UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
DATE:
April
8th,
2003
SUBJECT:
Pentachloronitrobenzene
(
PCNB).
(
List
A,
Case
No.
0128)
Briefing
Memorandum
to
Metabolism
Assessment
Review
Committee
to
discuss
PCNB
residues
of
concern
for
inclusion
in
dietary
risk
assessment.
Chemical
056502.

FROM:
Mohsen
Sahafeyan,
Chemist
(
HED/
RRB2)
Larry
Chitlik,
Toxicologist
(
HED/
TB)
Health
Effects
Division
(
7509C)

THROUGH:
Alan
Nielsen,
Branch
Senior
Scientist
Reregistration
Branch
II
Health
Effects
Division
(
7509C)

TO:
Yan
W.
Donovan,
Chemist,
RAB1/
HED
(
7509C)
Executive
Secretary,
MARC
1.
INTRODUCTION
Pentachloronitrobenzene
(
PCNB)
is
an
organochlorine
fungicide
registered
on
vegetables
(
cole
crops,
peppers,
beans,
peas),
field
crops
(
cotton,
peanuts,
potatoes),
turf
and
ornamentals.
It
is
applied
both
to
soil
and
seeds
and
is
a
re­
registration
chemical.

PCNB
formulations
registered
to
the
basic
producers,
Uniroyal
Chemical
Company
and
Amvac
Chemical
Corporation,
for
use
on
food/
feed
crops
include
flowable
concentrate
(
FlC),
water
dispersible
granular
(
WDG),
wettable
powder
(
WP),
emulsifiable
concentrate
(
EC),
granular
(
G),
dust
(
D),
and
ready­
to­
use
(
RTU)
formulations.
These
products
may
be
applied
as
pre­
plant
incorporated
applications,
in­
furrow
applications,
broadcast
applications,
or
banded
applications
using
ground
equipment
or
as
seed
treatments.
Depending
on
the
producer
and
the
manufacturing
procedure,
PCNB
impurities
can
include
hexachlorobenzene
(
HCB),
pentachlorobenzene
(
PCB)
and
tetrachloronitrobenzene
(
TCNB).

Tolerances
limiting
the
amount
of
the
impurity
hexachlorobenzene
(
HCB)
and
pentachlorobenzene
(
PCB)
have
been
proposed
for
residues
of
PCNB
(
PP#
1F1083,
Amendment
of
1/
83).
Both
registrants,
Amvac
and
Uniroyal,
have
agreed
for
PCNB
formulations
to
reduce
Page
­
2­
the
maximum
level
of
HCB
to
0.05%,
and
of
PCB
to
0.01%.
(
Letters,
J.
E.
Housenger,
SRRD
to
J.
K.
Smith,
Amvac,
and
W.
F.
Cummings,
Uniroyal,
10/
4/
94).

The
following
Table
summarizes
PCNB
tolerances.

Table1.1:
Summary
of
tolerances
Type
and
Magnitude
of
Tolerance
(
ppm)
Tolerance
Expression
Crop/
Commodity
40
CFR
Permanent,
0.1
ppm
PCNB
(
per
se)
cottonseed
180.291
(
a)

Regional
registration,
0.2
ppm
PCNB,
PCA,
MPCPS
(
also
known
as
PCTA)
collards,
kale,
mustard
greens
180.291
(
b)

Interim,
1
ppm
PCNB
(
per
se)
beans,
broccoli,
brussels
sprouts,
cabbage,
cauliflower,
garlic,
peppers,
potatoes1,
tomatoes,
peanuts
180.319
1.
The
only
potato
use
by
Uniroyal
is
as
a
Special
Local
Need
(
SLN).

Issues
to
be
Considered:

$
Residues
to
be
included
in
risk
assessment
and
tolerance
expression
for
plants.

$
Residues
to
be
included
in
risk
assessment
and
tolerance
expression
for
livestock
$
Residues
of
concern
in
rotational
crops.

$
Degradates
of
concern
in
water.
Page
­
3­
Table
1.2
:
Summary
of
major
and
minor
metabolites1,2,5
Matrix
Major
Metabolites/
Degradates
Found
1
Minor
Metabolites/
Degradates
2
Peanut
:
nutmeat
1
2,
4,
29,
38,
28,

Peanut:
hay
1,
4,
38
2,
28,
29
Potato5
4
1­
3,
5­
37,
39­
42
Cabbage
(
inadequate
study)
51,
52
3,
8,
49,
53,
54
Ruminants
2,
48,
50,
64,
83
8,
55,
12,56
Milk
2
Poultry
1,
2,
49,
48,
12,
52
3,
50,
58,
605
Eggs
(
yolk)
2
3,
7,
48
Rats
Rotational
Crops3
2,
66,
72/
826,
68/
816
1­
5,
7,
47,
49,
51,
52,
53,
65­
80
Water4
2,
3,
7
49,
84,
65,
52
1
Major
is
defined
as
comprising
>
10%
of
the
total
radioactive
residues
(
TRR)
in
a
plant
or
livestock
metabolism
study,
or
as
>
10%
of
the
applied
dose
in
an
environmental
fate
study.
The
metabolites
structures
corresponding
to
each
index
number
can
be
found
in
Table
2.14.
The
following
is
a
list
of
major
metabolites
corresponding
to
each
index
number.
1
=
pentachloronitrobenzene
(
PCNB)
2
=
pentachloroaniline
(
PCA)
3
=
pentachlorothioanisole
(
PCTA)
4
=
S­(
pentachlorophenyl)
malonylcysteine
(
PCP­
MalCys)
7
=
pentachlorobenzene
(
PCB)
12
=
tetrachloroaniline
methyl
sulfoxide
(
TCA
sulfoxide
isomers)
38
=
N­
malonyl­
S­(
tetrachloroaminophenyl)­
cysteine
48
=
pentachlorothiophenol
49
=
Pentachlorothioanisole
sulfoxide
(
PCTA
sulfoxide)
(
PCTASO)
50
=
tetrachlorothioanisole
51
=
tetrachlorophenyl
methyl
sulfoxide
(
TCPM
sulfoxide)
52
=
tetrachlorophenyl
methyl
sulfone
(
TCPM
sulfone)
64
=
N­(
pentachloroaniline)
glucuronide
66
=
tetrachlorobenzenesulfonic
acid
72
=
trichlorosulfophenyl
methyl
sulfone
81
=
N­
malonyl­
S­
trichloro­(
methylsulfonophenyl)­
L­
cysteine
83
=
glucuronide
of
NOHPCA
(
NOHPCA­
Gluc)

2
Minor
is
defined
as
comprising
<
10%
of
the
total
radioactive
residues
in
a
plant
or
livestock
metabolism
study,
or
as
<
10%
of
the
applied
dose
in
an
environmental
fate
study.
The
metabolites
names
and
structures
corresponding
to
each
index
number
can
be
found
in
Table
13.

3Rotational
Crops:
The
study
was
done
at
two
application
rates,
2
lb
ai/
A
and
10
lb
ai/
A
and
at
30,
120,
and/
or
365
days
after
treatment
(
DAT)
.
The
reported
values
in
the
above
Table
is
from
10
lb
ai/
A
and
365
DAT
for
turnip
and
lettuce,
and
10
lb
ai/
A
for
wheat
forage
and
straw.
Page
­
4­
4Other
major
metabolites/
degradates
in
water
included
HCB
which
is
a
manufacturing
contaminant
of
HCB.
Both
Uniroyal
and
Amvac,
the
technical
grade
producer
of
PCNB
have
reduced
the
level
of
HCB
to
0.05%
in
response
to
a
request
by
EPA
(
Letters,
J.
E.
Housenger,
SRRD
to
J.
K.
Smith,
Amvac,
and
W.
F.
Cummings,
Uniroyal,
10/
4/
94).
In
addition,
HCB
can
also
originate
from
other
chemicals.
Furthermore,
in
a
cumulative
risk
assessment
for
HCB
and
PCB
from
all
sources,
HED
concluded
that
the
risk
due
to
these
chemicals
is
below
the
level
of
concern
(
William
Smith,
"
Assessment
of
the
Dietary
Cancer
Risk
of
Hexachlorobenzene
and
Pentachlorobenzene
as
impurities
in
Chlorothalonil,
PCNB,
Picloram,
and
several
other
pesticides.
DP
Barcode
D243499.
Chemical
codes
061001
(
Hexachlorobenzene)
&
081901
(
Chlorothalonil)",
2/
26/
98)
5There
are
other
metabolites
that
are
not
shown
in
the
above
Table.
Those
metabolites
are
either
from
older
unacceptable
studies
that
for
the
sake
of
completion
are
listed
in
Table
2.14,
or
they
are
from
unrelated
tissues.
Those
metabolites,
by
their
index
number
from
Table
2.14,
are
listed
below.
43,
44:
found
in
potato
peels
(
older
inadequate
submission)
46:
found
in
goat
urine
57:
found
in
goat
urine;
also
in
potato
callus
and
peel
(
older
inadequate
submission)
59:
found
in
chicken
excreta
60:
found
in
chicken
kidney
61:
found
in
peanut
roots
62,
63:
found
in
potato
callus
and
peel
(
older
inadequate
submission)

6Apparently,
the
registrant
could
not
identify
these
two
compounds
apart.

The
following
Table
is
put
together
by
PCNB
toxicologist
and
contains
residues
of
toxicological
concern.
Although
this
Table
is
presented
in
the
toxicology
section
later
in
this
memorandum,
in
the
interest
of
comparison
with
the
above
Table
it
is
repeated
here.

Table
1.3:
Summary
of
residues
of
toxicological
concern
Raw
Agricultural
Commodity
Residues
of
Potential
Toxicological
Concern
Corresponding
metabolite
index
number
from
Table
2.14
Peanut
Nutmeat
and
Hay
PCNB,
S­(
pentachlorophenyl)
malonylcysteine
(
PCP­
MalCys),
N­
malonyl­
S­(
tetrachloroaminophenyl)­
cysteine
1,
4,
38
Potato
PCNB,
pentachloroaniline
(
PCA),
pentachlorothioanisole
(
PCTA),
N­
malonyl­
S­(
tetrachloroaminophenyl)­
cysteine
1,
2,
3,
38
Cabbage
(
NOTE:
residue
data
is
very
limited
and
incomplete
in
table
2,
pg.
18)
ppm
of
residue
not
calculated
since
recoveries
not
provided.)
Tetrachlorophenyl
methyl
sulfoxide
(
TCPM
sulfoxide),
Tetrachlorophenyl
methyl
sulfone
(
TCPM
sulfone)
Unable
to
determine
if
other
residues
of
concern
51,
52
Raw
Agricultural
Commodity
Residues
of
Potential
Toxicological
Concern
Corresponding
metabolite
index
number
from
Table
2.14
Page
­
5­
Rotational
crops:
Turnip
roots
and
tops
pentachloroaniline
(
PCA),
pentachlorothioanisole
(
PCTA)
2,
3
Lettuce
PCNB,
pentachloroaniline
(
PCA)
1,
2
Wheat
forage1
PCNB,
pentachloroaniline
(
PCA),
tetrachlorobenzenesulfonic
acid
(
C4SA)
(
no
quantitative
data
provided
as
per
footnote
c)
1,
2,
66
Wheat
straw1
PCNB,
trichlorobenzene
sulfonic
acid
(
C3SA),
tetrachlorobenzenesulfonic
acid
(
C4SA),
dichlorosulfophenyl
methyl
sulfone
(
C2MSSA)
trichlorosulfophenyl
methyl
sulfone
(
C3MSSA)
1,
67,
66,
73,
72
Goat
milk
and
tissues
tissues
(
liver,
Muscle
Kidney)
pentachloroaniline
(
PCA),
N­
glucuronide
of
PCA
(
PCA
­
Gluc),
pentachlorothiophenol
(
PCTP),
tetrachlorothioanisole
(
TCTA),
glucuronide
of
NOHPCA
(
NOHPCA­
Gluc),
N­
hydroxypentachloroaniline
(
NOHPCA)
2,
64,
48,
50,
83,
8
1
Secondary
residues
for
meat,
milk,
eggs
etc
not
specified
and
data
for
wheat
grain
not
provided.

2.
RESIDUE
CHEMISTRY
Pentachloronitrobenzene
(
PCNB)
is
a
fungicide
registered
for
use
on
a
variety
of
vegetable
and
field
crops,
turf,
and
ornamentals.
A
tolerance
of
0.1
ppm
has
been
established
for
residues
of
PCNB
per
se
in/
on
cottonseed
[
40
CFR
180.291
(
a)],
and
tolerances
with
regional
registration
of
0.2
ppm
have
been
established
for
the
combined
residues
of
PCNB
and
its
metabolites
pentachloroaniline
(
PCA)
and
methyl
pentachlorophenyl
sulfide
(
MPCPS)
in/
on
collards,
kale,
and
mustard
greens
[
40
CFR
180.291
(
b)].
Interim
tolerances
of
0.1
ppm
are
in
effect
for
residues
of
PCNB
per
se
in/
on
beans,
broccoli,
brussels
sprouts,
cabbage,
cauliflower,
garlic,
peppers,
potatoes,
and
tomatoes;
and
an
interim
tolerance
of
1
ppm
is
in
effect
for
peanuts
[
40
CFR
Page
­
6­
180.319].
The
maximum
total
application
rate
for
all
crops
ranges
from
1.5
lbs
ai/
A
for
hot
peppers
(
in­
furrow
application)
to
30
lbs
ai/
A
for
cole
crops
as
band
or
broadcast
or
row/
row
drench
type
of
application
(
per
draft
use­
closure
memo,
Jill
Bloom,
1/
23/
03)
.

Tolerances
limiting
the
amount
of
the
impurity
hexachlorobenzene
(
HCB)
and
pentachlorobenzene
(
PCB)
have
been
proposed
for
residues
of
PCNB
(
PP#
1F1083,
Amendment
of
1/
83).
Both
registrants,
Amvac
and
Uniroyal,
have
agreed
for
PCNB
formulations
to
reduce
the
maximum
level
of
HCB
to
0.05%,
and
of
PCB
to
0.01%.
The
Agency
has
determined
that
these
limits
will
reduce
dietary
risk
from
HCB
and
PCB
as
impurities
to
negligible
levels
for
PCNB
alone
based
on
a
comprehensive
risk
assessment
for
all
products
containing
HCB
and
PCB
(
William
Smith,
"
Assessment
of
the
Dietary
Cancer
Risk
of
Hexachlorobenzene
and
Pentachlorobenzene
as
impurities
in
Chlorothalonil,
PCNB,
Picloram,
and
several
other
pesticides.
DP
Barcode
D243499.
Chemical
codes
061001
(
Hexachlorobenzene)
&
081901
(
Chlorothalonil)",
2/
26/
98).

2.
A.
Summary
of
Metabolism
Studies
Plant
metabolism
studies
for
peanut,
potato
and
cabbage
were
submitted.
Cabbage
metabolism
study
was
deemed
unacceptable
since
acetone
soluble
residues
and
insoluble
residues
comprising
15%
(
up
to
3
ppm)
and
28%
(
up
to
5
ppm)
of
the
TRR
in
mature
cabbage
leaves
were
not
quantitatively
identified.

Additional
data
were
submitted
to
upgrade
animal
metabolism
studies
in
ruminants
and
poultry
to
acceptable.

2.
A.
1.
Plant
Metabolism
Studies:

2.
A.
1.
i.
Peanuts
Greenhouse
grown
peanut
plants
were
treated
with
[
14C­
U­
phenyl]
PCNB
as
either
a
preplant
incorporated
(
PPI)
application
at
15
lb
ai/
A
or
as
two
banded
applications
over
the
plants
at
pegging,
totaling
10
lb
ai/
A.
Samples
of
mature
peanut
and
hay
were
collected
from
different
applications
at
193
and
76
days
post­
treatment,
respectively.

Solvent
extraction
released
62­
66%
of
the
TRR
from
hay
and
nutmeats,
and
subsequent
acid
hydrolysis
released
an
additional
30­
43%
of
the
TRR.
In
analysis
of
peanut
hay,
the
entire
recovered
PCNB
(
18.8%
TRR)
was
from
chloroform
and
aqueous
extracts
whereas
in
peanut
nutmeats,
almost
2/
3
of
PCNB
(
62.4%
TRR)
was
in
methonal
extract
and
the
other
1/
3
was
recovered
after
acid
hydrolysis.
Radioactivity
in
residual
solids
accounted
for

5.8%
of
the
TRR,
and
the
overall
recovery
of
radioactivity
from
nutmeats
and
hay
was
100­
109%
of
the
TRR.
Page
­
7­
Metabolite
identities
were
confirmed
using
GC/
ECD,
GC/
MS
and/
or
LC/
MS.
Table
2
contains
identified
metabolites
in
peanut
nutmeats
and
hay.

Proposed
metabolic
pathway
of
PCNB
in
peanuts
(
The
following
Figure
after
Table
2.1
below)
involves
displacement
of
the
nitro
group
with
reduced
glutathione,
and
the
subsequent
metabolism
of
the
glutathione
moiety.

Table
2.1:
Summary
of
Characterization
and
Identification
of
Radioactive
Residues
in
Peanut
nutmeats
and
hay
following
two
banded
applications
of
[
14C]
PCNB
totaling
10.0
lb
ai/
A
(
5x
).

Metabolite
or
Fraction
Nutmeat
(
TRR
=
1.72
ppm)
Hay
(
TRR=
16.3
ppm)

%
TRR
ppm
%
TRR
ppm
PCNB1
96.6
1.7
18.8
3.1
PCA
Trace
­­
ND
­­

Metabolite
III1
ND
­­
53.1
8.7
Metabolite
IV
ND
­­
Trace
­­

Metabolite
VI1
ND
­­
19.8
3.2
Metabolite
VII
ND
­­
Trace
­­

Total
Identified
(
TI)
96.6
1.7
91.7
15.0
Total
Characterized
(
TC)
2
96.6
1.7
2.86
0.5
Total
Extractable
(
TE)
2
96.6
1.7
94.6
15.5
Total
Bound
(
TB)
3.4
<
0.1
5.84
0.9
%
Mass
Balance
2
100.0
100.4
1Corresponding
index
number
in
Table
2.14
for
major
metabolites:
PCNB
is
#
1,
Metabolite
III
is
#
4,
and
Metabolite
VI
is
#
38.

2TC
=
Sum
of
all
unidentified,
extractable
resides
TE
=
Sum
of
TI
and
TC
%
Mass
Balance
=
TE
%
TRR
+
TB
%
TRR
Page
­
8­
2.
A.
1.
ii.
Po
tato
[
14C­
UL­
phenyl]
PCNB
was
applied
to
potato
plants
growing
outdoors
as
a
preplant
incorporated
(
PPI)
application
to
the
soil
at
either
20
lb
ai/
A
(
1
X
maximum
use
rate)
or
60
lb
ai/
A
(
3
X
maximum
use
rate).
Treated
soil
was
hilled
around
the
plants
twice
during
the
growing
season,
as
per
standard
agricultural
practices.
Samples
of
mature
potato
tubers
were
collected
95
days
post­
Page
­
9­
treatment.

Solvent
extraction
released
92­
94%
of
the
TRR
from
tubers,
with
6.7­
9.9%
of
the
TRR
remaining
in
the
solids.
The
overall
recovery
of
radioactivity
from
tubers
accounted
for
100­
102%
of
the
TRR.
Detailed
quantitative
analyses
of
the
solubilized
14C­
residues
identified
parent
and
more
than
45
metabolites
in
potato
tubers.
The
metabolite
profile
was
similar
for
both
application
rates,
and
the
identified
components
together
accounted
for
60.1­
64.1%
of
the
TRR
The
14C­
residues
released
from
tubers
were
adequately
identified
and
quantified
using
HPLC,
and
the
identities
of
parent
and
the
numerous
metabolites
were
adequately
confirmed
using
HPLC/
MS,
HPLC/
MS/
MS,
GC/
MS,
and/
or
GC/
MS/
MS.
Table
3
contains
identified
metabolites
in
potatoes.

Proposed
metabolic
pathway
of
PCNB
in
potatoes
(
The
following
Figure
after
Table
3
below)
involves
the
displacement
of
a
chlorine
atom
by
glutathione;
displacement
of
the
nitro
group
with
reduce
glutathione
with
the
subsequent
metabolism
of
the
glutathione
moiety;
reduction
of
the
nitro
group;
reductive
dechlorination;
and
oxidative
dechlorination.

Although
14C­
residues
in
the
PES
fractions
accounted
for
<
10%
of
the
TRR,
several
attempts
were
made
at
characterizing
radioactivity
in
this
fraction.
For
the
"
3x­
treatment",
the
PES
fraction
accounted
for
9.9%
of
the
TRR.
Digestion
of
this
PES
fraction
with
cellulase
and
pectinase
enzymes
released
2.1%
of
the
TRR
and
 ­
amylase
and
isomaltase
digestion
released
another
1.1%
of
the
TRR.
Separate
acid
and
base
hydrolyses
released
4.2%
and
6.0%
of
the
TRR,
respectively,
from
the
PES
fraction;
however,
for
both
hydrolysates,
a
major
fraction
of
the
solubilized
radioactivity
was
retained
on
a
SPE
C
18
column
during
clean
up.
Protease
hydrolysis
also
released
4.7%
of
the
TRR
in
the
PES
fraction;
however,
the
majority
of
the
radioactivity
in
this
hydrolysate
was
associated
with
component
having
molecular
weights
>
3000.

Table
2.2:
Summary
of
Characterization
and
Identification
of
14C­
residues
in
Potatoes
harvested
at
maturity
following
a
PPI
application
of
[
14C]
PCNB
at
20
or
60
lb
ai/
A
(
1x
and
3x).

Metabolite
or
Fraction
Potato
(
1x)
(
TRR
=
1.12
ppm)
Potato
(
3x)
(
TRR=
3.54
ppm)

%
TRR
ppm
%
TRR
ppm
Principle
14C­
residues
(

3%
TRR)
PCNB
7.51
0.084
7.95
0.280
PCA
4.26
0.047
2.42
0.085
PCTA
3.48
0.039
2.71
0.096
PCP­
MalCys
9.80
0.112
10.09
0.357
AM
TCB
sulfonic
acid
4.75
0.054
3.85
0.136
Minor
residues
(<
3%
TRR)
a
PCAN
0.70
0.008
0.40
0.014
PCB
1.89
0.021
1.01
0.035
NOH
PCA
1.52
0.017
0.78
0.028
PCP­
GluCys
0.84
0.009
1.17
0.042
Metabolite
or
Fraction
Potato
(
1x)
(
TRR
=
1.12
ppm)
Potato
(
3x)
(
TRR=
3.54
ppm)

%
TRR
ppm
%
TRR
ppm
Page
­
10­
PCP­
GSH
1.22
0.014
1.58
0.056
PCP­
MalCys
ester
0.54
0.006
2.46
0.087
TCA
sulfoxide
isomers
0.13
0.001
0.09
0.004
TC­
MET­
A
sulfamate
0.02
<
0.001
0.12
0.004
TCNB
isomers
0.13
0.001
0.18
0.006
TCNB
sulfonic
acid
isomers
0.13
0.001
0.27
0.010
TCNTA
isomers
0.01
<
0.001
0.09
0.003
TCP
sulfoxide
0.70
0.008
0.34
0.012
TCTP
sulfoxide
0.78
0.009
0.81
0.029
AM
TCA
isomers
2.79
0.031
2.06
0.073
AM
TCA
sulfamate
0.48
0.005
0.44
0.016
OH
TCA
0.43
0.005
0.31
0.011
NOHAM
TCP
0.37
0.004
0.19
0.006
NOHAM
TCTA
isomers
0.66
0.007
0.22
0.007
TC­
MES­
P­
GSH
2.06
0.023
1.25
0.044
TC­
MES­
P­
MalCys
2.03
0.023
2.30
0.081
TCNP­
GSH
0.95
0.011
1.94
0.069
TCNP­
MalCys
1.19
0.014
1.55
0.055
TCP­
diGSH
1.99
0.022
1.51
0.054
TCP­
dithioacetate
1.52
0.017
2.00
0.071
TCP­
GluCys­
Cys
2.25
0.025
1.54
0.055
AC
TCP­
Cys­
CysHOG
1.07
0.012
1.19
0.042
RCA­
GluCys­
Cys
0.87
0.010
0.89
0.032
RCNP­
MalCysthioacetate
2.04
0.023
1.72
0.061
RCTA­
GluCys­
Cys
1.69
0.019
1.60
0.057
diAC
RCAN­
GSH­
Cys
1.47
0.017
1.15
0.041
diAC
RCTA­
diGluCys
1.87
0.021
2.00
0.071
Total
Identified
(
TI)
b
64.14
0.722
60.18
2.13
Total
Characterized
(
TC)
29.36
0.329
32.12
1.14
Total
Extractable
(
TE)
93.50
1.05
92.30
3.27
Total
Bound
(
TB)
6.74
0.075
9.92
0.351
%
Mass
Balance
100.2
102.2
a
The
full
chemical
name
for
each
metabolite
can
be
found
from
Table
2.14.
b
Although
quantitation
was
not
possible,
trace
(<
1%
TRR)
amounts
of
the
following
metabolites
were
also
identified
in
tubers:
TCTP
sulfonic
acid;
NOHAM
TCA;
RCNA
sulfoxide;
NOH
RC­
diMET­
A;
and
NOHAM
RC­
OME­
A.
TC
=
Sum
of
all
unidentified,
extractable
resides
TE
=
Sum
of
TI
and
TC
%
Mass
Balance
=
TE
%
TRR
+
TB
%
TRR
Page
­
11­
Page
­
12­
2.
A.
1.
iii.
Cabbage
Uniroyal
Chemical
Company,
Inc.
submitted
data
(
1990;
MRID
41562904)
pertaining
to
the
metabolism
of
PCNB
in
cabbage.
The
available
plant
metabolism
data
in
cabbage
are
insufficient
because
residues
were
not
quantitatively
identified.
The
acetone
soluble
residues
and
insoluble
residues
respectively
comprising
15%
(
up
to
3
ppm)
and
28%
(
up
to
5
ppm)
of
the
TRR
in
mature
cabbage
leaves
were
not
quantitatively
identified.

The
radiolabeled
mixture
was
incorporated
in
the
top
4
inches
of
a
container
of
growing
medium/
soil
at
a
field­
equivalent
rate
of
48
lb
ai/
A
(
ca.
1x
the
maximum
registered
rate).
On
the
day
of
treatment,
27­
day
old
cabbage
plants
were
transplanted
into
the
soil.
Cabbage
heads
were
harvested
55,
76,
and
160
days
(
full
maturity)
after
transplanting
to
treated
soil;
surrounding
leaves
of
mature
plants
were
harvested
separately.
All
samples
of
Page
­
13­
immature
and
mature
cabbage
were
stored
frozen
(
ca.
­
20
C)
until
analysis.

Table
2.3.
Distribution
and
characterization/
identification
of
14C­
residues
in
mature
cabbage
leaves
following
a
preplant
soil
application
of
[
14C]
PCNB.
_______________________________________________________________

Components
(
Code)
ppm
Percent
_______________________________________________________________

Nonextractable
residue
3.1­
5.0
27.8
Acetone
extract
1.6­
2.6
14.7
Methanol
extract
6.3­
10.4
57.5
RCHM
sulfone
(
1)
N.
C.
a
2.1
RCPM
sulfone
(
2A)
N.
C.
5.1
TCPM
sulfoxide
(
2B)
N.
C.
20.8
NOHPCA
(
3)
N.
C.
2.3
TCPM
sulfone
(
4)
N.
C.
24.1
PCTA
sulfoxide
(
5)
N.
C.
2.8
PCTA
(
6)
b
N.
C.
0.3
Total
Identifiedc
57.5
Total
Unidentified
Unk.
Unk.
Unaccounted
for
Unk.
Unk.
______________________________________________________________
Total
11­
17.9
100.0
a
N.
C.
=
Non­
calculable
by
the
study
reviewer
since
recoveries
from
the
C­
18
cartridge
and
the
HPLC
were
not
given.
b
Identified
by
GC
and
MS.
c
Percentage
based
on
identified
fraction
(
methanol
extract)
only.

2.
A.
2.
Livestock
Metabolism
Studies
In
Uniroyal's
ruminant
metabolism
study,
two
goats
were
dosed
orally
with
[
14C]
PCNB
for
five
consecutive
days
at
levels
equivalent
to
770
or
1,400
ppm
in
the
diet.
Based
on
Uniroyal's
currently
registered
uses
for
PCNB,
these
dietary
levels
are
equivalent
to
3850x
and
7000x
the
maximum
dietary
burden.

In
Uniroyal's
poultry
metabolism
study,
three
groups
of
laying
hens
were
dosed
orally
with
[
14C]
PCNB
for
six
consecutive
days
at
levels
equivalent
to
107,
274
or
512
ppm
in
the
diet.
Based
on
Uniroyal's
currently
registered
uses
for
PCNB,
these
dietary
levels
are
equivalent
to
430x,
1100x,
and
2050x
the
maximum
dietary
burden.

Table
2.4
(
below)
contains
information
on
residue
levels
of
PCNB
and
its
metabolites
from
livestock
metabolism
studies.
Page
­
14­

Table
2.4:
Revised
identification/
characterization
of
14C­
residues
in
milk
and
tissues
from
a
goat
dosed
for
5
consecutive
day
with
[
14C]
PCNB
at
50
mg/
kg
body
weight/
day,
which
is
equivalent
to
1400
ppm
in
the
diet
(
7000x
the
theoretical
dietary
burden
for
cattle).

Metabolite
(
Abbrev.)
Kidney
(
49.1
ppm)
a
Liver
(
45.5
ppm)
Muscle
(
2.3
ppm)
Milk
(
8.1
ppm)
b
Omental
Fat
(
27.0
ppm)
Renal
Fat
(
32.8
ppm)

%
TRR
PPM
%
TRR
PPM
%
TRR
PPM
%
TRR
PPM
%
TRR
PPM
%
TRR
PPM
N­
hydroxypentachloroaniline
(
NOHPCA)
­­
­­
4.4
2.0
­­
­­
­­
­­
­­
­­
­­
­­

tetrachloro(
methylthio)
thiophenol
(
TCTP
S­
Met)
4.5
2.2
0.9
0.42
­­
­­
­­
­­
­­
­­
­­
­­

pentachlorothiophenol
(
PCTP)
3.3
1.6
2.7
1.2
10.5
0.24
­­
­­
­­
­­
­­
­­

tetrachlorothioanisole
(
TCTA)
2.1
1.0
­­
­­
37.3
0.84
­­
­­
­­
­­
­­
­­

pentachloroaniline
(
PCA)
26.0
12.7
16.0
7.2
40.9
0.92
72.0
5.8
83.0
22.0
90.0
30.0
tetrachloroaniline
methyl
sulfoxide
(
TCA
sulfoxide)
2.3
1.1
­­
­­
­­
­­
­­
­­
­­
­­
­­
­­

pentachlorothiophenol
dimer
(
PCTP
dimer)
­­
­­
2.5
1.1
­­
­­
­­
­­
­­
­­
­­
­­

N­
glucuronide
of
PCA
(
PCA­
Gluc)
55.0
27.0
40.0
18.0
­­
­­
­­
­­
­­
­­
­­
­­

glucuronide
of
NOHPCA
(
NOHPCA­
Gluc)
­­
­­
28.0
12.0
­­
­­
­­
­­
­­
­­
­­
­­

Total
Identified
93.2
c
45.6
94.5
41.9
88.7
2.0
72.0
5.8
83.0
22.0
90.0
30.0
Unanalyzed
fractions
non­
polar
3.7
1.8
­­
­­
­­
­­
­­
­­
14.5
d
3.9
17.3
d
5.7
polar
­­
­­
­­
­­
10.5
e
0.8
­­
­­
­­
­­

Sample
loss
(
spill)
­­
­­
7.4
3.4
­­
­­
­­
­­
­­
­­
­­
­­

Unextracted/
precipitates
2.1
1.0
­­
­­
11.5
0.26
16.4
f
1.32
­­
­­
­­
­­

Identified/
Characterized
99.0
48.4
101.9
45.3
100.2
2.3
98.9
7.9
97.5
25.9
107.3
35.7
a
TRR
values
for
each
matrix
are
listed
in
parentheses.

b
The
current
TRR
value
for
milk
(
8.1
ppm)
was
calculated
by
the
Dynamac
reviewer
assuming
that
the
reported
5.8
ppm
value
for
PCA
represented
72.0%
of
the
TRR
in
milk.
However,
there
is
some
question
as
the
extract
TRR
value
to
use
for
milk.
The
original
review
reported
TRRs
from
radioassay
of
24.0
and
58.5
ppm
in
milk
from
the
low­
and
high­
dose
goat,
respectively.

However,
calculated
TRR
values
of
8.3­
11.7
ppm
are
obtained,
when
using
data
from
the
summary
table
of
the
previous
Agency
review
(
J.
Abbotts,
4/
24/
96)

c
Includes
16.1%
of
the
TRR
recovered
in
the
aqueous
fraction
following
protease
hydrolysis.
Residues
in
this
fraction
were
only
characterized.

d
Attempts
at
cleaning
up
the
hexane
fraction
from
fat
using
alumina
or
gel
permeation
chromatography
were
unsuccessful.

e
Fraction
was
separated
into
methanol
(
6.7%
TRR)
and
aqueous
(
3.8%
TRR)
fractions
following
purification
using
an
XAD­
4
column.

f
Comprised
for
residual
solids
from
the
initial
extraction
(
7.5%
TRR)
and
precipitates
that
formed
during
partitioning
(
9.2%
TRR).
Page
­
15­

Table
2.5:
Revised
identification/
characterization
of
14C­
residues
in
egg
yolk,
fat,
liver,
and
muscle
of
hens
dosed
for
5
consecutive
days
with
[
14C]
PCNB
at
39.4
mg/
chicken/
day,
equivalent
to
512
ppm
in
the
diet
(
2050
X
the
theoretical
dietary
burden
for
poultry).

Metabolite
(
Abbrev.)
Fat
(
10.1
ppm)
a
Liver
(
3.81
ppm)
Egg
yolk
(
5.75
ppm)
Thigh
muscle
(
0.71ppm)

%
TRR
PPM
%
TRR
PPM
%
TRR
PPM
%
TRR
PPM
Solvent
extractable
14C­
residues
b
pentachloronitrobenzene
(
PCNB)
45.7
4.62
­­
­­
­­
­­
­­
­­

pentachloroaniline
(
PCA)
13.7
1.38
­­
­­
11.0
0.63
­­
­­

pentachlorobenzene
(
PCB)
­­
­­
­­
­­
0.9
0.05
­­
­­

pentachlorothioanisole
(
PCTA)
­­
­­
­­
­­
2.1
0.12
5.6
0.04
pentachlorothioanisole
sulfoxide
(
PCTA
sulfoxide)
­­
­­
18.6
0.71
­­
­­
­­
­­

pentachlorothiophenol
(
PCTP)
­­
­­
55.9
2.13
4.0
0.23
­­
­­

tetrachloroaniline
methyl
sulfoxide
(
TCA
sulfoxide)
29.1
2.94
­­
­­
­­
­­
­­
­­

tetrachlorothioanisole
(
TCTA)
0.5
0.05
­­
­­
­­
­­
­­
­­

tetrachlorophenyl
methyl
sulfone
(
TCP
methyl
sulfone)
­­
­­
­­
­­
­­
­­
62.0
0.44
Table
2.5:
Revised
identification/
characterization
of
14C­
residues
in
egg
yolk,
fat,
liver,
and
muscle
of
hens
dosed
for
5
consecutive
days
with
[
14C]
PCNB
at
39.4
mg/
chicken/
day,
equivalent
to
512
ppm
in
the
diet
(
2050
X
the
theoretical
dietary
burden
for
poultry).

Metabolite
(
Abbrev.)
Fat
(
10.1
ppm)
a
Liver
(
3.81
ppm)
Egg
yolk
(
5.75
ppm)
Thigh
muscle
(
0.71ppm)

%
TRR
PPM
%
TRR
PPM
%
TRR
PPM
%
TRR
PPM
Page
­
16­
S­(
pentachlorophenyl)
thioacetate
­­
­­
6.6
0.25
­­
­­
­­
­­

Total
Identified
89.0
8.99
81.1
3.09
18.0
1.03
67.6
0.48
Unanalyzed
polar
fraction
NA
­­
NA
­­
NA
­­
40.8
0.29
Base
hydrolysate
NA
­­
36.6
c
1.39
28.8
d
1.65
19.5
e
0.14
Unextracted
f
0.5
0.05
­­
­­
46.5
2.67
6.4
0.05
Identified/
Characterized
89.5
9.0
117.7
4.48
93.3
5.35
134.3
0.96
a
TRR
values
for
each
matrix
are
listed
in
parentheses.
b
Solvent
extractable
14C­
residues
as
determined
in
the
original
submission.
c
GC/
MS
analysis
of
base­
solubilized
liver
14C­
residues
showed
two
large,
approximately
equal
peaks,
identified
as
PCA
and
PCTA,
along
with
trace
amounts
of
PCNB,
TCTP,
PCB,
and
HCB.
d
GC/
MS
anaylsis
of
the
yolk
base
hydrolysate
detected
a
single
large
peak
identified
as
PCTA,
along
with
trace
amounts
of
PCA,
PCNB,
PCB,
and
HCB.
e
The
base
hydrolysate
from
thigh
muscle
was
not
analyzed
due
to
low
14C­
residues.
f
14
C
­
Residues
remaining
in
the
solids
following
base
hydrolysis
with
1
N
NaOH
at
60
C.

Table
2.6:
Release
of
unextracted
14C­
residues
from
liver,
kidneys,
egg
yolk,
and
thigh
muscle
of
hens
dosed
for
5
consecutive
days
with
[
14C]
PCNB
at
39.4
mg/
chicken/
day,
equivalent
to
512
ppm
in
the
diet
(
2050x
the
theoretical
dietary
burden
for
poultry).

Fraction
Liver
(
3.81
ppm)
a
Kidney
b
(
7.29
ppm)
Egg
yolk
(
5.75
ppm)
Thigh
muscle
(
0.71ppm)

%
TRR
PPM
%
TRR
PPM
%
TRR
PPM
%
TRR
PPM
Solvent
extractable
14C­
residues
82.0
3.12
67.2
4.90
19.8
1.14
111.2
0.79
Unextracted
14C­
residue
c
35.2
1.34
32.8
2.39
75.3
4.33
25.9
0.18
Enzymes
pepsin
6.0
0.23
38.0
2.77
3.5
0.20
NA
d
­­

trypsi
n
5.8
0.22
18.1
1.32
5.6
0.32
NA
­­

lipase
NA
­­
NA
­­
3.7
0.21
NA
­­

protease
NA
­­
26.5
1.93
NA
­­
NA
­­

2N
HCl
6.3
0.24
3.2
0.24
3.6
0.21
8.3
0.06
1N
NaOH
e
36.6
f
1.39
26.2
g
1.91
28.8
h
1.65
19.5
0.14
Residual
solids
(
after
base
hydrolysis)
­­
­­
6.6
0.48
46.5
2.67
6.4
0.05
a
TRR
values
for
each
matrix
are
listed
in
parentheses.
Page
­
17­
b
Kidney
is
not
a
regulated
commodity
of
poultry,
but
the
data
were
include
here
for
purposes
of
comparison.
c
Separate
aliquots
of
unextracted
solids
separately
subjected
to
various
enzyme
hydrolyses
and
acid
and
base
hydrolyses.
d
NA
=
not
applicable.
e
With
the
exception
of
thigh
muscle,
base
hydrolysates
were
acidified,
partitioned
into
chloroform,
cleaned
up
by
florisil
column
chromatography
and
then
analyzed
by
GC/
MS.
f
GC/
MS
analysis
of
solubilized
liver
14C­
residues
showed
two
large,
approximately
equal
peaks,
identified
as
PCA
and
PCTA,
along
with
trace
amounts
of
PCNB,
TCTP,
PCB,
and
HCB.
g
GC/
MS
analysis
of
solubilized
kidney
14C­
residues
showed
a
single
large
peak
that
was
identified
as
PCA
h
GC/
MS
anaylsis
of
the
yolk
base
hydrolysate
detected
a
single
large
peak
identified
as
PCTA,
along
with
trace
amounts
of
PCA,
PCNB,
PCB,
and
HCB.

2.
B.
Confined
Accumulation
in
Rotational
Crops
Uniroyal
submitted
a
confined
rotational
crop
study
in
which
[
14C]
PCNB
was
applied
to
a
sandy
loam
soil
at
2.0,
10,
or
30
lb
ai/
A.
Turnips
were
planted
1
year
after
application
at
2.0
or
10
lb
ai/
A,
and
lettuce
(
10
lb
ai/
A
only)
and
wheat
(
all
rates)
were
planted
30,
120,
and
365
days
after
treatment.
Total
radioactive
residues
were
>
0.05
ppm
in
all
samples
except
wheat
grain
planted
1
year
after
application
at
2.0
lb
ai/
A.

The
following
Tables
contain
the
levels
of
PCNB
and
11
metabolites
that
were
analyzed
for
in
this
confined
accumulation
in
rotational
crops.

Table
2.7:
Identification
and
characterization
of
14C­
residues
in
turnip
roots
and
tops
planted
365
days
after
soil
treatment
with
[
14C]
PCNB
at
10.0
or
2.0
lb
ai/
A.

Component/
fractions
a
10
lb
ai/
A
rate
2
lb
ai/
A
rate
Turnip
tops
(
0.143
ppm)
b
Turnip
roots
(
0.243
ppm)
Turnip
tops
(
0.050
ppm)
Turnip
roots
(
0.054
ppm)

%
TRR
ppm
%
TRR
ppm
%
TRR
ppm
%
TRR
ppm
PCNB
ND
ND
ND
ND
ND
ND
ND
ND
PCA
ND
ND
44.20
0.107
1.14
0.004
46.15
0.025
PCTA
ND
ND
2.97
0.007
ND
ND
0.85
<
0.001
PTCASO/
C3MS
2.14
0.003
1.79
0.004
3.95
0.003
3.09
0.002
C5SA
6.02
0.009
0.75
0.002
5.37
0.003
1.89
0.001
Component/
fractions
a
10
lb
ai/
A
rate
2
lb
ai/
A
rate
Turnip
tops
(
0.143
ppm)
b
Turnip
roots
(
0.243
ppm)
Turnip
tops
(
0.050
ppm)
Turnip
roots
(
0.054
ppm)

%
TRR
ppm
%
TRR
ppm
%
TRR
ppm
%
TRR
ppm
Page
­
18­
PCP
0.43
0.001
1.49
0.004
0.57
<
0.001
1.41
0.001
C4MS
0.77
0.001
1.34
0.003
ND
ND
ND
ND
C4SA
11.35
0.016
0.78
0.002
8.09
0.005
8.96
0.005
C3MS
5.15
0.007
0.86
0.002
8.06
0.004
2.72
0.002
C3SA
1.19
0.002
4.17
0.011
10.37
0.005
2.97
0.002
C3MSSA/
C2MSMaCy
20.12
0.029
3.55
0.009
15.48
0.008
6.96
0.004
C2SA/
C3MSMaCy
18.09
0.026
16.17
0.039
23.13
0.011
6.11
0.003
Total
identified
65.3
0.094
78.1
0.190
76.2
0.044
81.1
0.046
Unknowns
c
22.26
0.031
4.34
0.010
10.03
0.005
4.74
0.003
Unanalyzed
fractions
Hexane
3.50
0.005
NA
NA
4.63
0.002
NA
NA
Aqueous
NA
NA
7.95
0.019
NA
NA
3.60
0.002
DCM
NA
NA
2.34
0.006
NA
NA
2.32
0.001
Residual
solids
8.98
0.013
7.30
0.018
9.18
0.004
8.24
0.004
Total
identifed/
characterized
100.0
0.143
100.0
0.243
100.0
0.055
100.0
0.056
a
Metabolite
structures
are
presented
in
Table
2.14.
b
TRR
values
determined
by
the
analytical
laboratory.
c
Each
unknown
accounted
for
<
0.01
ppm
Table
2.8:
.
Identification
and
characterization
of
14C­
residues
in
lettuce
planted
30,
120,
or
365
days
after
soil
treatment
with
[
14C]
PCNB
at
10.0
lb
ai/
A.

Component/
fraction
a
Lettuce
30­
DAT
(
0.108
ppm)
b
Lettuce
120­
DAT
(
0.095
ppm)
Lettuce
365­
DAT
(
0.427
ppm)

%
TRR
ppm
%
TRR
ppm
%
TRR
ppm
PCNB
21.2
0.023
0.8
<
0.001
1.3
0.006
PCB
0.4
<
0.001
<
0.1
<
0.001
<
0.1
<
0.001
PCAc
14.9
0.016
11.5
0.011
11.5
0.041
C4MeAcCy
d
2.6
0.003
11.5
0.011
3.0
0.013
PCTA
ND
ND
0.4
<
0.001
1.2
0.005
C5SA
6.3
0.007
2.2
0.002
5.5
0.024
C5MaCy
2.6
0.003
2.4
0.002
<
0.1
<
0.001
C4CyFCy
1.8
0.002
2.8
0.003
<
0.1
<
0.001
C4MS
isomers
<
0.1
<
0.001
15.6
0.015
6.4
0.027
C4SA
<
0.1
<
0.001
<
0.1
<
0.001
2.9
0.012
C4MaCyFCy
<
0.1
<
0.001
<
0.1
<
0.001
1.6
0.007
C3MS
<
0.1
<
0.001
5.6
0.006
6.5
0.028
C3SA
<
0.1
<
0.001
<
0.1
<
0.001
2.8
0.012
Component/
fraction
a
Lettuce
30­
DAT
(
0.108
ppm)
b
Lettuce
120­
DAT
(
0.095
ppm)
Lettuce
365­
DAT
(
0.427
ppm)

%
TRR
ppm
%
TRR
ppm
%
TRR
ppm
Page
­
19­
Total
identified
49.8
0.054
52.8
0.050
42.7
0.175
Unknowns
e
6.0
0.007
26.8
0.025
29.9
0.128
Solvent­
extracted
Solids
40.5
0.044
31.3
0.030
29.1
0.125
Enzymes
pH
5
1.5
0.002
2.2
0.002
2.3
0.010
Enzymes
pH
7
3.6
0.004
3.9
0.004
2.4
0.010
Proteases
9.9
0.011
10.1
0.010
7.4
f
0.032
KOH
hydrolysate
16.8
f
0.018
11.3
0.011
7.9
f
0.034
Residual
solids
10.3
0.011
3.7
0.004
2.4
0.010
Total
identified/
characterized
97.9
0.107
110.8
0.106
95.0
0.399
a
Metabolite
structures
are
presented
in
Table
2.14.
b
TRR
values
determined
at
the
analytical
laboratory.
c
Includes
PCA
release
by
the
protease
and
base
hydrolysis.
d
Metabolite
C4MeAcCy
is
referred
to
as
Conjugate
330
m/
z
in
the
appendix
pertaining
to
the
lettuce
analyses.
e
With
the
exception
of
the
365­
day
sample,
isolated
unknown
each
accounted
for
<
0.01
ppm.
In
the
365­
day
lettuce
sample,
unknowns
each
accounted
for

0.018
ppm.
f
Enzyme
and
base
hydrolysate
fractions
analyzed
by
HPLC.

Table
2.9:
Identification
and
characterization
of
14C­
residues
in
forage
from
wheat
planted
30
or
120
days
after
soil
treatment
with
[
14C]
PCNB
at
30
and
10
lb
ai/
A,
respectively.

Component/
fraction
a
Wheat
forage
30­
DAT;
30
lb
ai/
A
(
4.064
ppm)
b
Wheat
forage
120
DAT;
10
lb
ai/
A
(
3.347
ppm)

%
TRR
ppm
%
TRR
ppm
PCNB
0.64
0.026
ND
ND
PCB
ND
ND
PCTA
0.83
0.028
PCA
2.02
0.082
1.87
0.063
C5MX
C4MeAcCy

0.28

0.012
0.24
0.008
C3MS

0.28

0.012
ND
ND
C4SA
45.26
c
1.839
6.75
0.226
C4SANH
2.61
0.087
C5SA
6.46
0.216
C5G1
0.52
0.017
C4MaCyFCy
0.88
0.030
C3SA
5.21
0.175
C3SAOH
1.33
0.044
C5SAHx
1.70
0.057
C4CyCy
0.56
0.019
C3MSSA
0.82
0.027
Component/
fraction
a
Wheat
forage
30­
DAT;
30
lb
ai/
A
(
4.064
ppm)
b
Wheat
forage
120
DAT;
10
lb
ai/
A
(
3.347
ppm)

%
TRR
ppm
%
TRR
ppm
Page
­
20­
C4MXSA
1.13
0.038
Total
identified
NA
NA
30.9
1.035
Unknowns,
non­
polar
NA
NA
2.56
0.086
Unknowns,
polar
NA
NA
25.1
d
0.841
Solvent­
extracted
solids
39.8
1.618
34.8
1.164
Enzymes
pH
5
e
7.49
0.304
6.10
0.204
Enzymes
pH
6
e
3.98
0.162
4.06
0.136
Proteases
e
3.99
0.162
3.11
0.104
HCl/
dioxane
16.1
0.635
9.89
0.331
KOH
hydrolysate
6.78
0.276
5.31
0.178
Residual
solids
2.27
0.092
1.66
0.056
Total
identified/
characterized
88.5
3.578
89.1
2.971
a
Metabolite
structures
are
presented
in
Table
2.14.
b
TRR
values
determined
at
the
analytical
laboratory.
c
The
non­
polar
fraction
from
30­
DAT
forage
(
30
lb
ai/
A)
was
analyzed
by
HPLC,
but
no
quantitative
data
were
provided.
d
Designated
as
minor
unidentified
minor
metabolites.
e
Enzyme
digests
were
pooled
and
analyzed
by
HPLC.
No
quantitative
data
were
provided;
however,
the
chromatogram
showed
numerous
peaks.

Table
2.10:
Characterization
of
14C­
residues
in
grain
from
wheat
planted
30,
120,
or
365
days
after
soil
treatment
with
[
14C]
PCNB
at
30
or
10
lb
ai/
A.

Component/
fraction
a
Wheat
grain
30­
DAT;
30
lb
ai/
A
(
3.661
ppm)
b
Wheat
grain
120
DAT;
10
lb
ai/
A
(
0.941
ppm)
Wheat
grain
365
DAT;
10
lb
ai/
A
(
0.134
ppm)

%
TRR
ppm
%
TRR
ppm
%
TRR
ppm
Non­
polar
c
1.01
0.037
1.47
0.014
0.89
0.001
Polar
d
8.77
0.321
15.0
0.141
32.3
0.044
Solvent
extracted
solids
83.4
3.053
77.5
0.729
57.5
0.078
Enzymes
pH
5
e
55.4
2.026
42.0
0.395
22.4
0.031
Enzymes
pH
6
e
16.3
0.597
13.7
0.129
10.9
0.015
Protease
e
2.28
0.084
1.70
0.016
ND
ND
HCl/
dioxane
c
2.54
0.093
4.57
0.043
1.35
0.002
KOH
hydrolysate
c
4.54
0.166
17.3
0.163
23.6
0.032
Residual
solids
1.12
0.041
2.02
0.025
1.14
0.002
Total
characterized
92.0
3.365
97.8
0.926
92.6
0.127
a
Metabolite
structures
are
presented
in
Table
2.14.
b
TRR
values
determined
at
the
analytical
laboratory.
c
Fractions
were
not
further
analyzed.
d
HPLC
analyses
of
the
non­
polar
fractions
indicate
that
14C­
residues
were
composed
primarily
of
a
polar
fraction
A
and
two
minor
fractions,
E1and
F2;
however,
no
quantitative
data
were
provided.
In
related
analyses
of
forage
polar
extracts,
Fraction
A
was
characterized
by
GPC
as
consisting
of
metabolites
bound
or
incorporated
into
large
water­
soluble
molecules,
and
Fractions
E1
and
F2
were
identified
respectively
as
C3SA
(
trichlorobenzene
sulfonic
acid)
and
C5SA
(
pentachlorobenzene
sulfonic
acid).
e
The
enzymatic
fractions
were
pooled
by
sample
and
analyzed
by
HPLC;
however,
no
quantitative
data
were
provided.
The
chromatograms
indicated
that
14C­
residues
consisted
primarily
of
polar
compounds.
Page
­
21­
Table
2.11:
Identification
and
characterization
of
14C­
residues
in
straw
from
wheat
planted
120
days
after
soil
treatment
with
[
14C]
PCNB
at
2
or
10
lb
ai/
A.

Component/
fraction
a
Wheat
straw
120­
DAT;
2.0
lb
ai/
A
(
3.523
ppm)
b
Wheat
straw
120
DAT;
10
lb
ai/
A
(
16.826
ppm)

%
TRR
ppm
%
TRR
ppm
PCNB
0.09
0.0032
0.30
0.0502
PCB
PCTA
0.05
0.0016
ND
ND
C4MeAcCy
<
0.01
0.0185
PCA
0.35
0.0123
0.83
0.139
C3MS
0.50
0.0176
0.67
0.112
C4MX
0.56
0.0196
1.08
0.1823
C5MX
0.26
0.0091
0.81
0.1363
C2SA
0.68
0.024
1.90
0.3201
C3SA
9.12
0.3212
7.97
1.3406
C4SA
12.9
0.4552
14.56
2.4491
C5SA
1.70
0.060
3.47
0.5831
C4SANH
1.99
0.070
3.89
0.6537
C3SANH
ND
ND
0.44
0.0734
C2MSSA
3.33
0.1174
2.12
0.3563
C3MSSA
3.45
0.1214
2.76
0.4640
C4MXSA
1.51
0.0531
1.90
0.3193
C3MXSA
ND
ND
2.63
0.4432
C4MSSA
0.97
0.0343
0.64
0.1084
Total
identified
37.5
1.320
46.0
7.750
Solvent
extracted
solids
42.1
1.483
37.2
6.259
Phosphate
buffer
c
7.98
0.281
7.73
1.301

­
Amylase
c
4.04
0.141
3.64
0.613
Pronase
(
protein)
c
2.51
0.088
2.27
0.382
Pectinase
(
pectin)
c
1.41
0.050
0.88
0.148
HCl/
dioxane
(
lignin)
d
8.16
0.288
10.18
1.713
KOH
(
hemicellulose)
d
10.62
0.374
9.17
1.543
H2SO4
(
cellulose)
d
5.00
0.176
1.01
0.170
Residual
solids
3.66
0.129
1.04
0.175
Total
identified/
characterized
80.9
2.847
81.9
13.795
a
Metabolite
structures
are
presented
in
Table
2.14.
b
TRR
values
determined
at
the
analytical
laboratory.
c
Phosphate
buffer
extract
and
pooled
enzymatic
digestions
were
analyzed
by
RP­
HPLC,
but
no
quantitative
data
were
provided.
Chromatographic
profiles
of
both
analyses
showed
a
single,
large
unretained
peak
of
radioactivity
followed
by
a
broad
diffuse
peak
of
radioactivity.
d
Fractions
were
not
further
analyzed.
Page
­
22­
Page
­
23­
2.
C.
Residue
Analytical
Methods
Adequate
analytical
methodology
is
available
for
enforcing
tolerances
of
PCNB
residues,
as
currently
defined,
in
plant
commodities.
The
Pesticide
Analytical
Manual
(
PAM)
Vol.
II
currently
lists
two
GC
method
(
Methods
A
and
I)
for
the
determinating
residues
of
PCNB
per
se.
In
addition,
residues
of
PCNB,
its
metabolites
PCA
and
MPCPS,
and
the
impurities
PCB
and
HCB
are
completely
recovered
through
the
multi­
residue
methods
listed
in
PAM
Vol.
I
(
Methods
302,
303,
and
304).

Uniroyal
method
CAM­
24­
73
and
its
modifications
is
used
for
cabbage,
potatoes,
broccoli,
peppers,
beans,
tomatoes,
and
peanuts
and
method
CAM­
11­
72
for
cottonseed.
Uniroyal
has
submitted
a
method
description
and
validation
data
for
an
adequate
GC/
ECD
method
(
CAM­
24­
73
and
its
modification)
for
collecting
data
on
residues
of
PCNB,
PCA,
MPCPS,
PCB,
and
HCB.
Uniroyal
also
submitted
a
description
for
a
GC/
ECD
method
(
CAM­
11­
72)
for
determining
residues
in
cottonseed;
however,
method
validation
data
were
not
provided
for
this
method.
Data
are
required
validating
Method
CAM­
11­
72
as
modified
10/
28/
87
and
3/
15/
88
for
analysis
in
cottonseed.

In
CAM­
24­
73
method,
tissue
samples
are
homogenized
in
hexane
and
the
decanted
hexane
extract
is
analyzed
directly
by
GLC
electron
capture
detection
(
ECD).
In
the
modified
version
of
the
method,
the
solvent
isopropyl
alcohol/
hexane,
or
toluene/
hexane
mixture
and
a
cleanup
step
on
different
columns
depending
on
the
crop
is
added.
The
limit
of
detection
given
for
the
modified
method
was
0.002
ppm
for
vegetable
crops
and
0.005
ppm
for
oil
crops
(
peanuts).
The
method
is
listed
as
having
a
recovery
rate
above
70%
for
PCNB
and
metabolites.

The
Uniroyal
method
CAM­
11­
72
for
cottonseed
utilized
dry
blending,
soxhlet
extraction
with
hexane,
florisil
column
cleanup,
and
GLC­
ECD
analysis
with
a
3%
SE­
30
liquid
phase
on
the
column.
This
method
listed
a
sensitivity
level
of
0.005
ppm
(
limit
of
detection
unspecified)
for
PCNB
and
metabolites
and
a
residue
recovery
>
60%.
The
modified
method
for
cottonseed
involved
extraction
by
wet
blending
in
hexane
along
with
minor
differences
in
quantities
employed
and
cleanup
by
GPC
with
S­
X3
Biobeads.

In
conjunction
with
their
field
trial
data,
Amvac
has
submitted
a
method
description
and
validation
data
for
adequate
GLC/
ECD
methods
(
Amvac
Methods
MP­
PCNC­
MA1
and
MP­
PCNC­
MA2)
for
collecting
data
on
residues
of
PCNB,
PCA,
PCTA
(
MPCPS),
PCB,
HCB,
and
TCNB
in
plant
commodities.
Page
­
24­
Data
remain
outstanding
for
plant
and
animal
metabolism
studies.
If
metabolism
studies
reveal
the
presence
of
additional
metabolites
of
concern,
additional
validated
methods
for
data
collection
and
tolerance
enforcement
will
be
required.

In
addition,
the
available
residue
data
on
livestock
feed
items
indicate
that
tolerances
will
be
required
for
animal
commodities.
Therefore,
the
registrants
must
submit
methods
for
determining
PCNB
residues
of
concern
in
animal
commodities.

2.
D.
Multiresidue
Methods
The
Agency
has
determined
that
PCNB,
PCA,
MPCPS
(
PCTA),
PCB,
and
HCB
are
completely
recovered
through
PAM
Vol.
I,
Methods
302,
303
and
304.
No
additional
data
are
required
(
D.
Edwards,
8/
1/
86),
unless
additional
residues
of
concern
are
identified
in
the
plant
and
animal
metabolism
studies.

2.
E.
Crop
Field
Trials
and
Livestock
Feeding
Studies
The
following
Table
summarizes
maximum
residues
resulting
from
different
use
patterns
or
formulation
of
PCNB
products
on
each
use.
(
Important
note:
Almost
all
the
field
trial
data
that
were
submitted
from
either
registrants,
Uniroyal
and
Amvac,
were
the
result
of
older
products
in
which
HCB
and
PCB
had
higher
concentrations.
However,
the
resulting
residues
of
HCB
and
PCB
on
different
crops,
even
then
were
very
low
in
almost
all
cases.)

Table
2.12:
Summary
of
crop
field
trials
(
Note:
important
Table
footnotes)

crop
Application
timing
and
rate
RAC
PHI
(
days)
combined
resiudes
of
PCNB,
PCA,
PCTA
Potato1
Uniroyal
Not
supporting
Potato
Amvac
1
x
25
lb
ai/
A
(
PPI)
or
1x
11.6­
11.7
lb
ai/
14,500
ft
of
row
(
in­
furrow)
tubers
crop
maturity
(
89­
135
days
after
application)
<
0.06­
1.01
Garlic
Olin
1.5
x
maximum
label
rate
tubers
NN
<
0.008
Broccoli
Uniroyal
at
maximum
rate
(
30
lb
ai/
A)
broadcast,
banded,
and
transplant
soil­
drench
applications,
soil
64­
83
(
at
maturity)
<
0.01­
0.0943
Brussel
Sprouts
no
data
Cauliflower
no
data
Cabbage
Uniroyal
maximum
label
rate
(
30
lb
ai/
A)
soil
67­
125
days
(
at
maturity)
<
0.01­
0.0984
crop
Application
timing
and
rate
RAC
PHI
(
days)
combined
resiudes
of
PCNB,
PCA,
PCTA
Page
­
25­
Collard,
Kale,
Mustard
Greens
IR­
4
soil
(
preplant,
at
planting,
postplant,
spray
at
transplant
at
maximum
label
rate
<
0.2
(
tolerance)

Beans2
Uniroyal
soil
banded
application
at
planting
and
every
2­
week
for
a
total
of
maximum
rate
(
8
lb
ai/
A)
on
55
samples
snap
beans
14
das
<
0.25
­
<
0.432
Amvac
four
banded
applications,
totaling
7.5­
8.2
lb
ai/
A
(
maximum
label
rate
not
specified)
snap
beans
7,
10,
14,
20
days
<
0.063
­
<
2.38
Peppers3
Uniroyal
in­
furrow
at
planting
at
1x
maximum
rate
(
7.5
lb
ai/
A)
or
soil­
drench
application
at
transplanting
at
1.6
x
maximum
rate
peppers
71­
104
days
<
0.15
Tomatoes4
Uniroyal
in­
furrow
at
planting
at
1x
maximum
rate
(
7.5
lb
ai/
A)
or
soil­
drench
application
at
transplanting
at
1.6
x
maximum
rate
tomatoe
s
69­
113
days
<
0.15
Cotton5
Amvac
a
banded
application
or
infurrow
application
at
2.0
lb
ai/
A
lint
and
seed
135­
173
days
<
0.015­<
0.017
Peanuts6
Uniroyal
two
broadcast
or
banded
foliar
application
for
a
total
of
10
lb
ai/
A/
season
(
5
x
maximum
seasonal
use
rate)
mature
peanuts
43­
47
days
0.093­
0.330
Amvac
a
single
post­
emergence
application
at
pegging
at
10
lb
ai/
A
(
the
maximum
label
rate)
mature
peanuts
44­
51
days
0.158­
0.544
Seed
Treatment7
Uniroyal
No
seed
treatment
use
Amvac
see
foot
notes
1.
Potato:
In
addition
to
the
currently
regulated
compounds,
residues
of
PCB
were
<
0.005­
0.158
ppm
and
residues
of
2,3,4,5­
TCNB
were
<
0.005­
0.014
ppm
in
all
samples.
Residues
of
2,3,5,6­
TCNB
and
HCB
were
each
<
LOD
(<
0.005
ppm)
in/
on
all
potato
samples
from
both
types
of
application
and
both
formulations.
Page
­
26­
2.
Beans:
1)
combined
residues
include
PCNB,
PCA,
PCTA,
PCB
and
HCB;
however,
reanalysis
of
bean
samples
have
shown
that
residues
of
MPCPS,
PCB,
and
HCB
were
below
the
method
LOQ
(<
0.05
ppm).
2)
Other
beans
data
at
different
DATs
and
different
number
of
samples
showing
lower
residues.
3)
Amvac
submission
of
magnitude
of
residues
for
snap
beans
is
not
adequate
due
to
insufficient
trials
and
inadequate
geographical
representation.
4)
Amvac
submission
for
dry
beans
and
lima
beans
are
inadequate
as
well
(
data
are
not
presented
in
this
Table).
4)
Soybean
data
are
required
from
both
registrants.

3.
Peppers:
1)
The
available
storage
stability
data
indicate
substantial
residue
decline
during
storage.
The
combined
residue
(<
0.15)
is
calculated
by
Dynamac
considering
this
decline.
2)
Amvac
data
are
inadequate.
3)
Amvac
data
are
inadequate.

4.
Tomatoes:
1)
The
available
storage
stability
data
indicate
substantial
residue
decline
during
storage.
The
combined
residue
(<
0.15)
is
calculated
by
Dynamac
considering
this
decline.
2)
Amvac
data
are
inadequate.

5.
Cotton:
1)
Previous
Uniroyal
data
were
inadequate.
2)
New
submissions
from
Uniroyal
are
under
review.
3)
Data
from
both
registrants
for
cotton
gin
trash
is
required.

6.
Peanuts:
1)
The
reported
data
from
both
registrants
which
are
summarized
in
the
above
Table
are
not
adequate
due
to
insufficient
trials
and
inadequate
geographical
representation.
2)
A
few
types
of
formulation
and/
or
combination
of
use
rate
at
each
application
were
used.
The
summarized
data
in
the
above
Table
are
the
maximum
residues
found
amongst
all
types
of
applications.

7.
Amvac
has
submitted
a
study
following
uptake
of
radioactivity
in
corn,
peas,
rice,
safflower,
sugar
beets,
and
wheat
grown
from
seed
treated
with
[
14C]
PCNB.
Based
on
these
data
the
Agency
concluded
that
Amvac's
seed
treatments
are
food/
feed
uses
and
therefore
field
trial
data
as
a
result
of
seed
treatment
use
should
be
submitted.
Currently,
the
seed
treatment
uses
are
on
cereal
grains,
beans,
peas,
cotton,
peanuts,
safflower,
soybeans,
and
sugar
beets.
Amvac
seed
treatment
trial
on
soybean
at
10
x
maximum
rate
resulted
in
combined
residues
of
PCNB,
PCA,
and
PCTA
of
<
0.015
ppm.
These
data
will
support
separate
tolerances
of
0.02
ppm
in/
on
soybean
forage,
hay,
and
seeds.

Table
2.13
:
Feeding
studies
and
Magnitude
of
Residues
in
livestock
commodities.(
Note:
See
important
footnotes)

Commodity
Theoretical
Dietary
Burden
(
ppm)
Highest
Dose
Level
(
ppm)
Duration
PCNB
PCA
PCTA
combined
(
ppm)
LOD
Cattle
milk2,3
18.31
10
12­
15
weeks
ND
ND
ND
0.001­
0.018
0.001,
0.01
(
for
PCTA)
Cattle
Tissues2
(
Fat,
Liver,
Kidney,
Muscle)
35.21
10
12­
15
weeks
ND
0.062­
0.186
ND
0.062­
0.186
Hog
0.65
1
ND
ND
ND
Poultry
fat4,
5
0.25
1

0.176
Poultry
liver4,
5
0.25
1

0.033
Poultry
breast
muscle4,
5
0.25
1
ND
egg
yolk4,
5
0.25
1
NR
egg
whites4,
5
0.25
1
13­
15
weeks

0.006
Page
­
27­
NO
2
Cl
Cl
Cl
Cl
Cl
1.
Theoretical
Dietary
Burden
(
TDB)
for
beef
and
dairy
cattle
(
35.2
and
18.3
ppm)
are
calculated
based
on
potato
waste
and
potato
meal.
Since
Uniroyal
has
only
a
SLN
use
for
potato,
these
TDB
estimates
represent
the
regional
worst
case
and
are
used
for
tolerance
setting.
The
calculated
TDB
for
livestock
metabolism
studies
(
section
2.
A.
2
of
this
document)
was
not
based
on
potato
use
since
it
is
only
regional
use.

2.
Cows
dosed
with
1000
ppm
were
sacrificed
after
1
month
of
dosing.
Levels
of
dosing
were
0.1,
1,
10,
and
1000
ppm.

3.
HCB
levels
of
0.001­
0.018
ppm
were
detected
in
milk.
However,
since
the
registrant
has
decreased
the
levels
of
impurity
HCB
in
recent
formulation
to
very
low
levels,
there
is
no
expectation
of
HCB
residues
in
new
formulations.

4.
A)
Highest
dose
for
chickens
was
300
ppm,
the
combined
residues
(
PCNB,
PCA,
PCAT,
PCB,
and
HCB)
were
43.41
ppm
in
fat,
7.08
ppm
in
liver,
0.73
ppm
in
breast
muscle,
12.58
ppm
in
egg
yolk,
and
0.05
ppm
in
egg
whites.
B)
The
PCNB
dose
had
1.5%
HCB
as
a
part
of
formulation.
This
level
is
not
expected
to
be
seen
in
new
formulation
of
PCNB.

5.
Regarding
poultry
and
eggs:

In
fat
from
hens
dosed
at
0.05
ppm,
combined
residues
were
comprised
of
PCNB
(
0.018
ppm),
PCA
(
0.073
ppm),
and
HCB
(
0.066
ppm).
Residues
were
comprised
only
of
HCB
in
liver
(
0.017
ppm)
and
egg
yolk
(
0.014
ppm)
from
hens
dosed
at
0.05
ppm.
ND
=
not
detected
(
level
unspecified).
The
GC/
ECD
method
used
was
validated
to
0.002
ppm
for
each
analyte
(
combined
LOQ
of
0.006
ppm
for
PCNB,
PCA,
and
MPCPS).

6.
ND
=
Non­
detected
residue,
NR
=
not
reported
residue
2.
F.
Codex
Harmonization
As
there
are
no
established
or
proposed
Codex
maximum
residue
limits
(
MRLs)
for
PCNB,
harmonization
of
U.
S.
tolerances
with
Codex
is
not
required.

The
following
Table
lists
all
the
compounds
that
are
associated
with
PCNB
from
its
metabolism
in
plants,
animals,
toxicity
studies
and
water.

Table
2.14:
A
compiled
list
of
all
metabolites
of
PCNB
found
in
plant
metabolism,
animal
metabolism,
rotational
crops,
water,
and
rat
(
toxic)
studies.

#
Matrices
(
MRID
in
parentheses)
Chemical
Name
(
other
names
in
parenthesis)
Structure
1
Potato
(
45307303)
peanut
(
45307302)
peanut
roots
(
41562902)
whole
potato,
callus,
and
peel
(
41562903)
cabbage
leaves
(
41562904)
chicken
fat
(
41692801)
Rotational
crops:
lettuce,
wheat
forage,
wheat
straw
(
44577501)
pentachloronitrobenzene
(
PCNB)
#
Matrices
(
MRID
in
parentheses)
Chemical
Name
(
other
names
in
parenthesis)
Structure
Page
­
28­
NH
2
Cl
Cl
Cl
Cl
Cl
S
CH
3
Cl
5
SCH
2
CHCO
2
H
NHCCH
2
CO
2
H
O
Cl
5
SO
3
H
Cl
4
NH
2
CH
3
Cl
Cl
Cl
Cl
Cl
2
Potato
(
45307303)
peanut
(
45307302)
whole
potato
and
peel
(
41562903)
goat
liver
(
41692805)
goat
kidney
(
41692805)
goat
omental
fat
(
41692805)
goat
renal
fat
(
41692805)
goat
milk
(
41692805)
chicken
fat
(
41692801)
egg
yolk
(
41692801)
Rotational
crops:
turnip
top,
turnip
root,
lettuce,
wheat
forage,
wheat
straw
(
44577501)
pentachloroaniline
(
PCA)

3
Potato
(
45307303)
whole
potato
and
peel
(
41562903)
cabbage
leaves
(
41562904)
chicken
thigh
(
41692801)
egg
yolk
(
41692801)
Rotational
crops:
turnip
root,
lettuce,
wheat
forage,
wheat
straw
(
44577501)
pentachlorothioanisole
(
PCTA)

or,

(
methyl
pentachlorophenyl
sulfide,
MPCPS)

4
Potato
(
45307303)
peanut
(
45307302)
Rotational
crops:
lettuce
(
44577501)
S­(
pentachlorophenyl)
malonylcysteine
(
PCP­
MalCys)

(
C5MaCy)

5
Potato
(
45307303)
peanut
(
45307302)
Rotational
crops:
wheat
forage,
wheat
straw
(
44577501)
aminotetrachlorobenzene
sulfonic
acid
(
AM
TCB
sulfonic
acid)

(
C4SANH)

(
tetrachlorosulfanilic
acid)

6
Potato
(
45307303)
pentachloroanisole
(
PCAN)
#
Matrices
(
MRID
in
parentheses)
Chemical
Name
(
other
names
in
parenthesis)
Structure
Page
­
29­
Cl
5
NHOH
Cl
Cl
Cl
Cl
Cl
SCH
2
CHCOOH
Cl
Cl
Cl
Cl
Cl
NHCOCH
2
CH
2
CHCOOH
NH
2
SCH
2
CHCONHCH
2
COOH
Cl
Cl
Cl
Cl
Cl
NHCOCH
2
CH
2
CHCOOH
NH
2
SCH
2
CHCOOH
Cl
Cl
Cl
Cl
Cl
NHCOCH
2
COCH
3
O
7
Potato
(
45307303)
egg
yolks
(
41692801)
Rotational
crops:
lettuce,
wheat
forage,
wheat
straw
(
44577501)
pentachlorobenzene
(
PCB)

8
Potato
(
45307303)
peanut
root
(
41562902)
whole
potato,
callus,
and
peel
(
41562903)
cabbage
leaves
(
41562904)
goat
liver
(
41692805)
goat
urine
(
41692805)
chicken
kidney
(
41692801)
N­
hydroxypentachloroaniline
(
NOHPCA)

9
Potato
(
45307303)
potato
callus
and
peel
(
41562903)
S­(
pentachlorophenyl)­
 ­
glutamyl
cysteine
(
PCP­
GluCys)

10
Potato
(
45307303)
Rotational
crops:
wheat
forage
(
44577501)
S­(
pentachlorophenyl)
glutathione
(
PCP­
GSH)

11
Potato
(
45307303)
peanut
roots
(
41562902)
whole
potato
callus,
and
peel
(
41592903)
chicken
excreta
(
41692801)
S­(
pentachlorophenyl)
malonylcysteine
monomethyl
ester
(
PCP­
MalCys
ester)
#
Matrices
(
MRID
in
parentheses)
Chemical
Name
(
other
names
in
parenthesis)
Structure
Page
­
30­
NH
2
SOCH
3
Cl
4
NH­
SO
3
H
SCH
3
Cl
4
NO
2
Cl
4
SO
3
H
Cl
4
NO
2
NO
2
Cl
4
SCH
3
SOCH
3
Cl
4
OH
SOCH
3
Cl
4
SH
SO
3
H
Cl
4
SH
12
Potato
(
45307303)
chicken
fat
(
41692801)
goat
kidney
(
41692805)
tetrachloroaniline
methyl
sulfoxide
(
TCA
sulfoxide
isomers)

13
Potato
(
45307303)
tetrachloro­
methylthio­
aniline
sulfamate
(
TC­
MET­
A
sulfamate)

14
Potato
(
45307303)
potato
peel
(
41562903)
tetrachloronitrobenzene
(
TCNB
isomers)

15
Potato
(
45307303)
tetrachloronitrobenzene
sulfonic
acid
(
TCNB
sulfonic
acid
isomers)

16
Potato
(
45307303)
tetrachloronitrothioanisole
(
TCNTA
isomers)

17
Potato
(
45307303)
tetrachlorophenol
methyl
sulfoxide
(
TCP
sulfoxide)

18
Potato
(
45307303)
tetrachlorothiophenol
methyl
sulfoxide
(
TCTP
sulfoxide)

19
Potato
(
45307303)
tetrachlorothiophenol
sulfonic
acid
(
TCTP
sulfonic
acid)
#
Matrices
(
MRID
in
parentheses)
Chemical
Name
(
other
names
in
parenthesis)
Structure
Page
­
31­
NH
2
Cl
4
NH
2
N
H
SO
3
H
Cl
4
NH
2
NH
2
Cl
4
OH
NH
2
Cl
4
NHOH
NHOH
Cl
4
OH
NHOH
Cl
4
SCH
3
SCH
2
CHCONHCH
2
COOH
NHCOCH
2
CH
2
CHCOOH
NH
2
Cl
4
SOCH
3
20
Potato
(
45307303)
aminotetrachloroaniline
(
AM
TCA
isomers)

21
Potato
(
45307303)
aminotetrachloroaniline
sulfamate
(
AM
TCA
sulfamate)

22
Potato
(
45307303)
hydroxytetrachloroaniline
(
OH
TCA)

23
Potato
(
45307303)
N­
hydroxyamino­
tetrachloroaniline
(
NOHAM
TCA)

24
Potato
(
45307303)
N­
hydroxyamino­
tetrachlorophenol
(
NOHAM
TCP)

25
Potato
(
45307303)
N­
hydroxyaminotetrachlorothioanisole
(
NOHAM
TCTA
isomers)

26
Potato
(
45307303)
S­(
tetrachloro­
methyl
sulfoxyphenyl
glutathione
(
TC­
MES­
PGSH
#
Matrices
(
MRID
in
parentheses)
Chemical
Name
(
other
names
in
parenthesis)
Structure
Page
­
32­
SCH
2
CHCOOH
NHCOCH
2
COOH
Cl
4
SOCH
3
SCH
2
CHCONHCH
2
COOH
NHCOCH
2
CH
2
CHCOOH
NH
2
Cl
4
NO
2
SCH
2
CHCOOH
NHCOCH
2
COOH
Cl
4
NO
2
Cl
4
SCH
2
CHCONHCH
2
COOH
NHCOCH
2
CH
2
CHCOOH
NH
2
2
Cl
4
SCH
2
COOH
2
27
Potato
(
45307303)
S­(
tetrachloro­
methyl
sulfoxyphenyl
malonylcysteine
(
TC­
MESP
MalCys)

28
Potato
(
45307303)
peanut
(
45307302)
S­(
tetrachloronitrophenyl)
glutathione
(
TCNP­
GSH)

29
Potato
(
45307303)
Peanut
(
45307302)
S­(
tetrachloronitrophenyl)
malonylcysteine
(
TCNP­
MalCys)

30
Potato
(
45307303)
S,
S

­
(
tetrachlorophenyl)
diglutathione
(
TCP­
diGSH)

31
Potato
(
45307303)
S,
S

­
(
tetrachlorophenyl)
dithioacetate
(
TCP­
dithioacetate)
#
Matrices
(
MRID
in
parentheses)
Chemical
Name
(
other
names
in
parenthesis)
Structure
Page
­
33­
SCH
2
CHCOOH
Cl
4
SCH
2
CHCOOH
NHCOCH
2
CH
2
CHCOOH
NH
2
NH
2
SCH
2
CHCOOH
Cl
4
SCH
2
CHCOOH
NHCOCH
2
CH
2
CHCOOH
OH
NHCOCH
3
NH
2
NO
2
SOCH
3
Cl
3
NHOH
Cl
3
SCH
3
2
NHOH
OMe
NH
2
Cl
3
32
Potato
(
45307303)
S,
S

­
(
tetrachlorophenyl)­
 ­
glutamyl
cysteine­
cysteine
(
TCP­
GluCys­
Cys)

33
Potato
(
45307303)
acetyl
S,
S

­
(
tetrachlorophenyl)
cysteine­
cysteinyl
 ­
hydroxyglutarate
(
AC
TCP­
Cys­
CysHOG)

34
Potato
(
45307303)
trichloronitroaniline
methyl
sulfoxide
(
RCNA
sulfoxide)

35
Potato
(
45307303)
N­
hydroxy­
trichloro­
dimethylthioaniline
(
NOH
RC­
diMET­
A)

36
Potato
(
45307303)
N­
hydroxyamino­
trichloro­
methoxyaniline
(
NOHAM
RC­
OME­
A)
#
Matrices
(
MRID
in
parentheses)
Chemical
Name
(
other
names
in
parenthesis)
Structure
Page
­
34­
Cl
3
SCH
2
CHCOOH
NHCOCH
2
CH
2
CHCOOH
NH
2
NH
2
SCH
2
CHCOOH
NH
2
Cl
3
SCH
2
CHCOOH
NHCOCH
2
COOH
SCH
2
COOH
NO
2
Cl
3
SCH
2
CCOOH
NHCOCH
2
CH
2
CHCOOH
NH
2
SCH
2
CHCOOH
SCH
3
NH
2
SCH
2
CHCOOH
Cl
4
NH
2
NHCOCH
2
COOH
37
Potato
(
45307303)
S,
S

­
(
trichloroanilino)­
 ­
glutamylcysteine­
cysteine
(
RCAGluCys
Cys)

38
peanut
(
45307302)
N­
malonyl­
S­
(
tetrachloroaminophenyl)­
cysteine
39
Potato
(
45307303)
S,
S

­
(
trichloronitrophenyl)
malonyl
cysteine­
thioacetate
(
RCNP­
MalCysthioacetate

40
Potato
(
45307303)
S,
S

­
(
trichlorothioanisole)­
 ­
glutamyl
cysteine­
cysteine
(
RCTAGluCys
Cys)
#
Matrices
(
MRID
in
parentheses)
Chemical
Name
(
other
names
in
parenthesis)
Structure
Page
­
35­
Cl
3
SCH
2
CHCONHCH
2
COOH
NHCOCH
2
CH
2
CHCOOH
NHCOCH
3
SCH
2
CHCOOH
OMe
NHCOCH
3
Cl
3
SCH
3
SCH
2
CHCOOH
NHCOCH
2
CH
2
CHCOOH
NHCOCH
3
2
41
Potato
(
45307303)
diacetyl
S,
S

­
(
trichloro­
anisole)
glutathione­
cysteine
(
diAC
RCANGSH
Cys)

42
Potato
(
45307303)
diacetyl
S,
S

­
(
trichloro­
thioanisole)
diglutathione
(
diAC
RCTAdiGluCys

43
Potato
peel
(
41562903)
Tetrachloronitrophenol
(
TCNP)

44
potato
peel
(
41562903)
Tetrachlorophenol
(
TCP)

45
peanut
roots
(
41562902)
Tetrachloroaniline
(
TCA)

46
goat
urine
(
41692805)
Pentachloroaniline
sulfamate
#
Matrices
(
MRID
in
parentheses)
Chemical
Name
(
other
names
in
parenthesis)
Structure
Page
­
36­
SO
3
H
Cl
5
47
Rotational
crops:
turnip
top,
turnip
root,
lettuce,
wheat
forage,
wheat
straw
(
44577501)
C5SA
pentachlorobenzenesulfonic
acid
48
goat
liver
(
41692805)
goat
kidney
(
41692805)
chicken
excreta
(
41692801)
chicken
liver
(
41692801)
egg
yolk
(
41692801)
Pentachlorothiophenol
(
PCTP)

49
cabbage
leaves
(
41562904)
chicken
liver
(
41692801)
Rotational
crops:
turnip
top,
turnip
root,
wheat
forage,
wheat
straw
(
44577501)
Pentachlorothioanisole
sulfoxide
(
PCTA
sulfoxide)
(
PCTASO)
(
C5MX)

50
goat
kidney
(
41692805)
chicken
fat
(
41692801)
Tetrachlorothioanisole
(
TCTA)

51
cabbage
leaves
(
41562904)
Rotational
crops:
wheat
straw
(
44577501)
Tetrachlorophenyl
methyl
sulfoxide
(
TCPM
sulfoxide)
(
C4MX)

52
cabbage
leaves
(
41562904)
chicken
kidney
(
41692801)
chicken
thigh
(
41692801)
Rotational
Crops:
turnip
top,
turnip
root,
lettuce
(
44577501)
Tetrachlorophenyl
methyl
sulfone
(
TCPM
sulfone)
(
TCTASOO)
(
C4MS)
(
TCP
methyl
sulfone)
#
Matrices
(
MRID
in
parentheses)
Chemical
Name
(
other
names
in
parenthesis)
Structure
Page
­
37­
53
cabbage
(
41562904)
Rotational
crops:
turnip
top,
turnip
root,
lettuce,
wheat
forage,
wheat
straw
(
44577501)
Trichlorophenyl
methyl
sulfone
(
RCPM
sulfone)
(
C3MS)

54
cabbage
leaves
(
41562904)
Trichlorophenol
methyl
sulfone
(
RCHM
sulfone)

55
goat
liver
(
41692805)
goat
kidney
(
41692805)
goat
urine
(
41692805)
Tetrachloro
(
methylthio)
thiophenol
(
TCTP
S­
Met)

56
goat
liver
(
41692805)
Pentachlorothiophenol
dimer
(
PCTP
dimer)

57
potato
callus
and
peel
(
41562903)
goat
urine
(
41692805)
Pentachlorothiophenyl
conjugate
(
PCTP­
X)
#
Matrices
(
MRID
in
parentheses)
Chemical
Name
(
other
names
in
parenthesis)
Structure
Page
­
38­
58
chicken
excreta
(
41692801)
chicken
kidney
(
41692801)
chicken
liver
(
41692801)
chicken
thigh
(
41692801)
S­(
pentachlorophenyl)
thioacetate
59
chicken
excreta
(
41692801)
S­(
pentachlorophenyl)
thiopyruvate
60
whole
potato,
callus,
and
peel
(
41562903)
chicken
kidney
(
41692801)
S­(
pentachlorophenyl)
cysteine
(
PCP­
Cys)

61
peanut
roots
(
41562902)
S­[(
methylthio)
tetrachlorophenyl]­
2­
thioacetic
acid
(
MTCP­
TAA)

62
potato
callus
and
peel
(
41562903)
Pentachlorothiophenyl
glycoside
(
PCTP­
Gly)
#
Matrices
(
MRID
in
parentheses)
Chemical
Name
(
other
names
in
parenthesis)
Structure
Page
­
39­
SO
3
H
Cl
4
SO
3
H
Cl
3
SO
3
H
Cl
2
OH
Cl
5
63
potato
callus
and
peel
(
41562903)
Pentachlorophenol
glycoside
(
PCPGly

64
goat
liver
(
41692805)
goat
kidney
(
41692805)
N­(
pentachloroaniline)
glucuronide
(
PCA­
Gluc)

65
Rotational
Crops:
turnip
top,
turnip
root
(
44577501)
Pentachlorophenol
(
PCP)

66
Rotational
crops:
turnip
top,
turnip
root,
lettuce,
wheat
forage,
wheat
straw
(
44577501)
tetrachlorobenzenesulfonic
acid
(
C4SA)

67
Rotational
crops:
turnip
top,
turnip
root,
wheat
forage,
wheat
straw
(
44577501)
C3SA
trichlorobenzenesulfonic
acid
68
Rotational
crops:
turnip
top,
turnip
root,
wheat
forage
(
44577501)
C2SA
dichlorobenzenesulfonic
acid
#
Matrices
(
MRID
in
parentheses)
Chemical
Name
(
other
names
in
parenthesis)
Structure
Page
­
40­
S
CH
3
O
SO
3
H
Cl
4
S
CH
3
O
Cl
3
SO
3
H
S
CH
3
O
O
Cl
4
SO
3
H
S
CH
3
O
O
SO
3
H
Cl
3
S
CH
3
O
O
CL
2
SO
3
H
SO
3
H
Cl
3
NH
2
69
Rotational
crops:
wheat
forage,
wheat
straw
(
44577501)
C4MXSA
tetrachlorosulfophenyl
methyl
sulfoxide
(
tetrachlorothioanisole
sulfoxide,
sulfonic
acid)

70
Rotational
crops:
wheat
straw
(
44577501)
C3MXSA
trichlorosulfophenyl
methyl
sulfoxide
(
trichlorothioanisole
sulfoxide,
sulfonic
acid)

71
Rotational
crops:
wheat
straw
(
44577501)
C4MSSA
tetrachlorosulfophenyl
methyl
sulfone
(
tetrachlorothioanisole
sulfone,
sulfonic
acid)

72
Rotational
crops:
turnip
top,
turnip
root,
wheat
forage,
wheat
straw
(
44577501)
C3MSSA
trichlorosulfophenyl
methyl
sulfone
(
trichlorothioanisole
sulfone,
sulfonic
acid)

73
Rotational
crops:
wheat
straw
(
44577501)
C2MSSA
dichlorosulfophenyl
methyl
sulfone
(
dichlorothioanisole,
sulfonic
acid)

74
Rotational
crops:
wheat
forage,
wheat
straw
(
44577501)
C3SANH
trichlorosulfanilic
acid
#
Matrices
(
MRID
in
parentheses)
Chemical
Name
(
other
names
in
parenthesis)
Structure
Page
­
41­
SO
3
H
Cl
3
OH
SCH
2
CHCH
3
Cl
4
HNCCH
3
O
SCH
2
CHCO
2
H
SCH
2
CHCO
2
H
Cl
4
NHCOH
NHCOCH
2
CO
2
H
SO
3­
hexose
Cl
5
SCH
2
CHCO
2
H
SCH
2
CHCO
2
H
Cl
4
NH
2
NH
2
SCH
2
CHCO
2
H
SCH
2
CHCO
2
H
Cl
4
NHCOH
NH
2
75
Rotational
crops:
wheat
forage
(
44577501)
C3SAOH
hydroxy­
trichlorobenzene
sulfonic
acid
(
trichloro­
hydroxybenzene
sulfonic
acid)

76
Rotational
crops:
lettuce,
wheat
forage,
wheat
straw
(
44577501)
C4MeAcCy
N­{
1­
methyl­
2[(
tetrachlorophenyl)­
thio]
ethyl}
acetamide
(
tetrachlorophenyl
methyl
cysteine)

77
Rotational
crops:
lettuce,
wheat
forage
(
44577501)
C4MaCyFCy
S­(
tetrachlorophenyl)­
Nmalonylcysteine
S'­
formylcysteine
78
Rotational
crops:
wheat
forage
(
44577501)
C5SAHx
b
pentachlorobenzenesulfonic
acid
hexose
ester
79
Rotational
crops:
wheat
forage
(
44577501)
C4CyCy
S,
S'­
tetrachlorophenyl
dicysteine
80
Rotational
crops:
lettuce
(
44577501)
C4CyFCy
S­(
tetrachlorophenyl)­
cysteine­
S'­
formylcysteine
#
Matrices
(
MRID
in
parentheses)
Chemical
Name
(
other
names
in
parenthesis)
Structure
Page
­
42­
S
O
O
CH
3
SCH
2
CHCO
2
H
Cl
3
NHCCH
2
CO
2
H
O
S
O
O
CH
3
SCH
2
CHCO
2
H
Cl
2
NHCCH
2
CO
2
H
O
Cl
Cl
Cl
Cl
N
Cl
O
H
gluc
S
O
O
CH
3
Cl
5
81
Rotational
crops:
turnip
root,
lettuce
(
44577501)
C3MSMaCy
N­
malonyl­
S­
trichloro­
(
methylsulfonophenyl)­
L­
cysteine
S­(
trichlorophenyl
methyl
sulfone)­
malonyl
cysteine
82
Rotational
crops:
turnip
top,
turnip
root
(
44577501)
C2MSMaCy
N­
malonyl­
S­
dichloro­
(
methylsulfonophenyl)­
L­
cysteine
S­(
dichlorophenyl
methyl
sulfone)­
malonyl
cysteine
83
Goat
liver
(
41692805)
glucuronide
of
NOHPCA
(
NOHPCA­
Gluc)

84
Water
(
minor
degradate)
pentachlorothioanisole
sulfone
(
PCTASO2)
­
43­
3.
Toxicology
Section
a.
Toxicological
Endpoints:

Since
the
HIARC
has
completed
it
review,
a
copy
of
the
committee
report
is
appended.
A
summary
of
toxicology
endpoints
are
presented
below.

Table
3.1:
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
Table
3.1:
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
­
44­
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
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.
­
45­
b.
Rat
Metabolism
Although
the
HIARC
has
identified
the
rat
metabolism
study
as
a
significant
data
gap
and
a
new
special
study
has
been
required,
several
non­
guideline
and
unacceptable
(
but
potentially
upgradable)
rat
metabolism
studies
have
been
submitted
to
the
Agency
and
data
from
these
are
presented
below.
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
by
any
means
adequately
quantitated
at
this
time.
On
the
other
hand,
we
know
that
PCNB
does
not
bioaccumulate
at
the
scale
of
say
a
DDT
and
does
not
present
that
level
of
concern.
Most
of
what
we
currently
know
has
been
gained
from
the
literature
as
presented
under
Section
2
below.

1.
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.
­
46­
In
another
special
(
non­
guideline)
mechanistic
metabolism
study
(
MRID
44096601),
the
effect
of
pentachloronitrobenzene
on
thyroid
uptake
of
125Iodine
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
ug
[
125I]/
kg
body
weight
in
1
ml/
kg
0.9%
saline
(
thyroid
uptake
studies)
and
6/
dose
were
injected
iv
with
1ug
[
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
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.

2.
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
methylmercapto­
tetrachlorobenzene
(
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,
tetrachloroaminophenyl­
methylsulfoxide,
tetrachlorophenylmethyl
sulfoxide,
and
bis­
methylmercaptoaminotri­
chlorobenzene
and
five
other
unidentified
metabolites
were
also
noted
which
had
not
been
detected
after
the
single
low
dose
exposure.
­
47­
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
sulfur­
containing
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.

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
(
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%,
­
48­
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
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)­
Nacetylcysteine
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
sulfur­
containing
metabolites
produced
by
reaction
with
glutathione,
catalyzed
by
glutathione
S­
transferase,
(
2)
to
non
sulfur
containing
metabolites
by
denitration
to
pentachlorpphenol,
and
(
3)
by
reduction
to
pentachloroaniline.

The
table
below
presents
residues
of
potential
toxicological
concern.
Data
are
not
available
which
would
suggest
that
toxicity
of
the
principle
metabolite
residues
listed
in
this
table
are
of
greater
toxicological
concern
than
PCNB
itself.
However,
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
on
the
basis
of
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
might
be
overlooked
at
this
time.
In
addition,
the
metabolites
identified
in
this
table
were
identified
strictly
from
tables
included
in
a
draft
memo
that
did
not
include
the
complete
PCNB
tolerance
expression
(
including
all
potential
secondary
residues)
for
the
existing
RACs
(
See
page
4,
Section
1.(
a)
of
the
MARC
SOP
of
11/
4/
02).
Hence,
for
the
above
listed
reasons,
it
is
not
possible
to
confirm
inclusion
of
all
metabolites
of
toxicological
concern
at
this
time.
­
49­
Table
3.2:
Residues
of
Toxicological
Concern
Raw
Agricultural
Commodity
Residues
of
Potential
Toxicological
Concern
Corresponding
#

Peanut
Nutmeat
and
Hay
PCNB,
S­(
pentachlorophenyl)
malonylcysteine
(
PCPMalCys
N­
malonyl­
S­(
tetrachloroaminophenyl)­
cysteine
1,
4,
38
Potato
PCNB,
pentachloroaniline
(
PCA),
pentachlorothioanisole
(
PCTA),
N­
malonyl­
S­(
tetrachloroaminophenyl)­
cysteine
1,
2,
3,
38
Cabbage
(
NOTE:
residue
data
is
very
limited
and
incomplete
in
table
2,
pg.
18)
ppm
of
residue
not
calculated
since
recoveries
not
provided.)
Tetrachlorophenyl
methyl
sulfoxide
(
TCPM
sulfoxide),
Tetrachlorophenyl
methyl
sulfone
(
TCPM
sulfone)
Unable
to
determine
if
other
residues
of
concern
51,
52
Rotational
crops:
Turnip
roots
and
tops
pentachloroaniline
(
PCA),
pentachlorothioanisole
(
PCTA)
2,
3
Lettuce
PCNB,
pentachloroaniline
(
PCA)
1,
2
Wheat
forage1
PCNB,
pentachloroaniline
(
PCA),
tetrachlorobenzenesulfonic
acid
(
C4SA)
(
no
quantitative
data
provided
as
per
footnote
c)
1,
2,
66
Wheat
straw1
PCNB,
trichlorobenzene
sulfonic
acid
(
C3SA),
tetrachlorobenzenesulfonic
acid
(
C4SA),
dichlorosulfophenyl
methyl
sulfone
(
C2MSSA)
trichlorosulfophenyl
methyl
sulfone
(
C3MSSA)
1,
67,
66,
73,
72
­
50­
Goat
milk
and
tissues
tissues
(
liver,
Muscle
Kidney)
pentachloroaniline
(
PCA),
N­
glucuronide
of
PCA
(
PCA
­
Gluc),
pentachlorothiophenol
(
PCTP),
tetrachlorothioanisole
(
TCTA),
glucuronide
of
NOHPCA
(
NOHPCA­
Gluc),
N­
hydroxypentachloroaniline
(
NOHPCA)
2,
64,
48,
50,
83,
8
Chicken
(
liver,
fat,
egg
yolk,
thigh
muscle)
PCNB,
pentachloroaniline
(
PCA),
pentachlorothioanisole
sulfoxide
(
PCTA
sulfoxide),
pentachlorothioanisole
(
PCTA),
pentachlorothiophenol
(
PCTP),
tetrachloroaniline
methyl
sulfoxide
(
TCA
sulfoxide),
tetrachlorophenyl
methyl
sulfone
(
TCP
methyl
sulfone),
pentachlorobenzene
(
PCB)
1,
2,
49,
3,
48,
12,
52,
7
1
Secondary
residues
for
meat,
milk,
eggs
etc
not
specified
and
data
for
wheat
grain
not
provided.

LITERATURE
CITED
Kogel,
W.,
Muller
W.
F.,
Coulston
F.
and
Korte
F.
(
1979a)
Biotransformation
of
Pentachloronitrobenzene­
14C
in
Rhesus
Monkeys
After
Single
and
Chronic
Oral
Administration,
Institut
fur
Chemie
der
Technischen
Universitut
Munchen
D­
8050
Freising­
Weihenstephan,
Germany
and
Gesellschaft
fur
Strahlen­
und
Umweltforschung
mbH
Munchen,
Institut
fur
Okologische
Chemie,
International
Center
of
Environmental
Safety,
Chemosphere,
No.
2,
pp97­
105
1979.

Kogel,
W.,
Wolfgang
F.,
Muller
W.
F.,
Coulston
F.
and
Korte
F.
(
1979b)
Fate
and
Effects
of
Pentachloronitrobenzene
in
Rhesus
Monkeys,
Gesellschaft
fur
Strahlen­
und
Umweltforschung
mbH
Munchen,
Institut
fur
Okologische
Chemie,
International
Center
of
Environmental
Safety,
J.
Agric.
Food
Chem.
,
Vol.
27,
No.
6.
1979.

Kuchar,
E.
J.,
Geenty
F.
O.,
Griffith
W.
P.,
and
Thomas
R.
J.
(
1969)
Analytical
Studies
of
Metabolism
of
Terrachlor
in
Beagel
Dogs,
Rats,
and
Plants,
Chemicals
Division,
Olin
Mathieson
Chemical
Corp,
New
Haven
Conn
with
in­
life
feeding
conducted
at
the
Medical
College
of
Virginia,
J.
Agr.
Food
Chem.
,
Wol.
17,
No.
6,
Nov­
Dec.
1969.

O'Grodnick,
J.
S.,
Adamovics
J.
A.,
Blake
S.
H.
and
Wedig
J.,
(
1981)
The
Metabolic
Fate
of
14C­
labeled
pentachloronitrobenzene
in
Osborne­
Mendell
Rats,
Chemosphere,
10,
67­
72.
­
51­
4.
RESIDUES
IN
WATER
SECTION
(
prepared
by
EFED)

In
order
to
determine
which
degradates,
if
any,
should
be
included
in
the
human
drinking
water
exposure
assessment,
please
answer
the
following
questions
to
the
best
of
your
ability
and
create
tables
using
the
formats
provided
below.

5.
What
is
the
name
of
the
pesticide
and
what
uses
are
being
considered
in
this
assessment?

The
pesticide
is
pentachloronitrobenzene
(
PCNB),
a
contact
fungicide
being
considered
for
use
on
a
variety
of
crops
including
beets,
bulbs,
cereals,
coffee,
cole
crops,
cotton,
cucurbits,
ginseng,
horticultural
crops,
fruits,
jute,
legumes,
lettuce,
peanuts,
potatoes,
seed
treatments,
solanaceous
crops,
soybeans,
strawberries,
sugarbeets,
tobacco,
and
turf.

2.
Briefly
describe
the
environmental
persistence
of
the
pesticide.
What
are
expected
to
be
the
major
routes
of
degradation
in
the
environment
(
e.
g.
aerobic
soil
metabolism,
soil
photolysis,
etc)?
What
is
the
expected
persistence
in
soil
and
water
(
provide
available
half
lives)?

PCNB
is
expected
to
be
persistent
in
the
environment.
Based
on
guideline
study
data,
the
major
route
of
degradation
in
the
environment
is
expected
to
be
photodegradation
in
water;
microbially
mediated
metabolism
is
also
expected
to
occur,
with
more
rapid
degradation
in
anaerobic
environments
relative
to
aerobic
ones.
Degradation
half­
lives
for
the
compound
ranged
from
approximately
1
to
5
days
for
photodegradation
in
water,
were
a
range
of
77
to
189
days
for
aerobic
soil
metabolism,
and
were
a
range
of
9
to
<
30
days
for
anaerobic
soil
metabolism.
PCNB
is
stable
to
hydrolysis
and
to
photodegradation
on
soil.
Aquatic
metabolism
data
are
not
available.
Volatilization
of
the
compound
is
an
expected
route
of
dissipation
in
the
environment
and
was
observed
in
a
field
volatility
study;
however,
incorporation
of
PCNB
into
the
soil
should
minimize
the
losses
from
soil
due
to
volatilization.
Dissipation
half­
lives
for
PCNB
in
the
field
(
terrestrial)
varied
from
35
to
324
days,
with
a
mean
of
130
days
(
based
on
data
from
six
studies
from
which
valid
dissipation
half­
lives
could
be
determined).

3.
Briefly
describe
the
expected
mobility
of
the
pesticide.
Is
the
pesticide
volatile?
Does
the
pesticide
bind
soil
or
sediment
strongly
(
please
provide
K
d
or
K
oc)?

PCNB
is
expected
to
be
slightly
mobile
to
immobile
in
most
soils,
but
may
be
moderately
mobile
in
some
coarse­
textured
soils
that
are
low
in
organic
matter
content.
Measured
soil­
water
adsorption
coefficient
values
(
K
d)
in
four
soils
were
7.3
 
52;
the
corresponding
organic
matter
partitioning
coefficients
(
K
oc)
were
1521
 
4326.
In
a
second
study,
measured
soil­
water
adsorption
coefficient
values
(
K
d)
in
four
soils
were
64
 
1750;
the
corresponding
organic
matter
partitioning
coefficients
(
K
oc)
were
6966
 
150,682.
PCNB
is
moderately
volatile,
with
measured
laboratory
(
soil)
volatility
values
of
62.2
x
10­
3
 
171
x
10­
3

g/
cm2/
hr
and
4.31
x
10­
3
 
6.08
x
10­
3

g/
cm2/
hr
in
two
separate
studies.
In
the
first
study,
80%
of
the
applied
volatilized
from
soil
by
7
days;
in
the
second
study,
27
 
28%
of
the
applied
volatilized
from
soil
by
the
end
of
the
15­
day
study.
In
both
laboratory
volatility
studies,
the
maximum
volatilization
occurred
in
the
initial
24
­
52­
hours
after
application.
In
the
field,
PCNB
was
observed
to
volatilize
from
unvegetated
soil,
with
the
majority
(
65%)
of
the
volatilization
occurring
in
the
initial
two
days
of
the
13­
day
study.
4.
Briefly
describe
the
degradates
of
the
pesticide.
Identify
major
and
minor
degradates.
Provide
available
information
degradate
stability
and
mobility.

The
major
degradates
of
PCNB
are
pentachloroaniline
(
PCA),
pentachloroanisole
(
PCTA),
pentachlorobenzene
(
PCB),
and
the
manufacturing
contaminant
hexachlorobenzene
(
HCB).
Minor
degradates
identified
in
the
fate
studies
were
pentachlorothioanisole
sulfoxide
(
PCTASO),
pentachlorothioanisole
sulfone
(
PCTASO
2),
pentachlorophenol
(
PCP)
and
tetrachlorothioanisole
sulfone
(
TCTASOO).
The
degradates
PCA
and
PCTA
are
expected
to
be
immobile
in
soil,
based
on
respective
Kd
ranges
of
37
 
117
and
205
 
503
as
determined
in
guideline
mobility
(
laboratory)
studies
each
conducted
on
four
soils;
however,
in
field
studies,
PCA
was
detected
in
the
6
 
12"
layer
in
several
studies
(
although
it
is
possible
that
the
degradate
may
have
been
formed
there).
Laboratory
mobility
study
data
are
not
available
for
PCB
or
HCB.
Based
on
the
results
of
field
studies,
HCB
is
not
expected
to
be
mobile
in
the
soil,
but
PCB
was
detected
below
the
surface
layer
(
generally
at
6­
12")
in
several
studies.
However,
as
with
PCA,
it
is
possible
that
the
degradate
may
have
been
formed
there
during
the
study.

Based
on
laboratory
and
field
data,
the
degradates
PCTA,
PCA,
PCB,
PCTASO
and
PCTASO
2,
are
likely
to
be
persistent
in
the
environment.
While
measured
half­
lives
are
not
available
for
the
compounds,
data
from
the
laboratory
aerobic
soil
metabolism
studies
and
the
terrestrial
field
dissipation
studies
indicate
that
the
compounds
degrade
very
slowly,
and
may
be
considered
to
be
essentially
stable,
based
on
accumulation
patterns.
Maximum
concentrations
of
the
compounds
generally
occurred
(
in
both
the
lab
and
field
studies)
relatively
late
in
the
study
period.
However,
as
with
parent
PCNB,
the
degradate
PCTA
appears
to
degrade
more
rapidly
under
anaerobic
conditions
and,
therefore,
may
not
be
as
persistent
under
such
conditions.

5.
If
possible,
describe
the
effects
of
water
treatment
on
the
pesticide
and
degradates
that
may
reach
drinking
water
sources.

There
is
no
information
currently
available
on
the
effects
of
water
treatment
on
the
pesticide
and
its
degradates
that
may
reach
drinking
water
sources.

6.
Provide
any
other
pertinent
information
(
e.
g.
monitoring
data).

NAWQA
monitoring
data
are
not
available.
Based
on
information
contained
in
EPA
Pesticides
in
Ground
Water
Database,
A
Compilation
of
Monitoring
Studies:
1971­
1991,
National
Summary
,
PCNB
is
not
found
in
groundwater
at
significant
levels
or
frequencies.
In
sampling
of
1708
wells,
only
three
detections
(
all
below
the
established
maximum
contaminant
levle)
of
PCNB
occurred,
at
a
range
of
0.008
 
0.275
µ
g/
L.
Updated
monitoring
data
from
STORET
are
not
available;
it
is
no
longer
possible
to
query
either
the
historical
database
(
in
the
Legacy
Data
Center)
or
the
new
database
(
Modernized
STORET)
to
obtain
all
detections
of
a
specific
compound.

7.
Complete
the
table
below
for
the
pesticide
and
degradates.
­
53­
NO2
Cl
Cl
Cl
Cl
Cl
Table
1.
Parent
and
degradate
information
from
guideline
studies.

Chemical
Name
and
Structure
Concentration
or
Percentage
of
Applied
Dose
MRID
Study
Type
Reported
Values/
Notes
Maximum
Day
Parent:
PCNB
(
pentachloronitrobenzene)
NA
NA
40865301
40972601
hydrolysis
stable
at
pH
5,
7
and
9
NA
NA
42336201
aqueous
photolysis
t
½
=
27
hr
NA
NA
42606201
42606202
aqueous
photolysis
t
½
=
approx.
5
days
NA
NA
41004801
41713201
soil
photolysis
t
½
=
80
days
NA
NA
42911902
aerobic
soil
metabolism
t
½
=
189
days
NA
NA
41384501
41713202
42112801
aerobic
soil
metabolism
t
½
=
77
days
NA
NA
42094401
41203602
anaerobic
soil
metabolism
t
½
=
<
30
days
NA
NA
41384301
41686001
41713201
42112802
anaerobic
soil
metabolism
t
½
=
9
days
NA
NA
41648201
adsorption/
desorption
Kd
=
7.3
 
52
in
4
soils
NA
NA
00114168
adsorption/
desorption
Kd
=
64
 
1750
in
4
soils
NA
NA
41178001
laboratory
volatility
0.0622
 
0.107
µ
g/
cm2/
hr;
80%
of
applied
volatilized
by
7
days
0.00431
 
0.00
608
µ
g/
cm2/
hr
NA
42507401
laboratory
volatility
maximum
volatiliz.
occurred
in
initial
24
hours;
parent
applied
at
10
ppm
NA
NA
43751101
field
volatility
total
volatilized
PCNB
=
21.5
 
67.5
ng/
L
(
day
0);
1.40
 
1.56
ng/
L
(
day
13)
Chemical
Name
and
Structure
Concentration
or
Percentage
of
Applied
Dose
MRID
Study
Type
Reported
Values/
Notes
Maximum
Day
­
54­
NA
NA
41721401
terrestrial
field
dissipation1
t
½
=
324
days
(
potatoes;
MN;
loam
soil;
incorp.
4­
6");
parent
applied
at
25
lb
ai/
A
(
initially
9.2
ppm)

NA
NA
43887403
terrestrial
field
dissipation
DT50
=
bet.
30
 
60
days
(
CA;
sandy
loam
soil;
turf
plot);
DT50
=
<
1day
(
in
turf);
parent
applied
at
36
lb
ai/
A
(
max.
of
9.5
ppm
on
day
14)

NA
NA
42094403
42094404
41210501
terrestrial
field
dissipation
t
½
=
35
days
(
CA;
sandy
loam
soil;
turf
plot);
parent
applied
at
32.7
lb
ai/
A
(
initially
8.6
ppm)

NA
NA
42485901
41216401
terrestrial
field
dissipation
t
½
=
128
days
(
CA;
loamy
sand
soil;
broccoli);
parent
applied
at
30
lb
ai/
A
(
parent
max.
of
6.9
ppm
at
day
1)

NA
NA
42485902
41216402
terrestrial
field
dissipation
t
½
=
193
days
(
MN;
sandy
loam
soil;
potatoes);
parent
applied
at
25
lb
ai/
A
(
parent
max.
of
5.8
ppm
at
day
14)

NA
NA
43061501
terrestrial
field
dissipation
t
½
=
57
days
(
GA;
loamy
sand
soil;
bare
ground);
parent
applied
at
10
lb
ai/
A
(
initially
59.5
ppm)

NA
NA
43179301
40580202
bioaccumulation
in
fish
BFC's
=
370x
(
edible),
1800x
(
viscera),
and
960x
(
whole
fish);
PCNB
metabolizes
to
cystinyl
conjugate
in
<
2
hours
Chemical
Name
and
Structure
Concentration
or
Percentage
of
Applied
Dose
MRID
Study
Type
Reported
Values/
Notes
Maximum
Day
­
55­
NH2
Cl
Cl
Cl
Cl
Cl
NA
NA
41200001
41951701
bioaccumulation
in
fish
BFC's
=
400x
(
edible),
1800x
(
viscera),
and
1100x
(
whole
fish)

Degradate
1:
pentachloroaniline
(
PCA)
0.91
ppm
120,
180
42911902
aerobic
soil
metabolism
appears
to
be
relatively
stable
(
0.80
ppm
still
present
at
day
365);
parent
applied
at
10
ppm
1.35
ppm
122
41713202
42112801
41384501
aerobic
soil
metabolism
still
present
at
1.04
ppm
at
365
days;
parent
applied
at
10.5
ppm
87%
of
recovered
radioactivity
in
soil;
28%
of
recovered
in
flood
water
60
90
42094401
41203602
anaerobic
soil
metabolism
still
present
in
soil
at
84.1%
at
90
days;
was
present
at
only
23.4%
at
end
of
aerobic
period
(
day
30)
and
increased
to
87%
after
anaerobic
conditions
induced;
parent
was
9.65
ppm
at
start
of
anaerobic
period
70.3%
of
applied
in
soil
60
42112802
41384301
41686001
41713203
anaerobic
soil
metabolism
still
present
at
66.5%
of
applied
at
day
90;
parent
was
applied
at
10.5
ppm
NA
NA
43751101
field
volatility
3.32
 
9.61
ng/
L
(
day
0)
0.0
 
0.41
ng/
L
(
day
13)

NA
NA
43500501
adsorption/
desorption
Kd
=
37
 
117
in
4
soils
1.1
ppm
515
41721401
terrestrial
field
dissipation
incorp.
4­
6";
potatoes;
MN;
loam
soil;
parent
applied
at
25
lb
ai/
A
(
initially
9.2
ppm)
Chemical
Name
and
Structure
Concentration
or
Percentage
of
Applied
Dose
MRID
Study
Type
Reported
Values/
Notes
Maximum
Day
­
56­
0.77
ppm
241
43887401
terrestrial
field
dissipation
incorp.
4";
bare
ground;
CA;
loamy
sand
soil;
parent
applied
at
212
lb
ai/
A
(
range
of
89­
245
ppm
at
time
0)

2.5
ppm
269
43887402
terrestrial
field
dissipation
incorp.
4";
bare
ground;
GA;
sandy
loam
soil;
parent
applied
at
232
lb
ai/
A
(
range
of
139­
144
ppm
at
days
0­
30)

0.45
ppm
soil;
ND
in
turf
149
43887403
terrestrial
field
dissipation
CA;
sandy
loam
soil;
turf
plot;
parent
applied
at
36
lb
ai/
A
(
max.
of
9.5
ppm
on
day
14)

0.430
ppm
242
42094403
42094404
41210501
terrestrial
field
dissipation
CA;
sandy
loam
soil;
turf
plot;
parent
applied
at
32.7
lb
ai/
A
(
initially
8.6
ppm)

0.94
ppm
455
42485901
41216401
terrestrial
field
dissipation
broccoli;
CA;
loamy
sand
soil;
parent
applied
at
30
lb
ai/
A
(
parent
max.
of
6.9
ppm
at
day
1)

1.1
ppm
546
42485902
41216402
terrestrial
field
dissipation
potatoes;
MN;
sandy
loam
soil;
parent
applied
at
25
lb
ai/
A
(
parent
max.
of
5.8
ppm
at
day
14)

9.24
ppm
1
43061501
terrestrial
field
dissipation
bare
ground;
GA;
loamy
sand
soil;
parent
applied
at
10
lb
ai/
A
(
initially
59.5
ppm)
Chemical
Name
and
Structure
Concentration
or
Percentage
of
Applied
Dose
MRID
Study
Type
Reported
Values/
Notes
Maximum
Day
­
57­
SCH3
Cl
Cl
Cl
Cl
Cl
Degradate
2:
pentachlorothioanisole
(
PCTA)
0.81
ppm
120
42911902
aerobic
soil
metabolism
0.53
ppm
still
present
at
day
365;
parent
applied
at
10
ppm
0.20
ppm
30
41713202
42112801
41384501
aerobic
soil
metabolism
0.073
 
0.10
ppm
still
present
at
60
 
365
days;
parent
applied
at
10.5
ppm
3.2%
of
recovered
radioactivity
in
soil;
not
detected
in
test
water
0
42094401
41203602
anaerobic
soil
metabolism
appears
to
degrade
more
rapidly
in
anaerobic
soil
(
vs.
aerobic
soil);
parent
was
9.65
ppm
at
start
of
anaerobic
period
1.9%
of
applied
30
42112802
41384301
41686001
41713203
anaerobic
soil
metabolism
was
<
0.1%
of
applied
by
60
days;
parent
was
applied
at
10.5
ppm
NA
NA
43500502
adsorption/
desorption
Kd
=
205
 
503
in
4
soils
0.25
ppm
125/
295
41721401
terrestrial
field
dissipation
incorp.
4­
6";
potatoes;
MN;
loam
soil;
parent
applied
at
25
lb
ai/
A
(
initially
9.2
ppm)

0.20
ppm
241
43887401
terrestrial
field
dissipation
incorp.
4";
bare
ground;
CA;
loamy
sand
soil;
parent
applied
at
212
lb
ai/
A
(
range
of
89­
245
ppm
at
time
0)

0.73
ppm
269
43887402
terrestrial
field
dissipation
incorp.
4";
bare
ground;
GA;
sandy
loam
soil;
parent
applied
at
232
lb
ai/
A
(
range
of
139­
144
ppm
at
days
0­
30)
Chemical
Name
and
Structure
Concentration
or
Percentage
of
Applied
Dose
MRID
Study
Type
Reported
Values/
Notes
Maximum
Day
­
58­
Cl
Cl
Cl
Cl
Cl
0.47
ppm
soil;
6.3
 
6.6ppm
turf
90
14
 
59
43887403
terrestrial
field
dissipation
CA;
sandy
loam
soil;
turf
plot;
parent
applied
at
36
lb
ai/
A
(
max.
of
9.5
ppm
on
day
14)

0.117
ppm
242
42094403
42094404
41210501
terrestrial
field
dissipation
turf
plot;
CA;
sandy
loam
soil;
parent
applied
at
32.7
lb
ai/
A
(
initially
8.6
ppm)

0.40
ppm
28
42485901
41216401
terrestrial
field
dissipation
broccoli;
CA;
loamy
sand
soil;
parent
applied
at
30
lb
ai/
A
(
parent
max.
of
6.9
ppm
at
day
1)

0.12
ppm
56
42485902
41216402
terrestrial
field
dissipation
potatoes;
MN;
sandy
loam
soil;
parent
applied
at
25
lb
ai/
A
(
parent
max.
of
5.8
ppm
at
day
14)

0.14
ppm
120
43061501
terrestrial
field
dissipation
bare
ground;
GA;
loamy
sand
soil;
parent
applied
at
10
lb
ai/
A
(
initially
59.5
ppm)

161
 
232
ppb
(
edible);
1095
ppb
(
nonedible);
696
ppb
(
nonedible)
21,
28
21
28
43179301
bioaccumulation
in
fish
bluegill
sunfish;
28­
day
exposure
study
Degradate
3:
pentachlorobenzene
(
PCB)
0.27
ppm
60
42911902
aerobic
soil
metabolism
appears
to
be
relatively
stable
(
0.20
ppm
still
present
at
365
days);
parent
applied
at
10
ppm
0.075
ppm
241
43887401
terrestrial
field
dissipation
incorp.
4";
bare
ground;
CA;
loamy
sand
soil;
parent
applied
at
212
lb
ai/
A
(
range
of
89­
245
ppm
at
time
0)
Chemical
Name
and
Structure
Concentration
or
Percentage
of
Applied
Dose
MRID
Study
Type
Reported
Values/
Notes
Maximum
Day
­
59­
0.24
ppm
269
43887402
terrestrial
field
dissipation
incorp.
4";
bare
ground;
GA;
sandy
loam
soil;
parent
applied
at
232
lb
ai/
A
(
range
of
139­
144
ppm
at
days
0­
30)

0.08
ppm
soil;
0.13
 
0.20
ppm
turf
149
14­
90
43887403
terrestrial
field
dissipation
CA;
sandy
loam
soil;
turf
plot;
parent
applied
at
36
lb
ai/
A
(
max.
of
9.5
ppm
on
day
14)

0.031
ppm
151
42094403
42094404
41210501
terrestrial
field
dissipation
CA;
sandy
loam
soil;
turf
plot;
parent
applied
at
32.7
lb
ai/
A
(
initially
8.6
ppm)

0.20
ppm
56
42485901
41216401
terrestrial
field
dissipation
broccoli;
CA;
loamy
sand
soil;
parent
applied
at
30
lb
ai/
A
(
parent
max.
of
6.9
ppm
at
day
1)

0.18
ppm
546
42485902
41216402
terrestrial
field
dissipation
potatoes;
MN;
sandy
loam
soil;
parent
applied
at
25
lb
ai/
A
(
parent
max.
of
5.8
ppm
at
day
14)

0.030
ppm
158
43061501
terrestrial
field
dissipation
bare
ground;
GA;
loamy
sand
soil;
parent
applied
at
10
lb
ai/
A
(
initially
59.5
ppm)
Chemical
Name
and
Structure
Concentration
or
Percentage
of
Applied
Dose
MRID
Study
Type
Reported
Values/
Notes
Maximum
Day
­
60­
SCH3
Cl
Cl
Cl
Cl
Cl
O
SCH
3
Cl
Cl
Cl
Cl
Cl
O
O
OH
Cl
Cl
Cl
Cl
Cl
Degradate
4:
pentachlorothioanisole
sulfoxide
0.37
ppm
365
42911902
aerobic
soil
metabolism
appears
stable;
parent
applied
at
10
ppm
0.046
 
0.069
ppm
90
 
535
43061501
terrestrial
field
dissipation
bare
ground;
GA;
loamy
sand
soil;
parent
applied
at
10
lb
ai/
A
(
initially
59.5
ppm)

0.85
ppb
(
edible);
8.47
ppb
(
nonedible)
21
21
43179301
bioaccumlation
in
fish
bluegill
sunfish;
28­
day
exposure
Degradate
5:
pentachlorothioanisole
sulfone
0.61
ppm
365
42911902
aerobic
soil
metabolism
appears
stable;
parent
applied
at
10
ppm
Degradate
6:
PCP
(
pentachlorophenol)
2.0%
of
recovered
radioactivity
in
soil;
7.5%
in
flood
water
90
60
42094401
41203602
anaerobic
soil
metabolism
parent
was
9.65
ppm
at
start
of
anaerobic
period
0.16
ppm
14
43061501
terrestrial
field
dissipation
bare
ground;
GA;
loamy
sand
soil;
parent
applied
at
10
lb
ai/
A
(
initially
59.5
ppm)
Chemical
Name
and
Structure
Concentration
or
Percentage
of
Applied
Dose
MRID
Study
Type
Reported
Values/
Notes
Maximum
Day
­
61­
SCH3
Cl
Cl
Cl
Cl
O
O
Cl
Cl
Cl
Cl
Cl
Cl
Degradate
7:
TCTASOO
(
tetrachlorothioanisole
sulfone)
0.013
ppm
460
43061501
terrestrial
field
dissipation
bare
ground;
GA;
loamy
sand
soil;
parent
applied
at
10
lb
ai/
A
(
initially
59.5
ppm)

Manufacturing
Contaminant:
hexachlorobenzene
(
HCB)
0.038
ppm
0
43887401
terrestrial
field
dissipation
incorp.
4";
bare
ground;
CA;
loamy
sand
soil;
parent
applied
at
212
lb
ai/
A
(
range
of
89­
245
ppm
at
time
0)

0.03
ppm
0
­
30
43887402
terrestrial
field
dissipation
incorp.
4";
bare
ground;
GA;
sandy
loam
soil;
parent
applied
at
232
lb
ai/
A
(
range
of
139­
144
ppm
at
days
0­
30)

ND
soil;
ND
turf
NA
43887403
terrestrial
field
dissipation
CA;
sandy
loam
soil;
turf
plot;
parent
applied
at
36
lb
ai/
A
(
max.
of
9.5
ppm
on
day
14)

0.076
ppm
0
42094403
42094404
41210501
terrestrial
field
dissipation
turf
plot;
CA;
sandy
loam
soil;
parent
applied
at
32.7
lb
ai/
A
(
initially
8.6
ppm)

0.056
ppm
543
42485901
41216401
terrestrial
field
dissipation
broccoli;
CA;
loamy
sand
soil;
parent
applied
at
30
lb
ai/
A
(
parent
max.
of
6.9
ppm
at
day
1)
Chemical
Name
and
Structure
Concentration
or
Percentage
of
Applied
Dose
MRID
Study
Type
Reported
Values/
Notes
Maximum
Day
­
62­
0.025
ppm
56­
84
42485902
41216402
terrestrial
field
dissipation
potatoes;
MN;
sandy
loam
soil;
parent
applied
at
25
lb
ai/
A
(
parent
max.
of
5.8
ppm
at
day
14)

0.047
ppm
1
43061501
terrestrial
field
dissipation
bare
ground;
GA;
loamy
sand
soil;
parent
applied
at
10
lb
ai/
A
(
initially
59.5
ppm)

1Data
from
two
additional
terrestrial
field
dissipation
studies
(
MRIDs
43887401,
43887402)
were
not
included
in
the
table
because
the
half­
lives
(
272
and
459
days)
were
of
questionable
validity
due
to
data
variability.
­
63­
This
report
supersedes
the
previous
HIARC
report
dated
March
4,
2002
(
TXR
No.
0050586).
It
differs
from
the
previous
report
in
that
it
reflects
the
most
recent
formatting,
and
it
delineates
the
selection
of
the
FQPA
factor.
No
decision
regarding
the
FQPA
factor
was
made
previously.
APPENDIX
1:
HIARC
Document
TXR
No.

DATE:

MEMORANDUM
SUBJECT:
PCNB
­
Report
of
the
Hazard
Identification
Assessment
Review
Committee.

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

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

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

PC
Code:
056502
On
December
10,
2002,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
PCNB
with
regard
to
the
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
PCNB
was
also
evaluated
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996
in
accordance
with
the
2002
OPP
10X
Guidance
Document.
The
conclusions
drawn
at
this
meeting
are
presented
in
this
report.
­
64­
Committee
Members
in
Attendance
Members
present
were:
Ayaad
Assaad,
William
Burnam,
Jonathan
Chen,
Elizabeth
Doyle,
John
Liccione,
Susan
Makris,
Elizabeth
Mendez,
David
Nixon,
Jess
Rowland,
and
Brenda
Tarplee
Member(
s)
in
absentia:
Steve
Knizner
(
RARC
Rep.)
and
Pamela
Hurley
Data
evaluation
prepared
by:
Elizabeth
Doyle,
Toxicology
Branch
Also
in
attendance
were:
Paula
Deschamp
and
Mark
Dow
Data
Evaluation
/
Report
Presentation
Elizabeth
A.
Doyle
Chief,
Toxicology
Branch
­
65­
INTRODUCTION
On
December
10,
2002,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reconvened
to
evaluate
the
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
PCNB
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996
in
accordance
with
the
2002
OPP
10X
Guidance
Document,
and
discussed
the
magnitude
and
rationale
for
required
uncertainty
factors.
The
conclusions
drawn
at
both
meetings
are
presented
in
this
report.

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

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

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

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

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

1200
mg/
kg/
day.

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

b.
Developmental
Toxicity
Study
in
the
rat
(
gavage)
OPPTS
870.3700
­
66­
Executive
Summary:
In
an
oral
developmental
toxicity
study
(
MRID
41361201),
25
(
presumed)
pregnant
CRL:
CD
®
(
SD)
BR
rats/
dose
group
were
administered
pentachloronitrobenzene
(
PCNB
tech.,
98.5%
a.
i.;
hexachlorobenzene
contamination
0.09%)
at
doses
of
0,
250,
750
or
1500
mg/
kg/
day
from
days
6
through
15
of
gestation,
inclusive.
Doses
were
given
by
gavage
in
1%
aqueous
carboxymethyl
cellulose
vehicle
(
10
ml/
kg
body
weight).

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

1500
mg/
kg/
day.

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

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

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

Maternal
toxicity:
At
900
mg/
kg/
day,
abnormal
feces
(
soft,
liquid
or
dried;
total
incidence
45
in
11
does
vs.
15
in
4
does,
controls),
decreased
weight
gain
during
dosing
(­
75%
less
than
controls;
not
statistically
significant),
slightly
decreased
food
consumption
(­
16%
less
than
controls;
not
statistically
significant)
were
observed.
Abortions
(
days
24
and
25,
2/
20
vs.
0/
20,
controls)
and
premature
delivery
(
day
25,
1/
20
vs.
0/
20,
controls)
were
observed
and
these
3
does
also
had
associated
abnormal
feces,
weight
loss
and
decreased
food
consumption.
The
doe
with
premature
delivery
also
had
decreased
motor
activity
and
a
fluid­
filled
cecum,
one
abortive
female
had
gastric
ulceration
and
the
other
had
a
litter
with
4
late
resorptions
out
of
6
conceptuses.
No
mortality
was
observed.
The
maternal
toxicity
LOAEL
is
900
mg/
kg/
day,
based
on
clinical
signs
of
toxicity,
decreased
body
weight
gain
and
food
consumption
during
dosing,
abortions
and
premature
delivery.
The
maternal
toxicity
NOAEL
is
300
mg/
kg/
day.
­
67­
Developmental
toxicity:
There
were
no
treatment­
related
developmental
effects
reported
in
this
study
with
the
exception
of
a
slightly
increased
incidence
of
abortions
at
the
900
mg/
kg
dose
level
considered
by
HIARC
as
developmental
toxicity
due
to
the
associated
fetal
mortality.
The
developmental
toxicity
LOAEL
is
900
mg/
kg/
day
and
the
developmental
toxicity
NOAEL
is
300
mg/
kg/
day.

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

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

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

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

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

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

Parental
toxicity:
At
3000
ppm,
statistically
significantly
decreased
mean
premating
body
weights
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
­
68­
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.

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

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

3.
PCNB
studies
consistently
show
decreases
in
serum
enzyme
activities.
AST/
ALT
activities
decrease
in
a
dose
dependent
manner
by
as
much
as
30­
80%.
It
is
known
that
penicillamine,
cycloserine,
hydralazine,
and
in
particular
the
anti­
tuberculin
drug
isoniazid
can
decrease
the
activities
of
AST
and
ALT
at
therapeutic
doses.
The
mechanism
by
which
this
occurs
is
through
a
biochemical
interaction
between
the
drug
and
Vitamin
B6.
With
isoniazid
[
Balazs
et
al.
Arch.
Toxicol,
Suppl.
1,
159­
163
(
1978)]
this
is
thought
to
occur
through
combination
with
pyridoxal
or
pyridoxal
phosphate
to
form
a
hydrazone.
­
69­
Vitamin
B6
compromises
a
group
of
closely
related
compounds,
pyridoxine,
pyridoxal
and
pyridoxamine,
that
are
phosphorylated
in
vivo
by
pyridoxal
kinase
to
form
pyridoxal
phosphate.
Pyridoxal
phosphate
serves
as
a
cofactor
in
many
reactions,
including
decarboxylation
and
transamination
of
amino
acids,
deamination
of
hydroxy
amino
acids
and
cysteine,
conversion
of
tryptophan
to
niacin,
metabolism
of
fatty
acids,
protein
metabolism,
and
the
transport
of
certain
amino
acids
across
cell
membranes.
The
inhibition
of
pyridoxal
kinase
by
the
isoniazid­
pyridoxal
complex
occurs
at
concentrations
1000
times
less
than
those
required
to
inhibit
the
enzyme
containing
the
cofactor.

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

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

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

6.
Pre­
and/
or
Postnatal
Toxicity
­
70­
The
HIARC
concluded
that
there
is
not
a
concern
for
pre­
and/
or
postnatal
toxicity
resulting
from
exposure
to
PCNB.

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

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

C.
Special
FQPA
Safety
Factor(
s)

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

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

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

A.
Evidence
that
suggest
requiring
a
Developmental
Neurotoxicity
study:

There
is
no
evidence
supporting
the
requirement
for
a
DNT.

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

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

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

The
HIARC,
however,
did
require
a
comparative
thyroid
assay
in
young
and
adult
rats
which
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.
­
71­
The
absence
of
the
comparative
thyroid
study
resulted
in
a
database
uncertainty
factor
of
10x
(
UF
DB
of
10x)
which
was
applied
to
the
dietary
(
acute
and
chronic)
as
well
as
all
residential
exposure
(
incidental
oral,
dermal
and
inhalation)
scenarios.
The
HIARC
determined
that
the
10X
UF
DB
is
required
since
the
available
data
provide
no
basis
to
support
reduction
or
removal
of
the
default
10X
factor.

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

2.
Chronic
Reference
Dose
(
cRfD)

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

At
3000
ppm,
statistically
significantly
increased
relative
liver
weight
in
males
(+
20%
above
controls),
absolute
thyroid/
parathyroid
weight
in
males
(+
26%),
relative
thyroid/
parathyroid
weight
(+
35%,
males
and
+
24%,
females),
and
significantly
increased
incidence
of
microscopic
lesions
including
mild
hepatocellular
hypertrophy
(
27%,
males
and
38%,
females
vs.
0%,
controls),
mild
thyroid
hyperplasia
(
15%,
males
vs.
4%,
controls
and
16%,
females
vs.
0%,
controls)
and
thyroid
hypertrophy
(
42%,
males
vs.
0%,
controls
and
36%,
females
vs.
2%,
controls)
were
observed.
Sporadic
significantly
decreased
mean
body
weights
in
both
sexes
were
not
considered
biologically
significant.
At
6000
ppm,
these
effects
showed
a
dose­
response
and
in
addition,
statistically
significantly
decreased
mean
body
weight/
weight
gain
throughout
treatment
(
at
termination,
­
11%/­
15%
less
than
controls
in
males
and
­
12%/­
18%
in
females),
decreased
food
consumption
during
the
first
6
months,
increased
serum
cholesterol
(
females),
significantly
increased
relative
liver
weight
in
both
sexes
(+
25%,
males
and
+
20%,
females)
and
increased
incidence
of
thyroid
colloid
cysts
in
males
(
16%
vs.
4.1%,
controls)
were
observed.
At
the
12­
month
interim
sacrifice,
both
sexes
showed
slight
(
not
statistically
significant)
increases
in
liver
and
thyroid
weights
at
mid
and
high
dose
and
in
high
dose
females,
there
was
a
slightly
increased
incidence
of
visible
tan
foci
in
the
lungs.
There
were
no
treatment­
related
clinical
or
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).
­
72­
PCNB
caused
an
increased
incidence
of
thyroid
follicular
cell
adenomas
in
males
(
0%,
0%,
12.5%
and
10.2%,
control
to
high
dose;
p<
0.05
at
3000
ppm)
and
a
significantly
increasing
trend
(
p<
0.01).
Incidence
in
females
was
2.0%,
0%,
4.0%
and
8.7%
(
control
to
high
dose;
not
significant);
however,
a
significantly
increasing
trend
(
p<
0.05)
was
observed.
The
incidence
of
thyroid
follicular
cell
carcinoma
was
increased
at
6000
ppm
only
in
males
(
males
0%,
2.0%,
0%
and
4.1%;
females
2.0%,
0%,
0%
and
2.2%).
The
combined
incidence
of
thyroid
follicular
cell
adenomas
and
carcinomas
was
significantly
increased
in
males
at
3000
and
6000
ppm
(
control
to
high
dose,
0%,
2.0%,
12.5%,
14.3%;
p<
0.05)
but
not
females
(
4.0%,
0%,
4.0%
and
10.9%),
with
a
significant
trend
in
both
sexes
(
females
p<
0.05
and
males
p<
0.01).
The
incidence
of
follicular
cell
adenoma
in
historical
control
data
from
this
laboratory
did
not
exceed
11.1%
in
males
or
3.2%
in
females.
The
incidence
of
carcinoma
did
not
exceed
9.4%
in
males
or
3.2%
in
females.

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

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

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

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

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

Study
Selected:
Subchronic
Oral
Toxicity
in
male
rats
§
Nonguideline
MRID
No.:
42630801
Executive
Summary:
In
a
special
(
nonguideline)
subchronic
oral
toxicity
study
(
MRID
42630801),
75
male
Charles
River
CD
®
rats/
dose
were
administered
pentachloronitrobenzene
(
PCNB
tech.,
99.09%
a.
i.)
in
their
diet
at
levels
of
0,
20
or
6000
ppm
(
equivalent
to
average
daily
intakes
of
0,
1.0
or
333
mg/
kg/
day).
Groups
of
15
animals/
dose
were
sacrificed
at
7,
14,
30
or
90
days.
The
remaining
15
animals/
dose
group
at
day
90
were
fed
only
basal
diet
for
a
recovery
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
Chronic
RfD
=
(
NOAEL)
1
mg/
kg/
day
=
0.001
mg/
kg/
day
(
UF)
1000
­
73­
decreased
body
weight
gain
(
at
termination,
­
20%,
due
largely
to
a
pronounced
decrease
during
Week
1),
decreased
food
consumption
during
Week
1
only
(­
23%
below
controls),
increased
TSH
(+
31%
to
+
132%
above
controls;
significant
at
most
time
points),
decreased
T3
(­
9
to
­
26%
less
than
controls;
significant
at
most
time
points),
decreased
T4
(­
48
to
­
54%
less
than
controls,
significant
at
all
time
points),
decreased
rT3
(­
28%
at
day
90;
significant),
increased
relative
liver
weight
(+
12
to
+
18%
above
controls),
decreased
absolute
thyroid/
parathyroid
weights
(­
14%,
day
30)
and
increased
follicular
epithelial
hypertrophy
of
the
thyroid
(
trace
to
mild,
all
animals
at
all
sacrifice
times
vs.
0/
15
controls)
and
hepatocellular
hypertrophy
(
moderate,
all
animals
at
90
days,
vs.
0/
15,
controls).
There
were
no
treatment­
related
deaths
or
clinical
signs
observed.
Animals
maintained
on
basal
diet
for
an
additional
90
days
showed
complete
recovery.
The
following
were
not
evaluated:
hematology,
urinalysis,
organ
weights
and
gross/
microscopic
pathology,
with
the
exception
of
liver,
thyroid/
parathyroids.
The
study
LOAEL
is
20
ppm
(
1.0
mg/
kg/
day),
based
on
liver
and
thyroid
histopathology.
The
study
NOAEL
was
not
determined.

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

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

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

5.
Incidental
Oral
Exposure:
Intermediate­
Term
(
1
­
6
Months)

Study
Selected:
Subchronic
Oral
Toxicity
in
male
rats
§
Nonguideline
MRID
No.:
42630801
Executive
Summary:
See
Short
Term
(
1
day
to
1
month)
Incidental
Oral
Exposure
section.
­
74­
Dose
and
Endpoint
for
Risk
Assessment:
1
mg/
kg/
day.
A
NOAEL
was
not
identified
in
this
study.
As
noted
above
under
the
short­
term
incidental
oral
exposure,
no
adverse
effects
were
seen
up
to
30
days.
The
HIARC
determined
that
the
effects
seen
at
the
1
mg/
kg/
day
at
termination
were
minimal
and
therefore
this
dose
is
appropriate
for
this
exposure
risk
assessment.

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

6.
Dermal
Absorption
Dermal
Absorption
Factor:
33%

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

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

The
HIARC
extrapolated
a
dermal
absorption
factor
of
33%
based
on
the
ratio
of
333
mg/
kg/
day
(
based
on
the
presence
of
thyroid
hormone
changes
observed
at
7,
14,
and
30
days
at
the
333
mg/
kg/
day
dose
level
observed
in
the
male
90­
day
rat
feeding
study)
and
the
LOAEL
of
1000
mg/
kg/
day
in
the
21­
day
dermal
toxicity
study.
In
rats,
it
was
noted
that
thyroid
toxicity
was
the
common
toxicity
seen
via
both
routes
in
the
same
species
7.
Dermal
Exposure:
Short­
Term
(
1­
30
days)
Exposure
Study
Selected:
21­
Day
Dermal
Toxicity
Study
§
OPPTS
870.3200
MRID
No.:
42416002
Executive
Summary:
In
a
21­
day
dermal
toxicity
study
(
MRID#
42416002),
Charles
River
rats
were
exposed
dermally
to
PCNB
(
98%
a.
i)
by
application
of
the
moistened
solid
(
distilled
water
vehicle)
to
the
shaved
dorsal
skin
at
doses
of
0,
100,
300
and
1000
mg/
kg
for
6
hours
per
day,
five
days
per
week.
­
75­
In
the
high
dose
males,
dilatation
of
the
thyroid
follicles
was
observed
in
3/
5
animals
and
hypertrophy
of
the
thyroid
follicular
epithelium
was
observed
in
4/
5
animals.
These
changes
were
not
observed
in
any
of
the
other
dose
groups,
including
controls
or
in
any
females.
No
other
treatment­
related
effects
were
observed
in
either
males
or
females.
Based
on
these
findings,
the
NOAEL
is
300
mg/
kg/
day
and
the
LOAEL
is
1000
mg/
kg/
day
based
on
thyroid
effects.

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

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

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

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

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

9.
Dermal
Exposure
Long­
Term
(>
6
Months)

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

Dose
and
Endpoint
for
Risk
Assessment:
1
mg/
kg/
day
based
on
hepatocellular
hypertrophy,
hepatocellular
hyperplasia
(
females)
and
thyroid
hypertrophy
and
hyperplasia
at
150
mg/
kg/
day.

Comments
about
Study/
Endpoint:
This
dose/
end
point
study
was
also
used
to
establish
the
chronic
RFD.
Since
an
oral
dose
was
identified,
33%
dermal
absorption
should
be
used
in
routeto
route
extrapolation.

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

Study
Selected:
Subchronic
Oral
Toxicity
Study
in
Male
Rats
§
Nonguideline
­
76­
MRID
No.:
42630801
Executive
Summary:
See
Short
Term
(
1
day
to
1
month)
Incidental
Oral
Exposure
Dose/
Endpoint
for
Risk
Assessment:
1
mg/
kg/
day.
Although
a
NOAEL
was
not
identified
in
the
non­
guideline
male
study
at
90
days,
no
effects
were
observed
at
the
1
mg/
kg/
day
dose
level
at
interim
sacrifice/
hormone
assessment
intervals
conducted
at
7,
14,
and
30
days.
This
finding
was
considered
an
appropriate
endpoint
for
risk
assessment
by
HIARC
for
periods
up
to
30
days.
Comments
about
Study/
Endpoint:
In
the
absence
of
an
inhalation
study,
an
oral
study
was
selected.
Absorption
by
the
inhalation
route
should
be
considered
to
be
equivalent
to
absorption
by
the
oral
route.

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

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

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

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

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

Dose/
Endpoint
for
Risk
Assessment:
1
mg/
kg/
day
based
on
hepatocellular
hypertrophy,
hepatocellular
hyperplasia
(
females)
and
thyroid
hypertrophy
and
hyperplasia
at
150
mg/
kg/
day.

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

13.
Margins
of
Exposure
­
77­
Summary
of
target
Margins
of
Exposure
(
MOEs)
for
risk
assessment.

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

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

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

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

A
common
toxicological
endpoint
of
concern
(
thyroid
toxicity)
was
identified
for
the
oral,
dermal,
and
inhalation
(
oral
equivalent)
routes
of
exposure.
Therefore,
for
short,
intermediate
and
long
term
exposure
aggregate
risk
assessments,
these
routes/
durations
can
be
aggregated
for
the
appropriate
populations.

III.
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
1.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
OPPTS
870.4300
MRID
No.:
41987301
Executive
Summary:
In
an
oral
chronic
toxicity/
carcinogenicity
study
(
MRID
41987301),
50
Charles
River
CD
®
rats/
sex/
dose
group
were
administered
pentachloronitrobenzene
(
PCNB
­
78­
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
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.
­
79­
B.
Executive
Summary:
In
a
Chronic
Toxicity/
Oncogenicity
study
(
MRID
43015801),
groups
of
60
male
and
60
female
Crl:
CDBR
Sprague­
Dawley
rats
were
given
0,
5,
50,
500,
or
1000
mg/
kg
bodyweight
pentachloronitrobenzene
(
Technical
98%)
by
gavage
five
days
per
week
for
up
to
two
years.
When
adjusted
for
continuous
exposure,
these
dose
levels
were
equivalent
to
0,
3.6,
36,
357
or
714
mg/
kg/
day.
T
3,
T
4
and
TSH
parameters
were
not
examined.

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

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

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

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

2.
Carcinogenicity
Study
in
Mice
MRID
No.
45609101
­
80­
Citation:
National
Toxicology
Program.
March,
1986.
NTP
Technical
Report
on
the
Toxicology
and
Carcinogenesis
Studies
of
Pentachloronitrobenzene
in
B6C3
F1
Mice.
(
Pre­
publication
draft
report
no.
NIH
86­
2581)

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

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

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

Discussion
of
Tumor
Data:
No
carcinogenic
effects
were
noted.

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

3.3
Classification
of
Carcinogenic
Potential
The
carcinogenicity
of
PCNB
was
assessed
in
reviews
of
1977
(
special
review)
and
in
1986
and
1992.
In
1992,
HED's
Carcinogenicity
Peer
Review
Committee
(
CARC)
classified
PCNB
as
a
Group
C
­
possible
human
carcinogen
and
recommended
that
for
the
purpose
of
risk
characterization,
the
Reference
Dose
approach
should
be
used
for
quantification
of
human
risk.

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

Pentachloronitrobenzene
was
selected
for
genetic
toxicology
screening
by
the
National
Toxicology
Program
(
NTP).
Testing
included:
the
Salmonella/
mammalian
microsome
test,
induction
of
forward
gene
mutations
in
L5178Y
mouse
lymphoma
cells
and
induction
of
chromosome
aberrations
and
sister
chromatid
exchanges
(
SCEs)
in
Chinese
hamster
ovary
(
CHO)
cells.
Although
formal
DERs
do
not
exist
for
these
assays,
they
are
considered
acceptable
by
HED.

GENE
MUTATIONS
­
81­
1.
Salmonella
typhimurium/
mammalian
microsome
reverse
gene
mutation
assay:
Using
the
preincubation
procedure,
PCNB
(
95%)
was
negative
in
S.
typhimurium
strains
TA1535,
TA1537,
TA198
and
TA
100
up
to
high
doses
of
6666.7
to
10,000
ug/
plate
without
S(
activation
and
with
S9
activation
derived
from
rat
and
hamster
livers
induced
with
Aroclor
1254.
Compound
precipitation
was
seen
at
>
1000ug/
plate.
The
study
is
acceptable
and
satisfies
the
guideline
requirement
for
a
bacterial
gene
mutation
assay.

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

g/
mL
­
S9;
15

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

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

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

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

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

g/
mL
­
S9;
75

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

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

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

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

V.
HAZARD
CHARACTERIZATION
­
82­
The
Metabolism
Assessment
Review
Committee
(
MARC)
convened
on
October
14,
2001
to
consider
the
Uniroyal
and
Amvac
PCNB
data
bases.
They
concluded
that
they
could
find
no
evidence
that
the
chemical
composition
(
i.
e.
impurity
levels)
differences
among
the
formulations
tested
in
the
toxicity
studies
affected
the
NOAELS/
LOAELS
and
endpoints
found.
This
is
interpreted
as
indicating
that
the
data
bases
for
the
two
technicals
should
be
combined
for
purposes
of
risk
assessment
PCNB
is
used
as
a
non­
systemic
soil
treatment
fungicide
for
vegetables,
field
crops,
turf,
ornamentals
and
as
a
post­
harvest
treatment
on
banana
stems
and
rose
bushes.
It
is
also
a
seed
dressing
agent.
It
is
primarily
applied
as
a
spray,
through
sprinkler
irrigation
systems
or
granular
preparations
to
soil
and
is
formulated
as
an
emulsifiable
concentrate,
granules
or
wettable
powder.
Acute
toxicities
are
low
,
with
most
study
results
in
Toxicity
Categories
III
or
IV,
although
(
Uniroyal)
PCNB
has
been
identified
as
a
weak
sensitizer.

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

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

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

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

The
carcinogenicity
of
PCNB
was
assessed
in
reviews
of
1977
(
special
review)
and
in
1986
and
1992.
In
1992,
the
CPRC
classified
PCNB
as
a
Group
C­
possible
human
carcinogen
and
recommended
that
for
the
purpose
of
risk
characterization,
the
Reference
Dose
approach
should
be
used
for
quantification
of
human
risk.
­
83­
No
findings
of
significant
toxicological
concern
have
been
identified
in
developmental
toxicity
or
reproduction
study
data.
No
neurotoxicity
studies
have
been
identified
and
no
neurobehavioral
alterations
nor
evidence
of
neuropathological
effects
have
been
observed
in
available
data.

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

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

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

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

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

VII.
ACUTE
TOXICITY
­
84­
Acute
Toxicity
of
PCNB
(
Uniroyal)

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

Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
81­
1
Acute
Oral
41443101
LD
50
=
>
5050
mg/
kg
IV
81­
2
Acute
Dermal
41443102
LD
50
=
>
2020
mg/
kg
III
81­
3
Acute
Inhalation
41443103
LC
50
=
>
6.49
mg/
L
III
81­
4
Primary
Eye
Irritation
41443109
Slight
irritant
III
81­
5
Primary
Skin
Irritation
41443105
PII
=
0.0175
IV
81­
6
Dermal
Sensitization
40734001
Non
sensitizer
81­
8
Acute
Neurotoxicity
­
85­
VIII.
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION
Summary
of
Toxicological
Dose
and
Endpoints
for
PCNB
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
All
populations)
N/
A
N/
A
None
selected
Chronic
Dietary
(
All
populations)
NOAEL=
1.0
mg/
kg/
day
UF
=
1000
Chronic
RfD
=
0.001
mg/
kg/
day
FQPA
SF
=
1X
cPAD
=
chronic
RfD
FQPA
SF
=
0.001
mg/
kg/
day
Chronic/
Oncogenicity
Study
­
rat
LOAEL
=
150
mg/
kg/
day
based
on
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
­
86­
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.
­
87­
REVIEWER
NOTES:

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

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

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

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

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

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