Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
1
Draft,
do
not
cite
or
quote
Chapter
III.
Toxicokinetics
A.
Absorption
Trichloroacetic
acid
Older
short­
term
studies
with
mongrel
dogs
(
Hobara,
1988a)
and
male
B6C3F1
mice
(
Styles,
1991)
indicate
that
most
of
the
orally
administered
dose
of
TCA
is
rapidly
absorbed.

TCA
concentrations
in
the
plasma
or
liver
peak
in
the
first
hour
following
oral
dosing.
Similar
observations
are
reported
in
the
more
recent
studies
summarized
here.

Quantitative
evidence
for
systemic
absorption
of
TCA
following
oral
dosing
was
provided
in
a
toxicokinetic
study
by
Schultz
(
1999).
Male
F344
rats
were
given
single
oral
or
intravenous
(
IV)
doses
of
500
µ
mol/
kg
(
82
mg/
kg)
of
TCA.
Concentrations
of
the
parent
compound
were
monitored
in
blood
at
various
times
for
up
to
48
hours.
Concentrations
of
the
parent
compound
in
the
urine
and
feces
were
measured
at
48
hours
after
dosing.
Key
results
from
this
study
are
presented
in
Table
III­
1.
The
oral
bioavailability
of
the
administered
compound
was
determined
from
the
ratio
of
the
blood
area­
under­
the­
curve
(
AUC)
for
the
oral
and
IV
doses.
Based
on
this
measurement,
the
oral
bioavailability
was
reported
by
the
study
authors
as
116%
for
TCA.

Because
blood
levels
were
measured
from
the
jugular
vein,
any
first
pass­
metabolism
following
oral
dosing
would
not
be
accounted
for
in
the
oral­
bioavailability
calculation.
The
fact
that
the
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
2
Draft,
do
not
cite
or
quote
oral
bioavailability
is
high
suggests
that
TCA
is
not
extensively
metabolized
via
first­
pass
metabolism.
The
AUC
for
oral
dosing
was
slightly
greater
than
that
following
IV
dosing,
but
the
degree
of
absorption
cannot
be
greater
by
the
oral
route
since
IV
dosing
presumes
100%

absorption.
Thus,
the
reported
oral
bioavailability
of
116%
likely
reflects
measurement
or
statistical
variability
and/
or
differences
in
clearance
rate
by
the
two
routes
of
administration.
As
a
measurement
of
absorption
rate,
the
mean
time­
to­
peak
blood
concentration
was
determined,
and
found
to
be
1.55
hours
following
oral
dosing.
The
mean
absorption
time,
which
was
determined
as
the
difference
in
the
mean
residence
time
in
blood
following
dosing
via
oral
and
IV
routes,
was
reported
as
6
hours
for
TCA.
The
mean
absorption
time
is
dependent
on
clearance
from
the
blood
as
well
as
the
absorption
rate;
therefore,
the
longer
mean
absorption
time
as
compared
to
time­
to­
peak
blood
concentration
of
1.55
hours
might
also
reflect
slower
clearance
following
oral
dosing.
Taken
together,
the
data
from
this
study
show
that
TCA
is
readily
absorbed
following
a
single
oral
bolus
dose.
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
3
Draft,
do
not
cite
or
quote
Table
III­
1.
Toxicokinetic
Data
for
TCA
in
F344
Ratsa
Parameters
determined
following
IV
dosing
with
500
µ
mol/
kg
TCA
(
82
mg/
kg)

Area
under
blood
concentration­
time
curve
AUC
(
µ
M­
h)
5406
±
144b
Amount
excreted
in
urine
in
24
h
(%
Dose)
48.5
±
13.0
Steady­
state
apparent
volume
of
distribution
(
mL/
kg)
782
±
117
Total
body
clearance
(
mL/
hr­
kg)
92.5
±
2.5
Renal
clearance
(
mL/
hr­
kg)
42.1
±
9.9
Mean
residence
time
(
hr)
8.5
±
1.6
Elimination
half­
life
(
hr)
­
total
time
course
8.0
±
2.4
Unbound
fraction
in
plasma
(
f
u)
0.53
±
0.04
Blood/
plasma
concentration
ratio
0.76
±
0.16
Parameters
determined
following
oral
dosing
with
500
µ
mol/
kg
TCA
(
82
mg/
kg)

Area
under
blood
concentration­
time
curve
AUC
(
µ
M­
hr)
6304
±
1361
Maximum
concentration
in
blood
(
µ
M)
340
±
17
Mean
residence
time
(
hr)
14.5
±
4.7
Time
to
peak
blood
concentration
(
hr)
1.5
±
0.3
Mean
absorption
time
(
hr)
c
6.0
Oral
Bioavailability
(%)
d
116e
aAdapted
from
Schultz,
1999
bMean
±
standard
deviation
cCalculated
as
the
difference
between
the
mean
residence
time
following
IV
versus
oral
dosing
dThe
ratio
of
the
mean
values
for
AUC
for
oral
versus
IV
dosing
x
100%

eAlthough
the
study
authors
reported
estimated
values
of
116%
for
TCA,
this
value
likely
reflects
either
measurement
or
statistical
variability,
and/
or
differences
in
clearance
rate
between
oral
and
intravenous
routes
of
administration,
as
oral
bioavailability
cannot
actually
be
greater
than
100%.
Addendum
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Drinking
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Monochloroacetic
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and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
4
Draft,
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quote
TCA
also
appears
to
be
readily
absorbed
through
the
skin.
Kim
and
Weisel
(
1998)

investigated
the
potential
for
dermal
absorption
of
TCA
by
evaluating
the
correlation
between
exposure
to
TCA
(
swimming
pool
water
concentration
×
exposure
duration)
and
urinary
excretion
of
TCA
in
four
human
volunteers
(
two/
sex).
Swimming­
pool­
water
concentrations
were
measured
before
and
after
volunteers
either
walked
or
swam
in
the
pools
for
30
minutes.

TCA
concentrations
in
the
swimming
pool
water
varied
from
57
to
871
µ
g/
L
with
a
mean
of
420
µ
g/
L
and
a
median
of
278
µ
g/
L.
In
one
set
of
exposures,
the
four
subjects
simultaneously
walked
around
in
the
pool
(
dermal
exposure
only),
submerging
the
entire
body
exclusive
of
the
head
for
30
minutes.
In
another
set
of
exposures,
the
same
four
subjects
swam
for
30
minutes
(
resulting
in
both
dermal
exposure
and
presumed
oral
exposure
from
incidental
ingestion
of
pool
water).

Entire
urine
voids
were
collected
for
at
least
24
hours
before
exposure,
and
20­
40
hours
following
exposure,
at
approximately
3­
hour
intervals.
Additional
urine
samples
were
collected
5­
10
minutes
before
and
after
exposures.
During
the
24
hours
prior
to
and
following
exposure,

subjects
avoided
activities,
such
as
drinking
chlorinated
tap
water
or
visiting
the
dry
cleaners,

which
might
result
in
urinary
TCA
excretion.
Background
levels
of
TCA
were
calculated
from
the
amount
of
urinary
TCA
excreted
in
the
urine
void
during
the
3
hours
prior
to
pool­
water
exposure.
The
amount
of
urinary
TCA
associated
with
exposure
was
estimated
by
subtracting
background
levels
from
TCA
levels
in
the
urine
void
collected
5
to
10
minutes
following
the
exposure
period.
The
results
showed
that
urinary
TCA
levels
were
elevated
in
the
10­
minute
period
following
exposure,
and
generally
returned
to
pre­
exposure
levels
within
3
hours.

Postexposure
urinary
excretion
of
TCA
was
highly
variable,
ranging
from
approximately
1.1­
fold
to
Addendum
to
Drinking
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Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
5
Draft,
do
not
cite
or
quote
3.9­
fold
greater
than
background
excretion
levels.
Higher
exposures
resulted
in
higher
amounts
of
urinary
TCA
adjusted
to
the
subjects'
body
surface
area,
suggesting
a
dose­
response
relationship.
The
correlation
coefficient
for
TCA
exposure
and
amount
excreted
was
0.80
(
p=

0.00005).

In
another
study
by
the
same
authors
(
Kim
and
Wiesel,
1998),
one
male
and
one
female
volunteer
ingested
500
mL
of
chlorinated
drinking
water
containing
less
than
10
µ
g/
mL
of
TCA,

and
urine
was
collected
for
the
following
24
hours.
No
increase
in
TCA
levels
were
observed
following
ingestion,
which
the
authors
suggested
was
due
either
to
variability
in
background
excretion
rates
or
to
TCA
not
being
excreted
with
urine
within
the
time
period
that
urine
samples
were
collected.
The
rapid
appearance
of
TCA
in
urine
following
dermal
exposure
in
swimmingpool
water
suggested
that
dermal
absorption
of
TCA
was
rapid.
Skin
permeability
was
not
estimated
for
TCA.

These
studies
confirm
earlier
findings
and
demonstrate
that
TCA
is
readily
absorbed
by
the
oral
and
dermal
routes.
No
new
studies
were
identified
on
the
degree
or
rate
of
TCA
absorption
following
inhalation
exposure.

Monochloroacetic
acid
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
6
Draft,
do
not
cite
or
quote
Multiple
cases
of
human
systemic
poisoning
and/
or
lethality
following
acute
dermal
exposure
to
MCA,
via
accidental
splashing
with
molten
or
concentrated
MCA
solution
(
up
to
90%
MCA),
have
been
reported,
and
demonstrate
rapid
absorption
and
systemic
distribution
of
this
compound
following
direct
skin
contact
covering
at
least
10%
of
the
skin
surface
(
Millischer,

1988;
Kusch,
1990;
Kulling,
1992).

No
toxicokinetic
studies
in
animals
that
described
the
degree
or
rate
of
absorption
of
MCA
following
any
route
of
exposure
were
identified
in
the
literature.
However,
the
ability
of
MCA
to
induce
systemic
toxicity
following
oral
dosing
in
animals
(
e.
g.,
Berardi,
1987;
NTP,

1992;
DeAngelo,
1997)
shows
that
MCA
is
absorbed
by
the
gastrointestinal
tract.

B.
Distribution
Trichloroacetic
acid
Oral­
gavage
studies
in
rodents
revealed
that
orally­
administered
TCA
is
available
for
systemic
distribution
in
the
plasma
of
animals.
Styles
(
1991)
reported
that
in
male
B6C3F1
mice
administered
a
single
oral
dose
of
500
mg/
kg
[
2­
14C]
TCA,
43%
of
the
administered
radioactivity
was
found
in
the
liver
after
24
hours.
The
study
authors
considered
the
apparent
binding
in
liver
tissue
to
be
the
result
of
the
metabolism
of
TCA
and
subsequent
incorporation
of
metabolites
into
cellular
macromolecules.
In
another
single
dose
gavage
study,
male
F344
rats
and
B6C3F1
mice
Addendum
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quote
were
administered
20
or
100
mg/
kg
(
4/
dose
group)
[
14C]
TCA
radiolabeled
at
both
carbons
(
Larson
and
Bull,
1992).
The
majority
of
the
radiolabel
in
the
plasma
was
not
associated
with
plasma
protein,
suggesting
that
most
of
the
TCA
distributed
in
the
blood
would
be
available
for
tissue
uptake.
TCA
can
also
be
recirculated
systemically
and
has
been
reported
to
undergo
cholecystohepatic
circulation
as
well
as
reabsorption
from
the
urinary
bladder
(
Hobara,
1987a;

Hobara,
1988b).

Numerous
recent
animal
studies
have
been
conducted
to
assess
the
distribution
of
TCA.

Schultz
(
1999)
administered
male
F344
rats
a
single
oral
or
IV
dose
of
500
µ
mol/
kg
(
82
mg/
kg)

of
TCA
and
measured
the
parent
compound
in
venous
blood
at
various
times
for
up
to
48
hours.

The
fraction
of
TCA
in
plasma
not
bound
to
plasma
protein
(
the
unbound
fraction)
was
estimated
to
be
0.53.
The
blood/
plasma
concentration
ratio
for
TCA
was
0.76,
indicating
some
propensity
for
TCA
to
partition
to
the
plasma,
and
was
consistent
with
the
ability
of
TCA
to
bind
plasma
proteins.
Tissue
concentrations
were
not
measured
in
this
study,
but
based
on
the
similarity
between
the
apparent
volume
of
distribution
and
the
total
body­
water
volume
in
rats,
TCA
appeared
to
be
widely
distributed.
The
calculated
steady­
state
apparent
volume
of
distribution
was
782
mL/
kg
for
TCA,
while
the
authors
reported
the
total
body­
water
volume
for
rats
as
approximately
660
mL/
kg.
Further
evidence
supporting
wide
tissue
distribution
of
TCA
in
total
body
water
is
the
low
lipophilicity
of
TCA
at
physiological
pH.
The
octanol­
buffer
partition
coefficient
(
Log
D)
at
pH
7.4
was
reported
to
be
­
1.47
(
Schultz,
1999).
This
highly
negative
Addendum
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not
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quote
value
suggests
that
at
physiological
pH,
TCA
would
have
little
propensity
for
accumulation
in
lipid­
rich
tissues
and,
thus,
would
likely
be
distributed
in
body
water.

The
dose­
dependent
partitioning
of
TCA
between
blood
and
liver
was
examined
by
Templin
(
1993).
Male
B6C3F1
mice
were
administered
TCA
via
a
single
oral
dose
of
0.03,
0.12,

or
0.61
mmol/
kg
(
corresponding
to
5,
20,
or
100
mg/
kg),
and
blood
samples
were
taken
at
1,
2,

4,
6,
9,
12,
18,
and
24
hours
following
treatment.
Four
mice
per
treatment
group
were
euthanized
at
each
time­
point
and
all
blood
samples
were
analyzed
separately.
A
pharmacokinetic
analysis
was
conducted
to
determine
the
elimination
rate
constants,
area
under
the
blood
concentration
time
curve
(
AUC),
and
clearance
values;
TCA
plasma
protein
binding
was
also
assessed.

Based
on
both
peak
values
and
totals
(
AUC),
TCA
distribution
favored
the
blood
over
the
liver,
and
the
partitioning
of
TCA
into
the
blood
increased
with
increasing
dose
of
TCA
in
a
nonlinear
manner.
Dosing
with
0.03,
0.12,
or
0.61
mmol/
kg
TCA
resulted
in
peak
blood
concentrations
of
approximately
50,
250,
or
475
nmol/
mL,
respectively,
and
peak
concentrations
of
TCA
in
liver
of
approximately
50,
125,
or
175
nmol/
mL,
respectively,
as
estimated
from
a
figure
presented
in
the
paper.
Partitioning
to
blood
was
also
favored,
based
on
AUC
measurements.
For
example,
the
liver
AUC
to
blood
AUC
ratio
was
approximately
0.75
for
a
peak
TCA
blood
concentration
of
50
nmol/
mL,
and
approximately
0.45
for
a
peak
blood
concentration
of
450
nmol/
mL
(
estimated
from
a
figure
in
the
paper).
The
degree
of
plasma
Addendum
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protein
binding
was
also
concentration­
dependent.
The
amount
of
TCA
bound
to
plasma
constituents
was
estimated
in
vitro
by
incubating
[
14C]
TCA
(
position
of
carbon
radiolabel
not
specified)
with
plasma,
and
determining
the
amount
of
unbound
radioactivity
and
bound
radioactivity
(
radioactivity
added
minus
unbound
radioactivity).
At
TCA
concentrations
in
plasma
equal
to
or
below
306
nmol/
mL,
approximately
50­
57%
of
the
TCA
was
bound
to
plasma
constituents,
while
plasma­
constituent
binding
decreased
with
plasma
TCA
concentration
at
higher
TCA
concentrations.
Approximately
41,
34,
and
23%
of
TCA
was
bound
to
plasma
constituents
at
plasma
TCA
concentrations
of
306,
612,
and
1224
nmol/
mL,
respectively.
The
decrease
in
the
percent
of
the
bound
TCA
with
increasing
plasma
concentration
was
consistent
with
the
binding
parameters
for
TCA
estimated
by
Scatchard
plot
analysis
of
these
in
vitro
data.

The
estimated
K
D
(
the
plasma
concentration
of
TCA
resulting
in
half­
maximal
binding)
was
248
nmol/
mL
and
the
estimated
B
max
(
the
plasma
concentration
of
TCA
resulting
in
maximal
binding)

was
310
nmol/
mL.
Thus,
plasma
TCA
concentrations
of
306,
612,
and
1224
nmol/
mL
equaled
or
exceeded
the
binding
capacity
of
the
plasma,
and
a
lower
percent
of
the
TCA
in
the
plasma
was
bound
to
plasma
constituents.
Similarly,
based
on
the
determined
binding
parameters,
oral
doses
of
TCA
between
20
and
100
mg/
kg/
day,
which
resulted
in
peak
blood
concentrations
of
250
and
475
nmol/
mL,
respectively,
would
be
expected
to
result
in
nearly
half­
maximal
to
maximal
plasma
constituent
binding
in
the
mouse,
and
there
would
be
more
free
TCA
present
at
the
higher
dose.

The
concentration­
dependent
plasma
binding
is
toxicologically
significant
because
it
determines
the
distribution
of
TCA
from
blood
to
target
tissues.
In
addition,
plasma
binding
also
would
be
expected
to
sequester
free
TCA
and
thus
compete
with
TCA
metabolism.
Therefore,
as
plasma­
Addendum
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Document
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and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
10
Draft,
do
not
cite
or
quote
binding
capacity
is
exceeded
at
high
doses,
more
TCA
would
be
available
for
uptake
by
tissues.

The
role
plasma­
protein
binding
plays
in
the
distribution
of
TCA
may
be
of
added
significance
for
risk
assessment
because
of
potential
species
differences.
In
a
recent
review,
Lash
(
2000)
noted
that
TCA
is
bound
more
efficiently
to
plasma
proteins
in
the
mouse
than
in
humans,
but
quantitative
differences
were
not
presented.

Toxopeus
and
Frazier
(
1998)
investigated
the
kinetics
of
TCA
in
isolated
perfused
rat
liver
(
IPRL),
using
male
F344
rats.
The
IPRL
system
was
dosed
with
either
5
or
50
µ
mol
of
TCA,
and
TCA
concentrations
were
monitored
in
perfusion
medium
and
bile
for
2
hours.
Liver
viability
was
assessed
by
measuring
lactate
dehydrogenase
(
LDH)
leakage
into
perfusion
medium
and
by
the
rate
of
bile
production.
At
the
end
of
the
exposure
period,
the
concentration
of
TCA
in
liver
was
measured.
In
the
study
with
50
µ
mol
TCA,
the
total
TCA
concentration
(
free
and
bound)
in
perfusion
medium
decreased
slightly
during
the
first
30
minutes
and
then
remained
constant
for
the
duration
of
the
exposure
period;
the
total
TCA
concentration
in
the
perfusion
medium
was
relatively
constant
in
the
study
with
5
µ
mol
TCA.
At
the
high
dose,
approximately
93%
TCA
was
bound
to
albumin,
and
the
free
TCA
concentration
averaged
15.4
µ
M
at
5
minutes
of
exposure
and
14.9
µ
M
at
120
minutes.
At
the
low
dose,
96%
of
the
TCA
was
bound
to
protein,

and
the
free
TCA
concentration
was
approximately
constant
at
0.9
to
1
µ
M
over
the
study
period.

The
calculated
free­
TCA
concentration
in
the
liver
intracellular
space
was
higher
than
the
free­

TCA
concentration
in
the
perfusion
medium.
Enzyme
leakage
and
bile
flow
were
similar
at
both
TCA
exposure
levels
to
that
in
the
control
liver,
indicating
the
absence
of
hepatotoxicity.
The
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
11
Draft,
do
not
cite
or
quote
authors
concluded
that
the
binding
of
TCA
to
albumin
in
perfusion
medium
limits
the
uptake
of
TCA
by
the
liver,
and
that
TCA
is
virtually
unmetabolized
by
the
liver.
These
findings
are
consistent
with
those
from
in
vivo
mouse
studies
(
e.
g.,
Templin,
1993)
demonstrating
TCA
binding
to
serum
protein,
and
suggest
that
TCA
kinetics
are
determined
by
plasma­
protein
binding.

Yu
(
2000)
studied
the
tissue
distribution
of
TCA
in
male
F344
rats
injected
IV
with
radiolabeled
[
1­
14C]
TCA
at
doses
of
0,
6.1,
61,
or
306
µ
mol/
kg
(
0,
1,
10,
or
50
mg/
kg).
The
radiolabeled
14C
in
blood
and
tissues
was
measured
at
various
time
points
for
up
to
24
hours
post
injection
and
the
concentration
of
TCA
equivalents
was
determined.
Following
IV
injection,
the
concentration
of
TCA
equivalents
in
various
tissues
peaked
rapidly.
Overall
kinetic
behaviors
were
similar
at
all
three
doses.
No
TCA
metabolites
were
measured
in
plasma,
urine,
or
tissue
samples.
At
early
time
points,
the
highest
TCA
concentrations
were
measured
in
plasma,
followed
by
kidney,
red
blood
cells
(
RBC),
liver,
skin,
small
intestine,
large
intestine,
muscle
and
fat;
the
relative
order
of
these
concentrations
remained
unchanged
up
to
3
hours
following
dosing.
For
example,
at
3
hours
after
administration
of
306
µ
mol/
kg
(
50
mg/
kg)
TCA,
the
TCA­
equivalent
concentrations
were
roughly:
550
µ
mol/
L
in
plasma,
followed
by
400
µ
mol/
kg
in
the
kidney,
350
µ
mol/
kg
in
the
liver,
250
µ
mol/
kg
in
RBCs,
200
µ
mol/
kg
in
skin,
200
µ
mol/
kg
in
the
small
intestine,
200
µ
mol/
kg
in
the
large
intestine,
120
µ
mol/
kg
in
muscle,
and
30
µ
mol/
kg
in
fat.
Thus,

the
initial
distribution
of
TCA
in
tissues
appears
to
be
independent
of
dose,
although
at
the
high
dose,
some
nonlinear
behavior
was
noted.
However,
at
24
hours
following
dosing,
the
Addendum
to
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Water
Criteria
Document
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Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
12
Draft,
do
not
cite
or
quote
distribution
pattern
was
markedly
different,
reflecting
plasma
and
tissue
differences
in
terminal
disappearance
rate
constants.
Disappearance
of
TCA
equivalents
from
RBC,
muscle,
and
fat
was
similar
to,
or
faster
than,
plasma
at
all
doses;
disappearance
rate
constants
for
kidney
and
skin
were
slightly
lower
than
plasma,
whereas
liver
small
intestine,
and
large
intestines
demonstrated
significantly
slower
elimination.
The
most
notable
difference
at
24
hours
postexposure
was
between
plasma
and
the
liver,
when
the
total
concentration
of
TCA
equivalents
in
liver
greatly
exceeded
that
in
plasma,
perhaps
reflecting
the
slower
terminal
elimination
rate
constant
from
liver
compared
to
plasma
due
to
biological
incorporation
of
TCA
metabolites
into
hepatic
intracellular
components.

To
more
fully
explain
the
differences
of
kinetics
of
TCA
in
the
plasma
and
liver,
the
authors
studied
the
binding
characteristics
of
TCA
in
plasma
and
liver.
Based
on
in
vitro
experiments,
the
authors
concluded
that
there
is
much
stronger
binding
of
TCA
in
the
plasma
than
in
the
liver.
However,
the
authors
also
noted
that
it
was
not
possible
at
the
present
time
to
determine
whether
TCA
or
its
metabolite(
s)
binds
covalently
with
macromolecules
or
whether
radiolabeled
carbon
derived
from
TCA
is
metabolically
incorporated
into
macromolecules.
In
addition,
based
on
the
rate
of
formation
of
extractable
and
non­
extractable
radioactivity,
only
limited
TCA
metabolism
was
observed.
As
an
alternative
to
tissue
covalent
binding
or
metabolic
incorporation
into
liver
cells
to
explain
the
slower
elimination
rate
of
TCA
from
liver
as
compared
with
plasma,
the
authors
investigated
the
hepatic
intracellular
accumulation
of
TCA.
They
Addendum
to
Drinking
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Criteria
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for
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Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
13
Draft,
do
not
cite
or
quote
determined
that
TCA
binding
in
the
liver
was
negligible,
found
that
the
concentration
of
unbound
TCA
in
the
intracellular
space
was
significantly
higher
(
p
<
0.05)
than
the
biliary
concentration
of
free
TCA.
Since
the
difference
could
not
be
attributed
to
TCA
binding
in
the
liver,
the
authors
concluded
that
the
slower
elimination
rate
of
TCA
in
the
liver
results
from
TCA
being
transported
into
hepatic
cells
faster
than
it
is
transported
out
of
these
cells.

In
agreement
with
the
results
of
Yu
(
2000),
Abbas
and
Fisher
(
1997)
had
previously
determined
partition
coefficient
values
for
TCA
in
B6C3F1
mouse
tissues
by
a
centrifugation
method.
The
tissue
to
blood
partition
coefficients
were
1.18
for
the
liver,
0.88
for
the
muscle,

0.74
for
the
kidney,
and
0.54
for
the
lung.
These
data
support
the
conclusion
that
TCA
distributes
preferentially
to
the
liver
in
rats
and
mice.
In
contrast
to
the
partition
coefficients
determined
for
the
mouse,
the
tissue:
blood
partition
coefficients
for
humans
did
not
show
this
effect.
Using
PBPK
models
developed
by
Fisher
and
his
colleagues
and
incorporating
whole
blood
and
plasma
TCA
measurements
taken
from
human
volunteers
exposed
to
trichloroethylene.

,
Fisher
(
1998)
reported
human
tissue:
blood
partition
coefficients
of
0.66
for
the
liver,
0.66
for
the
kidney,
0.47
for
the
lung,
and
0.52
for
muscle.
Thus,
tissue:
blood
partitioning
may
differ
among
species.
Based
on
a
review
of
limited
data
from
animal
studies
and
in
vitro
assays,
Lash
et
al.
(
2000)
have
proposed
that
there
may
also
be
species
differences
in
plasma
protein
binding
of
TCA
between
humans
and
mice.
Addendum
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Document
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and
Trichloroacetic
Acid
EPA/
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OST/
HECD
III­
14
Draft,
do
not
cite
or
quote
No
additional
studies
were
identified
that
might
confirm
the
nature
and
extent
of
species
differences
in
TCA
distribution.
Indirect
evidence
in
humans,
primarily
from
studies
involving
exposure
to
chlorinated
solvents,
suggests
that
TCA
is
widely
distributed.
TCA
is
a
metabolite
of
trichloroethylene,
and
has
been
frequently
measured
in
the
urine
or
blood
of
humans
exposed
to
trichloroethylene
as
a
result
of
environmental
contamination
(
Ziglio,
1981;
Ziglio,
1983;

Vartiainen,
1993;
Skender,
1994;
Bruning,
1998)
and
in
human
volunteer
studies
(
NIOSH,
1973;

Brashear,
1997;
Fisher,
1998).
TCA
is
also
found
in
the
blood
and
urine
of
humans
without
known
chlorinated­
solvent
exposures
(
Hajimiragha,
1986)
and
in
individuals
exposed
to
low
concentrations
of
TCA
in
swimming
pool
and
drinking
water
(
Kim
and
Weisel,
1998).
These
studies
demonstrate
that
TCA,
whether
it
is
absorbed
from
external
sources
or
is
formed
as
a
downstream
metabolite
of
other
compounds,
appears
in
the
blood
and
urine
and
is
thus
available
for
systemic
distribution
in
humans.

No
studies
investigating
the
toxicokinetics
or
degree
of
maternal­
to­
fetus
or
blood­

tobreast
milk
transfer
of
TCA
were
located.

Monochloroacetic
Acid
No
toxicokinetic
studies
of
MCA
in
humans
have
been
identified.
However,
the
appearance
of
damage
to
multiple
organ
systems
in
humans
following
accidental
acute
dermal
exposure
to
molten
or
concentrated
MCA
solution
demonstrates
systemic
distribution
of
this
Addendum
to
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Water
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Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
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HECD
III­
15
Draft,
do
not
cite
or
quote
compound
following
dermal
exposure
(
Millischer,
1988;
Kusch,
1990;
Kulling,
1992).
As
further
support
for
this
conclusion,
detectible
levels
of
MCA
were
observed
in
the
blood
of
a
dermal
poisoning
patient
in
one
reported
case
(
Kulling,
1992).

Toxicokinetic
studies
in
animals
revealed
wide
tissue
distribution
of
MCA.
One
study
found
that
liver
and
kidney
levels
of
radioactivity
were
greater
than
levels
in
the
plasma,
brain,
or
heart
32
minutes
following
subcutaneous
administration
of
53
or
162
mg/
kg
[
14C]
MCA
(
position
of
carbon
radiolabel
not
specified)
to
male
Sprague­
Dawley
rats
(
Hayes,
1973).
An
IV­
dosing
study
revealed
initially
high
levels
of
radioactivity
in
the
liver
of
male
Sprague­
Dawley
rats
that
decreased
over
4
hours,
while
central
nervous
system,
thymus,
and
pancreas
levels
increased
(
Bhat,
1990).

Kaphalia
(
1992)
administered
a
single
oral
gavage
dose
of
100
µ
mol/
kg
(
about
10
mg/
kg)

of
[
1­
14C]
MCA
to
15
male
Sprague­
Dawley
rats.
Urine
was
collected
at
4,
8,
12,
24,
and
48
hours
following
treatment.
Three
rats
at
each
time
point
were
sacrificed
and
distribution
of
radioactivity
in
plasma,
red
blood
cells,
plasma
proteins,
and
major
organs
and
tissues
was
determined.
To
study
the
effect
of
treatment
with
a
higher
dose
on
the
distribution
of
radioactivity,
a
second
group
of
3
animals
was
administered
a
single
oral
gavage
dose
of
approximately
1000
µ
mol/
kg
(
100
mg/
kg)
[
1­
14C]
MCA
and
sacrificed
at
24
hours.
A
third
group
was
treated
with
the
higher
dose
(
100
mg/
kg)
daily
for
3
days,
and
sacrificed
at
24
hours
following
the
last
dose
to
evaluate
the
potential
for
bioaccumulation
of
MCA
and/
or
its
Addendum
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and
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III­
16
Draft,
do
not
cite
or
quote
metabolites
under
conditions
of
repeated
dosing.
End
points
examined
were
the
same
as
those
assessed
in
the
low­
dose
group.

In
the
low­
dose
(
100
µ
mol/
kg)
group
at
4
and
8
hours
post­
dosing,
maximum
radioactivity
was
observed
in
the
intestines
and
the
kidney,
followed
by
liver,
spleen,
testes,
lung,

brain,
and
heart.
Radioactivity
disappeared
from
the
intestine
more
rapidly
than
from
any
other
tissue
examined.
The
radioactivity
in
the
kidney
also
decreased
sharply,
but
not
as
fast
as
in
the
intestine.
The
elimination
phase
in
the
spleen,
testes,
and
heart
followed
a
similar
time
pattern
but
exhibited
a
much
slower
elimination
rate.
In
contrast,
radiolabel
in
the
liver
increased
from
4
to
8
hours
and
then
decreased
at
a
slower
rate
than
that
observed
in
the
kidney
or
intestine.
In
the
high­
dose
(
1000
µ
mol/
kg)
group,
radioactivity
in
various
tissues
at
24
hours
post­
dosing
were
1.4
to
3.8­
fold
higher
than
that
observed
in
the
low­
dose
group.
Following
three
daily
doses
at
the
high
dose,
radioactivity
was
significantly
increased
in
most
tissues
except
for
the
liver
and
spleen,

as
compared
with
radioactivity
observed
after
a
single
dose.
The
study
authors
concluded
that
some
accumulation
of
MCA
in
the
tissues
occurred
which
appeared
to
be
both
dose­
and
duration­
dependent.

Binding
of
MCA
to
red
blood
cells
and
hemoglobin
was
low
in
all
treated
groups.

However,
about
50%
of
the
total
radioactivity
in
the
plasma
was
present
in
dialyzed
plasma
in
the
low­
dose
group,
indicating
binding
of
the
radiolabel
to
the
plasma
proteins.
Plasma
protein
binding
was
approximately
73%
and
79%
of
total
radiolabel
in
the
single­
and
multiple­
dose
high­
Addendum
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III­
17
Draft,
do
not
cite
or
quote
dose
groups,
respectively.
These
values
were
considered
to
be
significantly
higher
that
those
found
at
the
same
time
points
in
the
low­
dose
group,
indicating
an
effect
of
dose
on
the
extent
of
protein
binding.
Affinity
chromatography
indicated
that
approximately
65%
of
the
total
plasma
radiolabel
was
associated
with
albumin
in
the
groups
receiving
either
a
single
or
multiple
dose
at
the
high
dose
level.

In
a
more
recent
study,
Saghir
(
2001)
examined
the
kinetics
of
MCA
in
adult
male
Sprague­
Dawley
rats
exposed
to
either
a
subtoxic
(
10
mg/
kg)
or
a
toxic
(
75
mg/
kg)
dose
via
intravenous
injection.
Doses
were
selected
on
the
basis
of
a
previous
study
in
which
rats
(
6­
7
dose
group)
were
treated
intravenously
with
non­
radiolabeled
MCA
at
doses
ranging
from
50
to
125
mg/
kg
and
observed
for
up
to
72
hours
following
injection
for
the
onset
of
toxicity
(
coma
and
mortality).
For
the
kinetics
study,
rats
were
administered
radiolabeled
MCA
(
carbon
position
of
radiolabel
not
specified)
at
either
the
subtoxic
or
toxic
dose,
and
5
animals
were
scheduled
for
sacrifice
at
each
of
the
following
post­
dosing
time
points:
5,
15,
45
minutes;
2,
4,
8,
and
16
hours.

However,
some
rats
treated
with
the
high
dose
died
at
the
last
4
time
points,
reducing
the
number
of
animals
per
group
to
three
or
four.
Blood
and
urine
samples
were
collected
and
various
organs
removed
and
analyzed
for
radioactivity.
The
gastrointestinal
tract
(
GIT)
was
separated
into
stomach
(
esophagus
and
stomach),
small
intestine,
and
large
intestine,
and
total
radioactivity
in
each
GIT
segment
was
quantified.
Average
plasma
concentration­
time
profiles
of
total
radioactivity
and
parent
MCA
measured
after
intravenous
injection
were
analyzed
by
a
compartmental
modeling
method
using
a
non­
linear
least­
square
regression
program;
the
best
fit
Addendum
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Criteria
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Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
18
Draft,
do
not
cite
or
quote
of
the
data
was
obtained
by
using
a
two­
compartment
model.
The
time
course
of
MCAassociated
radioactivity
in
selected
tissues
was
also
analyzed
to
determine
AUC
and
mean
residence
time
(
MRT).

MCA
was
rapidly
distributed
to
tissues.
After
5
minutes,
only
0.6
and
1.0%
of
the
radioactive
dose/
mL
remained
in
the
systemic
circulation
at
10
and
75
mg/
kg,
respectively.
Less
than
0.1%
of
dose/
mL
remained
in
the
plasma
at
8
hours
post
dosing.
Most
of
the
radioactivity
associated
with
plasma
was
parent
MCA.
The
MRT
of
MCA
in
plasma
was
about
4
hours
and
the
apparent
volume
of
distribution
at
steady
state
(
V
ss)
was
about
3
times
lower
at
the
toxic
dose
as
compared
with
the
subtoxic
dose.
Disappearance
of
radioactivity
and
of
parent
compound
from
plasma
followed
a
biexponential
pattern.
The
subtoxic
MCA
dose
was
rapidly
distributed
to
tissues
whereas
the
distribution
of
the
toxic
dose
to
tissues
was
much
slower.
The
AUC
of
total
radioactivity
and
of
parent
MCA
in
plasma
was
22­
23
times
higher
at
the
75
mg/
kg
dose
than
at
the
10
mg/
kg
dose,
instead
of
the
7­
to
8­
fold
decrease
expected
on
the
basis
of
dose
proportionality.
These
results
indicate
that
distribution
and/
or
clearance
was
significantly
slower
at
the
toxic
dose.
A
higher
percent
of
radioactivity
was
found
in
the
liver
and
kidney
at
the
subtoxic
dose
as
compared
with
the
toxic
dose.
At
the
low
dose,
the
time
course
of
concentrations
of
MCA
in
the
liver,
heart,
lungs,
brown
fat,
muscle,
and
skin
paralleled
the
plasma
concentration
and
peaked
at
5
minutes;
whereas
at
the
high
dose
the
concentration
in
the
liver
peaked
more
slowly
(
at
15
minutes).
MCA­
associated
radioactivity
entered
the
brain
rapidly
and
was
retained
there
at
almost
the
same
concentrations
throughout
the
study
period,
with
the
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
19
Draft,
do
not
cite
or
quote
percent
of
accumulation
being
proportionate
to
the
dose.
In
the
thymus,
the
distribution
of
radioactivity
occurred
in
two
distinct
phases
at
both
doses:
an
early
rapid
distribution,
followed
by
a
decline
within
15
minutes,
and
a
second
peak
at
about
4
hours
post­
injection
(
approximately
1%

of
the
dose/
gram
tissue
in
both
dose
groups).
Dose
proportionality
in
the
thymus
occurred
at
all
sampled
time
points.
Distribution
of
both
subtoxic
and
toxic
doses
was
slower
to
the
spleen
and
testes
than
to
other
tissues
and
was
within
the
expected
dose
proportionality.
A
large
fraction
of
both
doses
was
recovered
from
the
GIT
within
45
minutes
of
treatment.
At
5
minutes
postdosing
approximately
10%
of
each
dose
was
retained
in
the
GIT;
at
45
minutes,
GIT
recovery
was
47%
and
23%
of
the
subtoxic
and
toxic
doses,
respectively.
Most
of
the
GIT
radioactivity
was
located
in
the
small
intestine
and
was
rapidly
reabsorbed;
a
maximum
of
only
about
5%
of
dose
reached
the
large
intestine.
About
2­
3%
of
each
dose
was
found
in
the
colon
within
5
minutes
of
dosing
and
was
attributed
by
the
authors
to
be
due
to
direct
transport
from
the
blood
across
the
gut
wall.
This
study
provides
useful
information
about
the
distribution
of
MCA,
but
the
time
course
data
should
be
treated
with
caution,
since
the
intravenous
dosing
used
in
this
study
bypasses
the
first­
pass
metabolism
relevant
to
oral
exposure.

No
new
studies
were
identified
on
the
distribution
of
MCA
following
exposure
by
the
dermal
or
inhalation
routes.

C.
Metabolism
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
20
Draft,
do
not
cite
or
quote
Trichloroacetic
acid
Larson
and
Bull
(
1992)
reported
the
formation
of
CO
2,
glyoxylic
acid,
oxalic
acid,
glycolic
acid,
and
dichloroacetic
acid
(
DCA)
following
oral
administration
of
20
or
100
mg/
kg
[
14C]
TCA
(
position
of
carbon
radiolabel
not
given)
to
rats
and
mice.
The
authors
suggested
that
TCA
was
metabolized
by
a
reductive
dehalogenation
mechanism
to
form
DCA.
The
formation
of
lipid
peroxidation
induced
by
TCA
was
given
as
evidence
for
this
mechanism,
which
would
result
in
the
formation
of
free­
radical
intermediates
capable
of
binding
to
cellular
lipids.
The
liver
was
suggested
as
the
primary
site
of
TCA
metabolism,
based
on
decreased
TCA
metabolism
in
mongrel
dogs
following
hepatic
by­
pass
(
Hobara,
1987b).
Figure
III­
1
summarizes
potential
pathways
for
TCA
metabolism.
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
21
Draft,
do
not
cite
or
quote
C
l
C
C
l
C
l
C
O
OH
C
l
C
C
l
C
O
OH
C
C
O
C
l
C
C
O
OH
H
H
H
C
C
O
OH
HO
O
HO
G
lycine
CO2
Thiod
iglyco
late
G
lyo
xylic
a
c
id
Oxa
lic
a
cid
TCA
DCA
MCA
Adapted
from
B
ull,
2
00
0
a
nd
L
ash
e
t
a
l.
2000
H
O
G
lycolate
Figure
III­
1.
Proposed
metabolism
of
TCA
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
22
Draft,
do
not
cite
or
quote
The
formation
of
both
TCA
and
DCA
as
metabolites
of
trichloroethylene
or
chloral
hydrate
(
a
trichloroethylene
metabolite
upstream
of
TCA)
suggested
that
DCA
might
be
formed
from
TCA.
In
an
attempt
to
address
this
possibility,
Abbas
(
1996)
compared
TCA
and
DCA
kinetics
following
the
administration
of
trichloroethylene
or
chloral
hydrate.
Male
B6C3F1
mice
were
administered
IV
doses
of
chloral
hydrate
at
10,
100,
or
300
mg/
kg,
and
blood
and
urine
samples
were
collected
and
examined
for
chloral
hydrate
(
CH),
trichloroethanol
(
TCOH),

trichloroethanol
glucuronide
(
TCOG),
TCA,
and
DCA.
The
concentration
of
TCA
gradually
increased
and
approached
a
steady
state
over
a
4­
hour
period.
The
blood
AUC
for
TCA
was
26.8,
368,
and
818
µ
mol­
hour/
L
at
doses
of
10,
100,
and
300
mg/
kg,
respectively.
Significant
amounts
of
DCA
were
found
in
mouse
blood,
although
at
only
a
fraction
(
10­
20%)
of
the
TCA
concentration.
DCA
remained
in
systemic
circulation
over
a
4­
hour
period
and
mimicked
the
shape
of
the
TCA
concentration­
time
curve.
Based
on
unpublished
data
that
the
half­
life
of
DCA
in
mice
is
only
12
minutes,
the
authors
stated
that
the
continued
persistence
of
DCA
in
the
presence
of
TCA
suggested
that
DCA
formation
is
dependent
on
TCA
kinetics,
implying
that
DCA
is
formed
from
TCA.

Recent
evidence
calls
into
question
whether
DCA
is
a
metabolite
of
TCA,
or
at
least
the
degree
of
conversion.
Lash
et
al.
(
2000)
discussed
the
evidence
surrounding
this
controversy.

According
to
this
review,
Larson
and
Bull
(
1992)
may
have
over­
reported
DCA
concentrations
in
male
F344
and
B6C3F1
mice,
possibly
due
to
the
method
used
for
DCA
analysis.
Ketcha
(
1996,

as
cited
in
Lash,
2000)
suggested
that
the
analytical
methods
used
in
the
earlier
studies
might
have
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
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HECD
III­
23
Draft,
do
not
cite
or
quote
resulted
in
conversion
of
TCA
in
biological
samples
to
DCA,
and
led
to
over­
estimation
of
the
formation
of
DCA.
Based
on
these
reports,
Lash
et
al
(
2000)
concluded
that
the
"
true"

concentrations
of
DCA
in
biological
samples
reported
in
these
earlier
animal
studies
are
likely
to
be
lower
than
the
reported
values,
due
to
analytical
artifacts.
Thus,
the
degree
(
if
any)
of
TCA
metabolism
to
DCA
remains
unclear.

The
extent
of
TCA
metabolism
to
DCA
may
also
be
species­
dependent.
Volkel
(
1998)

exposed
3
male
and
3
female
volunteers,
along
with
Wistar
rats
(
3/
sex)
to
10,
20,
or
40
ppm
perchloroethene
(
tetrachloroethylene)
for
6
hours
via
inhalation
and
measured
metabolites
in
the
urine.
TCA
was
the
major
metabolite
recovered
in
the
urine
of
both
humans
and
rats,
with
urinary
excretion
being
more
rapid
in
rats
as
compared
with
humans.
Blood
concentrations
of
TCA
in
rats
were
also
consistently
much
higher
than
blood
concentrations
in
humans.
DCA
was
found
in
the
rat
urine
at
about
one­
tenth
the
concentration
of
TCA,
but
was
not
detected
in
any
of
the
human
urine
samples.
The
authors
concluded
that
levels
of
DCA
in
rat
blood
were
too
high
to
be
solely
due
to
TCA
metabolism.

Recent
evidence
has
suggested
that
rats
have
a
limited
capacity
for
TCA
metabolism.

Schultz
(
1999)
compared
renal
and
blood
clearance
of
TCA
following
a
single­
dose
of
500
µ
mol/
kg
administered
intravenously
administration
to
male
F344
rats
and
reported
blood,
renal,

and
nonrenal
clearance
rates
of
92.5,
42.1,
and
50.4
mL/
hr­
kg,
respectively.
Approximately
46%

of
the
clearance
of
TCA
from
the
blood
was
accounted
for
by
renal
clearance,
and
excretion
of
Addendum
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Draft,
do
not
cite
or
quote
TCA
in
the
feces
was
negligible.
Therefore,
as
much
as
54%
of
the
removal
of
TCA
from
the
blood
could
be
accounted
for
by
either
metabolism
or
tissue
sequestration.
No
data
were
provided
to
determine
the
degree
of
metabolism
in
different
tissues.
The
high
oral
bioavailability
of
TCA
suggests,
however,
that
the
liver
may
have
limited
ability
to
metabolize
TCA,
supporting
the
idea
that
tissue
sequestration
may
account
for
non­
renal
clearance
of
intravenously,
as
well
as
orally,
administered
TCA.

TCA
was
poorly
metabolized
in
F344
rats
given
IV
injections
of
radiolabeled
[
1­
14C]
TCA
at
doses
of
0,
6.1,
61,
or
306
µ
mol/
kg
(
0,
1,
10,
or
50
mg/
kg)
(
Yu,
2000).
Although
the
fraction
of
the
administered
radioactivity
excreted
in
the
urine
at
24
hours
post­
dosing
was
as
much
as
84%
at
the
high
dose,
HPLC
analyses
of
plasma,
urine,
and
liver
homogenate
were
unable
to
detect
any
of
the
reported
metabolites
of
TCA
(
oxalate,
DCA,
glyoxalate
or
glycolate).

Nevertheless,
about
8­
12%
of
the
radioactivity
was
eliminated
in
exhaled
air
as
CO
2,
indicating
that
some
TCA
was
metabolized.
Intravenous
administration
of
TCA
also
resulted
in
a
significant
increase
in
non­
extractable
[
1­
14C]­
label
in
the
liver
and
plasma.
The
non­
extractable
radiolabel
was
considered
by
the
authors
to
represent
metabolites
biologically
incorporated
into
hepatic
macromolecules
which
were
either
retained
in
the
liver
or
secreted
into
plasma.
Alternatively,
the
radiolabeled
carbon
may
have
been
covalently
bound
to
macromolecules
in
liver
plasma.
The
amount
of
TCA
metabolized
in
24
hours,
including
excretion
in
exhaled
air
and
non­
extractable
binding
in
the
liver
and
plasma,
was
estimated
to
be
less
than
20%
of
the
total
administered
dose.
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
25
Draft,
do
not
cite
or
quote
Few
data
are
available
on
enzyme
pathways
that
might
play
a
role
in
the
metabolism
of
TCA.
Pravacek
(
1996)
evaluated
the
hepatotoxicity
of
DCA
and
TCA
on
liver
slices
from
male
B6C3F1
mice,
as
well
as
the
metabolic
capacity
of
the
liver
for
these
two
compounds.
In
the
studies
evaluating
cytotoxicity
(
as
evidenced
by
potassium
content
and
liver
enzyme
leakage),
the
liver
slices
were
exposed
for
up
to
8
hours
at
concentrations
of
TCA
ranging
from
0
to
86
mM
(
14
mg/
mL)
TCA.
To
determine
if
TCA
treatments
can
alter
phase
I
or
phase
II
biotransformations,
the
liver
slices
were
exposed
to
a
low
or
high
concentration
of
DCA
or
TCA,

and
the
conversion
of
7­
ethoxycoumarin
to
7­
hydroxycoumarin
(
a
measure
of
phase
I
metabolism),
and
formation
of
sulfate
and
glucuronide
conjugates
of
hydroxycoumarin
(
a
measure
of
phase
II
metabolism)
were
assessed.
TCA
treatment
with
1000
µ
g/
mL
increased
phase
I
metabolism,
but
had
no
effect
on
phase
II
metabolism
at
either
25
or
1000
µ
g/
mL.
Metabolism
of
TCA
was
monitored
by
the
rate
of
removal
of
the
parent
compound.
The
removal
of
TCA
was
not
saturable
at
non­
cytotoxic
concentrations
over
the
range
of
concentrations
tested
(
0
to
5000
µ
g/
mL);
thus
neither
the
K
m
(
the
concentration
at
which
half­
maximal
metabolic
rate
is
reached)

or
V
max
(
maximum
metabolic
rate)
was
estimated.
In
contrast,
DCA
metabolism
was
saturable.

Based
on
this
difference
in
kinetics,
the
study
authors
suggested
that
TCA
and
DCA
might
be
metabolized
through
distinct
pathways,
a
finding
consistent
with
recent
data
demonstrating
that
the
primary
metabolic
pathway
for
DCA
is
NADPH
and
GSH­
dependent
(
e.
g.,
Lipscomb
et
al.,

1995;
Cornett
et
al.,
1997,
1999),
whereas
that
of
TCA
appears
to
be
mediated
by
cytochrome
P­

450
pathways.
However,
the
study
authors
noted
that
an
alternative
explanation
for
these
data
is
that
both
TCA
and
DCA
share
a
single
metabolic
pathway
which
has
a
lower
capacity
for
DCA.
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
26
Draft,
do
not
cite
or
quote
Ni
(
1996)
studied
the
mechanism
of
TCA­
induced
hepatic
toxicity
in
an
in
vitro
system.

Incubation
of
TCA
with
male
B
6C3F1
mouse­
liver
microsomes
resulted
in
free­
radical
generation
and
lipid
peroxidation.
Lipid­
peroxidation
products
that
were
observed
included
acetaldehyde,
formaldehyde,
malondialdehyde,
acetone,
and
propionaldehyde.
Incubation
with
liver
microsomes
from
mice
pretreated
with
pyrazole,
a
specific
cytochrome
P450
2E1
(
CYP2E1)

enzyme
inducer,
induced
about
2­
fold
higher
lipid
peroxidation.
The
authors
also
reported
that
in
the
same
experimental
system,
the
same
molar
concentration
of
chloral
hydrate
(
CH)
induced
lipid
peroxidation
to
the
same
extent
as
TCA,
and
the
CH­
induced
lipid
peroxidation
could
be
inhibited
by
2,4­
dichloro­
6­
phenylphenoxyethylamine,
a
general
cytochrome
P450
inhibitor.
Thus,
the
authors
suggested
that
cytochrome
P450
is
the
enzyme
system
responsible
for
metabolic
activation
of
TCA,
and
that
CYP2E1
might
be
the
primary
isoform
responsible
for
this
metabolism.

In
order
to
determine
if
TCA­
induced
lipid
peroxidation
(
see
study
summary
in
Chapter
V)
is
due
to
the
formation
of
radical
intermediates
following
dehalogenation
of
TCA
by
cytochrome
P450
enzymes,
Austin
(
1995)
evaluated
the
effects
of
pretreating
mice
with
TCA.

Male
B6C3F1
mice
were
pretreated
with
1000
mg/
L
(
estimated
to
be
228
mg/
kg/
day
by
the
study
authors)
TCA
in
drinking
water
for
14
days,
then
administered
300
mg/
kg
of
TCA,
DCA,
or
an
equivalent
volume
of
distilled
water
(
control)
by
gavage
as
an
acute
challenge.
Animals
were
sacrificed
9
hours
following
the
acute
challenge,
and
lipid
peroxidation,
peroxisome
proliferation,

and
TCA­
induced
changes
in
phase
I
metabolism
were
measured.
Measures
of
phase­
I
Addendum
to
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Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
27
Draft,
do
not
cite
or
quote
metabolism
included
(
1)
changes
in
12­
hydroxylation
of
lauric
acid
(
an
assay
specific
for
CYP4A
isoform
activity,
which
is
believed
to
be
associated
with
induction
of
peroxisome
proliferation
in
rats
and
mice
(
Gibson,
1989);
(
2)
changes
in
p­
nitrophenol
hydroxylation
(
an
assay
specific
for
CYP2E1
activity);
(
3)
immunoblot
analysis
for
induction
of
cytochrome
P450
isoforms
CYP2E1,

CYP4A,
CYP1A1/
2,
CYP2B1/
2,
and
CYP3A1;
and
(
4)
total
liver
P450.
Pretreatment
with
TCA
increased
12­
hydroxylation
of
lauric
acid,
demonstrating
an
increase
in
CYP4A
activity
(
and
apparently
reflecting
a
peroxisome­
proliferation
response),
whereas
p­
nitrophenol
hydroxylation
was
unchanged,
indicating
no
effect
on
CYP2E1
activity.
Immunoblot
analysis,
a
measure
of
the
amount
of
a
protein,
was
consistent
with
the
increase
in
CYP4A
activity.
Increased
band
intensities
on
the
immunoblot
appeared
to
occur
at
locations
corresponding
to
those
which
have
been
identified
as
the
CYP4A2
and
CYP4A3
isoform
bands.
Similarly,
immunoblot
analysis
was
consistent
with
the
absence
of
an
effect
on
CYP2E1
activity,
and
also
showed
no
changes
in
CYP1A1/
2,
2B1/
2,
and
3A1
protein
levels.
TCA
pretreatment
did
not
alter
the
overall
amount
of
total
liver
microsomal
P450.
These
data
demonstrate
that
pretreatment
of
mice
with
TCA
modifies
the
lipoperoxidative
responses
(
described
in
Chapter
V)
following
acute
challenge.
The
authors
suggested
that
this
results
from
activities
associated
with
peroxisome
proliferation
and
might
be
related
to
a
shift
in
the
expression
of
P450
isoforms.
The
increased
levels
of
CYP4A
in
TCA­
pretreated
mice
is
consistent
with
results
observed
in
other
studies
with
other
peroxisome
proliferators
(
Okita,
1992).
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
28
Draft,
do
not
cite
or
quote
TCA
may
be
converted
to
DCA
in
situ
in
the
gastrointestinal
tract
of
mice
(
Moghaddam,

1996,
1997).
Microflora
from
the
cecum
of
B6C3F1
mice
were
shown
to
be
able
to
metabolize
TCA
under
anaerobic
conditions.
As
further
evidence
for
the
microbial
metabolism
of
TCA
in
the
gut,
mice
depleted
of
microflora
by
antibiotic
treatment
and
then
treated
with
TCE
had
higher
gut­
TCA
levels
and
lower
gut­
DCA
levels
than
control
mice
receiving
similar
oral
doses
of
TCE
without
an
antibiotic.

Although
the
metabolism
of
TCA
to
DCA
has
been
proposed
(
Larson
and
Bull,
1992),
the
degree
to
which
this
reaction
occurs
has
been
debated
(
Lash,
2000),
and
the
mechanism
of
dehalogenation
of
TCA
has
not
been
conclusively
determined.
The
metabolism
of
both
TCA
and
DCA
to
similar
downstream
metabolites,
as
described
in
this
paragraph,
suggests
that
they
may
be
sequential
metabolites
in
the
same
pathway.
For
this
reason,
a
brief
summary
of
DCA
metabolism
is
included
here.
For
a
more
detailed
analysis
of
data
on
DCA
metabolism
the
reader
is
referred
to
the
Drinking
Water
Criteria
Document
for
DCA
(
U.
S.
EPA,
2001a).
DCA
is
essentially
completely
eliminated
by
metabolism,
undergoing
metabolic
conversion
via
dechlorination
and
oxygenation
to
yield
glyoxylate,
oxalate,
carbon
dioxide,
and
several
glycine
conjugates,
including
hippuric
acid
(
Crabb,
1981;
Evans
and
Stacpoole,
1982;
Lin,
1993;
James,
1998).
In
vitro
experiments
have
demonstrated
that
conjugation
with
glutathione
(
GSH)
is
the
primary
metabolic
conversion
pathway
for
DCA
in
B6C3F1
mouse,
F344
rat,
and
human­
liver
cytosol
(
Lipscomb,

1995;
James,
1997).
The
glutathione­
dependent
oxygenation
of
DCA
to
form
the
initial
major
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
29
Draft,
do
not
cite
or
quote
metabolite,
glyoxylic
acid,
is
catalyzed
by
glutathione­
S­
transferase
Zeta
(
GST­
Zeta)
(
Tong,

1998a;
Tong,
1998b).

In
summary,
the
metabolism
of
TCA
has
not
been
well­
characterized.
While
several
studies
have
suggested
that
TCA
is
metabolized
to
DCA
in
mice
(
Larson
and
Bull,
1992;
Abbas,

1996),
concerns
regarding
potential
over­
estimation
of
DCA
formation
reduce
confidence
in
these
findings
(
Lash,
2000).
TCA
appears
to
be
metabolized
to
only
a
limited
extent
in
rats
(
Schultz,

1999;
Toxopeus
and
Frazier,
1998;
Yu,
2000).
TCA
may
also
be
metabolized
differently
in
humans
than
in
rodents
(
Lash,
2000).
Enzyme
systems
responsible
for
TCA
metabolism
have
not
been
identified
in
vivo,
but
in
vitro
experiments
with
mouse
tissues
have
provided
limited
evidence
for
involvement
of
a
cytochrome
P450­
mediated
pathway
(
Ni,
1996;
Prevacek,
1996).

Monochloroacetic
acid
Bhat
(
1990)
suggested
that
MCA
can
undergo
dehalogenation
reactions
leading
to
the
formation
of
oxalate
and
glycine
in
male
Sprague­
Dawley
rats.
The
mechanism
for
removal
of
chlorine
from
MCA
was
not
described.
This
study
also
indicated
that
MCA
can
form
a
glutathione
conjugate,
which
after
further
degradation
is
excreted
in
the
urine.
In
another
rat
study
(
Bhat
and
Ansari,
1989),
MCA
was
found
to
react
with
lipids,
based
on
the
appearance
of
cholesteryl
chloroacetate
in
neutral
lipid
fractions
from
hepatic
lipid
extracts
from
treated
rats.

Figure
III­
2
presents
the
proposed
metabolism
for
MCA.
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
30
Draft,
do
not
cite
or
quote
Cl
Cl
GSCH
2
COOH
SCH
2
COOH
CH
2
CH
COOH
NH
2
SCH
2
COOH
CH
2
COOH
ClCH
2­
COOH
MCA
Cholesteryl
Chloroacetate
COOH
COOH
Oxalic
Acid
+
COOH
CH
2
NH
2
Glycine
Glutathione
(
GS)

S­
carboxylmethyl
glutathione
S­
carboxylmethyl
cysteine
Thiodiacetic
acid
Figure
III­
2.
Proposed
metabolic
pathway
of
MCA
(
Adapted
from
Bhat,
1990)
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
31
Draft,
do
not
cite
or
quote
In
the
Kaphalia
(
1992)
study,
the
distribution
of
radioactivity
in
plasma,
red
blood
cells,

plasma
proteins,
and
major
organs
and
tissues
was
determined
24
hours
following
a
single
oral
dose
of
either
100
or
1000
µ
mol/
kg
[
1­
14C]
MCA
(
approximately
10
and
100
mg/
kg,
respectively)

or
following
administration
of
1000
µ
mol/
kg
[
1­
14C]
MCA
(
approximately
100
mg/
kg)
daily
for
3
days.
About
50%
of
the
total
radioactivity
in
the
plasma
appeared
to
bind
with
plasma
protein
in
the
single­
dose,
low­
dose
group.
Plasma
protein
binding
was
significantly
higher
in
both
single
and
repeated­
dosing
high­
dose
groups,
with
the
bound
radiolabel
constituting
approximately
73%

and
79%
of
total
plasma
radiolabel
for
the
single­
and
multiple­
dose
groups,
respectively.

Affinity
chromatography
indicated
that
approximately
65%
of
the
total
plasma
radiolabel
was
associated
with
albumin
in
the
both
high­
dose
groups.
Although
MCA
was
absorbed
and/
or
eliminated
at
a
rapid
rate,
as
demonstrated
by
the
distribution
of
the
radiolabel
in
intestine
and
kidney
(
and
its
urinary
excretion),
absorption
and
elimination
phases
were
increased
in
other
tissues
including
liver,
lung,
and
heart,
as
evidenced
by
retention
of
significant
radiolabel
at
48
hours
following
exposure.
The
authors
hypothesized
that
these
results
might
be
due
to
MCA
conjugation
with
cholesterol
or
phospholipids
as
proposed
by
Bahat
and
Ansari,
(
1988)
and
Bahat
et
al
(
1990),
and
incorporation
of
glycine
into
proteins.
The
authors
did
not
rule
out
the
possibility
of
metabolic
incorporation
of
the
 ­
carbon
atom
into
plasma
protein
via
metabolism
of
MCA
to
glycine.
However,
they
concluded
that
the
contribution
of
this
pathway
to
MCA
metabolism
was
minor.
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
32
Draft,
do
not
cite
or
quote
In
the
Saghir
(
2001)
kinetics
study,
blood,
urine,
and
feces
samples
were
collected
and
assessed
for
total
radioactivity
and
parent
MCA
in
both
the
subtoxic
(
10
mg/
kg)
and
toxic
(
75
mg/
kg)
dose
groups.
The
presence
of
metabolite(
s)
was
determined
by
assessing
the
difference
between
total
radioactivity
and
parent
MCA.
For
bile
analysis,
additional
rats
(
number
not
specified)
were
treated
with
10
mg/
kg
MCA,
and
anesthetized
30
minutes
following
MCA
administration.
The
bile
duct
was
cannulated,
bile
was
collected
for
a
period
of
1
hour
and
analyzed
for
metabolite(
s).
Decreased
biotransformation
at
the
toxic
dose
was
noted
at
early
time
points
(
within
2
hours
post
dosing),
as
indicated
by
significantly
lower
biliary
excretion
of
the
metabolite(
s)
(
up
to
28%
less
than
at
the
subtoxic
dose)
and
higher
urinary
excretion
of
the
parent
MCA.
The
time
course
of
decreased
biotransformation
and
increased
retention
of
radioactivity
in
tissues
was
associated
with
the
time
of
onset
of
severe
toxicity
and/
or
lethality,
which
occurred
between
40
and
70
minutes
following
dosing
with
75
mg/
kg.
Rats
surviving
this
time
period
retained
a
larger
quantity
of
metabolite(
s)
in
the
GIT
and
lower
plasma
and
tissue
radioactivity
than
rats
dying
from
toxicity.
Metabolites
were
not
identified.
However,
radioactivity
found
in
bile
was
primarily
associated
with
one
major
unidentified
metabolite
that
was
more
polar
than
the
parent
compound;
the
authors
suggested
that
this
metabolite
was
a
glutathione
conjugate.
The
authors
also
concluded
that
the
rate­
determining
step
in
the
toxicity
of
MCA
is
its
detoxification
by
the
liver,
and
that
the
abrupt
onset
of
severe
toxicity
and/
or
death
observed
in
the
75
mg/
kg
group
was
a
consequence
of
the
rapid
overwhelming
of
the
detoxification
capacity
of
the
liver
via
metabolic
saturation.
These
conclusions
indicate
that
the
authors
consider
the
parent
MCA
to
be
the
active
toxic
moiety.
Alternatively,
MCA­
induced
toxicity
might
be
associated
with
the
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
33
Draft,
do
not
cite
or
quote
formation
of
lipophilic
metabolites
resulting
from
the
metabolism
of
the
parent
compound.
It
has
been
suggested
that
MCA
can
alkylate
free
amino
and
thiol
groups
of
amino
acids,
especially
under
conditions
of
glutathione
depletion
(
Hayes
et
al.,
1973).

Several
recent
studies
on
MCA
metabolism
provide
conflicting
evidence
regarding
the
involvement
of
glutathione
in
MCA
metabolism.
Previous
work
has
demonstrated
that
the
glutathione
conjugate,
2­
S­
glutathionyl
acetate,
was
produced
from
rat­
liver
microsomal
incubation
and
may
result
from
reaction
of
glutathione
with
MCA
(
Liebler,
1985).
To
further
explore
this
metabolic
pathway,
Dowsley
et
al.
(
1995)
studied
microsomal
incubations
of
MCA
and
glutathione.
They
found
that
the
glutathione
conjugate
did
not
form
under
these
conditions.

However,
the
authors
also
noted
that
they
could
not
exclude
the
possibility
of
interactions
of
MCA
and
glutathione
in
vivo.

Wijeweera
(
1998)
studied
the
effects
of
MCA
alone
or
with
1,1­
dichloroethylene
(
vinylidene
chloride)
in
Sprague­
Dawley
rat­
liver
slices
in
vitro.
Incubation
with
100
µ
M
MCA
resulted
in
a
depletion
of
glutathione
levels
that
was
statistically
significant
for
the
first
3
hours
of
exposure
(
decreased
by
37,
39,
and
45%
compared
to
control
levels
at
1,
2,
and
3
hours
of
treatment,
respectively).
This
concentration
of
MCA
had
no
effect
on
potassium
ion
release
from
cells
(
a
measure
of
cytotoxicity),
the
appearance
of
centrilobular
necrosis,
or
heat­
shock
protein
expression.
In
the
co­
treatment
experiments,
MCA
markedly
potentiated
the
hepatotoxicity
of
1,1­
dichloroethylene,
as
measured
by
potassium
ion
release,
centrilobular
necrosis,
and
heat­
shock
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
34
Draft,
do
not
cite
or
quote
protein
expression,
suggesting
that
depletion
of
cellular
glutathione
by
MCA
may
enhance
1,1­

dichloroethylene
toxicity.

Taken
together,
data
from
the
in
vivo
studies
of
Bhat
(
1990),
Bhat
and
Ansari
(
1989),

and
Saghir
(
2001)
suggest
that
MCA
may
form
glutathione
conjugates.
These
data
are
supported
to
some
extent
by
the
results
from
incubation
studies
with
tissue­
liver
slices
(
Wijeweera,
1998)
demonstrating
MCA­
associated
glutathione
depletion.
However,
glutathione
depletion
might
have
been
associated
with
other
factors
in
the
Wijeweera
(
1998)
experiments,

and
direct
measurements
in
in
vitro
studies
(
Dowsley,
1995)
did
not
find
evidence
for
glutathione
conjugation.
Therefore,
the
degree
to
which
MCA
conjugates
with
glutathione,
and
under
what
conditions,
is
not
known.

D.
Excretion
Trichloroacetic
acid
No
full
toxicokinetics
studies
were
identified
for
humans.
However,
TCA
in
urine
is
often
measured
as
a
biomarker
for
chlorinated­
solvent
exposure
or
exposure
to
disinfectant
by­
products
as
described
previously
in
the
distribution
section.
In
addition,
the
therapeutic
use
of
chloral
hydrate,
of
which
TCA
is
a
metabolite,
has
also
yielded
information
on
the
plasma
elimination
of
TCA.
Breimer
(
1974)
reported
that,
following
oral
administration
of
a
single
15
mg/
kg
dose
of
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
35
Draft,
do
not
cite
or
quote
chloral
hydrate
to
a
human
volunteer,
TCA
levels
in
blood
increased
rapidly
(
consistent
with
the
rapid
metabolism
of
chloral
hydrate
to
TCA)
and
were
maintained
for
up
to
9
hours
without
decreasing.
The
authors
noted
that
this
observation
was
consistent
with
a
long
half­
life
of
TCA
in
humans
of
up
to
4­
5
days.
The
slow
elimination
rate
in
humans
was
consistent
with
the
plasma
half­
life
of
approximately
5.5
days
observed
by
these
same
authors
in
a
dog
given
a
single
IV
dose
of
60
mg/
kg
chloral
hydrate.
Humbert
(
1994)
also
reported
on
the
plasma
clearance
of
TCA
as
part
of
a
human
pharmacokinetic
study
of
chloral
hydrate.
Plasma
levels
of
TCA
were
measured
for
3
hours
after
a
single
dose
of
40
mg/
kg
of
chloral
hydrate
in
a
neonate
(
age
and
sex
not
given),
and
for
14
days
after
a
single
dose
of
6.25
mg/
kg
in
an
adult
(
age
and
sex
not
given).

Dosing
route
was
not
reported
for
either
case.
In
the
neonate,
the
plasma
level
of
TCA
continued
to
rise
throughout
the
3­
hour
sample
period;
sampling
did
not
continue
long
enough
to
estimate
an
elimination
half­
life.
The
reported
TCA
half­
life
in
the
adult
was
4220
minutes
(
2.9
days).

Both
of
these
human
studies
(
Breimer,
1974;
Humbert,
1994)
suggest
that
TCA
is
long­
lived
in
the
plasma.
However,
only
limited
conclusions
regarding
TCA
elimination
can
be
drawn
from
these
studies.
The
observed
plasma­
elimination
rate
of
TCA
is
affected
by
the
rate
of
its
formation
from
chloral
hydrate
and
from
trichloroethanol,
another
major
chloral­
hydrate
metabolite,
and
by
the
inherent
elimination
rate
of
TCA.
Although
chloral
hydrate
is
rapidly
cleared
from
plasma,
trichloroethanol
displays
slower
removal
kinetics.
Since
TCA
is
a
metabolite
of
trichloroethanol,
the
long
plasma
half­
life
of
TCA
could
in
part
reflect
the
rate
of
trichloroethanol
metabolism
in
the
presence
of
either
trichlorethanol
or
chloral
hydrate.
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
1
C.
P.
Weisel,
Robert
Wood
Johnson
Medical
School,
Piscataway,
NJ.

EPA/
OW/
OST/
HECD
III­
36
Draft,
do
not
cite
or
quote
In
contrast
to
the
slow
TCA
elimination
observed
secondary
to
chloral
hydrate
metabolism,
rapid
elimination
kinetics
of
TCA
were
reported
in
humans
following
low­
dose
exposure
to
TCA
from
swimming­
pool
water.
Kim
and
Weisel
(
1998)
reported
rapid
clearance
of
TCA
following
dermal­
only
or
dermal­
plus­
oral
exposures
from
swimming­
pool
water.
In
one
set
of
exposures,
four
subjects
(
two/
sex)
walked
around
in
the
pool
(
dermal
exposure
only)
and
in
another
set
of
exposures,
the
same
four
subjects
swam
(
dermal
exposure
and
presumed
oral
exposure
from
incidental
ingestion
of
pool
water
during
swimming).
TCA
levels
in
the
urine
void
collected
5
to
10
minutes
after
the
30­
minute
exposure
in
the
pool
were
elevated
and
generally
returned
to
pre­
exposure
levels
within
3
hours.
Post­
exposure
urinary
excretion
of
TCA
was
1.1­

to
3.9­
fold
higher
than
background
excretion
levels,
as
estimated
from
TCA
levels
in
urine
voided
during
the
3
hours
prior
to
pool­
water
exposures.
Estimated
dermal
exposure
to
TCA
(
based
on
the
product
of
exposure
duration
and
TCA
concentration
in
the
pool
water)
was
positively
correlated
with
the
urinary
levels
of
this
compound.
The
authors
suggested
(
Weisel,
personal
communication)
1
that,
although
other
studies
have
reported
a
relatively
slow
elimination
rate
following
oral
or
inhalation
TCA
exposures
(
Breimer,
1974;
Humbert,
1994;
Volkel,
1998),
the
rapid
elimination
rate
observed
in
the
swimming­
pool
study
likely
resulted
from
route­
dependent
and
dose­
dependent
differences
in
TCA
kinetics.
TCA
pool
water
concentrations
were
low,

ranging
from
57
to
871
µ
g/
L,
with
a
mean
of
420
µ
g/
L
and
a
median
of
278
µ
g/
L.
These
dermal
exposures
resulted
in
doses
on
the
order
of
1
µ
g,
compared
with
doses
on
the
order
of
1
mg/
kg
in
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
37
Draft,
do
not
cite
or
quote
the
oral
studies.
This
low
dermal
dose
would
be
rapidly
excreted
by
the
kidneys
before
being
available
for
uptake
by
the
liver
as
occurs
following
oral
dosing.

Blood
elimination
half­
lives
of
TCA
are
fairly
rapid
in
rodents.
Blood
elimination
halflives
ranged
from
5.4
to
6.0
hours
for
male
B6C3F1
mice
administered
oral
gavage
doses
of
0.03,

0.12,
or
0.61
mmol/
kg
TCA
(
corresponding
to
5,
20,
and
100
mg/
kg)
(
Templin,
1993).
Similar
results
were
reported
by
Schultz
(
1999),
who
reported
that
the
elimination
half­
life
was
8
hours
for
F344
rats
after
IV
administration
of
500
µ
mol/
kg
(
82
mg/
kg)
of
TCA.

A
comparative
toxicokinetics
study
by
Volkel
(
1998)
suggests
that
there
are
differences
in
the
elimination
rate
of
TCA
between
rats
and
humans.
Human
volunteers
(
3/
sex)
and
Wistar
rats
(
3/
sex)
were
exposed
to
10,
20,
or
40
ppm
perchloroethene
(
tetrachloroethylene)
for
a
6­
hour
inhalation­
exposure
period.
The
blood
and
urine
levels
of
TCA,
a
major
metabolite
of
tetrachloroethylene,
were
evaluated
in
this
study.
Blood
levels
of
TCA
in
humans
were
approximately
10­
fold
lower
than
in
rats
immediately
after
the
exposure
to
40
ppm
tetrachloroethylene,
perhaps
reflecting
species
differences
in
the
absorbed
dose
of
the
parent
compound
or
differences
in
the
rate
of
formation
of
metabolites,
including
TCA,
from
tetrachloroethylene.
In
humans
exposed
to
40
ppm
tetrachloroethylene,
blood
levels
of
TCA
immediately
following
the
6­
hour
exposure
period
were
similar
to
those
measured
at
24
hours
post­
exposure,
suggesting
slow
clearance
of
TCA
from
the
blood.
In
contrast,
TCA
blood
concentrations
in
rats
at
24
hours
post­
exposure
were
decreased
to
36%
of
TCA
levels
measured
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
38
Draft,
do
not
cite
or
quote
immediately
following
exposure
to
the
40
ppm
tetrachloroethylene
for
6
hours.
These
results
suggest
that
rats
clear
TCA
from
the
blood
more
rapidly
than
do
humans.
Differences
in
urinary
elimination
of
TCA
in
rats
and
humans
were
also
observed.
The
cumulative
urinary
excretion
of
TCA
was
dose­
dependent
in
both
rats
and
humans,
but
the
cumulative
urinary
excretion
of
TCA
relative
to
body
weight
over
the
period
measured
(
78
hours
for
humans
and
72
hours
for
rats)
was
much
greater
for
rats
than
for
humans,
more
than
10­
fold
on
a
body
weight
basis.
The
finding
that
urinary
TCA
excretion
relative
to
body
weight
is
higher
in
rats
is
consistent
with
the
more
rapid
plasma
clearance
observed
in
these
rats.
However,
interpretation
of
these
data
in
terms
of
estimating
TCA
elimination
is
limited,
because
the
apparent
species
differences
in
TCA
clearance
might
reflect
differences
in
the
internal
dose
of
the
parent
compound
(
due
to
differences
in
systemic
absorption
of
the
inhaled
dose
and/
or
differences
in
the
metabolism
of
tetrachloroethylene
to
TCA)
or
true
differences
in
the
rate
of
TCA
excretion.
Urinary
excretion
was
more
rapid
in
the
rat,
as
indicated
by
a
mean
elimination
half­
life
in
urine
of
45.6
hours
in
humans
as
compared
with
11.0
hours
in
rats.
The
authors
suggested
that
the
slow
rate
of
TCA
excretion
in
humans
reflects
the
high
degree
of
TCA
binding
to
plasma
proteins.
The
variability
in
cumulative
TCA
excretion
or
excretion
rate
was
low
for
the
6
human
volunteers.
For
example,

the
coefficient
of
variation
for
the
urinary
elimination
half­
life
was
only
5.4%.
The
slower
urinary
and
blood
clearance
of
TCA
in
humans
suggests
that
for
a
given
internal
dose
of
TCA,
humans
are
likely
to
have
a
longer
systemic
exposure
to
TCA
than
rats.

The
toxicokinetics
studies
in
animals
show
that
the
major
route
of
excretion
of
TCA
is
in
the
urine,
with
a
minor
amount
exhaled
as
CO
2.
Mice
and
rats
given
single
oral
doses
of
TCA
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
39
Draft,
do
not
cite
or
quote
exhibited
similar
patterns
of
excretion
over
24
hours
(
mice)
or
48
hours
(
rats)
(
Larson
and
Bull,

1992).
Urinary
excretion
accounted
for
57­
72%
of
the
administered
dose,
roughly
90%
of
which
was
eliminated
as
TCA.
Other
urinary
metabolites
identified
included
glyoxylic
acid,
oxalic
acid,

and
glycolic
acid.
Exhalation
of
CO
2
accounted
for
5­
11%
of
the
administered
compound.

However,
concerns
about
the
analytical
methods
used
in
this
study
limit
confidence
in
the
results.

Experiments
in
mongrel
dogs
revealed
that
biliary
excretion
was
minimal
over
periods
up
to
2
hours
after
IV
administration
of
TCA
(
Hobara,
1986).

More
recent
studies
on
the
excretion
of
TCA
have
resulted
in
similar
findings.
Schultz
(
1999)
measured
parent­
compound
concentrations
in
the
blood,
urine,
and
feces
24
hours
after
oral
or
IV
dosing
of
male
F344
rats
with
500
µ
mol/
kg
TCA
(
82
mg/
kg).
The
urine
was
the
major
contributor
to
blood
clearance,
while
feces
made
a
minimal
contribution.
Apparent
renal
clearance
of
the
parent
compound
accounted
for
only
46%
of
the
total
clearance.
(
However,

some
of
the
apparent
renal
clearance
was
probably
attributable
to
tissue
binding.)
Putative
metabolites
of
TCA
were
not
measured,
and
neither
was
the
release
of
CO
2.
Therefore,
it
is
not
possible
to
determine
the
contribution
of
each
route
of
excretion
to
the
total
administered
dose
of
the
parent
compound.

Yu
(
2000)
also
reported
that
the
major
route
of
TCA
excretion
was
the
urine
following
IV
injection
of
radiolabeled
[
1­
14C]
TCA
at
doses
of
0,
6.1,
61
or
306
µ
mol/
kg
(
0,
1,
10,
or
50
mg/
kg)
in
male
F344
rats.
Within
9
hours
post­
injection,
approximately
35­
58%
of
the
TCA­
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
2
John
M.
Frazier,
Wright­
Patterson
Air
Force
Base,
Ohio
EPA/
OW/
OST/
HECD
III­
40
Draft,
do
not
cite
or
quote
associated
radioactivity
was
excreted
in
the
urine
at
all
three
dose
levels;
at
24
hours
postexposure
the
cumulative
urinary
excretion
had
increased
to
47­
84%
(
as
estimated
from
a
figure
in
the
paper
and
confirmed
by
the
senior
study
author
2)
.
Contributions
of
fecal
and
respiratory
excretion
to
the
total
excretion
were
much
lower.
Within
24
hours
post­
injection,
only
4­
7%
of
the
TCA­
associated
radioactivity
was
excreted
in
the
feces,
and
about
8­
12%
was
excreted
in
exhaled
air.
Urinary
excretion
was
rapid
and
dose­
dependent.
At
the
low
dose
of
6.1
µ
mol/
kg
(
1
mg/
kg)
TCA,
the
mean
fraction
of
the
initial
dose
excreted
in
the
urine
was
35%
at
9
hours
postinjection
and
this
percentage
had
increased
to
47%
at
24
hours
following
exposure.
At
the
high
dose
of
306
µ
mol/
kg
(
50
mg/
kg)
TCA,
the
fraction
of
the
initial
dose
excreted
in
urine
was
reported
as
58%
at
9
hours
post­
injection
and
84%
at
24
hours.
In
contrast,
the
percentage
of
administered
TCA
eliminated
via
the
feces
and
exhaled
in
the
breath
decreased
with
increasing
dose.
The
terminal
first­
order
rate
constants
for
TCA
disappearance
from
various
tissues
after
administration
of
6.1
µ
mol/
kg
(
1
mg/
kg)
were
determined.
As
measured
by
TCA­
derived
radioactivity,
elimination
from
the
liver,
small
intestine,
and
large
intestine
was
slower
than
elimination
from
the
plasma,
RBC,
muscle,
and
kidney.

Toxopeus
and
Frazier
(
1998)
investigated
the
kinetics
of
TCA
in
isolated
perfused
rat
liver
(
IPRL)
test
system,
using
livers
from
male
F344
rats.
The
livers
were
perfused
with
either
5
or
50
µ
mol
of
TCA,
and
TCA
concentrations
were
monitored
in
perfusion
medium
and
bile
for
2
hours.

Uptake
of
TCA
was
limited,
as
discussed
above
in
the
Distribution
Section.
The
total
TCA
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
41
Draft,
do
not
cite
or
quote
concentration
in
bile
remained
relatively
constant
throughout
the
exposure
period,
averaging
44
µ
M.
Bile
excretion
was
linear
over
time
and
cumulative
excretion
was
0.1%
of
the
total
dose
by
the
end
of
the
experiment,
suggesting
that
biliary
excretion
contributes
minimally
to
overall
elimination
of
TCA.

In
summary,
the
existing
data
demonstrate
that
urine
is
the
primary
route
of
excretion
of
TCA,
with
exhalation
of
CO
2
and
fecal
excretion
contributing
to
a
much
lesser
extent
(
Hobara,

1986;
Larson
and
Bull,
1992;
Templin
et
al.,
1993;
Schultz
et
al.,
1999;
Yu,
2000).
The
urine
is
also
an
important
route
of
excretion
in
humans,
although
no
quantitative
data
have
been
identified
to
estimate
the
relative
contributions
of
other
routes
of
excretion.
The
uptake
and
elimination
of
TCA
from
the
blood
appears
to
be
considerably
slower
in
humans
as
compared
to
rodents
(
Volkel,
1998;
and
reviewed
in
Lash,
2000).
However,
results
from
these
studies
should
be
treated
with
caution,
since
exposure
was
actually
to
TCE,
a
chemical
metabolized
to
TCA.
Thus,

apparent
species
differences
in
TCA
elimination
could
actually
be
due
to
differences
in
absorption
of
TCE
or
conversion
of
TCE
to
TCA.
Although
human
data
are
very
limited,
they
suggest
the
possibility
that
human
elimination
rates
might
be
route­
and
dose­
dependent.
Slow
removal
kinetics
in
humans
were
reported
following
oral
administration
of
chloral
hydrate
(
Breimer,
1974;

Humbert,
1994)
while
rapid
elimination
human
kinetics
were
reported
following
low
doses
resulting
from
acute
dermal
absorption
of
TCA
from
swimming­
pool
water
(
Kim
and
Weisel,

1998).
The
plasma
elimination
rate
is
of
major
significance
for
risk
assessment,
because
slower
elimination
kinetics,
if
true,
would
suggest
that
humans
would
receive
a
higher
cumulative
internal
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
42
Draft,
do
not
cite
or
quote
dose
of
TCA
(
AUC)
than
rodents
at
the
same
administered
dose,
if
absorption
is
similar
in
rodents
and
humans.
However,
the
data
are
insufficient
to
be
useful
in
the
assignment
of
uncertainty
factors
for
animal­
to­
human
extrapolation.

Monochloroacetic
acid
Approximately
50%
of
a
subcutaneous
dose
of
radiolabeled
MCA
was
excreted
in
the
urine
of
male
Sprague­
Dawley
rats
within
17
hours
of
dosing
(
Hayes,
1973).
Kaphalia
(
1992)

reported
that
urinary
excretion
of
MCA
and/
or
its
metabolites
was
rapid
in
male
Sprague
Dawley
rats
administered
a
single
oral
dose
of
100
µ
mol/
kg
(
approximately
10
mg/
kg);
about
90%
of
the
dose
was
excreted
in
the
urine
at
24
hours
postdosing.

In
the
kinetics
study
by
Saghir
(
2001),
blood,
urine,
bile
and
feces
samples
were
collected
and
assessed
for
total
radioactivity
and
parent
MCA.
The
gastrointestinal
tract
(
GIT)
was
separated
into
stomach
(
esophagus
and
stomach),
small
intestine,
and
large
intestine,
and
total
radioactivity
in
each
GIT
segment
(
and
contents)
was
quantitated.
Anuria
was
observed
at
about
4
hours
following
dosing
in
rats
administered
75
mg/
kg,
apparently
due
to
an
inability
to
empty
the
urinary
bladder
rather
than
a
decrease
in
urine
production.
The
rate
of
urinary
excretion
of
both
parent
MCA
and
MCA
metabolites
was
rapid.
Within
45
minutes
of
treatment,
6­
8%
of
both
doses
was
recovered
in
the
urine.
At
16
hours,
73%
and
58%
of
the
10
and
75
mg/
kg
doses,

respectively,
was
recovered
in
the
urine,
indicating
a
slower
rate
of
excretion
at
the
higher,
toxic
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
43
Draft,
do
not
cite
or
quote
dose.
Analysis
of
urine
samples
by
HPLC
indicated
that
parent
MCA
comprised
55%
and
68%

of
the
excreted
radioactivity
at
the10
and
75
mg/
kg
doses,
respectively,
and
that
a
greater
percentage
of
urinary
radioactivity
was
associated
with
metabolite
production
(
as
compared
with
parent
MCA)
at
the
lower
dose.
Very
little
radioactivity
was
excreted
in
the
feces
(
approximately
0.6­
2%).
However,
47%
and
23%
of
the
10
and
75
mg/
kg
doses,
respectively,
was
recovered
from
the
GIT
at
45
minutes
following
treatment,
with
most
of
the
radioactivity
being
retained
in
the
small
intestine.
GIT
radioactivity
was
associated
primarily
with
one
major
(
unidentified)

metabolite.
Rats
treated
with
10
mg/
kg
were
approximately
4
times
more
efficient
in
removing
MCA
metabolites
from
the
liver
into
the
bile
and
from
the
bile
into
the
GIT,
as
compared
with
rats
treated
with
75
mg/
kg.
A
maximum
of
5%
of
the
radioactivity
reached
the
large
intestine,

indicating
that
significant
resorption
occurred
in
the
small
intestine.
The
time
profile
of
MCA
concentrations
in
the
kidney
was
similar
to
that
in
the
GIT
and
was
considered
by
the
authors
to
be
consistent
with
the
hypothesis
that
metabolite(
s)
excreted
with
bile
were
being
resorbed
in
the
small
intestine
and
excreted
in
the
urine
following
further
metabolism.

A
fatal
MCA
poisoning
after
dermal
exposure
to
an
80%
solution
of
MCA
was
reported
by
Kulling
(
1992).
Measurements
of
plasma­
MCA
concentrations
4,
6,
8,
and
12
hours
after
exposure
found
33,
15,
7.8
and
0.22
mg/
L,
respectively.
Based
on
these
data,
MCA
is
rapidly
cleared
from
the
blood
in
humans.
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
44
Draft,
do
not
cite
or
quote
No
new
studies
were
identified
that
evaluated
the
excretion
of
MCA
following
dosing
by
the
inhalation
route.

E.
Bioaccumulation
and
Retention
Trichloroacetic
acid
No
new
studies
were
identified
that
evaluated
the
bioaccumulation
or
retention
of
TCA
following
longer­
term
dosing
by
the
oral,
dermal,
or
inhalation
routes.
The
plasma
elimination
half­
life
in
humans
following
oral
or
inhalation
exposure
to
trichloroethylene,
tetrachloroethylene,

or
chloral
hydrate
suggests
slow
clearance
of
TCA
(
Breimer,
1974;
Humbert,
1994;
Volkel,

1998).
Based
on
this
slow
elimination
rate,
chronic
exposure
to
high
oral
or
inhalation
doses
might
result
in
an
increase
in
internal
doses
of
TCA.
However,
these
data
from
dosing
with
chemicals
that
are
metabolized
to
TCA,
have
limited
utility
in
assessing
TCA
elimination
kinetics
because
the
influence
of
other
factors,
including
other
metabolites
and
alternate
metabolic
pathways
for
the
parent
compounds,
is
not
well­
characterized.
Rapid
TCA
clearance
was
observed
following
low­
dose
exposures
by
the
dermal
route
(
Kim
and
Weisel,
1998),
suggesting
a
limited
potential
for
bioaccumulation
at
doses
likely
to
result
from
environmental
exposures,

and/
or
route­
and
dose­
dependent
differences
in
elimination
and/
or
clearance.

Monochloroacetic
acid
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
45
Draft,
do
not
cite
or
quote
In
the
study
by
Kaphalia
(
1992),
repeated
oral
dosing
(
once
daily
for
three
consecutive
days)
with
1000
µ
mol/
kg
(
approximately
100
mg/
kg)
[
1­
14C]
MCA
resulted
in
an
increase
in
radioactivity
in
most
tissues,
except
for
the
liver
and
the
spleen,
of
male
Sprague­
Dawley
rats
at
24
hours
post­
dosing
as
compared
with
administration
of
a
single
dose
of
1000
µ
mol/
kg
[
1­
14C]

MCA
.
Further,
radioactivity
in
various
tissues
at
24
hours
postdosing
were
1.4
to
3.8­
fold
higher
in
rats
given
a
single
oral
dose
of
1000
µ
mol/
kg
[
1­
14C]
MCA
than
that
observed
in
animals
treated
with
a
single
oral
lower
dose
of
100
µ
mol/
kg
(
approximately
10
mg/
kg)
[
1­
14C]
MCA.

The
authors
concluded
that
tissue
accumulation
occurred
to
some
extent
and
was
both
dose­
and
exposure
duration­
dependent.
The
results
from
the
kinetics
study
by
Saghir
(
2001)
suggest
the
possibility
of
accumulation
or
retention
of
MCA
and/
or
its
metabolites
in
the
brain.
Male
Sprague­
Dawley
rats
were
treated
with
a
single
intravenous
injection
of
10
or
75
mg/
kg
radiolabeled
MCA
(
subtoxic
and
toxic
dose,
respectively).
Following
treatment,
MCA­
derived
radioactivity
in
the
plasma
and
most
other
tissues
declined
over
time
(
measured
at
various
time
points
up
to
16
hours
postdosing).
However,
MCA­
associated
radioactivity
rapidly
entered
the
brain
and
was
retained
there
at
almost
the
same
concentrations
throughout
the
16­
hour
study
period,
with
the
percent
accumulation
being
proportionate
to
the
dose.
MCA­
radioactivity
also
remained
higher
in
thymus
gland
tissue
from
2­
16
hours
following
exposure.
These
data
suggest
that
MCA
and/
or
its
metabolites
may
have
the
potential
to
accumulate
in
brain
tissue
and
the
thymus
gland.
No
new
studies
were
identified
that
evaluated
the
bioaccumulation
or
retention
of
MCA
following
longer­
term
dosing
by
the
oral,
dermal,
or
inhalation
routes.
Based
on
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
46
Draft,
do
not
cite
or
quote
metabolism
studies,
MCA
might
interact
with
lipids
to
form
lipid­
soluble
metabolites
such
as
cholesteryl
chloroacetate
(
Bhat
and
Ansari,
1989).

F.
PBPK
models
Abbas
and
Fisher
(
1997)
developed
PBPK
models
for
TCA
and
DCA
in
B6C3F1
mice
exposed
to
trichloroethylene
through
oral
dosing
(
by
gavage
in
corn
oil),
and
these
models
were
expanded
by
Greenberg
(
1999)
to
include
the
inhalation
route.
The
main
trichloroethylene
PBPK
model
was
linked
to
five
TCE
metabolite
sub­
models,
for
chloral
hydrate,
trichloroethanol,

trichloroethanol
glucuronide,
DCA,
and
TCA.
Each
sub­
model
contained
compartments
for
the
liver,
lung,
kidney,
and
body.
Abbas
and
Fisher
(
1997)
experimentally
determined
the
tissue:
blood
partition
coefficients
for
all
five
TCE
metabolites.
The
model
was
developed
using
literature
values
for
V
max
and
K
m
for
trichloroethylene,
literature
values
for
physiological
parameters,
and
the
experimentally­
determined
tissue
partition
coefficients.
Other
parameters
were
fit
using
data
for
trichloroethylene
and
metabolites
obtained
from
male
B6C3F1
mice
receiving
a
single
gavage
dose
of
1200
mg/
kg
trichloroethylene.
The
model
was
validated
using
the
other
doses
in
the
same
study
(
300,
600,
and
2000
mg/
kg).
Additional
parameters
for
the
inhalation
model
(
Greenberg,
1999)
were
developed
from
male
B6C3F1
mice
exposed
for
4
hours
to
600
ppm
trichloroethylene;
the
model
was
validated
with
data
from
a
separate
inhalation
study
conducted
at
110­
748
ppm
trichloroethylene.
The
TCA
model
adequately
described
the
TCA
concentrations
in
the
liver,
lungs,
kidneys,
and
blood
following
trichloroethylene
exposure,
as
well
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
47
Draft,
do
not
cite
or
quote
as
urinary
excretion
of
TCA
following
oral
and
inhalation
exposure
to
trichloroethylene.
But,
the
DCA
models
did
not
fit
the
experimental
data
as
well
as
the
TCA
models.
Since
the
TCA
and
DCA
observed
in
the
model
validation
studies
came
either
from
trichloroethylene
metabolism
or
from
conversion
of
other
trichloroethylene
metabolites,
the
results
of
directly
administering
TCA
or
DCA
could
not
be
determined.
In
addition,
the
first­
order
metabolic
rate
constants
for
the
conversion
of
TCA
to
DCA,
and
for
conversion
of
DCA
to
other
metabolites
were
markedly
different
in
the
oral
and
inhalation
models,
suggesting
that
there
might
be
route
dependency
in
the
metabolism
of
TCA
and
DCA.
However,
since
the
metabolic
rate
constants
were
estimated
from
TCA
and
DCA
derived
from
oral
versus
inhalation
exposure
to
trichloroethylene,
the
differences
in
TCA
and
DCA
metabolic
rate
constants
could
simply
be
secondary
to
metabolic
differences
upstream
of
TCA.

Fisher
(
1998)
developed
a
human
PBPK
model
for
trichloroethylene.
To
account
for
trichloroethylene
metabolism
and
excretion,
the
model
also
included
two
sub­
models,
one
for
TCA
and
one
for
trichloroethanol.
The
sub­
model
for
TCA
was
constructed
to
model
concentrations
of
TCA
in
human
blood
and
urine
following
inhalation
exposure
to
trichloroethylene.
These
sub­
models
included
compartments
for
lung,
kidney,
body,
and
liver.

The
model
was
optimized
using
sex­
specific
metabolic
rate
constants
and
partition
coefficients
for
humans
exposed
to
50
or
100
ppm
trichloroethylene.
Using
the
model,
the
authors
successfully
estimated
TCA
concentrations
in
the
blood
and
urine
in
exposed
males
and
females.
However,

since
the
TCA
modeled
in
this
study
came
from
trichloroethylene
metabolism,
rather
than
a
direct
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
48
Draft,
do
not
cite
or
quote
exposure
to
TCA,
the
usefulness
of
the
model
for
making
judgements
about
the
toxicokinetics
of
TCA
following
direct
exposures
is
limited.

G.
Summary
Trichloroacetic
acid
TCA
is
readily
absorbed
by
the
oral
route
in
rats
(
Schultz,
1999)
and
by
the
dermal
and
oral
routes
in
humans
(
Kim
and
Weisel,
1998).
Once
absorbed,
TCA
is
available
for
systemic
distribution,
based
on
the
appearance
of
TCA
in
blood
after
oral
exposure
in
rodents
(
Templin,

1993;
Schultz,
1999).
Tissue
distribution
of
TCA
appears
to
be
dependent
on
the
time
of
measurement
following
dosing.
For
example,
in
one
study
(
Yu,
2000),
radioactivity
following
administration
of
[
1­
14C]
TCA
levels
was
highest
in
plasma
and
well­
perfused
tissues,
such
as
the
kidney
and
liver,
for
up
to
3
hours
after
exposure.
However,
after
24
hours,
the
level
of
radioactivity
in
the
liver
exceeded
levels
in
the
plasma.
Intermediate
levels
of
radioactivity
were
measured
in
other
tissues
and
were
much
lower
in
fat.
TCA
appears
to
bind
plasma
proteins
(
Templin,
1993;
Toxopeus
and
Frazier;
1998;
Schultz,
1999;
Lash
et
al.,
2000;
Yu,
2000),
which
is
an
important
determinant
of
the
extent
to
which
TCA
partitions
from
plasma
into
target
tissues.

No
studies
were
identified
that
investigated
the
tissue
distribution
of
TCA
in
humans,
but
the
appearance
of
TCA
in
the
blood
and
urine
of
humans
exposed
to
chlorinated
solvents
or
orally
administered
chloral
hydrate
indicates
that
it
is
present
in
the
systemic
circulation
as
a
downstream
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
49
Draft,
do
not
cite
or
quote
metabolite.
No
studies
investigating
the
toxicokinetics
or
degree
of
maternal­
to­
fetus
or
bloodto
breast
milk
transfer
of
TCA
were
located.

TCA
is
not
readily
metabolized,
as
indicated
by
minimal
first­
pass
metabolism
in
the
liver
following
oral
dosing
with
TCA
(
Schultz,
1999)
and
by
limited
amounts
of
radioactivity
excreted
in
exhaled
air
or
present
as
non­
extractable
radioactivity
in
plasma
and
liver
following
IV
administration
of
[
1­
14C]
TCA
(
Yu,
2000).
Some
studies
suggest
that
TCA
is
metabolized
to
DCA
(
Larson
and
Bull,
1992;
Abbas,
1996).
However,
confidence
in
these
results
is
decreased
by
concerns
regarding
potential
over­
estimation
of
DCA
levels
due
to
analytical
artifacts
(
Lash,

2000).
The
enzymes
involved
in
TCA
metabolism
have
not
been
determined,
but
some
in
vitro
studies
suggest
the
involvement
of
cytochrome
P450s
(
Ni,
1996;
Pravecek
,1996).

The
primary
route
of
excretion
of
TCA
is
in
the
urine,
with
exhalation
of
CO
2
and
fecal
excretion
contributing
to
a
much
lesser
extent
(
U.
S.
EPA,
1994;
Templin
et
al.,
1993;
Schultz
et
al.,
1999;
Yu,
2000).
The
elimination
of
TCA
from
the
blood
appears
to
be
considerably
slower
in
humans
than
in
rodents
administered
chlorinated
solvents
of
which
it
is
a
downstream
metabolite
(
Volkel,
1998;
Lash,
2000).
Based
on
the
slower
elimination
rate
in
these
human
studies,
chronic
exposure
to
high
oral
or
inhalation
TCA
doses
might
result
in
an
increase
in
internal
doses
of
TCA.
On
the
other
hand,
rapid
clearance
was
observed
following
low­
dose
dermal
exposures
(
Kim
and
Weisel,
1998),
suggesting
limited
potential
for
bioaccumulation
at
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
50
Draft,
do
not
cite
or
quote
doses
likely
to
result
from
environmental
exposures,
and/
or
route­
and
dose­
dependent
differences
in
clearance
and/
or
elimination.

Monochloroacetic
acid
The
onset
of
poisoning
and
the
diversity
of
affected
target
organs
in
humans
following
accidental
acute
dermal
exposure
to
concentrated
MCA
solution
demonstrates
absorption
and
systemic
distribution
of
this
compound
following
direct
skin
contact
(
Millischer,
1988;
Kusch,

1990;
Kulling,
1992).
Systemic
toxicity
observed
in
animal
studies
following
oral
dosing
also
demonstrates
MCA
absorption
and
distribution
(
U.
S.
EPA,
1994;
DeAngelo,
1997;
Saghir,

2001).
Saghir
(
2001)
reported
that
radioactivity
following
an
IV
dose
of
[
14C]
MCA
(
position
of
carbon
radiolabel
not
given)
distributed
rapidly
into
tissues,
resulting
in
only
minimal
plasma
concentrations
at
45
minutes
following
dosing.
Radioactivity
in
the
liver,
heart,
lungs,
and
brown
fat
paralleled
the
levels
detected
in
plasma.
However,
levels
of
radioactivity
in
the
brain
displayed
different
kinetics
as
compared
with
plasma,
remaining
relatively
constant
throughout
the
measurement
period
(
to
16
hours
post­
exposure).
Radioactive
levels
in
the
thymus
gland
were
higher
2­
16
hours
post­
exposure
than
immediately
following
dosing,
suggesting
possible
accumulation.
No
studies
investigating
the
toxicokinetics
or
degree
of
maternal­
to­
fetus
or
blood­
to­
breast
milk
transfer
of
MCA
were
located.
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
51
Draft,
do
not
cite
or
quote
Some
studies
suggest
that
MCA
can
undergo
dehalogenation
reactions,
leading
to
the
formation
of
oxalate
and
glycine
(
Bhat,
1990).
However,
the
mechanism
for
removal
of
chlorine
from
MCA
was
not
described
and
the
role
of
glutathione
in
MCA
metabolism
remains
unclear.

These
studies
(
Bhat,
1990)
also
suggest
that
MCA
can
form
glutathione
conjugates.
These
data
are
supported
to
some
extent
by
the
results
from
incubation
studies
with
liver
slices
(
Wijeweera,

1998),
demonstrating
MCA­
associated
glutathione
depletion.
However,
glutathione
depletion
may
be
associated
with
other
factors
in
the
Wijeweera
(
1998)
experiments,
and
in
vitro
studies
(
Dowsley,
1995)
did
not
find
evidence
for
this
reaction.
Therefore,
the
degree
to
which
MCA
conjugates
with
glutathione,
and
under
what
conditions,
is
not
known.
The
data
from
the
Saghir
(
2001)
study
suggest
that
MCA­
associated
toxicity
occurs
when
animals
are
exposed
to
high
doses
of
MCA
that
saturate
the
detoxification
capacity
of
the
liver,
possibly
via
glutathione
depletion.
MCA
has
also
been
reported
to
bind
to
lipids,
as
indicated
by
the
appearance
of
cholesteryl
chloroacetate
in
neutral
lipid
fractions
from
hepatic
lipid
extracts
from
treated
rats
(
Bhat
and
Ansari,
1989).
Based
on
data
showing
a
dose­
dependent
increase
in
the
plasma
protein
binding
of
radiolabeled
carbon
in
rats
orally
treated
with
[
1­
14C]
MCA
and
slow
rates
of
radiolabel
elimination
in
a
number
of
tissues,
Kaphalia
et
al.
(
1992)
have
proposed
that
MCA­
associated
toxicity
might
be
due
to
the
formation
of
conjugates
with
proteins
and/
or
membrane
lipids.

Metabolic
incorporation
of
the
radiolabeled
carbon
via
metabolism
of
MCA
to
glycine
is
another
possible
metabolic
pathway,
although
Kaphalia
(
1992)
suggest
that
the
contribution
of
this
pathway
to
MCA
metabolism
is
likely
to
be
minor.
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
52
Draft,
do
not
cite
or
quote
MCA
is
rapidly
cleared
from
the
blood
in
humans,
based
on
a
case
report
from
a
dermal
poisoning
(
Kulling,
1992).
In
rats,
MCA
is
excreted
primarily
in
urine,
with
excretion
by
this
route
accounting
for
approximately
50%
of
a
single
subcutaneous
dose
within
16
or
17
hours
of
dosing
(
Hayes,
1973),
and
approximately
90%
within
24
hours
of
a
single,
orally­
administered
dose
(
Kaphalia,
1992).
Saghir
(
2001)
reported
that
excretion
of
radiolabeled
MCA
and/
or
metabolite(
s)
was
rapid
in
rats
administered
either
a
subtoxic
(
10
mg/
kg)
or
toxic
(
75
mg/
kg)
dose
via
IV
injection;
6­
8%
of
both
doses
was
recovered
in
the
urine
within
45
minutes.
At
16
hours,

urinary
excretion
at
the
toxic
dose
(
representing
58%
of
administered
compound)
was
slower
than
at
the
subtoxic
dose
(
representing
73%
of
administered
dose).
HPLC
analysis
of
urine
samples
showed
that
a
total
of
55%
and
68%
of
the
excreted
radioactivity
was
parent
MCA
at
the
10
and
75
mg/
kg
doses,
respectively.
These
values
represented
approximately
40%
of
the
injected
dose
at
both
dosages.
Although
very
little
radioactivity
(
0.6­
2%)
was
excreted
in
the
feces,
a
large
fraction
of
both
doses
was
recovered
from
the
GIT
within
45
minutes
of
treatment.
Most
of
the
radioactivity
was
concentrated
in
the
small
intestine,
and
a
maximum
of
about
5%
of
dose
reached
the
large
intestine,
indicating
significant
reabsorption
from
the
small
intestine.
The
time
profile
of
MCA
concentrations
in
the
kidney
was
similar
to
that
in
the
GIT,
consistent
with
the
authors'

conclusions
that
metabolite(
s)
excreted
with
bile
were
being
reabsorbed
in
the
small
intestine
and
excreted
in
the
urine.

Limited
animal
data
suggest
that
MCA
and/
or
its
metabolites
might
accumulate
in
body
tissue,
particularly
the
brain,
depending
on
dose
and/
or
exposure
duration
(
Saghir,
2001;
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
III­
53
Draft,
do
not
cite
or
quote
Kaphalia,
1992).
