Document ID: EPA-HQ-OW-2002-0043-0148
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2003-07-22T04:00Z

Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
1
Chapter
I.
Executive
Summary
This
document
is
an
addendum
to
the
Final
Draft
for
the
Drinking
Water
Criteria
Document
on
Chlorinated
Acids/
Aldehydes/
Ketones/
Alcohols
(
U.
S.
EPA,
1994)
and
provides
an
update
for
trichloroacetic
acid
(
TCA)
and
monochloroacetic
acid
(
MCA).
This
addendum
provides
study
descriptions
for
newer
studies
for
TCA
or
MCA
that
have
been
published
between
1994
and
2000,
as
well
as
a
few
key
studies
published
prior
to
1994
or
in
2001.
Brief
summaries
of
the
older
literature
are
introduced
as
appropriate
in
this
addendum
as
a
means
to
put
the
newer
data
into
perspective
and
for
synthesis
of
the
discussion
on
the
derivation
of
the
Health
Advisories
for
TCA
and
MCA.

MCA
and
TCA
are
hygroscopic
crystals
in
pure
form,
soluble
and
miscible
in
water,

respectively,
and
usually
exist
in
the
environment
in
aqueous
solutions.
The
molecular
weights
of
TCA
and
MCA
are
163.4
and
94.5,
respectively.
Chlorinated
acetic
acids
are
formed
during
chlorination
of
water
that
contains
organic
matter,
primarily
humic
and
fulvic
acids.
Formation
of
chlorinated
acetic
acids
is
higher
in
the
presence
of
humic
acid
fractions
of
water
than
in
the
presence
of
fulvic
acid.

TCA
is
readily
absorbed
by
the
oral
route
in
rats
and
by
the
dermal
and
oral
routes
in
humans.
Once
absorbed,
TCA
is
available
for
systemic
distribution,
based
on
the
detection
of
TCA
in
blood
after
oral
exposure.
Tissue
distribution
appears
to
be
time­
dependent;
following
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
2
intravenous
administration
of
radiolabelled
TCA;
the
highest
concentrations
were
in
plasma
followed
by
kidney,
and
liver
for
the
first
3
hours
following
exposure.
In
contrast;
radioactivity
in
the
liver
exceeded
that
in
plasma
at
24
hours
following
exposure,
perhaps
reflecting
the
slow
rate
of
elimination
from
the
liver.
Intermediate
levels
of
radioactivity
were
measured
in
other
tissues
and
were
lowest
in
fat.
TCA
appears
to
bind
plasma
proteins,
which
might
be
an
important
determinant
of
partitioning
of
TCA
from
the
plasma
to
target
tissues.
In
one
study,
the
unbound
fraction
of
TCA
in
plasma
was
0.53,
with
a
blood:
plasma
concentration
ratio
of
0.76,

suggesting
that
most
of
the
TCA
distributed
in
the
blood
would
be
available
for
uptake
and
distribution
to
tissues.
No
studies
were
identified
on
the
tissue
distribution
of
TCA
in
humans,

but
the
appearance
of
TCA
in
blood
and
urine
of
humans
orally
exposed
to
chlorinated
solvents
or
chloral
hydrate
indicates
that
it
is
present
in
the
systemic
circulation
as
a
downstream
metabolite.

No
studies
investigating
the
toxicokinetics
or
degree
of
maternal­
to­
fetus
or
blood­
to­
breast
milk
transfer
of
TCA
were
located
in
the
literature.

TCA
is
not
readily
metabolized,
based
on
minimal
first­
pass
metabolism
in
the
liver
following
oral
dosing,
and
limited
amounts
of
radioactivity
excreted
in
exhaled
air,
or
present
as
non­
extractable
radiolabel
in
plasma
and
liver,
following
i.
v
administration
of
radiolabeled
TCA.

Some
studies
suggest
that
TCA
is
metabolized
to
DCA.
The
enzymes
involved
in
TCA
metabolism
have
not
been
determined;
some
in
vitro
studies
suggest
that
biotransformation
is
likely
to
be
mediated
by
cytochrome
P450s
metabolic
pathways.
In
contrast,
the
primary
route
of
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
3
DCA
metabolism
has
recently
been
shown
to
be
NADPH
and
glutathione
transferase­
dependent.

The
significance
of
these
metabolic
routes
for
TCA
biotransformation
is
not
known.

The
primary
route
of
excretion
of
TCA
is
in
the
urine
(
57­
84%
of
administered
dose
is
excreted
after
24­
48
hours),
with
exhalation
of
CO
2
and
fecal
excretion
contributing
to
a
lesser
extent.
In
one
study,
the
elimination
half­
life
following
a
single
TCA
dose
was
approximately
8
hours
in
rats.
The
elimination
of
TCA
from
the
blood
appears
to
be
considerably
slower
in
humans
than
in
rodents
exposed
to
chlorinated
solvents,
suggesting
that
chronic
exposure
to
high
doses
might
result
in
an
increase
in
the
internal
dose
of
TCA.
However,
data
on
the
rates
of
TCA
elimination
are
based
on
studies
of
trichloroethylene
and
its
downstream
metabolites,
including
TCA.
Thus,
species
differences
might
be
due
to
differences
in
the
internal
dose
of
the
parent
compound
(
resulting
from
differences
in
systemic
absorption)
and/
or
in
the
rate
of
formation
of
TCA.
On
the
other
hand,
rapid
urinary
clearance
was
observed
in
humans
who
were
dermally
exposed
to
low
doses
of
TCA
by
walking
or
swimming
in
chlorinated
pool
water
for
30
minutes.

Urinary
TCA
levels
were
elevated
in
the
10­
minute
period
following
exposure
(
approximately
1.1­
to
3.9­
fold
greater
than
background
excretion
levels),
and
generally
returned
to
pre­
exposure
levels
within
3
hours.
Higher
exposures
resulted
in
higher
amounts
of
urinary
TCA,
adjusted
to
the
subjects'
body
surface
area,
suggesting
a
dose­
response
relationship.
TCA
pool
water
concentrations
ranged
from
57
to
871
µ
g/
L,
with
a
mean
of
420
µ
g/
L
and
a
median
of
278
µ
g/
L,

resulting
in
dermal
doses
of
approximately
1
µ
g.
The
rapid
elimination
rate
observed
in
the
swimming­
pool
study,
relative
to
oral
and
inhalation
animal
studies,
appeared
to
result
from
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
4
route­
dependent
and
dose­
dependent
differences
in
TCA
kinetics,
and
it
has
been
suggested
that
the
potential
for
TCA
bioaccumulation
at
environmentally­
relevant
human
exposures
is
likely
to
be
limited.

Based
on
human
case
studies
following
accidental
dermal
exposure
to
concentrated
solutions
of
MCA,
absorption
occurs
rapidly
and
distributes
to
a
diversity
of
target
organs.

Similar
findings
were
observed
in
orally­
dosed
animal
studies.
In
one
animal
study,
radioactivity
following
an
i.
v.
dose
of
radiolabeled
MCA
distributed
into
tissues
rapidly,
resulting
in
minimal
concentrations
in
the
plasma
at
45
minutes
following
dosing.
Radioactivity
in
the
liver,
heart,

lungs,
and
brown
fat
paralleled
levels
in
plasma.
However,
radioactivity
in
the
brain
displayed
different
kinetics
from
plasma,
with
levels
remaining
relatively
constant
from
15
minutes
to
16
hours
post­
exposure.
Similarly,
high
levels
of
radioactivity
were
observed
in
the
thymus
gland
from
2
to
16
hours
following
exposure.
No
studies
investigating
the
toxicokinetics
or
degree
of
maternal­
to­
fetus
or
blood­
to­
breast
milk
transfer
of
MCA
were
located.

The
metabolism
of
MCA
is
not
well
understood.
MCA
can
undergo
dehalogenation
reactions,
leading
to
the
formation
of
oxalate
and
glycine.
Some
in
vivo
animal
studies
and
in
vitro
assays
with
liver
tissue
slices
support
the
hypothesis
that
MCA
may
form
glutathione
conjugates.
It
has
been
suggested
that
the
primary
metabolic
pathway
involves
glutathione
conjugation
and
that
the
rate­
limiting
step
in
MCA
toxicity
is
liver
detoxification;
adverse
effects
occur
at
high
doses
due
to
metabolic
saturation
of
detoxification
pathways.
This
would
suggest
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
5
that
the
parent
MCA
is
the
active
toxic
moiety.
However,
other
investigators
have
hypothesized
that
MCA
toxicity
is
associated
with
the
formation
of
conjugates
with
proteins
and/
or
membrane
lipids,
resulting
from
the
metabolism
of
the
parent
compound.
This
hypothesis
is
based
on
data
showing
increased
retention
of
radiolabeled
MCA
in
plasma
protein,
as
well
as
liver,
heart
and
lung,
although
the
type
of
metabolites
was
not
specified.
MCA
has
also
been
shown
to
bind
with
lipids,
as
evidenced
by
the
appearance
of
cholesteryl
chloroacetate
in
neutral
lipid
fractions
from
hepatic
lipid
extracts
from
treated
rats.

MCA
is
excreted
primarily
in
urine
in
rats,
with
excretion
by
this
route
accounting
for
50%
or
more
of
orally­
or
intravenously­
administered
doses
within
16
or
17
hours.
Based
on
one
case
report
of
dermal
poisoning,
MCA
appears
to
be
rapidly
cleared
from
the
blood
in
humans.

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.

No
physiologically­
based
pharmacokinetic
(
PBPK)
models
have
been
developed
for
either
MCA
or
TCA
alone
(
i.
e.,
as
parent
compound).
However,
PBPK
models
for
TCA
and
DCA
in
B6C3F1
mice
exposed
to
trichloroethylene
via
oral
dosing
(
by
gavage
in
corn
oil)
or
inhalation
have
been
elucidated
by
several
investigators.
The
main
trichloroethylene
PBPK
model
was
linked
to
five
TCE
metabolite
sub­
models,
for
chloral
hydrate,
trichloroethanol,
trichloroethanol
glucuronide,
DCA,
and
TCA,
respectively.
Each
sub­
model
contained
compartments
for
the
liver,

lung,
kidney,
and
body.
The
tissue:
blood
partition
coefficients
for
all
five
TCE
metabolites
were
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
6
experimentally
determined.
The
model
was
developed
using
literature
values
for
V
max
and
K
m
for
trichloroethylene,
literature
values
for
physiological
parameters,
and
the
experimentallydetermined
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
other
doses
in
the
oral
study
(
300,
600,
and
2000
mg/
kg).
For
the
inhalation
model,
additional
parameters
were
developed
using
data
from
male
B6C3F1
mice
exposed
for
4
hours
to
600
ppm
trichloroethylene;
the
model
was
validated
with
data
from
a
separate
inhalation
mouse
study,
with
exposure
concentrations
ranging
from
110­
748
ppm
trichloroethylene.

The
TCA
models
adequately
described
the
TCA
concentrations
in
the
liver,
lungs,

kidneys,
and
blood
following
trichloroethylene
exposure,
as
well
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.
TCA
and
DCA
observed
in
the
model
validation
studies
came
either
from
either
trichloroethylene
metabolism
or
conversion
of
other
trichloroethylene
metabolites.
Thus,
the
results
of
direct
administration
of
either
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
of
these
two
chlorinated
acetic
acids.
However,
the
metabolic
rate
constants
for
TCA
and
DCA
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
7
were
derived
from
oral
versus
inhalation
exposure
to
trichloroethylene.
Thus,
differences
in
these
rate
constants
might
be
secondary
to
upstream
differences
in
TCE
metabolism.

A
human
PBPK
model
developed
for
trichloroethylene
included
two
sub­
models
to
account
for
metabolism
and
excretion
 
one
for
TCA
and
one
for
trichloroethanol.
The
submodel
for
TCA
was
constructed
in
order
to
model
concentrations
of
TCA
in
human
blood
and
urine
following
human
volunteer
inhalation
exposure
to
50
or
100
ppm
trichloroethylene,
using
sex­
specific
metabolic
rate
constants
and
partition
coefficients.
Predicted
TCA
concentrations
in
the
blood
and
urine
were
similar
to
those
observed
in
trichloroethylene­
exposed
males
and
females.
However,
TCA
modeled
in
this
study
resulted
from
trichloroethylene
metabolism,
not
from
direct
exposure.
Thus,
the
usefulness
of
the
model
for
understanding
the
toxicokinetics
of
TCA
following
direct
exposures
is
limited.

EPA's
Information
Collection
Rule
(
ICR)
database
contains
extensive
information
on
concentrations
of
MCA
and
TCA
in
drinking­
water
systems,
and
how
those
concentrations
vary
with
input­
water
characteristics
and
treatment
methods.
The
database
contains
information
from
6
quarterly
samples
from
7/
97
to
12/
98,
from
approximately
300
large
systems
covering
approximately
500
plants.
Based
on
these
data,
the
mean
concentrations
of
MCA
and
TCA
are
consistently
lower
in
groundwater
than
surface
water,
with
TCA
>
MCA
in
both
water
sources.

The
mean
concentrations
of
TCA
were
3.28
and
13.25

g/
L
in
groundwater
and
surface
water,
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
8
respectively,
whereas
the
mean
concentrations
of
MCA
were
0.76
and
1.28

g/
L
in
groundwater
and
surface
water,
respectively.

For
all
chemical­
disinfection
treatments
for
surface
water
and
groundwater,
the
mean
concentrations
of
TCA
were
significantly
higher
than
MCA.
Statistical
examination
of
the
data
for
surface
water
plants
showed
that
the
mean
concentrations
of
TCA
were
significantly
reduced
when
treatment
with
chlorine
was
followed
by
chloramine
than
when
only
free
chlorine
was
used.

There
were
no
significant
differences
in
the
mean
concentrations
of
TCA
among
the
common
disinfection
methods
(
non­
ozonation)
in
groundwater,
or
for
MCA
for
surface
water
or
ground
water.
However,
ozone
in
the
water­
treatment
plant
and
free
chlorine
or
free
chloramine
in
the
distribution
system
may
result
in
a
statistically
significant
reduction
in
the
formation
of
TCA
compared
to
that
observed
using
the
common
(
non­
ozonation)
chemical­
disinfection
processes
in
treating
surface
water.
However,
the
use
of
ozone
in
treating
surface
water
as
compared
to
the
common
(
non­
ozonation)
chemical­
disinfection
processes
did
not
result
in
statistically
significant
difference
in
MCA
concentrations.
In
addition,
there
were
no
statistically
significant
differences
in
MCA
and
TCA
concentrations
using
ozonation
in
treating
surface
water.

Statistical
analysis
of
the
ICR
data
indicated
that,
in
general,
for
a
given
influent
bromide
concentration
range
in
plants
treating
surface
water
or
groundwater,
the
mean
concentrations
of
TCA
are
significantly
higher
than
MCA.
Regression
analysis
showed
that
there
is
a
statistically
significant
correlation
between
influent
Total
Organic
Carbon
(
TOC)
concentration
and
the
mean
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
9
concentration
of
MCA
in
surface
water,
but
not
between
influent
TOC
concentration
and
the
mean
concentration
of
MCA
in
groundwater,
or
between
influent
TOC
concentration
and
the
mean
concentration
of
TCA
in
surface
or
groundwater.
Further,
no
consistently
significant
differences
between
the
mean
seasonal
concentrations
of
MCA
and
TCA
in
groundwater
or
surface
water
were
observed..

MCA
and
TCA
have
been
used
in
industry,
pharmaceutical
preparations,
and
in
hospitals.

Between
1981
to
1983,
10,912
workers
were
potentially
exposed
to
MCA
and
35,124
workers
were
potentially
exposed
to
TCA.

In
addition
to
MCA
and
TCA
concentrations
in
drinking
water,
there
are
some
limited
data
on
MCA
and
TCA
concentrations
in
air
and
food.
Concentrations
of
MCA
and
TCA
in
the
food
appear
to
be
comparable
to
those
in
drinking
water
and
may
contribute
significantly
to
the
overall
dose.
With
regard
to
inhalation
exposure,
the
reported
annual
average
ambient­
air
concentration
for
TCA
is
7

g/
m3
and
the
estimated
annual
time­
weighted
average
ambient­
air
concentration
for
MCA
is
63

g/
m3.
However,
additional
air
monitoring
data
are
needed
to
evaluate
whether
inhalation
exposure
is
a
significant
route
of
human
exposure.
Dermal
absorption
of
TCA
contributes
less
than
1%
of
total
doses
from
routine
household
uses
of
drinking
water,

and
dermal
exposure
from
MCA
is
likely
to
be
similarly
low.
Although
available
data
suggest
that
food
and
air
may
be
significant
sources
of
human
exposure
to
TCA
and
MCA,
these
data
are
inadequate
to
quantify
the
contributions
of
each
of
these
sources
for
an
overall
assessment
of
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
10
human
exposure.
Thus,
the
default
relative
source
contribution
(
RSC)
from
drinking
water
(
i.
e.,

20%)
is
used
to
estimate
lifetime
health
advisories
for
these
chlorinated
acetic
acids.

No
data
are
available
on
the
body
burden
of
MCA.
Very
limited
data
are
available
on
the
levels
of
TCA
in
blood
or
urine
resulting
from
direct
exposure
to
TCA.
Some
data
have
shown
that
exposure
to
chlorinated
solvents
such
as
tetrachloroethylene
and
trichloroethylene
contribute
to
the
total
TCA
body
burden.
However,
these
data
are
not
useful
in
estimating
total
body
burden
because
neither
environmental
intake
nor
the
kinetics
of
TCA
absorption
and
distribution
are
taken
into
account
when
TCA
is
a
downstream
metabolite
from
a
chlorinated
solvent.

In
short­
term
oral
toxicity
studies
with
TCA,
high
doses
of
approximately
600
mg/
kg/
day
resulted
in
decreased
food
consumption
and
body­
weight
loss.
Alterations
in
intermediary
carbohydrate
metabolism
(
e.
g.,
decreased
lactate
levels
in
several
tissues)
have
also
been
observed..
The
liver
has
consistently
been
identified
as
a
target
organ
for
TCA
toxicity
in
shortterm
and
longer­
term
studies.
Indicators
of
peroxisome
proliferation
have
been
primary
endpoints
evaluated,
with
mice
reported
to
be
more
sensitive
to
induction
of
peroxisome
proliferation
than
rats.
In
B6C3F1
mice
exposed
for
10
weeks
to
drinking
water
doses

125
mg/
kg/
day,
TCA
induced
peroxisome
proliferation
(
in
the
absence
of
effects
on
liver
weight);
the
No­
Observable­

Adverse­
Effects­
Level
(
NOAEL)
was
25
mg/
kg/
day.
In
F344
rats
exposed
to
TCA
in
drinking
water
for
up
to
104
weeks,
peroxisome
proliferation
was
observed
at
364
mg/
kg/
day,
but
not
at
32.5
mg/
kg/
day.
Increased
liver
weight
and
significant
increases
in
hepatocyte
proliferation
have
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
11
been
observed
in
short­
term
studies
in
mice
at
doses
as
low
as
100
mg/
kg/
day,
but
no
increase
in
hepatocyte
proliferation
was
noted
in
rats
given
TCA
at
similar
doses.
More
clearly
adverse
livertoxicity
endpoints,
including
increased
serum
levels
of
liver
enzymes
(
indicating
leakage
from
cells)
and/
or
histopathological
evidence
of
necrosis,
have
been
reported
in
rats,
but
generally
only
at
high
doses.
For
example,
in
a
2­
year
chronic
drinking­
water
bioassay
with
F344
rats,
increased
hepatocyte
necrosis
was
observed
only
at
the
highest
dose
tested,
364
mg/
kg/
day.

The
potential
reproductive
toxicity
of
TCA
has
not
been
adequately
tested.
No
animal
studies
were
identified
that
evaluated
this
endpoint.
The
results
of
an
in
vitro
fertilization
assay
indicated
that
TCA
might
have
the
potential
to
decrease
fertilization.
The
available
data
suggest
that
TCA
is
a
developmental
toxicant
at
maternally
toxic
doses.
In
the
presence
of
maternal
toxicity,
TCA
increased
resorptions,
decreased
implantations,
and
increased
cardiovascular
malformations
at
291
mg/
kg/
day
in
one
drinking
water
study,
and
decreased
fetal
weight
and
length,
and
increased
cardiovascular
malformations
at
330
mg/
kg/
day
in
another
gavage
study.

Neither
of
these
studies
identified
a
NOAEL.
Developmental­
toxicity
screening­
level
assays,

including
in
vitro
mouse
and
rat
whole­
embryo
culture
and
the
nonmammalian
Xenopus
assay
system
(
frog
embryo
teratogenesis
assay)
have
demonstrated
adverse
developmental
effects.
In
contrast,
testing
using
Hydra
(
freshwater
invertebrate
hydrozoa)
as
a
predictive
model
has
shown
that
TCA
is
not
likely
to
be
a
developmental
toxicant.
The
Hydra
system
is
an
assay
that
determines
the
degree
to
which
a
test
chemical
can
perturb
embryonic
development
at
maternally
subtoxic
doses,
and
is
designed
to
overestimate
developmental
hazard
potential.
Its
primary
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
12
utility
is
as
a
prescreening
assay
for
developmental
toxicity,
and
it
is
considered
to
be
more
sensitive
to
developmental
toxicity
than
most
in
vitro
mammalian
test
systems.

TCA
was
not
mutagenic
in
the
Ames
assay
in
Salmonella
typhimurium
strain
TA100
in
the
absence
of
metabolic
activation.
In
modified
Ames
assays
with
Salmonella
typhimurium,

mixed
results
were
reported.
TCA
was
weakly
mutagenic
in
a
mouse
lymphoma
assay.
Studies
reporting
the
effect
of
TCA
on
DNA
strand
breaks
have
also
yielded
mixed
results.
A
recent
study
found
that
chromosome
damage
is
not
induced
by
TCA
at
neutralized
pH;
in
contrast,

another
study
showed
evidence
of
TCA­
induced
clastogenicity
(
small
colonies)
in
mouse
lymphoma
cells
at
neutralized
pH.

In
carcinogenic
gavage
bioassays,
TCA
induces
liver
tumors
in
mice
but
not
in
rats.
This
observation
has
also
been
reported
in
more
recent
drinking­
water
studies.
One
mouse
study
showed
an
increased
incidence
of
hepatic
adenomas
in
female
B6C3F1
mice
at
drinking­
water
doses
of
262
mg/
kg/
day
and
higher.
In
contrast,
no
increase
in
liver
lesions
was
found
in
F344
rats
given
drinking­
water
doses
up
to
364
mg/
kg/
day.
In
addition,
a
variety
of
recent
studies
investigating
epigenetic
and
genetic
mechanisms
of
carcinogenicity
have
observed
either
TCAinduced
or
TCA­
promoted
liver
tumors
in
mice.
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
13
No
animal
studies
were
identified
on
the
potential
systemic
toxicity
of
TCA
following
dermal
or
inhalation
exposures.
However,
concentrated
solutions
of
TCA
applied
topically
to
shave
rabbit
skin
are
corrosive.

In
short­
term
MCA
toxicity
studies,
effects
in
mice
included
neurotoxicity
and
decreased
body
weight
at
high
doses
near
the
LD
50
of
260
mg/
kg.
In
lower­
dose
studies,
increased
nasal
discharge
and
lacrimation
were
observed
in
rats
at

7.5
mg/
kg/
day,
but
no
adverse
effects
were
observed
in
mice
treated
with
similar
doses.
Subchronic
and
chronic
oral­
dosing
studies
suggest
that
the
primary
targets
for
MCA­
induced
toxicity
include
the
heart
and
nasal
epithelium.
In
a
13­
week
oral­
gavage
study,
decreased
heart
weight
was
observed
at
30
mg/
kg/
day
(
equivalent
to
21.4
mg/
kg/
day
after
adjustment
for
intermittent
dosing)
and
cardiac
lesions
progressed
in
severity
with
increasing
dose
at

60
mg/
kg/
day.
Liver
and
kidney
toxicity
were
only
observed
at
higher
doses.
In
a
two­
year
chronic
bioassay,
MCA
administered
by
gavage
decreased
survival
and
increased
the
incidence
of
nasal
and
forestomach
hyperplasia
in
B6C3F1
mice
at

50
mg/
kg/
day
(
NTP,
1992).
In
a
two­
year
drinking
water
carcinogenic
bioassay
with
F344
rats,

increased
spleen
weight
was
noted
at
3.5
mg/
kg/
day.
Decreased
body
weight,
decreased
liver
and
kidney
weights,
decreased
spleen
weight,
and
increased
testes
weight
were
observed
at
doses

26.1
mg/
kg/
day;
these
changes
were
interpreted
by
study
authors
as
being
associated
with
dosedependent
decreases
in
body
weight.
Myocardial
degeneration
and
inflammation
of
the
nasal
cavities
were
also
observed
in
rats
exposed
to
59.9
mg/
kg/
day
during
the
104­
week
drinking
water
study,
confirming
the
nasal
cavities
and
heart
as
target
organs
of
MCA­
induced
toxicity.
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
14
No
studies
were
located
on
the
reproductive
toxicity
of
MCA,
and
the
potential
developmental
toxicity
of
MCA
has
not
been
adequately
tested.
In
one
developmental
toxicity
study,
markedly
decreased
maternal­
weight
gain
were
reported
in
pregnant
rats
exposed
to
193
mg/
kg/
day
MCA
during
gestation
days
(
GD)
1­
22,
without
evidence
of
developmental
toxicity.

However,
fetal
histopathology
was
limited
to
the
heart.
In
contrast,
an
increase
in
cardiovascular
malformations
in
pregnant
rats
exposed
to
140
mg/
kg/
day
during
GD
6­
15
was
reported
in
a
published
abstract.
This
dose
was
also
the
Low­
Observable­
Adverse­
Effects­
Level
(
LOAEL)
for
maternal
toxicity,
based
on
marked
decreases
in
dam
weight
gain.
However,
a
full
report
of
this
study
has
not
been
published.
In
non­
mammalian
screening
assays
using
the
Hydra
test
system,

MCA
was
predicted
to
be
a
potential
development
toxicant
in
mammals.
This
test
system
is
designed
to
overestimate
developmental
hazard
potential
and
is
considered
to
be
more
sensitive
to
developmental
toxicity
than
most
in
vitro
mammalian
test
systems;
its
primary
utility
is
to
identify
compounds
for
in
vivo
developmental
toxicity
testing.
Based
on
findings
in
the
Hydra
test
system,
MCA
would
be
considered
a
priority
compound
for
further
testing
in
vivo.

Genotoxicity
assays
with
MCA
has
yielded
mixed
results.
Two­
year
oral­
gavage
cancer
bioassays
with
male
and
female
F344
rats
and
B6C3F1
mice,
and
a
two­
year
drinking­
water
study
with
male
F344
rats,
have
not
shown
evidence
of
MCA­
induced
carcinogenicity.
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
15
No
animals
studies
on
the
potential
systemic
toxicity
of
MCA
following
dermal
or
inhalation
exposures
were
identified.
However,
concentrated
solutions
of
MCA
applied
topically
to
shaved
rabbit
skin
are
corrosive.

There
are
no
epidemiology
or
clinical
studies
investigating
the
potential
human
health
effects
of
either
TCA
or
MCA
by
any
route
of
exposure..
Human
health­
effects
data
for
TCA
and
MCA
are
limited
largely
to
case
reports
of
accidental
dermal
poisonings
and
dermal
injury
caused
by
the
use
of
TCA
in
chemical
skin
peeling
applications
and
topical
treatment
of
warts.
TCA
is
corrosive
to
human
skin.
This
characteristic
has
been
used
clinically
in
chemical
skin­
peeling
treatments
for
many
years,
in
which
concentrated
solutions
(
ranging
from
16.9%
to
50%
TCA)

have
been
employed.
No
studies
investigating
the
toxicity
of
TCA
in
humans
via
the
inhalation
route
were
located.

Case
reports
following
accidental
skin
exposure
to
concentrated
solutions
demonstrate
that
MCA
is
a
systemic
metabolic
poison
in
humans,
resulting
in
a
characteristic
progression
of
toxicity
that
can
be
fatal.
The
skin
burn
typically
intensifies
1
to
3
hours
following
exposure,

reaching
a
severity
of
second
or
third
degree.
Typical
clinical
signs
include
vomiting,
neurological
symptoms
such
as
convulsions,
and
cardiovascular
shock,
which
often
progress
to
coma.
Clinical
signs
include
severe
acidosis
with
hyperglycemia
and
hypokalemia,
low
urinary
output,
and
elevated
creatinine
phosphokinase.
Nonspecific
organ
lesions
of
the
liver,
grain,
heart,
and
kidney
have
been
reported.
The
onset
of
acidosis
is
thought
to
result
from
inhibition
of
the
Kreb's
cycle.
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
16
No
studies
investigating
the
toxicity
of
MCA
in
humans
via
the
oral
or
inhalation
routes
were
located.

TCA
induces
systemic,
non­
cancer
effects
in
animals
and
humans
that
can
be
grouped
into
three
categories:
metabolic
alterations,
liver
toxicity,
and
developmental
toxicity.
The
primary
site
of
TCA
toxicity
is
the
liver.
It
has
been
suggested
that
TCA
disrupts
regulation
of
pyruvate
dehydrogenase
activity,
leading
to
altered
carbohydrate
metabolism,
although
the
precise
mechanisms
are
unknown.
Other
hypotheses
include
TCA­
induced.
dysregulation
of
protein
kinases
that
modulate
glycogen­
phosphorylase
activity,
resulting
in
TCA­
induced
glycogen
accumulation
in
the
liver.
However,
in
a
study
with
dichloroacetic
acid
(
DCA),
no
alterations
in
glycogen­
phosphorylase
activity
associated
with
glycogen
accumulation
were
observed,
and
the
authors
suggested
that
TCA
might
also
not
be
acting
in
this
manner.
Proposed
alternative
mechanisms
include
alterations
in
the
molecular
structure
of
glycogen
leading
to
sequestration
of
the
glycogen
in
a
form
that
is
difficult
to
mobilize,
or
changes
in
serum
glucose
or
insulin
levels
resulting
in
glucose
accumulation.
Peroxisome
proliferation,
as
indicated
by
changes
in
markers
of
peroxisomal
proliferation
such
as
cyanide­
insensitive
palmitoyl­
CoA
oxidase
(
PCO)
and
increased
12­
hydroxylation
of
lauric
acid,
is
thought
to
play
a
role
in
at
least
some
of
the
observed
liver
effects
induced
by
TCA.
Although
TCA
induces
developmental
toxicity
in
rats
at
maternally
toxic
doses
and
in
a
number
of
in
vitro
test
systems,
the
mechanism
for
the
developmental
toxicity
is
not
known.
Physiologically­
based
pharmacokinetic
modeling
has
suggested
that
TCA
behaving
as
a
weak
acid
might
induce
developmental
toxicity
by
changing
the
intracellular
pH
in
the
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
17
fetal/
embryo
compartment
Alternately,
peroxisome
proliferation
might
be
involved
in
TCA's
developmental
toxicity;
however,
the
mode
of
action
is
unknown.

A
variety
of
mechanisms
have
been
suggested
as
contributing
to
TCA­
induced
liver
tumorigenesis.
Of
these,
peroxisome
proliferation
and
altered
regulation
of
cell
growth
have
the
most
supporting
data.
There
is
little
evidence
for
a
role
of
direct
genotoxicity
of
TCA
itself,

oxidative
DNA
damage,
or
regenerative
hyperplasia.
The
role
of
peroxisome
proliferation
is
unclear,
in
part
because
liver
tumors
are
only
induced
in
mice,
and
peroxisome
proliferative
response
are
activated
in
both
mice
and
rats.
Further,
humans
have
been
reported
to
be
less
affected
by
exposure
to
peroxisomal
proliferators
than
either
mice
or
rats,
and
thus
the
relevance
of
this
mode
of
tumor
induction
to
human
carcinogenesis
may
be
low
or
non­
existent.
A
more
convincing
argument
case
can
be
made
for
altered
regulation
of
cell
growth
and
proliferation
in
subpopulations
of
cells,
thus
providing
a
selective
growth
advantage
in
chemically­
or
spontaneously­
initiated
cells.

Acute
high
doses
of
MCA
cause
metabolic
acidosis
in
humans,
hypothesized
to
be
due
to
a
build
up
of
endogenously­
formed
acids
that
results
from
inhibition
of
a
key
enzyme
in
the
Kreb's
cycle.
MCA
exposure
also
induces
cardiovascular,
kidney,
and
liver
damage
in
fatal
cases
of
MCA
poisoning
in
humans,
with
the
spectrum
of
effects
being
similar
to
that
observed
in
rodents
following
subchronic
or
chronic
oral
toxicity
studies.
The
mechanism
for
the
apparent
targeting
of
the
heart
has
not
been
well
characterized
but
may
involve
inhibition
of
the
enzyme
activity
of
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
18
mitochondrial
aconitase
in
heart
muscle;
aconitase
is
an
important
enzyme
in
the
citric
acid
energy
cycle
(
Kreb's
cycle).
Mechanisms
of
liver
and
kidney
damage
have
also
been
largely
unexplored.

There
is
limited
evidence
that
glutathione
depletion
might
be
important
in
cellular
protection
from
MCA;
one
suggestion
is
that
depletion
of
cellular
thiols
might
be
related
to
the
observed
targetorgan
effects.
However,
the
results
of
in
vitro
studies
investigating
this
mechanism
are
mixed.

Nasal
discharge
and
lacrimation
were
reported
in
rats
following
short­
term
MCA
gavage
exposures.
In
chronic
bioassays,
MCA
induced
inflammation
and
hyperplasia
in
the
nasal
epithelium
of
mice
when
administered
by
gavage
and
chronic
nasal
inflammation
in
rats
when
given
in
drinking
water.
These
findings
might
reflect
the
irritant
properties
of
MCA;
however,
the
possibility
of
nasal
effects
occurring
secondarily
to
an
alternative
mechanism
cannot
be
excluded.

The
Health
Advisory
(
HA)
values
for
TCA
and
MCA
are
summarized
in
Table
I­
1.
For
TCA,
no
suitable
studies
were
identified
for
derivation
of
the
One­
Day
HA.
A
NOAEL
of
25
mg/
kg/
day
for
increased
relative
liver
weight,
accompanied
by
increases
in
indicators
of
peroxisomal
proliferation
in
B6C3F1
mice
given
TCA
in
drinking
water
for
21
days
was
used
to
derive
a
Ten­
Day
HA
of
3
mg/
L
(
3000
µ
g/
L)
for
a
10­
kg
child.
This
Ten­
Day
HA
was
used
as
a
conservative
value
for
the
One­
Day
HA.
A
NOAEL
of
36.5
mg/
kg/
day,
based
on
liver
histopathological
changes
observed
in
Sprague­
Dawley
rats
given
TCA
in
drinking
water
for
90
days,
was
used
to
derive
a
Longer­
Term
HA
of
0.4
mg/
L
(
400
µ
g/
L)
for
a
10­
kg
child
and
1
mg/
L
(
1000
µ
g/
L)
for
a
70­
kg
adult.
A
NOAEL
of
32.5
mg/
kg/
day,
based
on
liver
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
19
histopathological
changes
in
F344
rats
exposed
to
TCA
in
drinking
water
for
2
years,
was
used
to
calculate
a
DWEL
of
1
mg/
L
(
1000
µ
g/
L)
and
a
Lifetime
HA
value
of
0.02
mg/
L
(
20
µ
g/
L),

assuming
an
RSC
of
20%.

According
to
EPA's1999
Draft
Guidelines
for
Cancer
Risk
Assessment,
TCA
is
classified
as
"
suggestive
evidence
of
carcinogenicity",
because
the
evidence
from
animal
data
is
suggestive
of
carcinogenicity,
which
raises
a
concern
for
carcinogenic
effects,
but
is
not
sufficient
for
a
conclusion
regarding
human
carcinogenic
potential.

For
MCA,
no
suitable
studies
were
identified
for
derivation
of
the
One­
Day
HA.
Based
on
the
observation
of
nasal
discharge
in
rats
exposed
by
gavage
for
12
days
in
a
16­
day
period,
a
LOAEL
of
7.5
mg/
kg/
day
(
adjusted
to
5.6
mg/
kg/
day
to
account
for
intermittent
exposure)
was
used
to
derive
a
Ten­
Day
HA
of
0.2
mg/
L
(
200
µ
g/
L)
for
a
10­
kg
child.
This
Ten­
Day
HA
was
used
as
a
conservative
value
for
the
One­
Day
HA.
Based
on
decreased
relative
heart
weight
in
rats
given
MCA
by
gavage
5
days/
week
for
13
weeks,
a
LOAEL
of
30
mg/
kg/
day
(
adjusted
to
21.4
mg/
kg/
day
to
account
for
intermittent
exposure)
was
used
to
derive
a
Longer­
Term
HA
of
0.2
mg/
L
(
200
µ
g/
L)
for
a
10­
kg
child
and
0.7
mg/
L
(
700
µ
g/
L)
for
a
70­
kg
adult.
A
LOAEL
of
3.5
mg/
kg/
day
(
DeAngelo
et
al.,
1997)
for
increased
absolute
and
relative
spleen
weight
in
rats
exposed
to
MCA
for
104
weeks
in
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
20
According
to
EPA's
1999
Draft
Guidelines
for
Carcinogen
Risk
Assessment,
MCA
is
best
described
as
"
inadequate
for
an
assessment
of
human
carcinogenic
potential".
Although
well­
conducted
chronic
cancer
bioassays
performed
in
male
and
female
B6C3F1
mice
and
F344
rats
did
not
demonstrate
evidence
of
carcinogenicity,
the
route
of
compound
administration
was
via
oral
gavage,
only
two
doses
were
tested,
and
significant
mortality
was
observed
in
high­
dose
male
rats,
high­
dose
male
mice,
and
low­
and
high­
dose
female
rats.
These
high
mortality
rates
may
have
compromised
the
power
and
sensitivity
of
the
study
to
detect
MCA­
associated
tumor
effects,
should
they
have
occurred.
In
the
drinking
water
carcinogenesis
bioassay
with
male
F344
rats,
no
tumorigenic
effects
were
noted;
however,
female
rats,
potentially
more
sensitive
to
MCAassociated
effects,
were
not
tested,
and
the
group
sample
sizes
were
limited.
Thus,
this
descriptor
is
appropriate
for
MCA
carcinogenicity.
Addendum
to
Drinking
Water
Criteria
Document
for
Monochloroacetic
Acid
and
Trichloroacetic
Acid
EPA/
OW/
OST/
HECD
Draft,
do
not
cite
or
quote
I­
21
Table
I­
1.
Summary
of
Health
Advisory
Values
for
Drinking
Water
(
a)

Longer­
Term
HA
Lifetime
HA
Chemical
One­
Day
HA
Ten­
Day
HA
Child
Adult
TCA
3
3
0.4
1
0.02
MCA
0.2
0.2
0.2
0.7
amg/
L