Page
1
of
27
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
January
28,
2004
MEMORANDUM
FROM:
Kathryn
Boyle,
Chair
Lower
Toxicity
Pesticide
Chemical
Focus
Group
Registration
Division
TO:
Betty
Shackleford,
Associate
Director
Registration
Division
SUBJECT:
Recommendation
for
Tolerance
Reassessment
The
attached
science
assessment
discusses
the
toxicity
of
ethylenediaminetetraacetic
acid
(
EDTA)
and
various
ammonium,
calcium,
copper,
iron,
potassium,
manganese,
sodium
and
zinc
salts
of
EDTA.
EDTA
is
a
chelating
agent.
Its
ability
to
bind
heavy
metal
ions
can
be
used
to
sequester
these
trace
metals.
However,
trace
amounts
of
various
metals
are
necessary
for
the
proper
functioning
of
the
body.
If
instead,
these
minerals
were
bound
to
the
EDTA,
then
deficiencies
of
these
trace
metals
could
result.

In
fact,
the
toxic
effects
of
EDTA
are
considered
to
be
related
to
metal
deficiencies,
especially
a
deficiency
of
zinc.
However,
two
critical
pieces
of
information
informed
the
Agency's
evaluation
of
EDTA.
Two
developmental
toxicity
studies
were
performed
using
disodium
EDTA.
The
Agency
has
reviewed
the
toxicological
literature
on
both
of
these
studies.
In
one
study,
rats
were
maintained
on
de­
ionized
water
(
water
containing
no
trace
minerals).
The
test
animals
displayed
both
maternal
and
developmental
effects.
In
another
very
similar
study,
rats
that
were
maintained
on
tap
water
displayed
no
such
effects.
Thus,
the
availability
of
trace
metals,
particularly
zinc,
in
the
diet
and
drinking
water
work
to
prevent
deficiencies.

Additionally,
EDTA
and
its
salts
have
inherent
limitations
of
percent
in
the
formulation,
due
to
the
nature
of
the
chemical
interactions
during
manufacture,
on
the
amount
of
EDTA
that
would
be
incorporated
in
a
pesticide
product.
The
information
available
to
the
Agency
indicates
that
EDTA
concentrations
in
agricultural
products
do
not
exceed
5%
(
by
weight)
of
a
formulated
product
and
concentrations
in
products
that
could
be
used
in
and
around
the
home
do
not
exceed
1%
(
by
weight)
of
a
formulated
product.
Page
2
of
27
Based
on
its
review
and
evaluation
of
the
available
information,
EPA
concludes
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
the
general
population,
and
to
infants
and
children
from
aggregate
exposure
to
residues
of
EDTA
and
its
various
salts
from
their
uses
as
ingredients
in
pesticide
products.
The
following
three
exemptions
from
the
requirement
of
a
tolerance
as
established
in
40
CFR
180.1001
(
c)
are
reassessed:
disodium
zinc
ethylenediaminetetraacetate
dihydride,
ethylenediaminetetraacetic
acid,
and
ethylenediaminetetraacetic
acid
tetrasodium
salt.

Based
on
the
chelating
ability
of
EDTA
and
the
various
ammonium,
calcium,
copper,
iron,
potassium,
manganese,
sodium
and
zinc
salts
of
EDTA,
and
the
inherent
limitations
during
manufacture
of
a
pesticide
product,
the
Agency
will
limit
the
percent
of
EDTA
or
any
EDTA
salt
in
a
formulated
pesticide
product
to
5%
by
weight.
Based
on
this
limitation,
classification
as
List
4B
is
appropriate
for
the
following
chemicals:

Chemical
Substance
(
Common
Name)
CAS
Reg.
No.

Ethylenediaminetetraacetic
acid
(
EDTA)
60­
00­
4
Ethylenediaminetetraacetic
acid
(
EDTA)
calcium
disodium
salt
62­
33­
9
Ethylenediaminetetraacetic
acid
(
EDTA)
tetrasodium
salt
64­
02­
8
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
salt
139­
33­
3
Ethylenediaminetetraacetic
acid
(
EDTA)
trisodium
salt
150­
38­
9
Ethylenediaminetetraacetic
acid
(
EDTA)
tetrapotassium
salt
5964­
35­
2
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
salt,
dihydrate
6381­
92­
6
Ethylenediaminetetraacetic
acid
(
EDTA)
potassium
salt
7379­
27­
3
Ethylenediaminetetraacetic
acid
(
EDTA)
sodium
salt
7379­
28­
4
Ethylenediaminetetraacetic
acid
(
EDTA)
copper
(
II)
salt
12276­
01­
6
Page
3
of
27
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
copper
(
II)
salt
14025­
15­
1
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
zinc
salt
14025­
21­
9
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
iron
(
II)
salt
14729­
89­
6
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
manganese
(
I)
salt
15375­
84­
5
Ethylenediaminetetraacetic
acid
(
EDTA)
sodium
iron
(
III)
salt
15708­
41­
5
Ethylenediaminetetraacetic
acid
(
EDTA)
iron
(
III)
salt
17099­
81­
9
Ethylenediaminetetraacetic
acid
(
EDTA)
monosodium
salt
17421­
79­
3
Ethylenediaminetetraacetic
acid
(
EDTA)
tripotassium
salt
17572­
97­
3
Ethylenediaminetetraacetic
acid
(
EDTA)
diammonium
salt
20824­
56­
0
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
copper
(
II)
salt,
dihydrate
61916­
40­
3
Ethylenediaminetetraacetic
acid
(
EDTA)
tripotassium
salt,
dihydrate
65501­
24­
8
Ethylenediaminetetraacetic
acid
(
EDTA)
tetrasodium
salt,
trihydrate
67401­
50­
7
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
zinc
salt,
dihydrate
73513­
47­
0
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
copper
(
II)
salt,
trihydrate
73637­
19­
1
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
manganese
(
I)
salt,
dihydrate
73637­
20­
4
Page
4
of
27
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
January
28,
2004
MEMORANDUM
FROM:
Kathryn
Boyle,
Chair
Lower
Toxicity
Pesticide
Chemical
Focus
Group
Registration
Division
TO:
Betty
Shackleford,
Associate
Director
Registration
Division
SUBJECT:
Recommendation
for
Tolerance
Reassessment
The
attached
science
assessment
discusses
the
toxicity
of
ethylenediaminetetraacetic
acid
(
EDTA)
and
various
ammonium,
calcium,
copper,
iron,
potassium,
manganese,
sodium
and
zinc
salts
of
EDTA.
EDTA
is
a
chelating
agent.
Its
ability
to
bind
heavy
metal
ions
can
be
used
to
sequester
these
trace
metals.
However,
trace
amounts
of
various
metals
are
necessary
for
the
proper
functioning
of
the
body.
If
instead,
these
minerals
were
bound
to
the
EDTA,
then
deficiencies
of
these
trace
metals
could
result.

In
fact,
the
toxic
effects
of
EDTA
are
considered
to
be
related
to
metal
deficiencies,
especially
a
deficiency
of
zinc.
However,
two
critical
pieces
of
information
informed
the
Agency's
evaluation
of
EDTA.
Two
developmental
toxicity
studies
were
performed
using
disodium
EDTA.
The
Agency
has
reviewed
the
toxicological
literature
on
both
of
these
studies.
In
one
study,
rats
were
maintained
on
de­
ionized
water
(
water
containing
no
trace
minerals).
The
test
animals
displayed
both
maternal
and
developmental
effects.
In
another
very
similar
study,
rats
that
were
maintained
on
tap
water
displayed
no
such
effects.
Thus,
the
availability
of
trace
metals,
particularly
zinc,
in
the
diet
and
drinking
water
work
to
prevent
deficiencies.

Additionally,
EDTA
and
its
salts
have
inherent
limitations
of
percent
in
the
formulation,
due
to
the
nature
of
the
chemical
interactions
during
manufacture,
on
the
amount
of
EDTA
that
would
be
incorporated
in
a
pesticide
product.
The
information
available
to
the
Agency
indicates
that
EDTA
concentrations
in
agricultural
products
do
not
exceed
5%
(
by
weight)
of
a
formulated
product
and
concentrations
in
products
that
could
be
used
in
and
around
the
home
do
not
exceed
1%
(
by
weight)
of
a
formulated
product.
Page
5
of
27
Based
on
its
review
and
evaluation
of
the
available
information,
EPA
concludes
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
the
general
population,
and
to
infants
and
children
from
aggregate
exposure
to
residues
of
EDTA
and
its
various
salts
from
their
uses
as
ingredients
in
pesticide
products.
The
following
three
exemptions
from
the
requirement
of
a
tolerance
as
established
in
40
CFR
180.1001
(
c)
are
reassessed:
disodium
zinc
ethylenediaminetetraacetate
dihydride,
ethylenediaminetetraacetic
acid,
and
ethylenediaminetetraacetic
acid
tetrasodium
salt.

Based
on
the
chelating
ability
of
EDTA
and
the
various
ammonium,
calcium,
copper,
iron,
potassium,
manganese,
sodium
and
zinc
salts
of
EDTA,
and
the
inherent
limitations
during
manufacture
of
a
pesticide
product,
the
Agency
will
limit
the
percent
of
EDTA
or
any
EDTA
salt
in
a
formulated
pesticide
product
to
5%
by
weight.
Based
on
this
limitation,
classification
as
List
4B
is
appropriate
for
the
following
chemicals:

Chemical
Substance
(
Common
Name)
CAS
Reg.
No.

Ethylenediaminetetraacetic
acid
(
EDTA)
60­
00­
4
Ethylenediaminetetraacetic
acid
(
EDTA)
calcium
disodium
salt
62­
33­
9
Ethylenediaminetetraacetic
acid
(
EDTA)
tetrasodium
salt
64­
02­
8
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
salt
139­
33­
3
Ethylenediaminetetraacetic
acid
(
EDTA)
trisodium
salt
150­
38­
9
Ethylenediaminetetraacetic
acid
(
EDTA)
tetrapotassium
salt
5964­
35­
2
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
salt,
dihydrate
6381­
92­
6
Ethylenediaminetetraacetic
acid
(
EDTA)
potassium
salt
7379­
27­
3
Ethylenediaminetetraacetic
acid
(
EDTA)
sodium
salt
7379­
28­
4
Ethylenediaminetetraacetic
acid
(
EDTA)
copper
(
II)
salt
12276­
01­
6
Page
6
of
27
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
copper
(
II)
salt
14025­
15­
1
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
zinc
salt
14025­
21­
9
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
iron
(
II)
salt
14729­
89­
6
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
manganese
(
I)
salt
15375­
84­
5
Ethylenediaminetetraacetic
acid
(
EDTA)
sodium
iron
(
III)
salt
15708­
41­
5
Ethylenediaminetetraacetic
acid
(
EDTA)
iron
(
III)
salt
17099­
81­
9
Ethylenediaminetetraacetic
acid
(
EDTA)
monosodium
salt
17421­
79­
3
Ethylenediaminetetraacetic
acid
(
EDTA)
tripotassium
salt
17572­
97­
3
Ethylenediaminetetraacetic
acid
(
EDTA)
diammonium
salt
20824­
56­
0
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
copper
(
II)
salt,
dihydrate
61916­
40­
3
Ethylenediaminetetraacetic
acid
(
EDTA)
tripotassium
salt,
dihydrate
65501­
24­
8
Ethylenediaminetetraacetic
acid
(
EDTA)
tetrasodium
salt,
trihydrate
67401­
50­
7
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
zinc
salt,
dihydrate
73513­
47­
0
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
copper
(
II)
salt,
trihydrate
73637­
19­
1
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
manganese
(
I)
salt,
dihydrate
73637­
20­
4
Page
7
of
27
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
January
26,
2004
Memorandum
Subject:
Ethylenediaminetetraacetic
acid
(
EDTA)
and
the
salts
of
EDTA:
Science
Assessment
Document
for
Tolerance
Reassessment.

From:
Elissa
Reaves,
Toxicologist
Reregistration
Branch
2
Health
Effects
Division
(
7509C)

Through:
Pauline
Wagner,
Branch
Chief
Reregistration
Branch
2
Health
Effects
Division
(
7509C)

To:
Lower
Risk
Pesticide
Chemical
Focus
Group
Kathryn
Boyle,
Chair
Registration
Division
(
7505C)

Background:

Attached
is
the
Lower
Risk
Pesticide
Chemicals
Focus
Group's
science
assessment
for
EDTA
and
the
salts
of
EDTA.
This
assessment
summarizes
available
information
on
the
use,
physical/
chemical
properties,
toxicological
effects,
and
exposure
profile
of
these
EDTA
salts.
In
performing
this
assessment,
EPA
has
utilized
reviews
previously
performed
by
the
Federal
Drug
Administration
(
FDA)
and
relied
on
peer­
reviewed
evaluations
performed
by
the
Food
and
Agriculture
Organization
of
the
World
Health
Organization
(
FAO/
WHO),
and
the
Cosmetic
Ingredient
Review
(
CIR).

I.
Executive
Summary:

The
EDTA
salts
evaluated
in
this
report
include
ammonium,
calcium,
copper,
iron,
Page
8
of
27
potassium,
manganese,
sodium,
and
zinc.
EDTA
is
a
man­
made
amino
acid
chelating
(
binding)
agent
with
an
affinity
for
metals
such
as
lead,
mercury,
cadmium,
and
aluminum.
EDTA's
ability
to
complex
is
used
commercially
to
either
promote
or
inhibit
chemical
reactions,
depending
on
application.
EDTA
has
been
used
extensively
as
a
food
additive
to
sequester
trace
metals
that
catalyze
the
oxidation
of
oils,
vitamins,
and
unsaturated
fats
that
cause
rancidity,
flavor
changes,
and
discoloration.
Permissible
levels
of
EDTA
calcium
disodium
salt
in
food
range
from
25
to
800
ppm,
and
an
acceptable
daily
intake
of
2.5
mg/
kg
was
established
by
the
Joint
FAO/
WHO
Expert
Committee
on
Food
Additives
(
JECFA)
in
1973.
EDTA
has
also
been
used
in
food
contact
surface
sanitizing
solutions,
to
control
the
interactions
of
trace
metals
in
formulations
of
liquid
soaps,
cosmetics,
and
pharmaceuticals,
in
metal
working,
in
pulp
and
paper
processing,
in
rubber
and
polymer
chemistry,
and
in
textile
processing
and
dyeing.

EDTA
and
its
salts
are
eliminated
from
the
body,
95%
via
the
kidneys
and
5%
by
the
bile,
along
with
the
metals
and
free
ionic
calcium
which
was
bound
in
transit
through
the
circulatory
system.
The
binding
of
divalent
and
trivalent
cations
by
EDTA
can
cause
mineral
deficiencies,
which
seem
to
be
responsible
for
all
of
the
known
pharmacological
effects.
Sensitivity
to
the
toxic
effects
of
EDTA
is,
at
least
in
part,
related
to
the
deficiency
of
zinc.

The
available
ecotoxicity
data
for
EDTA
indicate
that
these
compounds
are
slow
to
degrade
under
typical
environmental
conditions
but
are
not
expected
to
bioconcentrate.
EDTA
compounds
range
from
practically
non­
toxic
to
moderately
toxic
on
an
acute
basis
depending
on
the
salt.
Algae
and
invertebrates
are
among
the
most
sensitive
species
based
on
predictive
modeling
for
acute
and
chronic
endpoints
for
EDTA,
depending
on
the
compound.
EDTA
and
its
salts
also
do
not
appear
to
be
very
toxic
for
terrestrial
wild
mammals
and
adverse
effects
from
reasonably
expected
agricultural
uses
are
not
expected.

Based
on
available
information
on
EDTA
and
its
salts,
their
expected
use
patterns,
their
safe
history
of
use
as
food
additives,
extensive
use
in
commercially­
available
pharmaceuticals,
and
their
low
risk,
the
Agency
has
determined
that
a
quantitative
risk
assessment
is
not
required
for
these
compounds.

II.
Use
Information:

There
are
several
variations
of
nomenclature
for
EDTA
and
its
salts.
Therefore,
this
document
will
refer
to
ethylenediaminetetraacetic
acid
as
EDTA.
The
salts
of
EDTA
will
be
presented
as
ethylenediaminetetraacetic
acid
(
EDTA)
sodium
salt,
etc.

The
tolerance
exemptions
being
reassessed
in
this
document,
the
40
CFR
location
of
the
established
tolerance
exemption,
and
the
use
pattern
as
an
inert
or
active
ingredient
are
listed
in
Table
1.
Page
9
of
27
Table
1.
Tolerance
Exemptions
Being
Reassessed
in
this
Document
Tolerances
Exemption
Expression
40
CFR

Limits
Uses
Ethylenediaminetetraacetic
acid
(
EDTA)
180.1001
(
c)
3%
pesticide
formulations,
sequestrant
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
zinc
salt,
dihydrate
180.1001
(
c)
­­
sequestrant
Ethylenediaminetetraacetic
acid
(
EDTA)
tetrasodium
salt,
trihydrate
180.1001
(
c)
5%
pesticide
formulations,
sequestrant

Residues
listed
in
section
(
c)
of
40
CFR
180.1001
are
exempted
from
a
tolerance
when
used
as
inert
ingredients
in
pesticide
formulations
when
applied
to
growing
crops
or
to
raw
agricultural
commodities
after
harvest.

Most
of
the
pesticide
products
in
which
EDTA
chemicals
are
incorporated
as
an
inert
ingredient
are
non­
food
products.
Residential
products
that
contain
EDTA
chemicals
typically
are
less
than
1%
of
the
formulation.
However,
the
tolerance
exemptions
are
needed
for
a
small
number
of
pesticide
products
applied
to
food
crops
containing
EDTA
chemicals.

The
following
Table
lists
identifying
information
for
EDTA
and
its
salts
which
are
currently
regulated
by
the
Agency.

Table
2.
EDTA
and
the
salts
of
EDTA
Chemical
Substance
(
Common
Name)
CAS
Reg.
No.
List
Classification*

Ethylenediaminetetraacetic
acid
(
EDTA)
60­
00­
4
3
Ethylenediaminetetraacetic
acid
(
EDTA)
calcium
disodium
salt
62­
33­
9
3
Ethylenediaminetetraacetic
acid
(
EDTA)
tetrasodium
salt
64­
02­
8
3
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
salt
139­
33­
3
3
Ethylenediaminetetraacetic
acid
(
EDTA)
trisodium
salt
150­
38­
9
3
Ethylenediaminetetraacetic
acid
(
EDTA)
tetrapotassium
salt
5964­
35­
2
3
Page
10
of
27
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
salt,
dihydrate
6381­
92­
6
3
Ethylenediaminetetraacetic
acid
(
EDTA)
potassium
salt
7379­
27­
3
3
Ethylenediaminetetraacetic
acid
(
EDTA)
sodium
salt
7379­
28­
4
­­

Ethylenediaminetetraacetic
acid
(
EDTA)
copper
(
II)
salt
12276­
01­
6
­­

Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
copper
(
II)
salt
14025­
15­
1
3
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
zinc
salt
14025­
21­
9
3
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
iron
(
II)
salt
14729­
89­
6
3
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
manganese
(
I)
salt
15375­
84­
5
3
Ethylenediaminetetraacetic
acid
(
EDTA)
sodium
iron
(
III)
salt
15708­
41­
5
3
Ethylenediaminetetraacetic
acid
(
EDTA)
iron
(
III)
salt
17099­
81­
9
3
Ethylenediaminetetraacetic
acid
(
EDTA)
monosodium
salt
17421­
79­
3
3
Ethylenediaminetetraacetic
acid
(
EDTA)
tripotassium
salt
17572­
97­
3
3
Ethylenediaminetetraacetic
acid
(
EDTA)
diammonium
salt
20824­
56­
0
3
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
copper
(
II)
salt,
dihydrate
61916­
40­
3
3
Ethylenediaminetetraacetic
acid
(
EDTA)
tripotassium
salt,
dihydrate
65501­
24­
8
­­

Ethylenediaminetetraacetic
acid
(
EDTA)
tetrasodium
salt,
trihydrate
67401­
50­
7
3
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
zinc
salt,
dihydrate
73513­
47­
0
3
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
copper
(
II)
salt,
trihydrate
73637­
19­
1
3
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
manganese
(
I)
salt,
dihydrate
73637­
20­
4
3
Page
11
of
27
*
Inert
ingredients
are
categorized
into
four
lists
as
described
in
the
52
FR
13305,
Inert
Ingredients
in
Pesticide
Products
Policy
Statement.
List
3
includes
inert
ingredients
of
unknown
toxicity,
inert
ingredients
that
have
not
yet
been
evaluated
for
list
reclassification.
­­
Not
available
in
OPPIN
Source:
OPPIN
database
10/
2003
According
to
the
OPPIN
database,
EDTA,
EDTA
sodium
salt,
EDTA
disodium
salt,
EDTA
trisodium
salt,
EDTA
tetrasodium
salt,
EDTA
potassium
salt,
EDTA
tripotassium
salt,
EDTA
tetrapotassium
salt,
EDTA
sodium
iron
(
III)
salt,
and
EDTA
copper
(
II)
salt
have
active
ingredient
PC
codes.
However,
only
tetrasodium
EDTA
and
EDTA
copper
(
II)
salt
have
current
registrations
and
sodium
iron
(
III)
EDTA
is
currently
pending
registration.
All
other
active
ingredient
uses
of
EDTA
salts
have
been
canceled.

Use
in
Food
Contact
Surface
Sanitizing
Solutions:

Tetrasodium
EDTA
is
currently
used
in
food
contact
surface
sanitizing
solutions
as
specified
under
21
CFR
178.1010
(
b)
(
19).
Disodium
EDTA
is
also
used
in
food
contact
surface
sanitizing
solutions
(
21
CFR
178.1010
(
b)
(
44)).

Use
in
Cosmetics:

EDTA
and
several
of
its
salts
function
as
chelating
agents
in
cosmetics.
A
safety
assessment
of
EDTA
and
several
salts
by
the
Cosmetic
Ingredient
Review
(
CIR
2002)
indicated
EDTA
was
used
in
over
4,000
cosmetic
formulations.
This
report
also
indicated
that
cosmetic
formulations
generally
contain
less
than
2%
of
EDTA
salts.
However,
historical
data
submitted
to
the
FDA
in
1984
revealed
one
formulation
for
each
EDTA
and
tetrasodium
EDTA
contained
concentrations
of
25%.
The
product
containing
a
25%
concentration
of
EDTA
was
not
identified.
Examples
of
products
containing
EDTA
chemicals
include:
bubble
baths,
bath
soaps
and
detergents,
deodorants,
facial
makeups
and
lotions,
colognes
and
toilet
waters,
hair
products
(
shampoos,
rinses,
conditioners,
dyes
and
colors),
nail
basecoats
and
undercoats,
and
nail
creams
and
lotions.

FDA
Uses:

EDTA:
EDTA
has
been
used
under
medical
supervision
to
treat
heavy
metal
poisoning.
Large
doses
of
EDTA
(
or
one
of
its
salts)
function
to
scavenge
the
heavy
metals
from
the
body.
EDTA
preferentially
binds
with
the
heavy
metal
present
with
the
resultant
complex
then
being
excreted.

Calcium
disodium
EDTA:
Calcium
disodium
EDTA
can
be
used
as
a
food
additive
and
is
permitted
for
direct
addition
to
food
for
human
consumption,
as
long
as
1)
the
quantity
of
the
substance
added
to
food
does
not
exceed
the
amount
reasonably
required
to
accomplish
its
intended
physical,
nutritive,
or
other
technical
effect
in
food,
and
2)
any
substance
intended
for
use
in
or
on
food
is
of
appropriate
food
grade
and
is
prepared
and
handled
as
a
food
ingredient
Page
12
of
27
(
21
CFR
172.120).
Certification
of
calcium
disodium
EDTA
when
used
as
a
diluent
in
color
additive
mixtures
for
food
use
is
not
necessary
for
the
protection
of
the
public
heath,
and
therefore
is
exempt
from
the
certification
under
section
721
(
c)
of
21
CFR
73.1.
Calcium
disodium
EDTA
may
also
be
used
to
promote
stability
of
color,
flavor,
texture
retention,
and
to
retard
struvite
(
mineral)
formation.
It
is
also
used
as
a
sequestering
agent
in
the
production
of
pharmaceuticals.
An
acceptable
daily
intake
(
ADI)
of
2.5
mg/
kg
calcium
disodium
EDTA
was
established
by
the
FAO/
WHO
(
1974).

Disodium
EDTA:
Disodium
EDTA
can
also
be
used
as
a
food
additive
for
direct
addition
to
food
for
human
consumption
in
specified
foods
and
is
not
to
exceed
prescribed
levels
under
21
CFR
172.135.
It
is
also
approved
by
FDA
as
a
component
of
sanitizing
solutions
for
use
on
food
processing
equipment
and
on
dairy­
processing
equipment
(
21
CFR
178.1010
(
b)
(
44)).
Disodium
EDTA
may
also
be
safely
used
in
designated
foods
as
a
stabilizer
for
vitamin
B12,
promoter
for
color
retention,
and
as
a
cure
accelerator
with
sodium
ascorbate
or
ascorbic
acid.

Tetrasodium
EDTA:
Tetrasodium
EDTA
can
be
used
in
sanitizing
solutions
for
use
on
food
processing
equipment
and
utensils
and
on
food­
contact
surfaces
in
public
eating
places
(
21
CFR
178.1010(
b)
(
19)).

Sodium
iron
EDTA:
A
provisional
maximum
tolerance
daily
intake
of
0.8
mg/
kg/
bw
was
established
by
the
Joint
FAO/
WHO
Committee
(
FAO/
WHO
2000)
at
the
end
of
the
twentyseventh
meeting.

High
Production
Volume
(
HPV)
Challenge
Program:

HPV
chemicals
are
those
that
are
manufactured
or
imported
into
the
United
States
in
volumes
greater
than
one
million
pounds
per
year.
There
are
approximately
3,000
HPV
chemicals
that
are
produced
or
imported
into
the
United
States.
The
HPV
Challenge
Program
is
a
voluntary
partnership
between
industry,
environmental
groups,
and
the
EPA
which
invites
chemical
manufacturers
and
importers
to
provide
basic
hazard
data
on
the
HPV
chemicals
they
produce/
import.
The
goal
of
this
program
is
to
facilitate
the
public's
right­
to­
know
about
the
potential
hazards
of
chemicals
found
in
their
environment,
their
homes,
their
workplace,
and
in
consumer
products.

The
Agency
notes
that
EDTA,
disodium
EDTA,
and
tetrasodium
EDTA
are
included
on
the
Agency's
list
of
chemicals
included
in
the
High
Production
Volume
(
HPV)
Challenge
Program.
These
chemicals
are
being
handled
by
SIDS
(
Screening
Information
Data
Set)
Program
and
have
been
confirmed
by
the
ICAA
(
International
Council
of
Chemical
Associations)
for
incorporation
in
the
HPV
initiative
of
the
ICAA.
However,
these
EDTA
chemicals
are
currently
not
sponsored
by
any
company
or
consortium.

Other
Uses:

EDTA:
EDTA
has
been
used
under
medical
supervision
to
treat
heavy
metal
poisoning.
Page
13
of
27
Large
doses
of
EDTA
(
or
one
of
its
salts)
function
to
scavenge
the
heavy
metals
from
the
body.
EDTA
preferentially
binds
with
the
heavy
metal
present
with
the
resultant
complex
then
being
excreted.

EDTA
is
also
used
as
a
chelating
agent
in
boiler
and
cooling
water,
in
nickel
plating,
and
in
wood
pulping
processes.
EDTA
is
also
in
detergents
for
household
and
textile
use,
industrial
germicides,
metal
cutting
fluids,
pharmaceuticals,
and
is
used
as
a
bleaching
agent
in
color
film
processing,
etching
agent
in
metal
finishing
and
semiconductor
production,
activator
in
butadienestyrene
co­
polymerization,
in
gas
scrubbing,
and
as
a
component
of
blood
anticoagulants
(
TOXNET
2003).

Trisodium
EDTA:
Trisodium
EDTA
salts
are
used
in
detergents,
liquid
soaps,
shampoos,
agricultural
chemical
sprays,
pharmaceutical
products,
oil
emulsions,
and
in
textiles
to
improve
dyeing,
scouring
and
detergent
operations.
Trisodium
EDTA
is
also
used
as
a
metal
chelating
agent,
in
metal
cleaning
and
plating,
in
the
treatment
of
chlorosis,
to
decontaminate
radioactive
surfaces,
as
a
metal
deactivator
in
vegetable
oils,
as
an
anticoagulant
of
blood,
as
an
eluting
agent
in
ion
exchange,
to
remove
insoluble
deposits
of
calcium
and
magnesium
soaps,
as
an
antioxidant,
in
the
clarification
of
liquids,
in
analytical
chemistry
spectrophotometric
titration,
to
aid
in
reducing
blood
cholesterol,
and
to
treat
lead
poisoning
and
calcinosis
(
NTP
2003).

III.
Physical/
Chemical
Properties:

As
a
group,
EDTA
and
the
EDTA
salts
are
white
crystalline
or
powder
in
structure.
The
effectiveness
of
EDTA
as
a
chelator
for
a
particular
metal
ion
is
given
by
its
stability
constant
with
the
metal
ion.
The
stability
constants
for
different
metal­
EDTA
complexes
vary
considerably,
and
any
metal
which
is
capable
of
forming
a
strong
complex
with
EDTA
will
at
least
partially
displace
another
metal
with
a
weaker
stability
constant
(
FAO/
WHO
2000).
The
EDTA
salts
are
soluble
in
water,
have
low
sorption
to
soil
and
sediments,
have
no
significant
vapor
pressure,
and
have
a
biodegredation
half­
life
of
weeks
to
months
(
EPA
2003).

Ethylenediaminetetraacetic
acid
(
EDTA)
(
Figure
of
EDTA
obtained
from:
http://
scifun.
chem.
wisc.
edu/
chemweek/
chel&
chlor/
chel&
chlor.
html)

IV.
Hazard
Assessment
The
key
toxicological
data
in
the
following
sections
were
obtained
from
published
reports
Page
14
of
27
by
peer
reviewed
committees
such
as
the
Joint
FAO/
WHO
Expert
Committee
on
Food
Additives
(
JECFA),
Scientific
Committee
on
Toxicity,
Ecotoxicity,
and
the
Environment
(
CSTEE),
Cosmetic
Ingredient
Review
(
CIR),
published
studies
in
peer
reviewed
journals,
as
well
as
from
NIOSH
(
www.
cdc.
gov/
niosh/
rtechs),
and
other
databases
available
on
websites
such
as
TOXNET
(
www.
toxnet.
nlm.
nih.
gov),
and
SIRI
(
http://
www.
hazard.
com/
msds/
index.
php).

In
general,
EDTA
and
the
salts
of
EDTA
are
a
group
known
as
sequestrants
which
have
the
ability
to
chelate
metals.
EDTA
is
not
totally
absorbed
when
ingested.
Various
sources
rate
the
absorption
as
poor
to
good
with
the
upper
limit
on
absorption
being
defined
numerically
as
20%.
Elimination
occurs
mainly
by
the
kidneys
(
95%)
with
some
(
5%)
via
the
bile
(
FAO/
WHO
1974,
CSTEE
2003,
CIR
2002).

In
the
sections
below,
the
available
toxicological
data
for
EDTA
and
specific
EDTA
salts
are
summarized
first
in
the
following
table,
followed
by
a
discussion
of
the
toxicity
of
EDTA,
salts
of
EDTA,
and
cations.

A.
Toxicological
data
available
for
EDTA
and
the
salts
of
EDTA:

Table
3.
Toxicity
data
for
EDTA
and
the
salts
of
EDTA1
Oral
LD50
mg/
kg
Chemical
CAS
No.
mouse
rat
Reference
Ethylenediaminetetraacetic
acid
(
EDTA)
calcium
disodium
salt
62­
33­
9
10,000
10,000
Oser
et
al.,
1963
as
cited
in
FAO/
WHO
1967;
SIRI
2003
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
salt
139­
33­
3
2050
2000
FAO/
WHO
1967
and
1974,
SIRI
2003
Ethylenediaminetetraacetic
acid
(
EDTA)
trisodium
salt
150­
38­
9
2150
2150
NTP
2003;
SIRI
2003
Ethylenediaminetetraacetic
acid
(
EDTA)
sodium
iron
(
III)
salt
15708­
41­
5
5,000
5,000
SIRI
2003
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
zinc
dihydrate
salt
73513­
47­
0
 
5,000
SIRI
2003
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
copper
(
II)
salt,
trihydrate
73637­
19­
1
 
1750
SIRI
2003
Ethylenediaminetetraacetic
acid
(
EDTA)
disodium
manganese
(
I)
salt,
dihydrate
73637­
20­
4
 
5,000
SIRI
2003
In
general,
EDTA
and
its
salts
are
mild
skin
irritants
but
considered
severe
eye
irritants.
A
report
by
the
Scientific
Committee
on
Toxicity,
Ecotoxicity,
and
the
Environment
(
CSTEE
2003)
Page
15
of
27
concluded
"
both
EDTA
and
tetrasodium
EDTA
are
mild
skin
irritants,
but
comparatively
potent
eye
irritants".
Similarly,
tetrasodium
EDTA
should
not
be
applied
to
the
eye
unless
first
neutralized,
because
it
forms
a
solution
sufficiently
alkaline
to
be
injurious
to
the
eye
(
Grant,
1986
as
cited
in
TOXNET).

The
greatest
risk
in
the
human
body
will
occur
when
the
EDTA
attempts
to
scavenge
the
trace
metals
used
and
required
by
the
body.
The
various
toxicity
studies,
particularly
the
Kimmel
(
1977)
and
Schardein
et
al.
(
1981)
studies,
indicate
that
developmental
effects
will
occur
if
the
body
is
not
properly
supplemented
with
necessary
trace
metals.

Several
short
term
studies,
reviewed
by
FAO/
WHO
in
1974,
reported
no
adverse
effects
from
administering
doses
up
to
5%
of
EDTA
and
its
salts
to
lab
rodents
daily
and
for
several
weeks.
Only
diarrhea
and
lowered
food
consumption
were
reported
in
animals
given
5%
disodium
EDTA.
However,
abnormal
effects
were
seen
in
animals
that
were
fed
mineral
deficient
diets.
Abnormal
symptoms
were
observed
in
male
and
female
rats
fed
a
low
mineral
diet
(
0.54%
Ca
and
0.013%
Fe)
with
the
addition
of
0%,
0.5%,
or
1%
disodium
EDTA
for
205
days.
Rats
fed
a
low
percent
of
disodium
EDTA
in
the
diet
for
short
term
studies
with
adequate
minerals
showed
no
signs
of
toxicity.
Rats
fed
0.5%
disodium
EDTA
for
44­
52
weeks
were
without
deleterious
effects
on
weight
gain,
appetite,
activity
and
appearance.
Rats
fed
1%
disodium
EDTA
with
adequate
mineral
diet
for
220
days
showed
no
evidence
of
dental
erosion.

Disodium
EDTA
administered
by
different
routes;
3%
in
diet,
gastric
intubation,
or
subcutaneously,
produced
different
teratogenic
rates
in
rats
(
Kimmel
1977).
Disodium
EDTA
administered
to
pregnant
rats
on
Days
7
to
14
of
gestation
by
dietary
admixture
(
954
mg/
kg/
day)
produced
maternal
toxicity
and
fetal
death
and
malformations
in
71%
of
the
offspring.
Rats
given
1250
mg/
kg
or
1500
mg/
kg
by
gavage
exhibited
more
maternal
toxicity
than
the
diet
group,
but
produced
only
21%
malformations
in
the
offspring
at
the
lower
dose.
The
subcutaneously
administration
of
375
mg/
kg
was
also
maternally
toxic,
but
did
not
result
in
malformations
in
the
offspring.
Differences
in
toxicity
and
teratogenicity
are
probably
related
to
absorption
differences
and
interaction
with
metals.
Animals
in
the
study
by
Kimmel
(
1977)
were
maintained
on
deionized
water
and
possibly
became
zinc
deficient,
thus
causing
teratogenicity
in
the
offspring.
Similarly,
EDTA
and
four
of
its
salts
(
disodium,
trisodium,
calcium
disodium,
and
tetrasodium)
were
administered
to
pregnant
rats
during
Days
7
and
14
of
gestation
(
Schardein
et
al.,
1981).
Equimolar
doses
based
on
1,000
mg/
kg
(
58.4
to
83.2
mg/
ml)
given
by
gastric
intubation
produced
no
teratogenic
effects
on
the
offspring,
even
at
maternally
toxic
doses.
Unlike
the
study
by
Kimmel
(
1977),
the
rats
were
given
tap
water
ad
libitum
and
probably
did
not
suffer
from
zinc
deficiency.

The
Agency
reviewed
data
from
an
early
teratogenicity
study
submitted
for
disodium
EDTA
(
EPA
1979).
Female
Sprague­
Dawley
rats
were
administered
disodium
EDTA
in
the
diet
ranging
from
2%
to
3%,
or
3%
EDTA
plus
1,000
ppm
zinc,
during
pregnancy.
The
conclusions
in
the
memo
reported
that
"
disodium
EDTA
ingested
during
pregnancy
is
teratogenic
in
rats
at
2%
in
the
diet
and
greater."
However,
it
was
also
concluded
that
the
diet
"
supplemented
with
1000
ppm
zinc
prevented
the
detrimental
effects
of
EDTA
during
pregnancy
in
the
rat."
Effects
Page
16
of
27
from
disodium
EDTA
in
the
young
were
likely
due
to
"
an
induced
deficiency
of
zinc..."
and
that
"
cells
undergoing
rapid
growth
and
development
are
particularly
sensitive
to
deficiency
of
zinc."
Likewise,
evaluation
of
EDTA
and
tetrasodium
EDTA
by
the
CSTEE
(
2003)
concluded
that
"
teratogenicity
is
most
likely
due
to
zinc
depletion
by
the
very
high
doses
applied...".

The
FAO/
WHO
Expert
Committee
on
food
additives
(
1974)
reviewed
acute
toxicity
data
for
calcium
disodium
EDTA
and
disodium
EDTA.
The
Expert
Panel
commented
that
"
the
use
of
calcium
disodium
EDTA
is
preferable
to
that
of
disodium
EDTA."
In
fact,
the
Expert
Panel
concluded
that
"
because
of
disodium
EDTA's
effect
on
calcium,
the
use
of
disodium
EDTA
as
a
food
additive
was
not
recommended."
However,
the
Committee
also
concluded
that
"
under
certain
circumstances,
necessitating
an
accurate
complexing
of
calcium,
disodium
EDTA
may
be
used
provided
no
excess
of
disodium
EDTA
remains
and
the
only
compound
finally
present
is
calcium
disodium
EDTA."

A
2002
safety
assessment
of
EDTA,
calcium
disodium
EDTA,
diammonium
EDTA,
dipotassium
EDTA,
disodium
EDTA,
TEA­
EDTA,
tetrasodium
EDTA,
tripotassium
EDTA,
trisodium
EDTA,
HEDTA,
and
trisodium
HEDTA
was
performed
by
an
expert
panel
of
the
Cosmetic
Ingredient
Review
(
CIR).
This
assessment
considered
numerous
toxicological
studies,
including
various
acute,
subchronic,
and
chronic/
carcinogenicity
toxicity
studies,
and
mutagenicity
studies.
This
report
also
details
extensive
use
of
these
EDTA
salts
in
numerous
cosmetic
products
with
EDTA
salt
formulations
most
commonly
used
at

2%,
although
a
few
formulations
were
reported
using
up
to
10%
and
25%.
Based
on
the
available
information,
the
panel
concluded
that
"
EDTA,
calcium
disodium
EDTA,
diammonium
EDTA,
dipotassium
EDTA,
disodium
EDTA,
TEA­
EDTA,
tetrasodium
EDTA,
tripotassium
EDTA,
trisodium
EDTA,
HEDTA,
and
trisodium
HEDTA,
are
safe
as
used
in
cosmetic
formulations."

Trisodium
EDTA
was
tested
in
a
bioassay
for
carcinogenicity
by
the
National
Cancer
Institute.
Trisodium
EDTA
administered
to
male
and
female
rats
at
low
(
3,750
ppm)
or
high
(
7,500
ppm)
concentrations
for
103
weeks
produced
no
compound­
related
signs
of
chemical
toxicity,
and
tumor
incidence
was
not
related
to
treatment
(
NCI,
1977).
The
CSTEE
(
2003)
also
evaluated
this
study
by
the
National
Cancer
Institute
and
concluded
that
"
there
is
no
concern
for
EDTA
with
regard
to
carcinogenicity."

EDTA
has
been
demonstrated
to
affect
inhibition
of
DNA
synthesis
in
primary
cultures
of
mammalian
cells,
which
may
be
due
to
impairment
of
enzymes
involved
in
DNA
replication
(
Heindorff
et
al.,
1983).
EDTA
has
also
been
demonstrated
to
enhance
mutagen­
induced
aberration
frequencies
in
Drosophila
melanogaster,
Chlamydomonas
reinhardi,
Neurospora
crassa
and
Zea
mays
by
interfering
with
the
DNA
repair
process
that
takes
place
after
exposure
to
mutagens
(
Heindorff
et
al.,
1983).

Mutagenicity
studies
such
as
mouse
lymphoma
were
negative
for
EDTA
and
its
salts
except
for
a
few
positive
tests
when
administered
with
sterile
distilled
water.
Genotoxicity
studies
for
EDTA
and
its
salts
were
mixed
positive
and
negative
results,
depending
on
assay
type
and
cell
type
(
CCRIS
2003
and
Genetox
2003).
The
RTECS
(
2003)
database
for
EDTA
reported
the
Page
17
of
27
following
mutation
data:
DNA
damage
in
mouse
lymphocyte
at
40,500

mol/
L;
DNA
inhibition
in
hamster
fibroblast
at
500

g/
L
and
in
rat
other
cell
types
at
600

mol/
L;
unscheduled
DNA
synthesis
in
hamster
embryo
at
100

mol/
L;
mutation
in
mammalian
somatic
cells
in
mouse
lymphocyte
at
25,
200

mol/
L;
and
sister
chromatid
exchange
in
hamster
embryo
at
30

mol/
L.

B.
Cations:
Calcium,
Copper,
Iron,
Manganese,
Potassium,
Sodium,
and
Zinc:

Cations
such
as
calcium,
copper,
iron,
manganese,
potassium,
sodium,
and
zinc
are
required
for
proper
functioning
of
human
biological
systems.
For
risk
assessment
purposes,
an
important
feature
of
these
cations
is
that
overall
the
body
does
have
an
effective
means
of
processing
them.
The
primary
means
of
exposure
to
these
cations
is
ingestion.
Therefore,
the
following
section
focuses
on
the
dietary
exposure
of
these
cations
and
the
body's
requirements
for
these
cations.
The
importance
of
each
cation
is
briefly
discussed
in
the
following
section.

Calcium:
The
human
body
burden
of
calcium
is
approximately
1
kg
for
a
70
kg
adult;
thus,
1/
70th
of
our
weight
is
calcium.
The
calcium
cation
is
necessary
for
bone
and
teeth
formation.
It
is
also
important
to
the
proper
functioning
of
nerves,
enzymes,
and
muscles,
and
plays
a
role
in
blood
clotting
and
the
maintenance
of
cell
membranes.
The
recommended
daily
allowances
(
RDAs)
for
calcium
are
1000
mg/
day
for
adults
aged
19
to
50
years,
and
1200
mg/
day
for
individuals
older
than
50
years.

Copper:
Copper
is
an
essential
element
for
all
biota
and
is
naturally
found
in
a
wide
variety
of
mineral
salts
and
organic
compounds,
and
in
the
metallic
form.
At
least
12
major
proteins
require
copper
as
an
integral
part
of
their
structure.
Copper
is
essential
for
the
utilization
of
iron
in
the
formation
of
hemoglobin.
Adverse
health
effects
are
related
to
both
deficiency
and
excess.
Except
for
occasional
acute
incidents
of
copper
poisoning,
few
effects
are
noted
in
normal
populations.
The
mean
daily
dietary
intake
in
adults
ranges
between
0.9
and
2.2
mg.
The
acceptable
range
of
oral
intake
(
AROI)
is
20

g/
kg
body
weight
per
day
for
adults
and
50

g/
kg
body
weight
per
day
for
infants
(
WHO
1998).

Iron:
The
human
body
burden
of
iron
is
approximately
4
g
for
males,
2.5
g
for
females
or
approximately
38
mg/
kg
body
weight.
Iron
is
essential
for
the
synthesis
of
heme
proteins
which
function
in
the
process
of
oxygen
transport
and
oxidative
metabolism
that
includes
haemoglobin,
myoglobin,
the
cytochromes
as
well
as
catalases
and
peroxidases.
The
allowable
daily
intake
(
ADI)
is
0.5
mg/
kg
(
WHO
2003a).

Manganese:
Manganese
is
an
essential
trace
element
for
both
animals
and
man.
It
is
necessary
for
the
formation
of
connective
tissue
and
bone,
growth,
carbohydrate
and
lipid
metabolism,
embryonic
development
of
the
inner
ear,
and
reproductive
functions.
Daily
intake
on
manganese
is
estimated
at
2­
3
mg/
day
in
adults
and
at
least
1.25
mg/
day
in
pre­
adolescent
children
(
WHO
1981).

Potassium:
The
human
body
burden
of
potassium
is
approximately
140
g
for
a
70
kg
adult.
The
potassium
cation
is
important
in
regulating
blood
pressure,
regulating
cellular
water
Page
18
of
27
content,
maintaining
proper
pH
balance,
and
transmission
of
nerve
impulses.
It
helps
to
regulate
the
electrical
activity
of
the
heart
and
muscles.
The
potassium
RDA
is
900
mg/
day.

Sodium:
The
human
body
burden
of
sodium
is
approximately
20
g
for
a
70
kg
adult.
The
sodium
cation
is
necessary
for
the
nerves
and
muscles
to
function
properly.
It
is
the
principal
cation
of
extracellular
fluid,
and
helps
to
maintain
the
body's
water
balance.
These
electrolytes,
the
electrically
charged
ions
in
the
body
fluids,
consist
to
a
great
extent
of
sodium
and
potassium.
There
is
no
Recommended
Daily
Allowance
(
RDA)
for
sodium.

Zinc:
Zinc
is
an
essential
element
in
the
nutrition
of
man.
It
functions
as
an
integral
part
of
numerous
enzymes.
The
daily
intake
for
an
adult
ranges
from
14
to
20
mg/
day.
The
recommended
dietary
allowance
(
RDA)
for
adult
mean
and
women
is
15
mg/
day;
however,
the
requirement
for
zinc
changes
throughout
life.
The
Food
and
Nutrition
Board
of
the
United
States
(
1980
as
cited
in
WHO
2003b)
evaluated
zinc
dietary
allowances
and
recommended
zinc
as
follows:
2
mg
for
infants
0.5
years,
5
mg
for
0.5­
1.0
years,
10
mg
for
children
1­
10
years,
15
mg
for
mean
and
women
11­
51+
years,
20
mg
for
pregnant
women,
and
25
mg
for
lactating
women.
Similar
figures
were
recommended
by
WHO
(
2003b).

C.
Ammonium
Salt
Ammonium
phosphates
dissociate
to
the
negatively
charged
anion
and
the
positively
charged
ammonium
cation
(
NH
4
+).
Humans
cannot
convert
atmospheric
nitrogen
to
any
form
that
can
be
used
as
part
of
any
of
the
various
metabolic
cycles.
Therefore,
reduced
nitrogen
(
NH
4
+)
has
to
enter
the
body
from
an
outside
source.
These
sources
are
the
nitrogen­
containing
amino
acids
in
protein
which
are
consumed
daily
as
part
of
the
diet.
Although
the
human
body
can
produce
some
amino
acids,
ten
amino
acids
are
considered
"
essential"
amino
acids,
i.
e.,
they
must
be
consumed
in
the
diet.

Generally
the
body
works
to
maintain
a
balance
of
nitrogen
intake
and
nitrogen
excretion.
The
estimated
daily
ammonia
intake
through
food
and
drinking
water
is
18
mg.
In
contrast,
4000
mg
of
ammonia
per
day
are
produced
endogenously
in
the
human
intestine.

Ammonia
and
the
ammonium
ion
are
integral
components
of
normal
human
metabolic
processes.
Ammonia
is
released
following
deamination
that
occurs
when
protein
is
used
by
the
body
for
energy
production.
The
liver
converts
ammonia
via
the
urea
cycle
into
urea.
According
to
FDA
in
the
"
Evaluation
of
the
Health
Aspects
of
Certain
Ammonium
Salts
as
Food
Ingredients"
(
1974),
"
the
normal
liver
so
readily
detoxifies
ammonium
ion
from
alimentary
sources
that
blood
concentrations
of
ammonium
salts
do
not
rise
to
the
levels
necessary
to
evoke
toxic
response."
Approximately
80%
of
the
body's
excess
nitrogen
is
eliminated
through
the
kidneys
as
urea,
approximately
25
to
30
grams
per
day.

D.
Structure
Activity
Team
Report
(
SAR)
Assessments
performed
by
OPPT
Page
19
of
27
There
are
SAR
assessments
for
15
of
the
EDTA
salts.
The
evaluations
for
EDTA,
tetrasodium
EDTA
trihydrate,
disodium
EDTA,
sodium
EDTA,
trisodium
EDTA,
and
potassium
EDTA
indicate
no
absorption
through
the
skin.
A
low
to
moderate
concern
for
human
health
effects
was
expected
due
to
good
absorption
through
the
lungs
and
GI
tract.
With
the
exception
of
EDTA,
which
is
expected
to
be
absorbed
through
all
routes,
concerns
for
human
health
effect
included
cardiotoxicity,
effects
on
blood
clotting,
developmental
toxicity,
and
neurotoxicity
as
CNS
effects
from
the
chelation
of
metals
such
as
calcium,
magnesium,
and
iron
in
vivo.

The
SAR
assessments
for
the
remaining
9
salts
including
calcium
disodium
EDTA,
disodium
zinc
EDTA
dihydrate,
disodium
zinc
EDTA,
ferric
EDTA,
sodium
ferric
EDTA,
disodium
cupric
EDTA,
disodium
cupric
EDTA
trihydrate,
disodium
manganese
EDTA,
and
disodium
manganese
EDTA
dihydrate
indicated
no
absorption
through
the
skin
but
expected
good
absorption
through
the
lungs
and
GI
tract.
The
evaluations
indicated
low
concern
for
human
health
effects
due
to
the
binding
of
other
metals
present
(
e.
g.,
copper,
zinc,
iron).

E.
Special
Considerations
for
Infants
and
Children
Based
on
available
Agency
information,
EDTA
and
its
salts
used
in
formulations
for
agricultural
use
sites
have
certified
limits
of
less
than
4%
by
weight.
Likewise,
concentrations
in
formulations
for
residential
use
sites
have
certified
limits
of
less
than
1%
by
weight.
Therefore,
given
the
wide
spread
occurrence
of
EDTA
in
the
food
supply,
the
amount
of
EDTA
that
can
be
applied
to
food
as
a
result
of
its
agricultural
or
residential
uses
should
not
significantly
increase
the
existing
amounts
in
the
food
supply.

EDTA
and
its
salts
should
not
pose
a
teratogenic
concern
based
on
previous
studies
in
lab
rodents.
Study
results
indicate
no
teratogenic
effects
are
likely
in
lab
rodents
at
doses
up
to
1000
mg/
kg
(
Schardein
et
al.,
1981).
Adequate
minerals
in
the
diet
and
administration
of
tap
water
prevented
possible
teratogenic
effects
of
EDTA
during
pregnancy.
Teratogenic
effects
observed
in
lab
rodents
noted
by
Kimmel
(
1977)
were
likely
due
to
animals
maintained
on
deionized
water
and
a
semi­
purified
diet,
and
housed
in
nonmetallic
caging.
Infants
and
children
will
unlikely
be
exposed
to
high
concentrations
as
in
lab
rodents.
The
maximum
human
consumption
of
EDTA
and
its
salts
in
foods
was
reported
to
be
on
the
order
of
0.4
mg/
kg/
day
(
Schardein
et
al.,
1981).
Infants
and
children
also
generally
drink
tap
water
instead
of
deionized
or
distilled
water.

EDTA
is
also
used
therapeutically
in
adults
and
pregnant
women.
A
therapeutic
dose
of
1.2
to
2.0
grams
per
day
is
generally
given
to
adults
(
Domingo,
1998).
Information
is
also
available
indicating
EDTA
treatment
of
pregnant
women
is
possible
without
affecting
the
development
of
the
fetus.
Treatments
of
EDTA
to
pregnant
women
include
75
mg/
kg/
day
calcium
disodium
EDTA
for
seven
days
and
1
gram
twice
a
day
for
three
days,
under
medical
supervision.
Healthy,
normal
infants
were
delivered
four
weeks
and
eight
days
after
chelation
therapy,
respectively
(
Domingo,
1998).

EPA
also
believes
there
would
be
a
very
low
exposure
of
infants
to
EDTA.
First,
Page
20
of
27
premature
or
very
young
infants
ingest
only
formula
or
breast
milk.
(
It
is
generally
recommended
that
infants
not
consume
solid
food
until
4
to
6
months
of
age).
Regulation
of
infant
formulas
is
under
the
purview
of
the
FDA
(
www.
fda.
gov/
fdac/
features/
596_
baby.
html).
Calcium
disodium
EDTA,
disodium
EDTA,
and
tetrasodium
EDTA
are
used
as
direct
food
additives
(
21
CFR
172.120,
172.135,
and
178.1010,
respectively).
However,
all
manufacturers
of
infant
formula
must
begin
with
safe
food
ingredients,
which
are
approved
either
generally
as
safe
or
approved
as
food
additives
for
use
in
infant
formula.
Neither
EDTA
nor
the
salts
of
EDTA
are
currently
approved
by
the
FDA
for
use
in
infant
formula.
Therefore,
infants
consuming
only
infant
formula
or
breast
milk
would
be
exposed
to
very
low
amounts
of
EDTA.
Second,
even
if
young
infants
were
to
be
fed
some
solid
food,
given
the
characteristics
of
EDTA
and
its
salts,
residues
are
not
likely
to
be
present
at
concentrations
for
potential
sensitivity.

Once
past
this
several
month
time­
period,
there
is
no
longer
a
concern
for
potential
sensitivity
to
infants
and
children.
Older
infants,
like
adults,
process
EDTA
through
well
understood
metabolic
pathways.
A
safety
factor
analysis
has
not
been
used
to
assess
the
risk.
For
the
same
reasons
the
additional
tenfold
safety
factor
is
unnecessary.

V.
Exposure
Assessment
Exposure
to
EDTA
and
salts
of
EDTA
may
be
through
FDA­
approved
uses
as
food
additives,
in
sanitizing
solutions,
pharmaceutical
products,
or
through
their
use
in
soaps,
shampoos,
or
cosmetics.
EDTA
has
also
been
administered
safely
under
medical
supervision
as
treatment
for
heavy
metal
poisoning.

Residues
from
the
formulations
in
agriculture
use
sites
(
certified
limits
<
4%
by
weight)
and
residential
use
sites
(<
1%
of
typical
formulations)
are
not
likely
to
exceed
levels
currently
consumed
in
commonly
eaten
foods.
In
addition,
the
use
of
EDTA
and
EDTA
salts
in
pesticide
products
is
expected
to
result
in
much
lower
exposure
than
the
FDA­
regulated
use
of
these
compounds,
as
well
as
lower
exposure
than
the
use
in
pharmaceuticals
or
cosmetic
products.
For
example,
EDTA
and
its
salts
were
reported
to
FDA
as
used
in
over
4,000
cosmetic
formulations
for
cosmetic
products
such
as
baby
products,
shampoos,
and
skin
care
preparations
which
generally
contained
<
2%
of
EDTA
salts.
Historical
data
submitted
to
the
FDA
in
1984
indicated
that
EDTA
and
tetrasodium
EDTA
each
were
used
in
one
formulation
with
concentrations
as
high
as
25%.
These
cosmetic
formulations
containing
EDTA
and
its
salts
may
remain
in
contact
with
body
surfaces
for
a
few
minutes
to
as
long
as
a
few
days
(
CIR
2002).
EDTA
and
its
salts
are
not
absorbed
through
the
skin
(
dermal
contact).
The
salts
of
EDTA
are
of
low
risk
to
humans,
since
absorption
through
ingestion
is
of
lower
toxicity,
especially
with
sufficient
trace
minerals
within
the
daily
diet.
There
is
no
reason
to
expect
that
reasonable
use
will
constitute
any
significant
hazard.
Therefore,
a
quantitative
screening­
level
exposure
assessment
has
not
been
conducted.

VI.
Risk
Characterization
As
noted
previously,
EDTA,
disodium
EDTA,
and
tetrasodium
EDTA
are
included
on
the
Agency's
list
of
chemicals
included
in
the
High
Production
Volume
(
HPV)
Challenge
Program.
Page
21
of
27
EDTA
and
its
salts
have
traditionally
been
administered
medically
as
effective
treatment
to
heavy
metal
poisoning.
Some
of
the
EDTA
salts
are
also
approved
by
the
FDA
as
food
additives
and
sanitizing
solutions,
as
previously
discussed.
Residues
from
the
pesticide
use
of
EDTA
or
its
salts
are
not
likely
to
exceed
levels
commonly
consumed
in
the
daily
diet.

Taking
into
consideration
all
available
information
on
EDTA
and
its
salts,
including
the
relatively
low
risk
via
oral
and
dermal
routes,
FDA's
allowance
of
specific
EDTA
salts
as
direct
food
additives;
their
presence
in
soaps,
shampoos,
cosmetics,
and
cleaning
products,
as
well
as
their
historical
use
in
the
treatment
of
heavy
metal
poisoning,
the
use
of
EDTA
or
its
salts
as
inert
and
active
ingredients
in
pesticide
products
are
unlikely
to
pose
a
significant
hazard
to
the
general
public
or
any
population
subgroup.
Exposure
from
the
aforementioned
uses
are
expected
to
result
in
human
exposure
below
any
dose
level
that
could
possibly
produce
an
adverse
effect.
As
a
result,
HED
is
conducting
a
qualitative
approach
to
assessing
human
health
risks
from
exposure
to
EDTA
and
its
salts.

VII.
Environmental
Fate/
Ecotoxicity/
Drinking
Water
Considerations:

Environmental
Fate
Characterization
The
environmental
fate
and
occurrence
of
EDTA
and
its
salts
have
been
well
studied.
SAR
assessments
performed
by
OPPTS
for
15
EDTA
salts
contains
summaries
of
the
environmental
fate
of
EDTA.
The
Hazardous
Substance
Database
(
TOXNET)
also
contains
extensive
summaries
of
the
environmental
fate
of
EDTA.
In
addition,
the
hazardous
substance
database
(
HSDB)
information
has
been
supplemented
with
11
volumes
(
sequential
Volumes
2
through
12
with
MRIDs
459249001
through
459249011)
that
Neudorff
North
America
submitted
to
the
Agency
(
Neudorff
2003)
to
provide
required
environmental
fate
information.
Summary
information
was
also
obtained
from
the
Danish
Environmental
Protection
Agency
(
DEPA
2003)
website
(
http://
www.
mst.
dk/
udgiv/
publications/
2001/
87­
7944­
596­
9/
html/
kap07_
eng.
htm#
7.6)
to
essentially
confirm
the
assessment
from
the
previously
mentioned
sources.

EDTA
is
a
strong
organic
acid
(
approximately
1000
times
stronger
than
acetic
acid),
and
does
not
appear
to
occur
naturally.
It
has
a
high
affinity
for
alkaline­
earth
ions
(
for
example,
calcium
and
magnesium)
and
heavy­
metal
ions
(
for
example,
lead
and
mercury).
This
affinity
generally
results
in
the
formation
of
highly
stable
and
soluble
hexadentate
chelate
complexes.
EDTA's
ability
to
complex
is
used
commercially
to
either
promote
or
inhibit
chemical
reactions,
depending
on
application.

The
primary
sources
of
EDTA
release
to
the
environment
are
domestic
sewage
(
for
example,
from
use
in
detergents,
soaps,
and
cleaning
products)
and
industrial
effluents
(
for
example,
from
the
bleaching
of
textiles
and
paper;
processing
of
photographic
material;
electroplating;
bottle
cleaning;
and
industrial
cleaning
of
pipe
and
tank
systems).
EDTA
is
also
used
as
a
food
additive,
as
an
"
inert"
ingredient
in
pesticides,
in
pharmaceuticals,
and
in
a
variety
of
consumer
products.
EDTA
is
also
released
through
land
disposal
of
products
which
contain
EDTA.
Detergent
preparations
are
probably
the
predominant
source
of
EDTA
found
in
domestic
Page
22
of
27
sewage,
contributing
an
estimated
100
parts
per
billion
(
ppb)
to
the
total
concentration
of
EDTA
in
average
sewage
streams,
with
smaller
amounts
probably
originating
from
food
and
other
consumer
products.
As
is
also
given
in
the
ecotoxicological
section
of
this
document,
effluent
from
a
sewage
treatment
plant
in
England
had
EDTA
concentrations
that
ranged
from
200
to
1200
ppb,
while
environmental
water
concentrations
in
a
river
in
England
ranged
from
zero
to
1120
ppb.
Workers
involved
in
the
manufacture
or
use
of
EDTA
may
be
exposed
by
inhalation
and
dermal
contact.
Based
on
its
uses,
the
most
probable
routes
of
general
human
exposure
to
EDTA
would
be
ingestion
and
dermal
contact.

When
released
to
soil,
EDTA
is
mobile
and
expected
to
complex
trace
metals
and
alkaline
earth
metals,
thereby
causing
an
increase
in
the
total
solubility
of
the
metals.
EDTA
may
eventually
predominate
as
the
Fe(
III)
chelate
in
acidic
soils
and
as
the
Ca
chelate
in
alkaline
soils.
EDTA
and
its
chelates
are
expected
to
leach
readily
through
soil.
When
released
to
water,
EDTA
is
also
expected
to
form
soluble
complexes
with
trace
metals
and
alkaline
earth
metals.
It
would
not
be
expected
to
sorb
appreciably
to
sediments
or
suspended
solids
in
water,
and
is
known
not
to
be
retained
or
altered
chemically
in
typical
water
treatment
facilities.
(
However,
it
has
been
reported
recently
(
MRID
45924907,
journal
article
published
in
2001)
that,
depending
in
a
complex
way
upon
speciation
and
local
conditions,
some
sorption
(
approximately
6
to
25%)
occurred
within
a
contact
time
of
one
month
in
a
sediment
removed
from
a
lake
in
Finland.)

As
discussed
further
below,
when
released
to
soil
or
water
EDTA
is
slow
to
degrade,
with
aerobic
biodegradation
(
mineralization)
being
the
dominant
mechanism.
Recalcitrance
to
degradation
is
associated
with
the
high
thermodynamic
stability
of
metal
complexes
and
is
problematic
for
treatment
facilities.
Only
in
technically
specialized
bioreactors
and/
or
with
specially
selected
microbial
populations
can
biodegradation
be
accelerated.
Biodegradation
in
subsoil
or
under
anaerobic
conditions
is
essentially
negligible.
Abiotic
degradation
in
the
environment
(
except
for
photolysis,
as
discussed
below)
is
also
negligible.
Results
in
sediments
were
similar
to
those
for
soil.
Although
EDTA
is
slow
to
degrade
under
typical
environmental
conditions,
based
on
experimental
results
with
bluegill
sunfish
and
its
intrinsic
physicochemical
properties
(
ionic
nature
and
water
solubility),
EDTA
is
not
expected
to
bioconcentrate.

In
a
variety
of
representative
United
States
soils,
common
values
for
the
degree
of
aerobic
metabolism
of
EDTA
(
mineralization
as
evidenced
by
carbon
dioxide
production
from
radiolabeled
positions)
at
a
temperature
of
30
0C
and
soil
concentrations
of
2­
4
ppm
are
13­
45%
after
15
weeks
and
65­
70%
after
45
weeks.
Rates
of
metabolism
followed
first­
order
kinetics.
Based
on
these
rates,
the
OPP
reviewer
extrapolates
the
first­
order
aerobic
soil
metabolism
halflives
at
30
0C
to
range
roughly
from
17
to
75
weeks
(
4
to
18
months).
Results
in
three
sediments
after
four
weeks
of
incubation
were
similar,
with
OPP
reviewer­
extrapolated
first­
order
aerobic
half­
lives
ranging
roughly
from
48
to
76
weeks
(
11
to
18
months).
There
is
good
evidence
that
co­
metabolism
is
the
mechanism
for
EDTA
biodegradation.
Microbial
oxidation
occurs
at
all
three
carbon
centers
(
carboxyl,
acetate­
2,
and
ethylene­
1,2
bridge),
indicating
complete
mineralization
eventually.
The
rate
of
biodegradation
of
EDTA
in
soils
is
reported
to
vary
among
soils
with
rates
depending
upon
environmental
factors
such
as
pH,
temperature,
soil
classification,
organic
matter,
and
types
and
population
of
microbes.
Page
23
of
27
Based
on
its
physicochemical
properties
and
collateral
experimental
results,
EDTA
is
not
expected
to
volatilize
from
soil
or
water.
When
released
to
the
atmosphere,
EDTA
should
sorb
to
particulate
matter,
and
appears
to
have
the
potential
to
photolyze.

Compounds
identified
as
possible
biodegradation
products
of
the
ammonium
ferric
chelate
of
EDTA
are
as
follows:
ethylenediamine
triacetic
acid
(
ED3A),
iminodiacetic
acid
(
IDA),
N,
N­
ethylenediamine
diacetic
acid
(
N,
N­
EDDA),
N,
N'­
EDDA,
ethylenediamine
monoacetic
acid
(
EDMA),
nitrilotriacetic
acid
(
NTA)
and
glycine.
In
water,
EDTA
may
react
with
photochemically
generated
hydroxyl
radicals
(
half­
life
of
approximately
230
days
or
8
months).
The
following
photodegradation
products
of
Fe(
III)­
EDTA
have
been
identified:
carbon
monoxide,
formaldehyde,
ED3A,
N,
N­
EDDA,
N,
N'­
EDDA,
IDA,
EDMA
and
glycine.

Ecotoxicity
and
Ecological
Risk
Characterization
Predicted
toxicity
based
on
structure
activity
relationships
performed
by
OPPT,
indicate
EDTA
ranges
from
practically
non­
toxic
to
moderately
toxic
on
an
acute
basis
depending
on
the
salt.
EDTA
per
se,
appears
less
toxic
than
many
of
the
salts
reviewed.
Algae
is
the
most
sensitive
species
on
a
chronic
basis.
Table
4
lists
the
estimated
toxicity
for
several
compounds
of
EDTA.
Algae
and
invertebrates
are
among
the
most
sensitive
species
based
on
predictive
modeling
for
acute
and
chronic
endpoints
for
EDTA
depending
on
the
compound.
Based
on
the
environmental
fate
profile
of
EDTA
and
its
salts,
exposures
from
labels
uses
are
unlikely
to
reach
concentrations
necessary
to
elicit
effects
in
most
aquatic
organisms.
Using
laboratory
rat
data
as
a
surrogate
for
terrestrial
wild
mammals
and
birds,
EDTA
and
its
salts
do
not
appear
to
be
very
toxic
and
adverse
effects
from
labeled
uses
are
not
expected.
Page
24
of
27
Table
4.
Ecotoxicity
of
EDTA
and
Selected
Salts
Property
EDTA;
Sodium
EDTA;
Disodium
EDTA;
Trisodium
EDTA;
Tetrasodium
EDTA;
and
Potassium
EDTA;
Sodium
Hydrogen
Ferric
EDTA;
Fe
(
III)
EDTA
Disodium
Manganese
EDTA;
Disodium
Cupric
EDTA;
Disodium
Zinc
EDTA
Disodium
Manganese
üEDTA;
Disodium
Cupric
üEDTA;
Disodium
Zinc
üEDTA
Calcium
Disodium
EDTA
Fish
(
96­
h
LC50;
mg/
L)
430
100
20
100
Daphnia
(
48­
h
LC50;
mg/
L)
100
100
14
100
Green
Algae
(
96­
h
EC50;
mg/
L)
3.0
30
25
60
Fish
(
Chronic;
mg/
L)
10
10
3.0
10
Daphnia
(
Chronic;
mg/
L)
23
10
2.0
10
Algae
(
Chronic;
mg/
L)
0.88
9
12
6.3
Monitoring
for
EDTA
in
surface
water
has
been
extensively
studied,
but
only
a
few
reported
concentrations
were
readily
available
for
this
review.
Concentrations
of
EDTA
have
been
measured
to
as
high
as
1120
ppb
(
1.1
ppm)
in
the
Lea
River,
England.
In
addition,
concentrations
have
been
measured
in
sewage
effluent,
mainly
from
detergent
products,
ranging
from
200
to
1200
ppb
(
0.2
to
1.2
ppm).
With
the
exception
of
chronic
risks
to
algae,
measured
concentrations
in
surface
do
not
exceed
the
toxicity
endpoints
for
aquatic
organisms.

VIII.
Cumulative
Exposure:

Section
408(
b)(
2)(
D)(
v)
of
the
FFDCA
requires
that,
when
considering
whether
to
establish,
modify,
or
revoke
a
tolerance,
the
Agency
consider
"
available
information"
concerning
the
cumulative
effects
of
a
particular
pesticide's
residues
and
"
other
substances
that
have
a
common
mechanism
of
toxicity."

EPA
does
not
have,
at
this
time,
available
data
to
determine
whether
EDTA
and
its
salts
have
a
common
mechanism
of
toxicity
with
other
substances.
Unlike
other
pesticides
for
which
EPA
has
followed
a
cumulative
risk
approach
based
on
a
common
mechanism
of
toxicity,
EPA
has
not
made
a
common
mechanism
of
toxicity
finding
as
to
EDTA
and
its
salts
and
any
other
substances
and
EDTA
and
its
salts
do
not
appear
to
produce
a
toxic
metabolite
produced
by
other
substances.
For
the
purposes
of
this
tolerance
action,
therefore,
EPA
has
not
assumed
that
the
EDTA
and
its
salts
have
a
common
mechanism
of
toxicity
with
other
substances.
For
information
regarding
EPA's
efforts
to
determine
which
chemicals
have
a
common
mechanism
of
toxicity
and
to
evaluate
the
cumulative
effects
of
such
chemicals,
see
the
policy
statements
released
by
EPA's
Page
25
of
27
Office
of
Pesticide
Programs
concerning
common
mechanism
determinations
and
procedures
for
cumulating
effects
from
substances
found
to
have
a
common
mechanism
on
EPA's
website
at
http://
www.
epa.
gov/
pesticides/
cumulative/.

References:
CCRIS
(
Chemical
Carcinogenesis
Research
Information
System).
2003.
On­
line
Scientific
Search
Engine,
National
Library
of
Medicine,
National
Institute
of
Health.
(
Http://
toxnet.
nlm.
nih.
gov/
cgi­
bin/
sis/
htmlgen?
CCRIS)
Search
term:
EDTA
(
July
3,
2002)

CSTEE
(
Scientific
Committee
on
Toxicity,
Ecotoxicity,
and
the
Environment).
2003.
Opinion
on
the
results
of
the
Risk
Assessment
of:
Tetrasodium
EDTA
and
Edetic
Acid
(
EDTA).
Human
Health
Part.
European
Commission.
Brussels.
2003.
Pp1­
7.

CIR
(
Cosmetic
Ingredient
Review).
2002.
Final
Report
on
the
Safety
Assessment
of
EDTA,
Calcium
Disodium
EDTA,
Diammonium
EDTA,
Dipotassium
EDTA,
Disodium
EDTA,
TEAEDTA
Tetrasodium
EDTA,
Tripotassium
EDTA,
Trisodium
EDTA,
HEDTA,
and
Trisodium
HEDTA.
International
Journal
of
Toxicology
21(
Suppl.
2):
95­
142.

DEPA
(
Danish
Environmental
Protection
Agency).
2003.
EDTA
and
Tetrasodium
EDTA.
(
Http://
www.
mst.
dk/
udgiv/
publications/
2001/
87­
7944­
596­
9/
html/
kap07_
eng.
htm#
7.6)
(
December,
2003)

Domingo,
J.
L.
1998.
Reproductive
Toxicology
Review:
Developmental
Toxicity
of
Metal
Chelating
Agents.
Reproductive
Toxicology
12
(
5):
499­
510.

EPA
(
Environmental
Protection
Agency).
1979.
Accession
No.
234008.
Memorandum
from
Robert
Jaeger
to
A.
E.
Castillo.
"
Versene
100."
Teratogenicity
Data.
February
9,
1979.
pp
1­
8.

EPA
(
Environmental
Protection
Agency).
Office
of
Pollution
Prevention
and
Toxics.
2003.
Structure
Activity
Team
Report.
Disodium
EDTA
(
14025­
21­
9),
Disodium
Zinc
EDTA
(
73513­
47­
0),
Disodium
copper
EDTA
(
73637­
19­
1),
Disodium
Manganese
EDTA
(
15375­
84­
5),
Disodium
Manganese
EDTA
(
73637­
20­
4),
Calcium
Disodium
EDTA
(
62­
33­
9),
Disodium
Cupric
EDTA
(
14025­
15­
1),
Iron
EDTA
(
17099­
81­
9),
Sodium
Iron
EDTA
(
12389­
75­
2),
Sodium
EDTA
(
17421­
79­
3),
Trisodium
EDTA
(
150­
38­
9),
Disodium
EDTA
(
139­
33­
3),
Potassium
EDTA
(
7379­
27­
3),
EDTA
(
60­
00­
4),
Tetrasodium
EDTA
(
67401­
50­
7).

FAO/
WHO
(
Food
and
Agriculture
Organization
of
the
United
Nations/
World
Health
Organization).
1967.
Joint
FAO/
WHO
Expert
Committee
on
Food
Additives.
FAO
Nutrition
Meetings,
Report
Series
No.
40A,
B,
C,
WHO/
Food
Add./
67.29.
Calcium
Disodium
EDTA.
In:
Toxicological
evaluation
of
some
antimicrobials,
antioxidants,
emulsifiers,
stabilizers,
flourtreatment
agents,
acids
and
bases.
Rome,
13­
20
December,
1965,
Geneva,
11­
18
October,
1966.
(
Http://
www.
inchem.
org/
documents/
jecfa/
jecmono/
40abcj10.
htm)
(
May
18,
2002)
(
MRID
46108601)
Page
26
of
27
FAO/
WHO
(
Food
and
Agriculture
Organization
of
the
United
Nations/
World
Health
Organization).
1974.
Joint
FAO/
WHO
Expert
Committee
on
Food
Additives.
WHO
Food
Additives
Series
No.
5.
Ethylenediaminetetraacetate,
Disodium
and
Calcium
Disodium
Salts.
In:
Toxicological
evaluation
of
some
food
additives
including
caking
agents,
antimicrobials,
antioxidants,
emulsifiers,
and
thickening
agents.
25
June­
4
July
1973.
Geneva.
(
Http://
www.
inchem.
org/
documents/
jecfa/
jecmono/
v05je25.
htm)
(
October
1,
2003)

FAO/
WHO
(
Food
and
Agriculture
Organization
of
the
United
Nations/
World
Health
Organization).
2000.
International
Programme
on
Chemical
Safety.
WHO
Food
Additives
Series
No.
44.
Joint
FAO/
WHO
Expert
Committee
on
Food
Additives.
Safety
Evaluation
of
Certain
Food
Additives
and
Contaminants.
Sodium
Iron
Ethylenediamine
Tetraacetic
Acid.
53rd
meeting.
Geneva.
(
Http://
www.
inchem.
org/
documents/
jecfa/
jecmono/
v44jec06.
htm)
(
January
7,
2004)

GENE­
TOX
2003.
On­
line
Scientific
Search
Engine,
National
Library
of
Medicine,
National
Institute
of
Health.
(
Http://
www.
toxnet.
nlm.
nih.
gov)
On­
line
Scientific
Search
Engine,
Search
term:
EDTA
(
July
3,
2002)

Heindorff,
K.,
Aurich,
O.,
Michaelis,
A.,
and
Rieger,
R.
1983.
Genetic
toxicology
of
ethylenediaminetetraacetic
acid
(
EDTA).
Mutation
Research/
Reviews
in
Genetic
Toxicology
Vol
115:
2,
June
1893m
Pages
149­
173.
(
Http://
www.
sciencedirect.
com)
(
October
1,
2003)

TOXNET
(
National
Library
of
Medicine,
Specialized
Information
Services).
Hazardous
Substance
Databank
(
HSDB).
(
http://
www.
toxnet.
nlm.
nih.
gov)
On­
line
Scientific
Search
Engine,
Search
term:
EDTA
(
9/
26/
03),
Tetrasodium
EDTA
(
December
5,
2000).

Kimmel,
C.
A.
1977.
Effect
of
route
of
administration
on
the
toxicity
and
teratogenicity
of
EDTA
in
the
rat.
Toxicology
and
Applied
Pharmacology.
40:
pp
299­
306.

NCI
1977.
National
Cancer
Institute.
Bioassay
of
trisodium
ethylenediaminetetraacetate
trihydrate
(
EDTA)
for
possible
carcinogenicity.
Carcinogenesis.
Technical
Report
Series.
No.
11.

Neudorff
2003.
W.
Neudorff
GMBH
KG.
Submission
of
Environmental
Fate
Data
in
Support
of
the
Reregistration
of
Ethylenediaminetetraacetic
Acid
(
EDTA).
Transmittal
of
11
Studies.
MRIDs
45924901
through
45924911.

NTP
(
National
Toxicology
Program).
2003.
NTP
Chemical
Repository.
Ethylenediaminetetraacetic
Acid,
Trisodium
Salt.
150­
38­
9.
(
Http://
ntp­
server.
niehs.
nih.
gov/
htdocs/
CHEM_
H&
S/
NTP_
Chem1/
Radian150­
38­
9.
html)
(
October
23,
2003)

RTECS
(
Registry
of
Toxic
Effects
of
Chemical
Substances).
National
Institute
for
Occupational
Safety
and
Health
(
NIOSH).
(
Http://
www.
cdc.
gov/
niosh/
rtecs/
ah3d6aa8.
html)
On­
line
Scientific
Search
Engine.
Search
term:
EDTA
(
June
26,
2002)
Page
27
of
27
Schardein,
J.
L.,
Sakowski,
R.
Petrere,
J.,
and
Humphrey,
R.
R.
1981.
Teratogenesis
studies
with
EDTA
and
its
salts
in
rats.
Toxicology
and
Applied
Pharmacology
61:
pp
423­
428.

SIRI
(
Safety
Information
Resources,
Inc.)
2003.
Toxicology
Reports.
(
Http://
www.
hazard.
com/
msds/
index.
php)
On­
line
Scientific
Search
Engine.
Search
term:
EDTA
(
January
2004),
disodium
EDTA
(
September
30,
2003),
trisodium
EDTA
(
September
30,
2003),
sodium
iron
EDTA
(
September
30,
2003),
73513­
47­
0:
disodium
zinc
EDTA
(
September
30,
2003),
73637­
19­
1:
disodium
copper
EDTA
(
September
30,
2003),
73637­
20­
4:
disodium
manganese
EDTA
(
September
30,
2003).

WHO
(
World
Health
Organization).
1981.
International
Programme
on
Chemical
Safety.
Environmental
Health
Criteria
17.
Manganese.
Geneva.
(
Http://
www.
inchem.
org/
documents/
ehc/
ehc/
ehc017.
htm)
(
October
2,
2003)

WHO
(
World
Health
Organization).
1998.
International
Programme
on
Chemical
Safety.
Environmental
Health
Criteria
200.
Copper.
Geneva.
(
Http://
www.
inchem.
org/
documents/
ehc/
ehc/
ehc200.
htm)
(
October
2,
2003)

WHO
(
World
Health
Organization)
2003a..
WHO
Food
Additives
Series
18.
Iron.
Geneva.
(
Http://
www.
inchem.
org/
documents/
jecfa/
jecmono/
v18je18.
htm)
(
October
2,
2003)

WHO
(
World
Health
Organization)
2003b.
WHO
Food
Additives
Series
17.
Zinc.
Geneva.
(
Http://
www.
inchem.
org/
documents/
jecfa/
jecmono/
v17je33.
htm)
(
October
2,
2003)
