Document ID: EPA-HQ-OPP-2002-0280-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-10-02T04:00Z

Page
1
of
8
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
February
28,
2002
MEMORANDUM
SUBJECT:
Tolerance
Review
of
Compounds
of
the
Citric
Acid
Cycle
(Kreb's
Cycle)
as
Inert
Ingredients
in
Terrestrial
and/
or
Aquatic
Agricultural
and
Non­
Agricultural
Uses
FROM:
Sid
Abel,
Senior
Environmental
Scientist
Environmental
Fate
and
Effects
Division
(7507C)

TO:
Kathryn
Boyle,
Inerts
Team
Lead
Registration
Division
(7505C)

This
memorandum
transmits
the
Environmental
Fate
and
Effects
Division's
(EFED)
exposure
and
risk
assessment
of
compounds
of
the
Citric
Acid
Cycle
(also
known
as
the
Kreb's
Cycle).
The
assessment
is
based
on
readily
available
information
from
the
Agency
and
peer
reviewed
public
literature
sources.
Information
contained
in
these
sources
permits
EFED
to
conduct
a
qualitative
assessment
of
environmental
exposures
and
risks.

If
you
should
have
any
questions
concerning
the
information
within,
please
contact
me
at
305­
7346.
Page
2
of
8
Conclusions
A
review
of
the
readily
available
information
on
the
compounds
that
make
up
the
Citric
Acid
Cycle
(also
known
as
the
Kreb's
Cycle)
is
sufficient
to
conduct
a
qualitative
assessment
of
the
potential
exposures
and
risks
associated
with
their
use
as
pesticide
inert
ingredients.
Environmental
loadings
are
attributable
to
natural
(plants
and
animal
materials)
and
anthropogenic
(food
additives,
drugs,
and
related
products)
sources.
Available
data
indicate
that
they
rapidly
dissociate
in
the
aquatic
environment
at
environmentally
relevant
pH's
to
the
corresponding
acid
(anion)
and
its
respective
cation
(H
+
,Ca
+
,K
+
,Na
+
,NH4
+
,Mg
2+
,
among
others).
Anions
of
the
respective
compounds
undergo
aerobically
mediated
mineralization
in
days
to
weeks;
mineralization
is
complete
degradation
to
CO2
and
water.
Half­
lives
are
anticipated
to
be
shorter.
Under
anaerobic
conditions,
the
anions
are
expected
to
mineralize
in
a
matter
of
weeks.
These
compounds
are
expected
to
be
predominantly
found
in
the
non­
absorbed/
adsorbed
state
in
aquatic
environments
based
on
fugacity
modeling.

Photodegradation
will
also
plays
a
role
in
the
dissipation
of
the
compounds,
but,
generally
will
occur
at
a
lower
rate,
i.
e.,
half­
lives
may
be
longer
than
biodegradation.
Mobility
of
the
anions
is
expected
to
be
high
based
on
adsorption
estimates,
however,
migration
to
ground
water
should
be
substantially
mediated
through
their
rapid
biodegradation,
volatilization,
or
through
their
uptake
and
utilization
within
plant
cells.
Runoff
to
surface
is
expected
to
dominate
the
nondegradation
pathways
of
dissipation.
Partitioning
to
air
is
expected
to
be
low
from
water
sources
(based
on
the
Henry's
Law
constant)
and
high
from
dryer
surfaces
such
as
soils
(based
on
volatility).
Bioconcentration
is
not
expected
to
occur.

Shallow
aquifer
ground
water
concentrations
of
the
anions
of
the
citric
acid
cycle
may
reach
low
part
per
milligram
(ppm)
under
conditions
of
exaggerated
surface
contamination
(1­
100
ppm)
such
as
those
observed
beneath
landfills
and
wood­
treatment
facilities.
However,
they
are
generally
found
in
the
low
parts
per
billion
(ppb)
elsewhere
(<
100
ppb)
some
of
which
is
attributable
to
natural
sources
(http://
toxnet.
nlm.
nih.
gov).
Surface
water
concentrations
(fresh
water
and
marine­
estuarine)
have
been
reported
to
reach
the
low­
to
mid­
ppb
range
(10­
300
ppb).
As
with
ground
water
occurrence,
surface
water
concentrations
can
be
attributed
to
natural
sources
as
well.
No
data
were
available
to
determine
the
effects
of
drinking
water
treatment
on
concentrations
of
the
anions
at
the
consumer
tap.
Based
on
the
strong
oxidizing
nature
of
the
chlorination
step
of
treatment
utilities
and
the
chemical
structure
of
these
compounds,
it
is
unlikely
that
these
compounds
will
be
found
in
treated
water
at
concentrations
equivalent
to
those
found
in
the
environment.
There
are
no
ambient
water
quality
criteria
or
drinking
water
maximum
contaminant
or
health
advisory
levels
for
these
compounds.

Based
on
the
Agency's
toxicity
categories,
as
a
group,
these
compounds
would
be
classified
as
slightly
toxic
to
practically
non­
toxic
to
aquatic
organisms.
Terrestrial
organism
toxicity,
using
mammal
data
as
a
surrogate
for
the
absence
of
avian
data,
indicate
that
these
compounds
would
be
classified
as
slightly
toxic
to
practically
non­
toxic
except
via
the
inhalation
route
where
toxicity
is
significantly
greater,
one
or
more
orders
of
magnitude
greater
depending
Page
3
of
8
on
the
compound.
At
anticipated
environmental
concentrations,
substances
associated
with
the
citric
acid
cycle
are
not
expected
to
exceed
the
available
toxicity
data
for
both
aquatic
and
terrestrial
organisms
to
include
exposures
and
risks
via
the
inhalation
route.

Introduction
The
compounds
contained
in
this
review
are
grouped
together
because
of
their
close
structural
relationships,
carboxylic
acids
and
their
salts,
and
the
role
each
plays
in
cell
metabolism,
specifically
in
the
tricarboxylic
acid
cycle
(also
known
as
the
citric
acid
or
Kreb's
cycle).
The
compounds
subject
to
this
review
are
as
follows:
acetic
acid,
acetic
acid
ammonium
salt,
acetic
acid
calcium
salt,
acetic
acid
magnesium
salt,
acetic
acid
manganese
salt,
acetic
acid
potassium
salt,
acetic
acid
sodium
salt,
citric
acid,
citrate,
citric
acid
sodium
salt,
citric
acid
sodium
salts,
fumaric
acid
and
malic
acid.
These
compounds
are
naturally
occurring
in
foods
and
essential
to
normal
metabolic
processes.

Critic,
fumaric
and
malic
acid
play
key
roles
in
the
metabolic
energy
system
called
the
Citric
Acid
Cycle
or
Kreb's
Cycle.
The
cycle
consists
of
a
series
of
enzymatic
chemical
reactions
occurring
within
the
cell
that
are
responsible
for
the
final
breakdown
of
food
molecules
to
form
carbon
dioxide,
water,
and
energy.
Citric,
fumaric,
and
malic
acid
are
the
integral
components
in
this
reaction,
each
being
used
over
and
over
again
to
produce
energy.
They
are
not
found
in
appreciable
amount
as
waste
products
from
animals
as
they
play
a
key
role
in
the
acid­
base
balance
within
animal
systems.
This
process
is
active
in
all
animals
and
higher
plants
and
is
carried
out
in
the
mitochondria
(American
Chemical
Council,
2001).

Acetic
Acid
and
its
Salts
The
chemical
structures,
physical­
chemical
properties,
environmental
fate
behavior,
and
aquatic
and
terrestrial
toxicity
of
these
compounds
are
similar.
Acetic
acid
and
its
salts
undergo
dissociation
in
aqueous
media
at
pH's
commonly
found
in
the
environment
to
the
acetate
anion
and
the
respective
cations.
The
toxicity
of
each
compound
is
driven
by
acetate,
with
the
cations
playing
a
minor
role.
Table
1
provides
key
environmental
physical­
chemical
properties
and
fate
data.
Biodegradation
appears
to
be
the
most
significant
removal
mechanism
following
the
dissociation
of
the
compound
into
the
acetate
anion
and
respective
salt.
Data
indicate
that
acetic
acid
and
sodium
acetate
(acetic
acid,
sodium
salt)
photodegrade,
although
the
rate
is
substantially
slower
than
that
of
biodegradation.
Fugacity
modeling
predicts
73%
of
any
acetic
acid
released
to
the
environment
would
partition
to
water
based
on
solubility
and
partition
coefficients,
with
the
remainder
partitioning
into
the
air.
Therefore,
the
data
suggest
that
acetic
acid
and
its
salts
are
not
persistent
in
the
environment.

Ecotoxicity
data
for
aquatic
and
terrestrial
animals
are
available
for
four
of
the
seven
compounds,
Table
1.
The
ecotoxicity
data
indicate
that
these
compounds
are
slightly
to
practically
nontoxic
on
an
acute
basis.
The
three
remaining
salts
are
closely
related
to
the
other
salts
in
structure,
properties
and
behavior
and
would
be
expected
to
have
similar
toxicity.
Terrestrial
Page
4
of
8
animal
toxicity
based
on
available
mouse
and
rat
data
would
indicate
acetic
acid
is
practically
nontoxic
on
an
acute
basis
and
no
chronic
effects
were
observed
in
available
studies.

Citric
Acid
and
its
Salts
Citric
acid
and
its
salts
are
comprised
of
four
compounds,
which
include
citric
acid,
sodium
citrate,
tripotassium
citrate,
and
trisodium
citrate.
The
chemical
structures
and
available
data
indicate
that
the
physical­
chemical
properties,
environmental
fate
behavior,
and
aquatic
and
terrestrial
toxicity
of
these
four
compounds
are
similar,
Table
2.
As
in
the
case
of
the
other
acids
and
salts
in
this
category,
citric
acid
and
its
salts
undergo
dissociation
in
aqueous
media
into
the
citrate
anion
and
the
respective
cations.
The
toxicity
of
each
compound
is
driven
by
citrate,
with
the
cations
playing
a
minor
role.

These
compounds
are
highly
water
soluble
and
of
moderate
to
low
volatility.
Data
on
the
environmental
fate
of
citric
acid
and
its
trisodium
salt
indicate
that
citric
acid
and
its
salts
dissociate
into
their
respective
cations
and
the
citrate
anion,
which
is
subsequently
readily
biodegraded.
Studies
indicate
that
citric
acid
and
its
trisodium
salt
are
readily
biodegraded
(90­
98%
degradation
after
48
hours).
Fugacity
modeling
predicts
that
100%
of
any
citric
acid
released
to
the
environment
would
partition
to
water
based
on
solubility
and
partitioning
coefficients.
Therefore,
the
existing
data
indicates
that
citric
acid
and
its
salts
are
not
persistent
in
the
environment.

Aquatic
toxicity
data
for
fish,
Daphnia
and
algae
are
available
for
citric
acid
and
its
trisodium
salt
and
indicate
that
these
compounds
practically
non­
toxic
on
an
acute
basis,
with
LC50
values
ranging
from
120
to
>18,
000
mg/
L,
Table
2.
Terrestrial
animal
toxicity
based
on
available
mouse
data
would
indicate
citric
acid
is
practically
non­
toxic
on
an
acute
basis
and
no
chronic
effects
were
observed
in
available
studies.

Fumaric
Acid
Available
data
indicate
that
fumaric
acid
is
highly
soluble
in
water
and
has
low
volatility.
Fugacity
modeling
predicts
that
virtually
all
(99.8%)
of
any
fumaric
acid
released
to
the
environment
would
partition
to
water
based
on
solubility
and
partitioning
coefficients.
Fumaric
acid
dissociates
into
fumate
and
hydrogen
ion
followed
by
fumate
undergoing
degradation
by
both
biotic
and
abiotic
mechanisms.
Nearly
complete
biodegradation
was
observed
after
21
days
under
aerobic
conditions,
Table
3.
These
data
indicate
that
fumaric
acid
is
not
persistent
in
the
environment.

Aquatic
LC50
values
for
fish
and
Daphnia
were
greater
than
200
mg/
L.
The
value
for
the
more
sensitive
algae
was
41
mg/
L.
These
data
indicate
that
fumaric
acid
is
slightly
to
practically
non­
toxic
to
aquatic
animals
and
plants
on
an
acute
basis.
Terrestrial
animal
toxicity
based
on
Page
5
of
8
available
rat
data
would
indicate
fumaric
acid
is
practically
non­
toxic
on
an
acute
basis
and
no
chronic
effects
were
observed
in
available
studies.

Malic
Acid
Malic
acid
is
highly
soluble
in
water
and
has
a
low
volatility.
Malic
acid
dissociates
into
malate
and
hydrogen
ion
and
pH's
commonly
found
in
the
aquatic
environment.
Malate
is
considered
readily
biodegradable
in
soil
and
water
and
fugacity
modeling
predicts
that
100%
of
any
malic
acid
released
to
the
environment
would
partition
to
water
based
on
solubility
and
partitioning
coefficients,
Table
3.
Based
on
these
data,
malic
acid
is
not
likely
to
be
persistent
in
the
environment.

Data
on
the
aquatic
toxicity
of
malic
acid
to
aquatic
invertebrates
are
available.
No
data
on
toxicity
to
fish
and
algae
were
available.
A
48­
hour
LC50
for
Daphnia
magna
was
240
mg/
L,
which
classifies
malic
acid
as
practically
non­
toxic
to
aquatic
invertebrates
on
an
acute
basis.
Given
this
data
and
the
aquatic
toxicity
data
for
the
structurally
related
compounds
in
this
category,
malic
acid
is
likely
to
be
practically
non­
toxic
to
other
aquatic
species
on
an
acute
basis.
Terrestrial
animal
toxicity
based
on
available
rat
data
would
indicate
malic
acid
is
practically
nontoxic
on
an
acute
basis
and
no
chronic
effects
were
observed
in
available
studies.

References
American
Chemistry
Council,
2001.
U.
S.
High
Production
Volume
(HPV)
Chemical
Challenge
Program,
Assessment
Plan
for
Acetic
Acid
and
Salts
Category.
Prepared
by:
American
Chemistry
Council,
Acetic
Acid
and
Salts
Panel,
June
28,
201.

TOXNET
2002.
Online
Scientific
Search
Engine,
National
Library
of
Medicine,
National
Institutes
of
Health.
Search
results
for
Acetic
Acid
and
salts,
Citric
Acid
and
salts,
and
Fumaric
Acid.

U.
S.
EPA,
1992.
Reregistration
Eligibility
Decision
(RED):
Citric
Acid
Fact
Sheet.
Office
of
Prevention,
Pesticides
and
Toxic
Substances.
EPA­
738­
F­
92­
017.
June
1992.
Page
6
of
8
Table
1.

Chemical
Properties
of
Acetic
Acid
and
Salts
Chemical
Property
Acetic
Acid
Acetic
Acid,
Ammonium
salt
Acetic
Acid,
Calcium
salt
Acetic
Acid,
Magnesium
salt
Acetic
Acid,
Manganese
salt
Acetic
Acid,
Potassium
salt
Acetic
Acid,
Sodium
salt
Vapor
Pressure
(mmHg)

11.4
@

20
o
C
1.

4x10
­4
@25
o
C
14.7
@25
o
C
NA
NA
7.

08x10
­7
@25
o
C
7.

08x10
­7
@25
o
C
Log
Kow
­0.17
­2.79
­0.97
NA
NA
­3.72
­3.72
Kd's
(Koc)

0.

65
(228)

Clastic
mud
0.085
(6.5)
muddy
sand
0.046
(27)
carbonate
sand
NA
NA
NA
NA
NA
NA
Water
Solubility
(g/
L)

50
@20
o
C
1,

480
@4
o
C
430
@25
o
C
very
solu
ble
soluble
2530g/
L
@25
o
C
365g/
L
@20
o
C
pKa
4.

76
@25
o
C
NANANANANA
NA
Photodegradation
50%
after
21
days
NA
NA
NA
NA
NA
6.

6%

after
17h
Biodegradation
99%
after
7
days
using
AS
days
to
weeks
(SAR)

Readily
biodegrades
NA
NA
NA
100%
after
5
days
using
AS
Fish
Acute
Toxicity
96h
LC50
)

75mg/
L
(Lowest
value
­

Bluegill
sunfish)

238mg/
L
(mosquito
fish)

NA
NA
NA
>6100mg/
L
(rainbow
trout)

100mg/
L
(zebra
fish)
Daphnia
Acute
Toxicity
65mg/
L
48h
EC50
)

NA
NA
NA
NA
7170mg/
L
24h
LC50
)

>1000mg/
L
48h
EC50
)
Page
7
of
8
Algae
Toxicity
4000mg/
L
(8­
day
growth
inhibition)

NA
NA
NA
NA
NA
2460mg/
L
after
60­
h
growth
inhibition)
Mammal
Acute
Oral
(LD50
)

4960
mg/
kg­
bw
(mouse)

NA
4280mg/
kg­
bw
(rat)

8610mg/
kg­
bw
(rat)

3730mg/
kg
bw
(rat)

3250mg/
kg­
bw
(rat)

3530mg/
kg­
bw
(rat)
AS:

Activated
Sludge.
SAR:

Structure
Activity
Relationship.
NA:
Not
Available.
Table
2.

Chemical
Properties
of
Citric
Acid
and
Salts
Chemical
Property
Citric
Acid
Citric
Acid,

Sodium
salt
Citric
Acid,

Tripotassium
salt
Citric
Acid,

Trisodium
salt
Vapor
Pressure
(mmHg@
25
o
C)

3.7x10
­9
@25
o
C
NA
NA
2.

09x10
­12
@25
o
C
Log
Kow
­1.72
NA
NA
­0.28
Water
Solubility
(g/
L
@25
o
C)

1330g/
l
@20
o
C
NA
NA
~425g/
L
@25
o
C
pKa
pK1:

3.

13;

pK2:
4.76;
pK3:
6.4
NA
NA
NA
Photodegradation
NA
NA
NA
NA
Biodegradation
98%
after
48­
h
using
domestic
sewage
NA
NA
90%
after
48­
h
using
AS
Fish
Acute
Toxicity
(96h­
LC50
)

1516mg/
L
(Bluegill
sunfish)

NA
NA
>18000­
32000mg/
L
(guppy)
Daphnia
Acute
Toxicity
120mg/
L
(72h­
EC50
)

NA
NA
5600­

10000mg/
L
(48h­
EC50
)
Algae
Toxicity
640mg/
L
8­

day
growth
inhibition)

NA
NA
>18000­
32000mg/
L
96h
EC50
)
Mammal
Acute
Oral
5790mg/
kg­
bw
(mouse)

7100mg/
kg­
bw
(mouse)

NA
NA
Page
8
of
8
Table
3.

Chemical
Properties
of
Fumaric
and
Malic
Acid
Chemical
Property
Fumaric
Acid
Malic
Acid
Vapor
Pressure
(mmHg@
25
o
C)

1.54x10
­4
4.6x10
­6
Log
Kow
0.33
@23
o
C
­1.26
Water
Solubility
(g/
L
@25
o
C)

7g/
L
592g/
L
pKa
pK1:

3.

02;

pK2:
4.46
@18
o
C
pK1:

3.
4;

pK2:

5.

05
Photodegradation
50%

degradation
after
7.3h
50%

degradation
after
2
days
Biodegradation
98%
after
21
days
using
domestic
sewage
readily
biodegrades
Fish
Acute
Toxicity
245mg/
L
(48h­
LC50
­zebrafish))

NA
Daphnia
Acute
Toxicity
212
mg/
L
(48h­
EC50
)

240mg/
L
(48h­
EC50
)
Algae
Toxicity
41mg/
L
(72h­
EC50
­

green
algae)

NA
Rat
Acute
Oral
9300mg/
kg­
bw
(female
rat)

1600­

3200mg/
kg­
bw
(mouse,
rat)