawan,
MI.
Study
Lab
Project
No.
399­
122.
January
5,
1993.
Unpublished
43469301,
43469302,
43469303.
Phillips,
R.
(
1994)
Two
Generation
Reproduction
Toxicity
Study
in
Rats
with
Pentachloronitrobenzene
(
PCNB)
(
MRD­
89­
505).
Exxon
Biomedical
Sciencies,
Inc.
Toxicology
Laboratory,
east
Millstone,
NJ,
Lab
Project
ID
No.
150535,
June
1,
1994.
Unpublished
43015801.
Plutnick,
R.
T.
(
1993)
Two­
Year
Chronic
toxicity/
Oncogenicity
Study
in
Rats
with
Pentachloronitrobenzene
(
PCNB
,
MRD­
890505­
batch
II)
Exxon
Biomedical
Sciencies,
Inc.,
Toxicology
Lab,
Mettlers
road,
CN
2350,
east
Millstone,
NJ
08875­
2350.
November
8,
1993.
Unpublished
43469301,
43469302,
43469303.
Phillips,
R.
(
1994)
Two
Generation
Reproduction
Toxicity
Study
in
Rats
with
Pentachloronitrobenzene
(
MRD­
89­
505).
Exxon
Biomedical
Sciences,
Inc.
Toxicology
Laboratory,
east
Millstone,
NJ.
Laboratory
Project
ID
No.
150535,
June
1,
1994.
Unpublished.

44096601.
Shea,
Paul
(
1996)
Biliary
Excretion
of
Labeled
Thyroxine
and
Thyroid
Uptake
of
Labeled
Iodine
in
PCNB
Treated
Rats.
Biodevelopment
Laboratories,
Cambridge,
MA.
Laboratory
Project
ID
10601.
June
1996.
Unpublished
44096602.
Kosser,
David
C.
(
1996)
Biliary
Excretion
of
[
125I]­
thyroxine
and
Thyroid
Uptake
of
[
I]
in
Pentachloronitrobenzene
(
PCNB)­
Treated
Rats.
MPI
research,
Mattawan,
MI
(
formerly
IRDC).
Laboratory
Study
Identification
No.
399­
179.
April
17,
1996.
Unppublished
LITERATURE
REFERENCES
CPRC
(
1992)
Second
Carcinogenicity
Peer
Review
of
PCNB.
Memorandum
from
Pam
Hurley
and
Esther
Rinde
dated
December
18,
1992
FQPA
Consideratons
for
PCNB
(
2002)
Memorandum
from
Laurence
D.
Chitlik
dated
November
21,
2002
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
Page
47
chemicals.
Environ
Molec
Mutagen
10(
Suppl
10):
1­
176.

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
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.

HIARC
(
2001a)
Report
of
the
Hazard
Indentification
Assessment
Committee.
Memorandum
from
Laurence
Chitlik,
dated
January
9,
2001
HIARC
(
2001b)
Report
of
the
Hazard
Indentification
Assessment
Committee.
Memorandum
from
Laurence
D.
Chitlik
dated
March
4,
2002
HIARC
(
2003)
Hazard
Identification
Assessment
Committee
Meeting
of
December
10,
2002
Concerning
FQPA
Assessment
for
PCNB..
Memorandum
from
Elizabeth
A.
Doyle
Kogel,
W.,
Muller,
W.
F.,
Coulston,
F.,
Korte,
F.
1979a.
Fate
and
Effects
of
Pentachloronitrobenzene
in
Rhesus
Monkeys.
J.
Agric.
Food
Chem.,
Vol
27,
No.
6,
1979
Kogel,
W.,
Muller,
W.
F.,
Coulston,
F.,
Korte,
F.
1979b.
Biotransformation
of
Pentachloronitrobenzene­
14
in
Rhesus
Monkeys
after
Single
and
Chronic
Oral
Administration,
Pergamon
Press
Ltd.
Chemosphere
No.
2,
pp
97­
105
Kuchar,
E.
J.
Geenty,
F.
O.,
Griffith,
W.
P.
and
Thomas
R.
J.,
1969.
Analytical
Studies
of
Metabolism
of
terrachlor
in
Beagle
Dogs,
Rats,
and
Plants.
J.
Agr.
Food
Chem.
Vol.
17,
No.
6,
Nov­
Dec
1969
MARC
(
2001)
Report
of
the
Metabolism
Assessment
Review
Committee
(
combining
of
AMVAC
and
Uniroyal
data
bases).
Memorandum
of
October
14,
2001
National
Toxicology
Program.
1987.
Toxicology
and
Carcinogenesis
Studies
of
Pentachloronitrobenzene
in
B6C3
F1
Mice.
(
CAS
No.
82­
68­
8)
NTP
Technical
Report
Series
Nol.
325.
NIH
Publication
No.
87­
2581.
No
MRID
or
accession
number
assigned.

O'Grodnick,
J.
S.,
Adamovics,
J.
A.,
Blake,
S.
M.,
and
Wedig,
J.
1981.
The
Metabolic
Fate
of
14­
CLabeled
Pentachloronitrobenzene
in
Osborne­
Mendell
Rats.
Pergamon
Press
Ltd.,
Chemosphere
Vol.
10,
pp
67­
72.
1981
Toxicology
Branch
Peer
Review
Committee
(
1986)
Peer
Review
on
Pentachloronitrobenzene.
Memorandum
from
Judith
Hauswirth
dated
August
27,
1986
Page
48
10.0
APPENDICES
Tables
for
Use
in
Risk
Assessment
Page
49
10.1
Toxicity
Profile
Summary
Tables
10.1.1
Acute
Toxicity
Table
­
See
Section
4.1
10.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
Guideline
#/
Study
Type
MRIDNo.(
year)/
Classification/
Doses/
SPONSOR
Results
1870.4300
2­
YR
CHRONIC/
CARCINOGENIC
RAT
FEEDING
41987301
(
1991)
0,
1,
150,
300
mg/
kg/
day
(

/

)
/
Acceptable/
UNIROYAL
Increase
in
thyroid
follicular
cell
adenomas
and
carcinomas
in

at
150mg/
kg/
day
&
300
mg/
kg/
day
(
p<
0.05)
&
a
trend
in

Systemic
NOAEL=
1
mg/
kg/
day
Systemic
LOAEL=
150
mg/
kg/
day
based
on
an
increase
in
hepatocellular
hypertrophy,
hepatocellular
hyperplasia
(
females)
and
thyroid
hypertrophy
and
hyperplasia
870.4300
2­
YR
CHRONIC
TOXICITY/
ONCOGENICITY
GAVAGE
RAT
43015801
(
1993)
0,
3.6,
36,
357,
714
mg/
kg/
day
(

/

)
/
Acceptable/
AMVAC
NOAEL=
3.6
mg/
kg/
day

and
36
mg/
kg/
day

Negative
for
neoplasia
LOAEL=
36
mg/
kg/
day

and
357
mg/
kg/
day

870.4200b
2­
YR
CARCINOGENICITY
IN
MICE
NTP
TR325
(
1987)
0,
400,
AND
1000
mg/
kg/
day

0,
600
AND
1400
mg/
kg/
day

/
Acceptable
NO
INCREASED
NEOPLASIA
BUT
REDUCED
SURVIVAL
DECREASED
SENSITIVITY
OF
STUDY
870.4100b
1
YR
CHRONIC
FEEDING
­
DOG
41718600
&
41718601
(
1993)
0,
0.375,
3.75,
AND
37.5
mg/
kg/
day
(
used
dog
conversion
factor)
(

/

)
UNIROYAL
NOAEL=
3.75
mg/
kg/
day
LOAEL=
37.5
mg/
kg/
day
based
on
increased
serum
ALP
and
cholesterol,
increased
liver
weight
and
hepatocellular
hypertrophy.

870.3800
2­
GENERATION
REPRODUCTION
(
RAT)
43469301,
43469302,
43469303/
(
1994)
0,
10,
100,
1000
mg/
kg/
day/
Acceptable
AMVAC
NOAEL=
10
mg/
kg/
day

100
mg/
kg/
day

LOAEL=
100
mg/
kg/
day

and
1000
mg/
kg/
day

based
on
increases
in
hepatocellular
hypertrophy
and
thyroid
follicular
cell
hypertrophy/
hyperplasia.

870.3800
2­
GENERATION
REPRODUCTION
(
RAT)
41918701
(
1991)
0,
1.2,
169,
344
mg/
kg/
day
(

)
&
0,
1.5,
218,
455
mg/
kg/
day
(

)
/
Acceptable/
UNIROYAL
Parental
NOAEL
=
1.2
mg/
kg/
day

,
1.5
mg/
kg/
day

Reproductive/
Developmental
NOAEL=
1.2
mg/
kg/
day
Parental
LOAEL=
169
mg/
kg/
day

,
218
mg/
kg/
day

based
on
decreased
body
weight
and
weight
gain.
Reproductive/
developmental
LOAEL=
169
mg/
kg/
day
based
on
decreased
mean
pup
weights.
Page
50
870.3700a
DEVELOPMENTAL
TOX
RAT
(
GAVAGE)
40588601
(
1988)
0.
30,
600,
1200
mg/
kg/
day
/
Acceptable/
UNIROYAL
Maternal
NOAEL=
Maternal
>
1200
mg/
kg/
day
Developmental
NOAEL
>
1200
mg/
kg/
day
Maternal
LOAEL
>
1200
(
HDT)
Developmental
NOAEL
>
1200
(
HDT)

870.3700b
DEVELOPMENTAL
TOX
RABBIT
(
GAVAGE)
41361301
(
1989)
0,
100,
300,
AND
900
mg/
kg/
day
/
Acceptable/
AMVAC
Maternal
NOAEL
=
300
mg/
kg/
day
Developmental
NOAEL
>
900
mg/
kg/
day
Maternal
LOAEL=
900
mg/
kg/
day
based
on
clinical
signs
of
toxicity,
decreased
body
weight
gain
and
food
consumption,
abortions
and
premature
delivery
Developmental
LOAEL
>
900
(
HDT)

870.3700b
DEVELOPMENTAL
TOX
RABBIT
(
GAVAGE)
40717102
(
1988)
0,
6.25,
12.5,
125
and
250
mg/
kg/
day/
Acceptable
(
combination
of
two
studies)/
UNIROYAL
Maternal
NOAEL=
12.5
mg/
kg/
day
Developmental
NOAEL=
125
mg/
kg/
day
Maternal
LOAEL
125
mg/
kg/
day
based
on
decreased
maternal
body
weight
and
body
weight
gain
at
125
mg/
kg/
day
and
mortality,
abortions
and
weight
loss
at
250
mg/
kg/
day
Developmental
LOAEL=
250
mg/
kg/
day
based
on
decreased
fetal
weights
870.3700a
DEVELOPMENTAL
TOX
RAT
(
GAVAGE)
41361201
(
1989)
0,
250,
750,
1500
mg/
kg/
day
AMVAC
Maternal
NOAEL
>
1500
mg/
kg/
day
Developmental
NOAEL=
250
mg/
kg/
day
Maternal
LOAEL
>
1500
mg/
kg/
day
(
HDT)
Developmental
LOAEL=
750
mg/
kg/
day
based
on
increases
in
the
incidences
of
thoracic
vertebrae/
fetus,
average
pairs
of
thoracic
ribs/
fetus
and
other
variations
non­
guideline
7,
14,
30
OR
90­
DAY
SUBCHRONIC
(
MALE
RAT)
42630801
(
1993)
0,
1.0,
&
333
mg/
kg/
day
ACCEPTABLE
NONGUIDELINE
UNIROYAL
NOAEL
(
90
Day)
<
1.0
mg/
kg/
day
LOAEL
(
90
Day)
1.0
mg/
kg/
day
based
on
liver
and
thyroid
hypertrophy.
After
14
&
30
DAYS:
thyroid
follicular
epithelial
hypertrophy
observed
at
333
mg/
kg/
day
level
870.3100
13
Week
SUBCHRONIC
ORAL
(
GAVAGE)
RAT
42416001
(
1992)
0,
5,
10,
100,
OR
1000
mg/
kg/
day

/

/
Acceptable/
AMVAC
NOAEL=
100
mg/
kg/
day
(

/

)
LOAEL=
1000
mg/
kg/
day
(

/

)
(
HDT)

870.3200
21­
DAY
DERMAL
(
RAT)
42413901
42713401&
42713402
/
(
1992)
0,
30,
300,
or
1000
mg/
kg/
day
/
Acceptable/
UNIROYAL
Systemic
NOAEL
>
1000
mg/
kg/
day
Systemic
LOAEL
>
1000
mg/
kg/
day
(
HDT)

870.3200
21­
DAY
DERMAL
(
RAT)
42416002
(
1992)
0,
100,
300
&
1000
mg/
kg/
day
(

/

)
/
Acceptable
AMVAC
NOAEL
=
300
mg/
kg/
day
LOAEL
=
1000
mg/
kg/
day
Page
51
870.7600
SKIN
PENETRATION
STUDY
OF
OLIN'S
TERRACLOR
FORMULATIONS
(
20%
DUST
AND
75%
WP)
255226/
250698
(
1983)
/
Not
Acceptable/
OLIN/
UNIROYAL
APPROX.
30%
RECOVERY
AFTER
5
DAYS
AND
ONLY
1
TO
2%
AFTER
4
HOUR
EXPOSURE
non­
guideline
METABOLISMSPECIAL
NONGUIDELINE
(
RAT)
44096601
(
1996)
Not
Acceptable/
UNIROYAL
N/
A
non­
guideline
METABOLISMSPECIAL
NONGUIDELINE
(
RAT)
44096602
(
1996)
Not
Acceptable/
UNIROYAL
N/
A
Page
52
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
hepatocelluar
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
hepatocelluar
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
Page
53
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
hepatocelluar
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.
Page
54
