Document ID: EPA-HQ-OPP-2004-0300-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2004-08-18T04:00Z

Page
1
of
48
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
August
24,
2004
MEMORANDUM
FROM:
Kathryn
Boyle,
Inerts
Team
Minor
Use,
Inerts,
and
Emergency
Response
Branch
Registration
Division
TO:
Dan
Rosenblatt,
Chief
Minor
Use,
Inerts,
and
Emergency
Response
Branch
Registration
Division
SUBJECT:
Science
Assessment
for
ATBC
and
TEC
The
attached
science
assessment
discusses
the
toxicity
of
acetyl
tributyl
citrate
and
triethyl
citrate.
The
Lower
Toxicity
Pesticide
Chemical
Focus
Group
reviewed
several
draft
assessments
of
this
document.
The
Inerts
Team
coordinated
the
review
process
and
prepared
the
science
assessment.

The
information
used
to
perform
this
assessment
are
information
from
the
internet
on
(
1)
World
Health
Organization
(
WHO)
evaluations,
(
2)
British
Industrial
Biological
Research
Association
(
BIBRA)
abstracts,
and
(
3)
the
Opinion
of
the
European
Commission,
Health
and
Consumer
Protection
Directorate­
General
(
CSTEE),
and
(
4)
structure­
activity­
relationship
(
SAR)
assessments
performed
on
surrogate
chemicals
as
prepared
by
the
Agency's
Office
of
Pollution
Prevention
and
Toxics..

The
Agency
is
performing
a
qualitative
risk
assessment.
Given
that
the
oral
NOAELs/
NOEL
is
1000
mg/
kg/
day
in
several
studies,
a
quantitative
approach
is
not
needed
for
this
risk
assessment.
However,
to
better
understand
the
potential
exposure
patterns,
the
Agency
is
bracketing
some
of
the
potential
residential
exposures
for
ATBC
and
TEC.
Page
2
of
48
Science
Assessment
for
Acetyl
Tributyl
Citrate
(
ATBC)
and
Triethyl
Citrate
(
TEC)

1.
Purpose
of
Assessment
This
review
serves
two
purposes.
First,
in
Pesticide
Petitions
8E4966
and
8E4967,
the
petitioner
Morflex
requested
that
the
Agency
establish
four
new
tolerance
exemptions
for
the
use
of
acetyl
tributyl
citrate
(
ATBC)
(
citric
acid,
2­(
acetyloxy)­,
tributyl
ester)
(
CAS
Reg.
No.
77­
90­
7)
and
triethyl
citrate
(
TEC)
(
citric
acid,
triethyl
ester)(
CAS
Reg.
No.
77­
93­
0)
when
used
as
solvents
(
inert
ingredients)
under
40
CFR
180.
910
and
180.930
[
formerly
180.1001
(
c)
and
(
e)].
Second,
there
is
an
existing
tolerance
exemption
for
acetyl
tributyl
citrate
used
in
animal
ear
tags
that
is
subject
to
tolerance
reassessment
in
40
CFR
180.930
[
formerly
180.1001(
e)].

2.
Executive
Summary
The
petitioner,
Morflex,
submitted
a
toxicity
database
that
includes
several
studies,
including
a
2­
generation
reproductive
study,
and
articles
from
open
literature.
Other
reliable
sources
of
information
used
to
perform
this
assessment
are
information
from
the
internet
on
(
1)
World
Health
Organization
(
WHO)
evaluations,
(
2)
British
Industrial
Biological
Research
Association
(
BIBRA)
abstracts,
and
(
3)
the
Opinion
of
the
European
Commission,
Health
and
Consumer
Protection
Directorate­
General
(
CSTEE),
and
(
4)
structure­
activity­
relationship
(
SAR)
assessments
performed
on
surrogate
chemicals
as
prepared
by
the
Agency's
Office
of
Pollution
Prevention
and
Toxics..

The
Agency
is
performing
a
qualitative
risk
assessment.
Given
that
the
oral
NOAELs/
NOEL
is
1000
mg/
kg/
day
in
several
studies,
a
quantitative
approach
is
not
needed
for
this
risk
assessment.
However,
to
better
understand
the
potential
exposure
patterns,
the
Agency
is
bracketing
some
of
the
potential
residential
exposures
for
ATBC
and
TEC.

3.
Use
Patterns
Use
Pattern
(
Non­
Pesticidal)

ATBC
is
used
as
a
plasticizer
in
food­
grade
plastic
wrap:
it
is
added
during
the
manufacturing
process
of
these
plastic
wraps
to
increase
flexibility
and
reduce
brittleness.
Both
ATBC
and
TEC
are
used
in
coatings
for
pharmaceutical
tablets
and
in
plastic
tubings
for
administration
of
drug
and
blood
products.
ATBC
is
also
used
as
a
plasticizer
in
children's
toys.

FDA
Uses:

TEC
is
affirmed
GRAS
(
generally
recognized
as
safe)
under
21
CFR
184.1911
when
used
as
a
flavoring
agent,
a
solvent
and
vehicle,
and
a
surface­
active
agent.
There
are
also
other
FDAapproved
uses:
component
of
resinous
and
polymeric
coatings,
component
of
paper
and
paperboard,
and
under
21
CFR
181.27
as
a
prior
sanctioned
plasticizer.
Page
3
of
48
ATBC
is
approved
as
a
synthetic
flavoring
substance
under
21
CFR
172.515.
It
is
also
approved
as
a
component
of
resinous
and
polymeric
coatings,
a
component
of
paper
and
paperboard,
and
under
21
CFR
181.27
as
a
prior
sanctioned
plasticizer.

4.
Description
of
Chemicals
Table
1:
Description
of
Chemicals
Parameter
Acetyl
Tributyl
Citrate
(
ATBC)
Triethyl
Citrate
(
TEC)

manufacture
prepared
by
esterification
of
butyl
alcohol
with
citric
acid,
followed
by
acetylation
prepared
by
esterification
of
ethyl
alcohol
with
citric
acid
physical
form
practically
colorless,
oily
liquid
essentially
odorless,
practically
colorless,
oily
liquid
molecular
formula
C
20
H
34
O
8
C
12
H
20
O
7
molecular
weight
402.5
276.3
vapor
pressure
(
mm
Hg
@
20
oC)
5.2
x
10­
2
6.4
x
10­
3
5.
Toxicity
Profile:
Studies
Submitted
by
the
Petitioner
The
petitioner,
Morflex,
submitted
studies
that
were
conducted
using
either
ATBC
or
TEC.
The
ATBC
database
is
the
more
extensive
of
the
two
and
includes
a
2­
generation
reproductive
study
and
metabolism
studies.
The
results
of
the
Agency's
2002
review
and
evaluation
in
robust
summary
format
are
in
Appendix
2.
In
2004,
the
2­
generation
reproductive
study
was
re­
evaluated
to
consider
why
there
was
such
variation
in
the
results
of
the
rat
90­
day,
2­
year,
and
reproduction
oral
studies.
The
results
of
this
re­
evaluation
are
in
Appendix
3.
The
Table
below
summarizes
the
NOAELs
(
no­
observed­
adverse
effects
level),
LOAELs
(
lowestobserved
adverse­
effects
level),
NOEL
(
no­
observed­
effect
level),
and
LOEL
(
lowest­
observedeffect
level).

Table
2:
ATBC
Toxicity
Information
Study
Result
or
NOAELs/
LOAELs
acute
oral
toxicity
(
rat)
LD
50
>
30
g/
kg
(
Toxicity
Category
IV)

primary
eye
irritation
(
rabbit)
not
a
severe
ocular
irritant
(
Toxicity
Category
III)

primary
dermal
irritation
(
rabbit)
did
not
induce
irritation
(
Toxicity
Category
IV)

primary
dermal
sensitization
(
guinea
pig)
not
a
dermal
sensitizer
repeated
insult
patch
test
(
human)
not
a
dermal
sensitizer
Page
4
of
48
90­
day
oral
(
rat)
(
in
the
diet)

dose
levels:
(
0,
100,
300,
1000
mg/
kg/
day)
NOAEL
is
equal
to
or
greater
than
1000
mg/
kg/
day,
the
highest
dose
tested
(
HDT)
LOAEL
was
not
determined,
but
would
be
greater
than
1000
mg/
kg/
day
2­
year
oral
(
rat)
(
in
the
diet)

dose
levels:
(
0,
200,
2000,
200,000
ppm)
NOAEL
is
equal
to
or
greater
than
20,000
ppm
or
1000
mg/
kg/
day,
the
highest
dose
tested
(
HDT)
LOAEL
was
not
determined,
but
would
be
greater
than
1000
mg/
kg/
day
2­
year
dog
dose
levels:
(
0,
140
mg/
kg/
day)
NOAEL
is
equal
to
or
greater
than
140
mg/
kg/
day,
the
highest
dose
tested
(
HDT)
LOAEL
was
not
determined,
but
would
be
greater
than
140
mg/
kg/
day
2­
generation
reproductive
(
rat)
(
in
the
diet)

dose
levels:
(
0,
100,
300,
1000
mg/
kg/
day)
Parental
NOEL
is
equal
to
or
greater
than
1000
mg/
kg/
day,
the
highest
dose
tested
(
HDT)
LOEL
not
determined,
but
would
be
greater
than
1000
mg/
kg/
day
Reproductive
NOAEL
is
equal
to
or
greater
than
1000
mg/
kg/
day,
the
highest
dose
tested
(
HDT)
LOAEL
not
determined,
but
would
be
greater
than
1000
mg/
kg/
day
Offspring
NOEL
is
equal
to
or
greater
than
1000
mg/
kg/
day,
the
highest
dose
tested
(
HDT)
LOEL
not
determined,
but
would
be
greater
than
1000
mg/
kg/
day
In
vitro
Cytotoxicity
at
1
mg%
for
4
hours
was
not
cytotoxic
to
mammalian
cells
Gene
Mutation
not
mutagenic
Cytogenetics
did
not
induce
chromosomal
aberrations
Metabolism
(
rat)
ATBC
readily
absorbed
and
rapidly
excreted
in
urine
and
feces
within
48
hours
Metabolism
(
human
serum
and
rat
liver
homogenates)
human
serum
and
rat
liver
homogenates
are
capable
of
metabolizing
ATBC
resulting
in
n­
butanol
and
tributyl
citrate
as
intermediate
products
Table
3:
TEC
Toxicity
Information
Study
Result
or
NOAELs/
LOAELs
Page
5
of
48
acute
oral
toxicity
(
rat)
LD
50
=
7
mL/
kg
(
Toxicity
Category
IV)

primary
eye
irritation
(
rabbit)
not
a
severe
ocular
irritant
(
Toxicity
Category
IV)

primary
dermal
irritation
(
rabbit)
did
not
induce
dermal
irritation
(
Toxicity
Category
IV)

dermal
sensitization
(
guinea
pig)
TEC
is
a
strong
dermal
sensitizer
repeated
insult
patch
test
(
human)
not
a
dermal
sensitizer
2­
year
oral
(
rat)
(
in
the
diet)

dose
levels:
(
0,
30,
200,
600
mg/
kg/
day)
inconclusive;
effects
noted
at
600
mg/
kg/
day
two
range­
finding
(
dog)
studies
dose
levels:
(
0,
0.05,
0.25
mL/
kg)
with
increase
to
2.5
to
3.5
mL/
kg
for
7
to
12
weeks
when
considered
together
NOAEL
=
250
mg/
kg
LOAEL
=
approximately
2.5
to
3.5
g/
kg
gene
mutation
results
varied:
not
mutagenic
in
S
typhimurium
or
in
Saccaromyces
cerevisiae
mouse
fibroblasts
72
hour
cultures:
ID
50
is
6mM
ID
100
is
12mM
another
mouse
fibroblast
study
was
inconclusive
6.
SAR
Assessment
Performed
by
OPPT
SAR
(
structure
activity
relationship)
assessments
have
not
been
performed
for
ATBC
and
TEC.
However,
SAR
assessments
of
three
structurally
similar
chemicals
were
performed
on
December
11,
1996,
by
the
Office
of
Pollution
Prevention
and
Toxics
(
OPPT).
The
results
of
these
three
assessments
acetyl
triethyl
citrate,
tributyl
citrate,
and
trimethyl
citrate
are
discussed
below:

For
all
three
chemicals,
absorption
would
be
expected
to
be
good
for
all
routes
of
exposure.
The
esters
were
expected
to
hydrolyze.
No
significant
adverse
effects
were
expected;
therefore,
all
three
chemicals
were
judged
to
be
of
low
toxicity.

7.
Toxicity
Profiles
Prepared
by
the
British
Industrial
Biological
Research
Association
(
BIBRA)

ATBC
The
BIBRA
ATBC
profile
was
prepared
in
1989.
In
preparing
this
profile,
BIBRA
reviewed
the
available
acute,
subchronic,
chronic,
and
reproductive
toxicity
studies,
and
Page
6
of
48
metabolism
and
mutagenicity
studies.
(
Some
of
these
were
the
same
studies
evaluated
by
the
Agency.)
The
summary
of
the
BIBRA
dossier
(
submitted
by
the
petitioner)
indicated
that
while
"
the
studies
of
reproduction
and
carcinogenicity
are
to
a
standard
of
reporting
that
is
less
than
adequate
by
current
standards,
it
is
considered
that
they
do
provide
an
indication
of
the
general
lack
of
adverse
effect
of
chronic
exposure
to
this
substance."

An
abstract
of
the
BIBRA
profile
was
located
on
the
internet
(
Toxnet,
SISa).
It
reads
as
follows:

"
Acetyl
tributyl
citrate
exhibited
a
low
acute
oral
toxicity
in
laboratory
animals.
Limited
studies
in
rats
involving
repeated
administration
in
the
diet
failed
to
identify
any
particular
target
organs.
However,
injection
studies
highlighted
the
central
nervous
system
and
blood
as
the
site
of
toxic
attack
in
various
species
of
laboratory
animals.
Acetyl
tributyl
citrate
was
not
mutagenic
in
an
Ames
bacterial
assay."

It
should
be
noted
that
the
reproductive
study
submitted
to
the
Agency
was
conducted
in
1994
and
was
therefore
not
available
for
inclusion
in
the
BIBRA
profile.

TEC
This
BIBRA
profile
was
prepared
in
1998.
The
abstract
was
obtained
from
the
internet
(
Toxnet,
SISb)

"
Triethyl
citrate
was
not
an
irritant
to
the
skin
of
humans
and
laboratory
animals.
In
dilute
form,
it
showed
no
sensitizing
potential
in
humans.
Acute
toxicity
was
low
by
the
oral,
dermal
and
inhalation
routes
in
laboratory
animals.
Single
oral
treatment
caused
kidney
damage
in
rats,
and
central
nervous
system
(
CNS)
effects
were
seen
following
oral
or
injection
administration
to
various
species
of
laboratory
animal.
In
limited
studies,
repeated
oral
doses
were
tolerated
by
rats
but
caused
liver
damage
in
dogs
and
CNS
effects
in
cats.
Rats
exposed
repeatedly
to
the
vapor
showed
lung
damage.
Triethyl
citrate
was
non­
carcinogenic
when
given
orally
to
rats
in
a
limited
study
and
was
non­
mutagenic
in
an
Ames
bacterial
test
and
in
yeast.
Its
hydrolysis
products
are
citric
acid
and
ethanol."

8.
Evaluations
by
the
World
Health
Organization
(
WHO)

TEC
was
evaluated
by
WHO
in
1966,
1977,
1981,
1984,
1999,
and
2000.

The
following
conclusions
were
extracted
from
Food
Additive
Series
14
available
on
the
internet
at
www.
inchem.
org/
documents/
jecfa/
jecmono/
v14je21.
htm.
No
absorption
or
metabolism
were
available
at
the
time
of
this
review.
However,
"[
i]
t
is
likely
that
triethyl
citrate
will
be
hydrolyzed
to
its
component
parts,
citrate
and
ethanol
in
vivo.
Data
from
two­
year
feeding
studies
suggest
that
rats
can
tolerate
up
to
2.0
g/
kg.
Dogs
toleranted
up
to
0.25
ml/
kg
bw
for
six
months
without
effects.
Triethyl
citrate
was
not
mutagenic
in
several
microbiological
assays."

Based
on
the
two­
year
rat
study,
WHO
estimated
a
temporary
acceptable
daily
intake
(
ADI)
for
man
of
1
­
10
mg/
kg/
bw.
WHO
also
stipulated
that
"
repeat
metabolic
studies
in
several
species,
preferably
including
man"
be
submitted
by
1981.
Page
7
of
48
Once
this
information
were
available,
TEC
was
reviewed
in
Food
Additive
Series
19.
(
See
www.
inchem.
org/
documents/
jecfa/
jecmono/
v19je12.
htm).
An
ADI
of
0
­
20
mg/
kg
bw
for
TEC
was
established
(
based
on
the
same
rat
study
as
the
previous
temporary
ADI)
in
which
there
were
no
toxicological
effects
when
rats
were
fed
a
diet
which
was
4%
(
40,000
ppm
or
2
g/
kg
body
weight)
TEC.

The
ADI
was
reviewed
again
in
1999
and
was
maintained.
It
was
stated
that
there
was
"[
n]
o
safety
concern
at
current
levels
of
intake
when
used
as
a
flavouring
agent."

In
2000
(
see
www.
inchem.
org/
documents/
jecfa/
jecmono/
v44je10.
htm,
Food
Additive
Series
44),
the
use
of
both
TEC
and
ATBC
as
flavoring
agents
was
evaluated
by
WHO.
The
intake
for
ATBC
was
determined
to
be
less
than
1800
ug/
person/
day.
The
intake
for
TEC
was
determined
to
be
3400
ug/
person/
day
in
Europe
and
2400
ug/
person/
day
in
the
United
States.
No
concerns
were
identified
for
either
chemical
based
on
the
level
of
intake
(
which
is
less
than
the
ADI),
and
on
an
understanding
of
the
fate
of
the
chemicals
in
the
body
after
hydrolysis
occurs.

9.
Scientific
Committee
on
Toxicity,
Ecotoxicity
and
the
Environment
(
CSTEE)

The
following
is
extracted
from
the
January
8,
2004,
"
Opinion
on
the
Risk
Assessment
for
Acetyl
Tributyl
Citrate
(
ATBC)
Plasticizer
Used
in
Children's
Toys"
performed
by
CSTEE
of
the
European
Commission,
Health
and
Consumer
Protection
Directorate­
General.

In
1999,
CSTEE
had
indicated
that
a
risk
assessment
on
use
of
citrates
as
a
plasticizer
in
children's
toys
could
not
be
performed
due
to
a
lack
of
exposure
data.

"
Therefore,
a
study
examining
the
extraction
of
ATBC
from
PVC
disks
cut
from
a
custom
molded
ball
and
two
commercially
available
toys
[
was]
performed
with
human
volunteers
(
5
males
and
5
females,
18
to
30
years
old)....
Volunteers
were
instructed
to
move
the
disks
in
their
mouths,
draw
upon,
apply
pressure
with
the
tongue
or
lightly
chew
the
disks
for
four
consecutive
15
minute
intervals.
All
saliva
was
collect
for
subsequent
analysis
of
ATBC
content.
The
mean
rates
for
ATBC
migration
rates
were
1.53,
1.75
and
2.19

g/
min"
and
"
the
highest
migration
rate
was
found
to
be
10.1

g
ATBC/
min".

"
Using
the
highest
ATBC
migration
rate
of
10.1

g/
min
at
a
maximum
mouthing
duration
of
180
min
for
a
child
weighing
8.0
kg
and
assuming
that
all
the
extracted
ATBC
is
swallowed,
an
estimated
daily
intake
via
oral
exposure
becomes
227

g
per
kg
bodyweight.
This
is
clearly
a
worst­
case
situation
since
the
maximal
extraction
rate
from
a
large,
male
adult
and
a
mouthing
duration
of
180
minutes
were
used
in
the
calculation."

10.
Human
Health
Hazard
Characterization
The
toxicological
databases
for
these
chemicals
are
a
mixture
of
guideline
studies
performed
in
the
last
15
years
and
older
studies
from
the
1970s
and
1950s.
These
older
studies
are
more
difficult
to
evaluate
given
the
different
standards
of
reporting
that
existed
some
years
ago.

Both
ATBC
and
TEC
have
low
acute
oral
toxicity
(
Toxicity
Category
IV).
Ocular
irritation
is
moderate.
Both
are
Toxicity
Category
IV
for
dermal
irritation.
Neither
are
human
Page
8
of
48
sensitizers.

Both
chemicals
have
been
reviewed
by
other
entities.
None
of
these
organizations
indicated
any
specific
concerns
for
ATBC
or
TEC.

In
a
rat
metabolism
study,
ATBC
was
readily
absorbed
and
rapidly
excreted
in
urine
and
feces
within
48
hours.
The
following
metabolites
were
detected
in
the
urine:
acetyl
citrate,
monobutyl
citrate,
acetyl
monobutyl
citrate,
dibutyl
citrate,
and
acetyl
dibutyl
citrate.
ATBC
was
hydrolyzed
in
both
human
and
rat
liver
homogenates
resulting
in
n­
butanol
and
tributyl
citrate
(
TBC).
However,
in
human
serum
the
half­
life
was
7
hours
versus
30
minutes
in
the
rat.
These
in
vivo
and
in
vitro
studies
indicate
that
ATBC
is
hydrolysed.

No
metabolism
studies
were
reviewed
for
TEC.
However,
it
is
expected
that
all
citrate
esters
would
undergo
hydrolysis
to
citric
acid
and
the
corresponding
alcohol.
For
TEC,
this
would
be
ethanol.
The
human
body
is
able
to
effectively
metabolize
both
ethanol
and
citric
acid.
Thus,
the
human
body
has
known
pathways
to
metabolize
TEC
hydrolysis
metabolites.

Based
on
the
submitted
studies,
neither
ATBC
or
TEC
is
mutagenic.

The
ATBC
two­
generation
reproductive
toxicity
study
was
recently
re­
evaluated
by
the
Agency.
No
adverse
reproductive
performance
was
observed
at
any
dose.
The
reproductive
toxicity
NOAEL
was
1000
mg/
kg/
day,
the
highest
dose
tested.
A
LOAEL
was
not
observed.
The
parental
NOEL
and
the
offspring
NOEL
is
1000
mg/
kg/
day.
The
parental
LOEL
and
the
offspring
LOEL
was
not
observed.

The
available
information
consists
of
the
FDA­
affirmed
GRAS
status
of
TEC,
the
abstracts
of
the
BIBRA
toxicity
profiles,
several
evaluations
by
the
World
Health
Organization,
the
SAR
assessments
of
the
structurally­
related
chemicals,
the
CSTEE
Opinion,
and
the
toxicity
studies
submitted
by
the
petitioner.
Taken
together
the
weight
of
evidence
of
the
available
information
indicate
a
chemical
of
lower
toxicity.

11.
Type
of
Assessment
The
Agency
is
performing
a
qualitative
risk
assessment.
Given
that
the
oral
NOAELs/
NOEL
is
1000
mg/
kg/
day
in
several
studies,
a
quantitative
approach
is
not
needed
for
this
risk
assessment.
However,
to
better
understand
the
potential
exposure
patterns,
the
Agency
will
bracket
some
of
the
potential
residential
exposures
for
acetyl
tributyl
citrate
and
triethyl
citrate.

12.
Additional
Safety
Factor
for
the
Protection
of
Infants
and
Children
The
toxicity
database
for
ATBC
includes
a
rat
oral
reproductive
toxicity
study
in
which
NOELs
of
1000
mg/
kg/
day
were
identified.
There
are
also
the
SARs
on
structurally­
related
citrate
esters
which
did
not
indicate
any
concerns
for
developmental
or
reproductive
toxicity.

ATBC,
given
the
additional
acetylation
step,
is
the
more
complex,
larger
molecule.
The
acetylation
step
also
increases
the
number
of
possible
metabolites
as
evidenced
by
the
results
of
the
ATBC
rat
metabolism
study.
ATBC
data
can
be
used
as
surrogate
data
for
TEC.
TEC
cannot
be
used
as
surrogate
data
for
ATBC.
ATBC
is
the
more
toxic
of
the
two
chemicals
and
has
the
larger
available
database.
Page
9
of
48
There
is
sufficient
information
for
the
Agency
to
judge
the
potential
for
developmental
and
reproductive
effects
of
ATBC
and
TEC.
No
additional
data
are
needed
to
assess
the
toxicity
of
ATBC
and
TEC.
There
is
no
reason
to
expect
that
the
reasonably,
foreseeable
uses
of
ATBC
and
TEC
will
constitute
any
significant
hazard.
EPA
has
not
used
a
safety
factor
analysis
to
assess
the
risk.
For
the
same
reasons
the
additional
tenfold
safety
factor
is
unnecessary.

13.
Screening­
level
Exposure
and
Risk
Assessment
Various
publicly­
available
screening­
level
models
were
used
to
estimate
some
of
the
existing
levels
of
exposure
that
could
occur
in
and
around
the
home.
To
assure
protectiveness,
these
models
create
estimates
that
are
deliberately
intended
to
over­
estimate
exposure.
See
Appendix
1
for
the
models
and
assumptions
used.
All
modeling
(
with
the
exception
of
the
CSTEE
plastic
toy
scenario)
was
performed
by
EPA.

Table
4:
Screening­
Level
ATBC
Exposure
Estimates
Conducted
through
Modeling
Type
of
Exposure
Population
Subgroup
Potential
Exposure
Level
Dietary
­
Food
(
as
a
result
of
application
to
crops)
US
General
0.12
Females
(
13­
49
years
old)
0.087
Children
(
1­
2
years
old)
0.422
Dietary
­
Drinking
Water
US
General
0.0018
Females
(
13­
49
years
old)
0.002
Children
(
1­
2
years
old)
0.0064
Dietary
­
Food
(
As
a
result
of
use
in
plastic
wrap)
US
General
0.021
Females
(
13­
49
years
old)
0.025
Children
(
1­
2
years
old)
0.15
Dietary
­
Food
(
As
a
result
of
use
as
a
flavoring)
US
General
0.26
Females
(
13­
49
years
old)
0.03
Children
(
1­
2
years
old)
0.18
Residential
(
laundry
detergent)
(
combined
dermal
and
inhalation)
Adult
0.04326
Residential
(
cleaning
product)(
combined
dermal
and
inhalation)
Adult
0.2021
Children's
Plastic
Toy
Children
(
1­
2
years
old)
0.227
Page
10
of
48
Table
5:
Screening­
Level
TEC
Exposure
Estimates
Conducted
through
Modeling
Type
of
Exposure
Population
Subgroup
Potential
Exposure
Level
Dietary
­
Food
(
as
a
result
of
application
to
crops)
US
General
0.120
Females
(
13­
49
years
old)
0.087
Children
(
1­
2
years
old)
0.422
Dietary
­
Drinking
Water
US
General
0.011
Females
(
13­
49
years
old)
0.013
Children
(
1­
2
years
old)
0.04
Dietary
­
Food
(
As
a
result
of
use
as
a
flavoring)
US
General
0.034
Females
(
13­
49
years
old)
0.04
Children
(
1­
2
years
old)
0.24
Residential
(
laundry
detergent)(
combined
dermal
and
inhalation)
adult
0.00523
Residential
(
cleaning
product)(
combined
dermal
and
inhalation)
adult
0.1621
All
screening­
level
exposures
are
much
less
than
any
of
the
NOAELs/
NOELs
from
the
repeated
dose
oral
toxicity
studies.

14.
Risk
Characterization
The
Agency
believes
that
ATBC
and
TEC
are
of
low
toxicity.
Of
highest
consideration
in
this
judgement
is
the
body's
ability
to
effectively
metabolize
both
ATBC
and
TEC
to
citric
acid
and
the
corresponding
alcohols.
The
metabolism
studies
provided
by
the
petitioner
were
helpful
in
reaching
this
determination.

Both
of
these
chemicals
are
well­
studied.
FDA,
WHO,
and
CSTEE
have
all
conducted
assessments
on
the
uses
of
these
chemicals.
No
toxicological
concerns
were
specified
in
any
of
the
reviews
and
evaluations.

The
Agency
has
used
various
screening­
level
models
to
estimate
some
of
the
existing
levels
of
exposure
to
ATBC
and
TEC.
To
assure
protectiveness,
these
estimates
are
deliberately
intended
to
over­
estimate
exposure.
Page
11
of
48
Given
the
information
on
the
metabolism
of
the
chemicals,
the
consistent
pattern
of
NOAELs/
NOELs
of
1000
mg/
kg/
day,
an
understanding
of
the
metabolism
of
ATBC
and
TEC,
and
very
over­
estimated
exposure
numbers,
there
is
no
need
to
pursue
further
numerical
refinements
to
the
estimated
exposures.
No
further
refinement
or
information
are
needed
to
assess
ATBC
or
TEC.
There
is
a
sufficient
order
of
magnitude
difference
between
the
NOAELs/
NOELs
and
the
screening­
level
exposure
estimates.

15.
Ecotoxicity
Assessment
(
performed
by
OPP):

Aquatic
Organisms
Estimated
environmental
concentrations
(
EECs)
are
used
to
predict
exposure
to
aquatic
organisms.
Surface
water
concentrations
were
estimated
using
the
GENEEC
(
GENeric
Estimated
Environment
Concentration
Version
2.0)
model
based
on
a
maximum
application
rate
of
1
lb/
acre.
Results
are
reported
in
Table
4.

Table
6:
Tier
I
upper
tenth
percentile
EECs
(
ppm)
in
surface
water
(
GENEEC
2.0)
for
TEC
and
ATBC
Method
of
Application
Application
Rate
(
lbs/
acre)
TEC
ATBC
Maximum
60­
day
average
Maximum
60­
day
average
Aerial
1
0.058
0.053
0.0038
0.00036
OPP
used
the
ECOSAR
(
Ecological
Structure
Activity
Relationship)
software
program
to
estimate
the
toxicity
of
ATBC
and
TEC
to
aquatic
organisms.
Risk
is
estimated
as
a
function
of
the
modeled
EECs
and
the
predicted
toxicity.

ATBC
is
practically
non­
toxic
to
aquatic
organisms
(
fish
and
daphnia).
The
risk
quotients
(
RQ)
(
see
Tables
below)
indicate
that
exposure
to
ATBC
at
1
lb/
acre
does
not
exceed
the
LOC
(
level
of
concern)
for
risk
to
fish,
invertebrates,
and
aquatic
plants.
Acute
risk
to
fish
and
invertebrates
is
not
expected
at
application
rates
less
than
or
equal
to
47
pounds
per
acre
and
34
pounds
per
acre,
respectively.
Chronic
risk
to
fish
is
not
expected
at
application
rates
less
than
828
lb/
acre.
Toxicity
data
are
not
available
to
assess
chronic
risk
to
invertebrates.
Currently,
EPA
does
not
assess
chronic
risks
to
plants.

TEC
is
practically
non­
toxic
to
aquatic
organisms
(
fish
and
daphnia).
The
risk
quotients
indicate
that
exposure
to
triethyl
citrate
at
1
lb/
acre
does
not
exceed
the
LOC
for
risk
to
fish,
invertebrates,
and
plants
(
see
Tables
below).
Acute
risk
to
fish
and
invertebrates
is
not
expected
at
application
rates
less
than
28
and
6260
pounds
per
acre,
respectively.
The
RQ
for
fish
indicates
that
the
LOC
is
not
exceeded
for
chronic
toxicity
at
an
application
rate
of
1
pounds
per
acre.
Chronic
risk
to
fish
is
not
expected
at
application
rates
less
than
7320
pounds
per
acre.
Toxicity
data
are
not
available
to
assess
chronic
risk
to
invertebrates.
Page
12
of
48
Table
7:
Acute
Toxicity
of
TEC
and
ATBC
to
Aquatic
Organisms
(
based
on
application
rate
of
1
lb/
acre)

Organism
Toxicity
(
ppm)
EEC2
(
ppm)
Risk
Quotient
(
EEC/
Toxicity)

ATBC
Fish
96­
hr
LC
50=
3.6
0.0038
<
0.05
Invertebrates
(
daphnia)
48­
hr
LC
50=
2.6
0.0038
<
0.05
Plants
(
green
algae)
96­
hr
EC
50=
0.31
0.0038
<
1
TEC
Fish
96­
hr
LC
50=
327
0.058
<
0.05
Invertebrates
(
daphnia)
48­
hr
LC
50=
7262
0.058
<
0.05
Plants
(
green
algae)
96­
hr
EC
50=
24.5
0.058
<
1
Table
8:
Chronic
Toxicity
of
TEC
and
ATBC
to
Aquatic
Organisms
(
based
on
application
rate
of
1
lb/
acre)

Organism
Toxicity
(
ppm)
EEC2
(
ppm)
Risk
Quotient
(
EEC/
Toxicity)

ATBC
Fish
0.298
0.00036
<
1
TEC
Fish
388
0.053
<
1
Terrestrial
Organisms
The
limited
acute
toxicity
data
indicate
that
ATBC
and
TEC
are
practically
non­
toxic
to
mammals.
The
Agency
does
not
expect
risk
to
mammals
on
an
acute
basis
from
the
use
of
ATBC
and
TEC
when
applied
at
equal
to
or
less
than
6
and
16
pounds
per
acre,
respectively.

When
applied
at
1
pound
per
acre,
ATBC
is
not
expected
to
cause
chronic
risks
to
mammals.
For
TEC,
chronic
risks
to
terrestrial
organisms
could
not
be
determined
because
toxicity
data
are
not
available.
Page
13
of
48
Data
on
the
toxicity
of
TEC
and
ATBC
to
avian
species
are
not
available.
Therefore,
it
is
assumed
that
birds
have
the
same
sensitivity
to
TEC
and
ATBC
as
mammals.

16.
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."

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
acetyl
tributyl
citrate,
triethyl
citrate
or
any
citrate
esters.
These
esters
do
not
appear
to
produce
a
toxic
metabolite
produced
by
other
substances.
These
are
lower
toxicity
chemicals;
therefore,
the
resultant
risks
separately
and/
or
combined
should
also
be
low.
For
the
purposes
of
this
action,
therefore,
EPA
has
not
assumed
that
acetyl
tributyl
citrate
or
triethyl
citrate
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
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/.

17.
Conclusions
Based
on
the
review
and
evaluation
of
the
information
discussed
in
this
assessment,
the
Agency
finds
that
exempting
acetyl
tributyl
citrate
(
ATBC)
(
citric
acid,
2­(
acetyloxy)­,
tributyl
ester)
(
CAS
Reg.
No.
77­
90­
7)
and
triethyl
citrate
(
TEC)
(
citric
acid,
triethyl
ester)(
CAS
Reg.
No.
77­
93­
0)
from
the
requirement
of
a
tolerance
will
be
safe.

Based
on
the
NOAELs
of
1000
mg/
kg/
day
in
several
studies
and
on
their
acute
toxicity
profiles,
both
ATBC
and
TEC
are
classified
as
List
4A.

18.
References
EPA/
OPPa.
Amendment
to
EFED
Assessment:
Review
of
the
Inert
Ingredients
Triethyl
Citrate
and
Acetyl
Tributyl
Citrate
(
Mahoney,
August
12,
2002,
D284809))

EPA/
OPPb.
EFED
Assessment:
Review
of
the
Inert
Ingredients
Triethyl
Citrate
and
Acetyl
Tributyl
Citrate
(
Mahoney
and
Abdel­
Saheb,
May
29,
2002,
D281963,
D270599,
D272539)

EPA/
OPPT.
OPPT
Structure
Activity
Team
Review
of
Seven
Esters
(
Rebecca
Jones,
January
9,
1997)

Toxnet
SISa.
Specialized
Information
Service.
On­
line
Scientific
Search
Engine,
National
Library
of
Medicine,
National
Institute
of
Health.
Http://
www.
toxnet.
nlm.
nih.
gov.
Search
term:
acetyl
tributyl
citrate;
Abstract
of
BIBRA
toxicity
profile
(
data
entered
1990);
accessed
2004.

Toxnet
SISb.
Specialized
Information
Service.
On­
line
Scientific
Search
Engine,
National
Page
14
of
48
Library
of
Medicine,
National
Institute
of
Health.
Http://
www.
toxnet.
nlm.
nih.
gov.
Search
term:
triethyl
citrate;
Abstract
of
BIBRA
toxicity
profile
(
data
entered
1998);
accessed
2004.
Page
15
of
48
Appendix
1:
Screening­
Level
Exposure
Assessments
for
Acetyl
Tributyl
Citrate
(
CAS
Reg.
No.
77­
90­
7)
and
Triethyl
Citrate
(
CAS
Reg.
No.
77­
93­
0)

Dietary
(
Food)
Exposure
DEEM
Model
Assumptions
­
Actual
crop­
specific
residue
data
for
active
ingredients
can
be
utilized
as
surrogate
data
for
inert
ingredient
residue
levels
(
including
secondary
residues
in
meat,
milk,
poultry
and
eggs)
­
Inert
ingredients
are
used
on
all
crops
and
100%
of
all
crops
are
"
treated"
with
inert
ingredients
­
No
adjustment
made
for
%
of
inert
in
formulation,
application
rate,
or
multiple
applications
of
different
active
ingredient
formulations
­
Considers
only
preharvest
applications
Dietary
modeling
was
performed
utilizing
the
highest
established
tolerance
level
residue
for
each
commodity.

Table
1.
Estimated
Chronic
Dietary
Exposure1
for
a
Generic
Inert
Ingredient
Population
Subgroup2
Estimated
Exposure,
mg/
kg/
day
U.
S.
Population
(
total)
0.120
All
infants
(<
1
year)
0.245
Children
(
1­
2
years)
0.422
Children
(
3­
5
years)
0.310
Children
(
6­
12
years)
0.174
Youth
(
13­
19
years)
0.100
Adults
(
20­
49
years)
0.087
Adults
(
50+
years)
0.086
Females
(
13­
49
years)
0.087
1Exposure
estimates
are
based
on
highest­
tolerance­
level
residues
of
high­
use
active
ingredients
for
all
food
forms,
including
meat,
milk,
poultry,
and
eggs.
2Only
representative
population
subgroups
are
shown.
Page
16
of
48
Dietary
Exposure
as
a
Result
of
Use
in
an
Ear
Tag
The
use
of
ATBC
in
cattle
ear
tags,
was
not
considered
in
the
above
dietary
estimates.
ATBC
can
be
used
as
the
plasticizer
for
the
ear
tags.
Ear
tags
(
generally
no
more
than
30
grams
total
weight)
would
be
applied
to
the
animal
once
a
year,
and
then
used
for
5
to
6
months.
It
is
first
of
all
highly
unlikely
that
all
of
the
plasticizer
component
of
the
ear
tag
would
migrate
into
the
animal
during
the
5
to
6
months.
Any
ATBC
that
did
migrate
into
the
cattle,
would
very
likely
be
metabolized,
and
then
excreted.
Therefore,
the
use
of
such
ear
tags
should
not
contribute
significantly
to
secondary
residues
in
livestock.
Page
17
of
48
Dietary
Exposure
as
a
Result
of
Use
as
a
Flavoring
Triethyl
citrate
was
determined
to
be
used
at
a
level
of
2400
ug/
person/
day
in
the
United
States.
ATBC
was
determined
to
be
used
at
a
level
of
less
than
1800
ug/
person/
day.
These
exposures
can
be
translated
to
mg/
kg/
day
using
standardized
body
weight
assumptions.

Dietary
Exposure
from
Use
of
TEC
and
ATBC
as
a
Flavoring
Population
SubGroup
Body­
Weight
Dietary
Exposure
mg/
kg/
day
TEC
U.
S.
General
Population
70
kg
0.034
Females
(
13­
49
years
old)
60
kg
0.04
Children
(
1­
2
years
old)
10
kg
0.24
ATBC
U.
S.
General
Population
70
kg
0.026
Females
(
13­
49
years
old)
60
kg
0.03
Children
(
1­
2
years
old)
10
kg
0.18
Page
18
of
48
Dietary
Exposure
as
a
Result
of
Use
in
Plastic
Wraps
An
article
in
open
literature
suggested
a
daily
intake
of
1.5
mg
ATBC
as
a
result
of
use
in
microwaves
and
wrapping
of
food
items
such
as
cheese.
This
exposure
can
also
be
translated
to
mg/
kg/
day
using
standardized
body
weight
assumptions.

Dietary
Exposure
from
Use
of
ATBC
in
Plastic
Wrap
Population
SubGroup
Body­
Weight
mg/
kg/
day
U.
S.
General
Population
70
kg
0.021
Children
(
1­
2
years
old)
10
kg
0.15
Females
(
13­
49
years
old)
60
kg
0.025
Page
19
of
48
CEM
Inputs
ID
Number:
Unknown
Product:
ATBC
Chemical
Name:
ATBC
Scenario:
Laundry
Detergent
Population:
Adult
Molecular
Weight
(
g/
mole):
402.5
Vapor
Pressure
(
torr):
0.052
Weight
Fraction
­
Median
(
unitless):
0.05
Weight
Fraction
­
90%
(
unitless):
0.19
Inhalation
Inputs
Frequency
of
Use
(
events/
yr):
312
Years
of
Use:
57
Mass
of
Product
Used
per
Event
­
Median
(
g):
200
Mass
of
Product
Used
per
Event
­
90%
(
g):
400
Inhalation
Rate
During
Use
(
m3/
hr):
0.55
Duration
of
Use
­
Median
(
hours/
event):
0.333
Inhalation
Rate
After
Use
(
m3/
hr):
0.55
Duration
of
Use
­
90%
(
hours/
event):
0.667
Zone
1
Volume
(
m3):
20
Whole
House
Volume
(
m3):
369
Air
Exchange
Rate
(
air
exchanges/
hr):
0.45
Body
Weight
(
kg):
71.8
Activity
Patterns
User:
1111111235542467422744411
Start
Time:
9
Non­
User:
1111111132442477422744411
Room
of
Use:
5.
Utility
Room
Hour:
0
6
12
18
Dermal
Inputs
Frequency
of
Use
­
Body
(
events/
yr):
52
SA/
BW
­
Body
(
cm2/
kg):
15.6
Amount
Retained
/
Absorbed
to
Skin
(
g/
cm2­
event):
1.13e­
05
Avg.
Time,
LADDpot,
LADCpot
(
days):
2.74e+
04
Avg.
Time,
ADDpot,
ADCpot
(
days):
2.08e+
04
Avg.
Time,
ADRpot,
Cppot
(
days):
1.00e+
00
Page
20
of
48
CEM
Inhalation
Exposure
Estimates
ID
Number:
Unknown
Scenario:
Laundry
Detergent
Population:
Adult
Inhalation
Rate
(
m3/
day):
0.55
Years
of
Use
(
years):
57
Body
Weight
(
kg):
71.8
Frequency
of
Use
(
events/
year):
312
Exposure
Units
Result
AT
(
days)

Chronic
Cancer
LADDpot
(
mg/
kg­
day)
3.19e­
02
2.74e+
04
LADCpot
(
mg/
m3)
1.74e­
01
2.74e+
04
Chronic
Non­
Cancer
ADDpot
(
mg/
kg­
day)
4.20e­
02
2.08e+
04
ADCpot
(
mg/
m3)
2.29e­
01
2.08e+
04
Acute
ADRpot
(
mg/
kg­
day)
7.57e­
01
1.00e+
00
Cppot
(
mg/
m3)
1.06e+
02
1.00e+
00
LADD
­
Lifetime
Average
Daily
Dose
(
mg/
kg­
day)
LADC
­
Lifetime
Average
Daily
Concentration
(
mg/
m3)

ADD
­
Average
Daily
Dose
(
mg/
kg­
day)
ADC
­
Average
Daily
Concentration
(
mug/
m3)

ADR
­
Acute
Dose
Rate
(
mg/
kg­
day)
Cp
­
Peak
Concentration
(
mg/
m3)

Note:
75
years
=
2.738e+
04
days
pot
­
potential
dose
Note:
The
general
Agency
guidance
for
assessing
short­
term,
infrequent
events
(
for
most
chemicals,
an
exposure
of
less
than
24
hours
that
occurs
no
more
frequently
than
monthly)
is
to
treat
such
events
as
independent,
acute
exposures
rather
than
as
chronic
exposure.
Thus,
estimates
of
long­
term
average
exposure
like
ADD
or
ADC
may
not
be
appropriate
for
use
in
assessing
risks
associated
with
this
type
of
exposure
pattern.
(
Methods
for
Exposure­
Response
Analysis
for
Acute
Inhalation
Exposure
to
Chemicals
(
External
Review
Draft).
EPA/
600/
R­
98/
051.
April
1998
Page
21
of
48
CEM
Dermal
Exposure
Estimates
ID
Number:
Unknown
Scenario:
Laundry
Detergent
Population:
Adult
Years
of
Use
(
years):
57
SA/
BW
Body
(
cm2/
kg):
15.6
Frequency
of
Use
(
events/
year):
52
Exposure
Units
Result
AT
(
days)

Chronic
Cancer
LADDpot
(
mg/
kg­
day)
9.54e­
04
2.74e+
04
Chronic
Non­
Cancer
ADDpot
(
mg/
kg­
day)
1.26e­
03
2.08e+
04
Acute
ADRpot
(
mg/
kg­
day)
3.35e­
02
1.00e+
00
LADD
­
Lifetime
Average
Daily
Dose
(
mg/
kg­
day)

ADD
­
Average
Daily
Dose
(
mg/
kg­
day)

ADR
­
Acute
Dose
Rate
(
mg/
kg­
day)

Note:
75
years
=
2.738e+
04
days
pot
­
potential
dose
Note:
The
general
Agency
guidance
for
assessing
short­
term,
infrequent
events
(
for
most
chemicals,
an
exposure
of
less
than
24
hours
that
occurs
no
more
frequently
than
monthly)
is
to
treat
such
events
as
independent,
acute
exposures
rather
than
as
chronic
exposure.
Thus,
estimates
of
long­
term
average
exposure
like
ADD
or
ADC
may
not
be
appropriate
for
use
in
assessing
risks
associated
with
this
type
of
exposure
pattern.
(
Methods
for
Exposure­
Response
Analysis
for
Acute
Inhalation
Exposure
to
Chemicals
(
External
Review
Draft).
EPA/
600/
R­
98/
051.
April
1998
Page
22
of
48
CEM
Inputs
ID
Number:
Unknown
Product:
TEC
Chemical
Name:
TEC
Scenario:
Laundry
Detergent
Population:
Adult
Molecular
Weight
(
g/
mole):
276.3
Vapor
Pressure
(
torr):
0.0064
Weight
Fraction
­
Median
(
unitless):
0.05
Weight
Fraction
­
90%
(
unitless):
0.19
Inhalation
Inputs
Frequency
of
Use
(
events/
yr):
312
Years
of
Use:
57
Mass
of
Product
Used
per
Event
­
Median
(
g):
200
Mass
of
Product
Used
per
Event
­
90%
(
g):
400
Inhalation
Rate
During
Use
(
m3/
hr):
0.55
Duration
of
Use
­
Median
(
hours/
event):
0.333
Inhalation
Rate
After
Use
(
m3/
hr):
0.55
Duration
of
Use
­
90%
(
hours/
event):
0.667
Zone
1
Volume
(
m3):
20
Whole
House
Volume
(
m3):
369
Air
Exchange
Rate
(
air
exchanges/
hr):
0.45
Body
Weight
(
kg):
71.8
Activity
Patterns
User:
1111111235542467422744411
Start
Time:
9
Non­
User:
Room
of
Use:
5.
Utility
Room
Hour:
0
6
12
18
Dermal
Inputs
Frequency
of
Use
­
Body
(
events/
yr):
52
SA/
BW
­
Body
(
cm2/
kg):
15.6
Amount
Retained
/
Absorbed
to
Skin
(
g/
cm2­
event):
1.13e­
05
Avg.
Time,
LADDpot,
LADCpot
(
days):
2.74e+
04
Avg.
Time,
ADDpot,
ADCpot
(
days):
2.08e+
04
Avg.
Time,
ADRpot,
Cppot
(
days):
1.00e+
00
Page
23
of
48
CEM
Inhalation
Exposure
Estimates
ID
Number:
Unknown
Scenario:
Laundry
Detergent
Population:
Adult
Inhalation
Rate
(
m3/
day):
0.55
Years
of
Use
(
years):
57
Body
Weight
(
kg):
71.8
Frequency
of
Use
(
events/
year):
312
Exposure
Units
Result
AT
(
days)

Chronic
Cancer
LADDpot
(
mg/
kg­
day)
3.02e­
03
2.74e+
04
LADCpot
(
mg/
m3)
1.64e­
02
2.74e+
04
Chronic
Non­
Cancer
ADDpot
(
mg/
kg­
day)
3.97e­
03
2.08e+
04
ADCpot
(
mg/
m3)
2.16e­
02
2.08e+
04
Acute
ADRpot
(
mg/
kg­
day)
7.15e­
02
1.00e+
00
Cppot
(
mg/
m3)
9.99e+
00
1.00e+
00
LADD
­
Lifetime
Average
Daily
Dose
(
mg/
kg­
day)
LADC
­
Lifetime
Average
Daily
Concentration
(
mg/
m3)

ADD
­
Average
Daily
Dose
(
mg/
kg­
day)
ADC
­
Average
Daily
Concentration
(
mug/
m3)

ADR
­
Acute
Dose
Rate
(
mg/
kg­
day)
Cp
­
Peak
Concentration
(
mg/
m3)

Note:
75
years
=
2.738e+
04
days
pot
­
potential
dose
Note:
The
general
Agency
guidance
for
assessing
short­
term,
infrequent
events
(
for
most
chemicals,
an
exposure
of
less
than
24
hours
that
occurs
no
more
frequently
than
monthly)
is
to
treat
such
events
as
independent,
acute
exposures
rather
than
as
chronic
exposure.
Thus,
estimates
of
long­
term
average
exposure
like
ADD
or
ADC
may
not
be
appropriate
for
use
in
assessing
risks
associated
with
this
type
of
exposure
pattern.
(
Methods
for
Exposure­
Response
Analysis
for
Acute
Inhalation
Exposure
to
Chemicals
(
External
Review
Draft).
EPA/
600/
R­
98/
051.
April
1998
Page
24
of
48
CEM
Dermal
Exposure
Estimates
ID
Number:
Unknown
Scenario:
Laundry
Detergent
Population:
Adult
Years
of
Use
(
years):
57
SA/
BW
Body
(
cm2/
kg):
15.6
Frequency
of
Use
(
events/
year):
52
Exposure
Units
Result
AT
(
days)

Chronic
Cancer
LADDpot
(
mg/
kg­
day)
9.54e­
04
2.74e+
04
Chronic
Non­
Cancer
ADDpot
(
mg/
kg­
day)
1.26e­
03
2.08e+
04
Acute
ADRpot
(
mg/
kg­
day)
3.35e­
02
1.00e+
00
LADD
­
Lifetime
Average
Daily
Dose
(
mg/
kg­
day)

ADD
­
Average
Daily
Dose
(
mg/
kg­
day)

ADR
­
Acute
Dose
Rate
(
mg/
kg­
day)

Note:
75
years
=
2.738e+
04
days
pot
­
potential
dose
Note:
The
general
Agency
guidance
for
assessing
short­
term,
infrequent
events
(
for
most
chemicals,
an
exposure
of
less
than
24
hours
that
occurs
no
more
frequently
than
monthly)
is
to
treat
such
events
as
independent,
acute
exposures
rather
than
as
chronic
exposure.
Thus,
estimates
of
long­
term
average
exposure
like
ADD
or
ADC
may
not
be
appropriate
for
use
in
assessing
risks
associated
with
this
type
of
exposure
pattern.
(
Methods
for
Exposure­
Response
Analysis
for
Acute
Inhalation
Exposure
to
Chemicals
(
External
Review
Draft).
EPA/
600/
R­
98/
051.
April
1998
Page
25
of
48
CEM
Inputs
ID
Number:
Unknown
Product:
ATBC
Chemical
Name:
ATBC
Scenario:
General
Purpose
Cleaner
Population:
Adult
Molecular
Weight
(
g/
mole):
402.5
Vapor
Pressure
(
torr):
0.052
Weight
Fraction
­
Median
(
unitless):
0.05
Weight
Fraction
­
90%
(
unitless):
0.19
Inhalation
Inputs
Frequency
of
Use
(
events/
yr):
300
Years
of
Use:
57
Mass
of
Product
Used
per
Event
­
Median
(
g):
61.5
Mass
of
Product
Used
per
Event
­
90%
(
g):
123
Inhalation
Rate
During
Use
(
m3/
hr):
0.55
Duration
of
Use
­
Median
(
hours/
event):
0.667
Inhalation
Rate
After
Use
(
m3/
hr):
0.55
Duration
of
Use
­
90%
(
hours/
event):
1.42
Zone
1
Volume
(
m3):
20
Whole
House
Volume
(
m3):
369
Air
Exchange
Rate
(
air
exchanges/
hr):
0.45
Body
Weight
(
kg):
71.8
Activity
Patterns
User:
1111111221542467422744411
Start
Time:
7
Non­
User:
1111111132442477422744411
Room
of
Use:
2.
Kitchen
Hour:
0
6
12
18
Dermal
Inputs
Frequency
of
Use
­
Body
(
events/
yr):
300
SA/
BW
­
Body
(
cm2/
kg):
15.6
Amount
Retained
/
Absorbed
to
Skin
(
g/
cm2­
event):
3.6e­
05
Avg.
Time,
LADDpot,
LADCpot
(
days):
2.74e+
04
Avg.
Time,
ADDpot,
ADCpot
(
days):
2.08e+
04
Avg.
Time,
ADRpot,
Cppot
(
days):
1.00e+
00
Page
26
of
48
CEM
Inhalation
Exposure
Estimates
ID
Number:
Unknown
Scenario:
General
Purpose
Cleaner
Population:
Adult
Inhalation
Rate
(
m3/
day):
0.55
Years
of
Use
(
years):
57
Body
Weight
(
kg):
71.8
Frequency
of
Use
(
events/
year):
300
Exposure
Units
Result
AT
(
days)

Chronic
Cancer
LADDpot
(
mg/
kg­
day)
1.36e­
01
2.74e+
04
LADCpot
(
mg/
m3)
7.40e­
01
2.74e+
04
Chronic
Non­
Cancer
ADDpot
(
mg/
kg­
day)
1.79e­
01
2.08e+
04
ADCpot
(
mg/
m3)
9.74e­
01
2.08e+
04
Acute
ADRpot
(
mg/
kg­
day)
1.51e+
00
1.00e+
00
Cppot
(
mg/
m3)
6.35e+
01
1.00e+
00
LADD
­
Lifetime
Average
Daily
Dose
(
mg/
kg­
day)
LADC
­
Lifetime
Average
Daily
Concentration
(
mg/
m3)

ADD
­
Average
Daily
Dose
(
mg/
kg­
day)
ADC
­
Average
Daily
Concentration
(
mug/
m3)

ADR
­
Acute
Dose
Rate
(
mg/
kg­
day)
Cp
­
Peak
Concentration
(
mg/
m3)

Note:
75
years
=
2.738e+
04
days
pot
­
potential
dose
Note:
The
general
Agency
guidance
for
assessing
short­
term,
infrequent
events
(
for
most
chemicals,
an
exposure
of
less
than
24
hours
that
occurs
no
more
frequently
than
monthly)
is
to
treat
such
events
as
independent,
acute
exposures
rather
than
as
chronic
exposure.
Thus,
estimates
of
long­
term
average
exposure
like
ADD
or
ADC
may
not
be
appropriate
for
use
in
assessing
risks
associated
with
this
type
of
exposure
pattern.
(
Methods
for
Exposure­
Response
Analysis
for
Acute
Inhalation
Exposure
to
Chemicals
(
External
Review
Draft).
EPA/
600/
R­
98/
051.
April
1998
Page
27
of
48
CEM
Dermal
Exposure
Estimates
ID
Number:
Unknown
Scenario:
General
Purpose
Cleaner
Population:
Adult
Years
of
Use
(
years):
57
SA/
BW
Body
(
cm2/
kg):
15.6
Frequency
of
Use
(
events/
year):
300
Exposure
Units
Result
AT
(
days)

Chronic
Cancer
LADDpot
(
mg/
kg­
day)
1.75e­
02
2.74e+
04
Chronic
Non­
Cancer
ADDpot
(
mg/
kg­
day)
2.31e­
02
2.08e+
04
Acute
ADRpot
(
mg/
kg­
day)
1.07e­
01
1.00e+
00
LADD
­
Lifetime
Average
Daily
Dose
(
mg/
kg­
day)

ADD
­
Average
Daily
Dose
(
mg/
kg­
day)

ADR
­
Acute
Dose
Rate
(
mg/
kg­
day)

Note:
75
years
=
2.738e+
04
days
pot
­
potential
dose
Note:
The
general
Agency
guidance
for
assessing
short­
term,
infrequent
events
(
for
most
chemicals,
an
exposure
of
less
than
24
hours
that
occurs
no
more
frequently
than
monthly)
is
to
treat
such
events
as
independent,
acute
exposures
rather
than
as
chronic
exposure.
Thus,
estimates
of
long­
term
average
exposure
like
ADD
or
ADC
may
not
be
appropriate
for
use
in
assessing
risks
associated
with
this
type
of
exposure
pattern.
(
Methods
for
Exposure­
Response
Analysis
for
Acute
Inhalation
Exposure
to
Chemicals
(
External
Review
Draft).
EPA/
600/
R­
98/
051.
April
1998
Page
28
of
48
CEM
Inputs
ID
Number:
Unknown
Product:
TEC
Chemical
Name:
TEC
Scenario:
General
Purpose
Cleaner
Population:
Adult
Molecular
Weight
(
g/
mole):
276.3
Vapor
Pressure
(
torr):
0.0064
Weight
Fraction
­
Median
(
unitless):
0.05
Weight
Fraction
­
90%
(
unitless):
0.19
Inhalation
Inputs
Frequency
of
Use
(
events/
yr):
300
Years
of
Use:
57
Mass
of
Product
Used
per
Event
­
Median
(
g):
61.5
Mass
of
Product
Used
per
Event
­
90%
(
g):
123
Inhalation
Rate
During
Use
(
m3/
hr):
0.55
Duration
of
Use
­
Median
(
hours/
event):
0.667
Inhalation
Rate
After
Use
(
m3/
hr):
0.55
Duration
of
Use
­
90%
(
hours/
event):
1.42
Zone
1
Volume
(
m3):
20
Whole
House
Volume
(
m3):
369
Air
Exchange
Rate
(
air
exchanges/
hr):
0.45
Body
Weight
(
kg):
71.8
Activity
Patterns
User:
1111111221542467422744411
Start
Time:
7
Non­
User:
Room
of
Use:
2.
Kitchen
Hour:
0
6
12
18
Dermal
Inputs
Frequency
of
Use
­
Body
(
events/
yr):
300
SA/
BW
­
Body
(
cm2/
kg):
15.6
Amount
Retained
/
Absorbed
to
Skin
(
g/
cm2­
event):
3.6e­
05
Avg.
Time,
LADDpot,
LADCpot
(
days):
2.74e+
04
Avg.
Time,
ADDpot,
ADCpot
(
days):
2.08e+
04
Avg.
Time,
ADRpot,
Cppot
(
days):
1.00e+
00
Page
29
of
48
CEM
Inhalation
Exposure
Estimates
ID
Number:
Unknown
Scenario:
General
Purpose
Cleaner
Population:
Adult
Inhalation
Rate
(
m3/
day):
0.55
Years
of
Use
(
years):
57
Body
Weight
(
kg):
71.8
Frequency
of
Use
(
events/
year):
300
Exposure
Units
Result
AT
(
days)

Chronic
Cancer
LADDpot
(
mg/
kg­
day)
1.06e­
01
2.74e+
04
LADCpot
(
mg/
m3)
5.76e­
01
2.74e+
04
Chronic
Non­
Cancer
ADDpot
(
mg/
kg­
day)
1.39e­
01
2.08e+
04
ADCpot
(
mg/
m3)
7.58e­
01
2.08e+
04
Acute
ADRpot
(
mg/
kg­
day)
5.43e­
01
1.00e+
00
Cppot
(
mg/
m3)
8.71e+
00
1.00e+
00
LADD
­
Lifetime
Average
Daily
Dose
(
mg/
kg­
day)
LADC
­
Lifetime
Average
Daily
Concentration
(
mg/
m3)

ADD
­
Average
Daily
Dose
(
mg/
kg­
day)
ADC
­
Average
Daily
Concentration
(
mug/
m3)

ADR
­
Acute
Dose
Rate
(
mg/
kg­
day)
Cp
­
Peak
Concentration
(
mg/
m3)

Note:
75
years
=
2.738e+
04
days
pot
­
potential
dose
Note:
The
general
Agency
guidance
for
assessing
short­
term,
infrequent
events
(
for
most
chemicals,
an
exposure
of
less
than
24
hours
that
occurs
no
more
frequently
than
monthly)
is
to
treat
such
events
as
independent,
acute
exposures
rather
than
as
chronic
exposure.
Thus,
estimates
of
long­
term
average
exposure
like
ADD
or
ADC
may
not
be
appropriate
for
use
in
assessing
risks
associated
with
this
type
of
exposure
pattern.
(
Methods
for
Exposure­
Response
Analysis
for
Acute
Inhalation
Exposure
to
Chemicals
(
External
Review
Draft).
EPA/
600/
R­
98/
051.
April
1998
Page
30
of
48
CEM
Dermal
Exposure
Estimates
ID
Number:
Unknown
Scenario:
General
Purpose
Cleaner
Population:
Adult
Years
of
Use
(
years):
57
SA/
BW
Body
(
cm2/
kg):
15.6
Frequency
of
Use
(
events/
year):
300
Exposure
Units
Result
AT
(
days)

Chronic
Cancer
LADDpot
(
mg/
kg­
day)
1.75e­
02
2.74e+
04
Chronic
Non­
Cancer
ADDpot
(
mg/
kg­
day)
2.31e­
02
2.08e+
04
Acute
ADRpot
(
mg/
kg­
day)
1.07e­
01
1.00e+
00
LADD
­
Lifetime
Average
Daily
Dose
(
mg/
kg­
day)

ADD
­
Average
Daily
Dose
(
mg/
kg­
day)

ADR
­
Acute
Dose
Rate
(
mg/
kg­
day)

Note:
75
years
=
2.738e+
04
days
pot
­
potential
dose
Note:
The
general
Agency
guidance
for
assessing
short­
term,
infrequent
events
(
for
most
chemicals,
an
exposure
of
less
than
24
hours
that
occurs
no
more
frequently
than
monthly)
is
to
treat
such
events
as
independent,
acute
exposures
rather
than
as
chronic
exposure.
Thus,
estimates
of
long­
term
average
exposure
like
ADD
or
ADC
may
not
be
appropriate
for
use
in
assessing
risks
associated
with
this
type
of
exposure
pattern.
(
Methods
for
Exposure­
Response
Analysis
for
Acute
Inhalation
Exposure
to
Chemicals
(
External
Review
Draft).
EPA/
600/
R­
98/
051.
April
1998
Page
31
of
48
Drinking
Water
Exposure
(
see
http://
www.
epa.
gov/
oppefed1/
models/
water/
index.
htm)

Surface
and
groundwater
drinking
water
concentrations
were
based
on
modeling
using
a
single
application
of
1
lb/
acre.
Surface
water
concentrations
were
modeled
using
FIRST.
Groundwater
concentrations
were
modeled
using
SCI­
GROW.
Concentrations
are
linearly
scalable
based
on
application
rate.
­
The
surface
water
chronic
concentration
for
ATBC
is
0.44
ppb.
­
The
groundwater
concentration
for
either
ATBC
or
TEC
is
4.28
ppb.
­
The
surface
water
chronic
concentration
for
TEC
is
26.8
ppb.

The
TEC
26.8
ppb
and
the
ATBC
4.28
ppb
concentrations
in
drinking
water
were
converted
to
mg/
kg/
day
using
standard
Agency
assumptions:
(
1)
consumption
of
1
liter
of
water
per
day
for
infants
and
children
and
2
liters
of
water
per
day
for
adults,
and
(
2)
body
weights
of
10
kg
for
children
1­
2
years,
and
70
kilograms
for
the
US
general
population.

TEC
Generic
Screening
Drinking
Water
Exposure
Estimates
­
Chronic
Population
Subgroup
Exposure
(
mg/
kg/
day)

1
lb/
acre
application
rate
5
lb/
acre
application
rate
15
lb/
acre
application
rate
US
General
0.00076
0.0038
0.011
Females
(
13­
49
years
old)
0.00089
0.00447
0.013
Children
(
1­
2
years
old)
0.0027
0.013
0.040
Page
32
of
48
ATBC
Generic
Screening
Drinking
Water
Exposure
Estimates
­
Chronic
Population
Subgroup
Exposure
(
mg/
kg/
day)

1
lb/
acre
application
rate
5
lb/
acre
application
rate
15
lb/
acre
application
rate
US
General
0.00012
0.00061
0.0018
Females
(
13­
49
years
old)
0.00014
0.00071
0.0021
Children
(
1­
2
years
old)
0.00043
0.0021
0.0064
Page
33
of
48
Appendix
2:
Robust
Summaries
Prepared
by
EPA
(
D270588,
D281694)

8.
Acute
Oral
Toxicity
of
Acetyl
Tributyl
Citrate
and
Triethyl
Citrate
The
objective
of
the
various
studies
considered
was
to
determine
the
toxicity
of
triethyl
citrate
and
acetyl
tributyl
citrate.
Acute
toxicity
studies
were
performed
on
both
cats
and
Wistar
rats.
The
reported
studies
were
performed
by
either
gavage
or
in
the
diet.
Some
studies
were
a
single
dose
and
in
others
dosing
occurred
for
periods
of
2
months.

The
effects
of
both
chemicals
were
the
same.
Clinical
signs
including
nausea,
vomiting
,
ataxia,
weakness,
muscle
twitching,
tremors,
reflex
hyperexcitability,
depression
of
body
temperature,
gasping
and
shallow
respiration,
prostration,
convulsions,
respiratory
failure,
(
central
origin),
circulatory
depression,
and
death
were
manifested
within
a
few
minutes
after
administration.
Death
occurred
in
2
hours
to
about
2
days
or
recovery
in
4
hours
to
3
days.
There
was
no
macroscopic
or
microscopic
damage
observed
to
thoracic
and
abdominal
organs.
These
experiments
also
suggested
that
more
than
4
hours
are
required
to
clear
25%
of
the
chemical
from
the
body.

The
ATBC
rat
acute
oral
LD
50
>
30
g/
kg:
Toxicity
Category
IV.
The
TEC
rat
acute
oral
LD
50
=
7
mL/
kg,
Toxicity
Category
IV.

Reference:
MRID
45221221.
Gold,
H.
et
al.
(
1959)
On
the
Pharmacology
of
Triethyl,
Acetyl
Triethyl,
Tributyl,
and
Acetyl
Tributyl
Citrates
by
Oral
Administration
in
Rats
and
Cats:
Lab
Project
Number:
ATBC/
TEC
51147­
26.
Unpublished
study
prepared
by
Cornell
University
Medical
College.
34
p.
Reliability:
Provides
sufficient
information
for
regulatory
purposes.

9.
Toxicity
of
Acetyl
Tributyl
Citrate
Primary
Eye
Irritation
Species/
Strain:
Rabbits/
Albino
Conclusions:
ATBC
induced
ocular
irritation,
characterized
by
moderate
erythema
in
one
animal
for
up
to
24
hours
and
irritation
subsided
by
48
hours
postinstillation
Not
a
severe
ocular
irritant:
Toxicity
Category
III.
Method:
0.1
ml
ATBC
(
purity
unknown)
was
instilled
in
the
left
conjunctival
sac
of
3
male
albino
rabbits
and
observed
for
72
hours
post­
dosing
for
eye
irritation.
GLP:
Yes
Test
Substance:
ATBC,
purity
unknown
Results:
Moderate
erythema
was
observed
in
1/
3
rabbits
for
up
to
24
hours
and
was
cleared
by
48
hours.
Reference:
MRID
45221213.
Chas.
Pfizer
(
1975)
Eye
and
Dermal
Irritation
of
Citroflex
A2
(
Triethylcitrate)
and
Citroflex
A4:
Lab
Project
Number:
ATBC/
TEC
51147­
15.
Unpublished
study.
5
p.
Reliability:
Provides
sufficient
information
for
regulatory
purposes.

Primary
Dermal
Irritation
Species/
Strain:
Rabbits/
Albino
Conclusions:
ATBC
did
not
induce
irritation.
Toxicity
Category
IV.
Page
34
of
48
Method:
1
ml
ATBC
(
purity
unknown)
was
applied
to
abdominal
skin,
daily,
for
4
days.
Animals
were
observed
for
dermal
irritation
for
36
hours
post­
last
application.
In
addition,
two
3
week
dermal
studies
in
rabbits,
one
with
intact
skin
and
another
with
abraded
skin
were
also
performed.
GLP:
Yes
Test
Substance:
ATBC,
purity
unknown
Results:
No
dermal
irritation..
Reference:
MRID
45221213.
Chas.
Pfizer
(
1975)
Eye
and
Dermal
Irritation
of
Citroflex
A2
(
Triethylcitrate)
and
Citroflex
A4:
Lab
Project
Number:
ATBC/
TEC
51147­
15.
Unpublished
study.
5
p.
Reliability:
Provides
sufficient
information
for
regulatory
purposes.

Dermal
Sensitization
Species/
Strain:
Guinea
Pig
Conclusions:
ATBC
is
not
a
dermal
sensitizer
in
guinea
pigs
Method:
Maximization
method
was
employed
to
evaluate
the
sensitization
potential
of
ATBC.
GLP:
Yes
Test
Substance:
ATBC,
purity
unknown
Results:
No
animal
showed
positive
signs
of
sensitization
during
the
first,
second,
or
third
challenges
at
either
the
24
or
48
hour
observations.
Barely
perceptible
erythema
was
observed
during
the
first
challenge
phase
in
the
untreated
controls
(
1/
4)
at
48
hours.
Reference:
MRID
45221220
Philp,
J.
(
1976)
Sensitization
Potential
of
Citroflex
A2,
Citroflex
A4
and
Citroflex
2
in
Guinea
Pigs:
Lab
Project
Number:
ATBC/
TEC
51147­
25.
Unpublished
study
prepared
by
Unilever
Research
Laboratory.
40
p.
Reliability:
High
­
Guideline
method
was
used.

Human
Sensitization
Species:
Human
volunteers
Conclusions:
ATBC
is
not
a
dermal
sensitizer
to
humans
Methods:
Human
volunteers
were
applied
with
Webril
patch
moistened
with
0.4
mL
of
test
substance
to
the
upper
arm
for
24
hours
followed
by
a
24
or
48
hour
recovery
period
according
to
the
method
of
Draize.
Nine
induction
treatments
followed
by
single
challenge
treatment
were
performed.
Test
sites
were
observed
for
dermal
irritation
immediately
prior
to
patch
application
at
the
second
through
ninth
visits
and
following
the
tenth
visit.
GLP:
Yes
Test
Substance:
ATBC,
unknown
purity
Results:
No
evidence
of
dermal
irritation
was
observed
following
any
induction
treatment
or
the
challenge
treatment.
Reference:
MRID
45221201
Guillaume,
R.
(
1978)
Repeated
Insult
Patch
Test:
Acetyl
Tributyl
Citrate
(
in
Humans):
Lab
Project
Number:
ATBC/
TEC
51147­
1.
Unpublished
study
prepared
by
Hill
Top
Research.
24
p.
Reliability:
High.
Tested
in
the
population
of
concern.
It
satisfies
the
purpose
for
which
it
was
intended:
to
evaluate
the
irritative
properties
of
ATBC
and
to
determine
if
hyperactivity
to
ATBC
would
occur
following
repeated
application
in
humans.
Page
35
of
48
Subchronic
Oral
Toxicity
Species/
Strain:
Rat/
Sprague
Dawley
Conclusion:
Not
toxic
up
to
1,000
mg/
kg/
day
(
HDT)
Method:
Groups
of
20
rats/
sex/
dose
received
in
the
diet
dose
levels
of
0,
100,
300,
or
1000
mg/
kg/
day
for
90
days.
All
rats
were
checked
once
daily
for
clinical
signs
of
toxicity.
Body
weights
and
food
consumption
were
measured
weekly.
Hematology
and
clinical
chemistry
were
analyzed.
Water
consumption
was
measured
daily.
All
animals
were
subjected
to
a
detailed
evaluation
of
clinical
signs
of
neurotoxicity
and
functional
deficits.
A
gross
necropsy
was
performed
and
tissues
from
the
controls
and
1000
mg/
kg/
day
were
examined
histopathologically.
GLP:
Yes
Test
Substance:
Acetyl
tributyl
citrate,
purity
>
98%
Results:
No
systemic
toxicity
was
noted
up
to
1,000
mg/
kg/
day.
There
were
transient
decreases
in
food
consumption,
decreases
in
body
weights,
and
slight
increases
in
absolute
and
relative
weights
observed
in
high
dose
males
and
females;
however,
there
was
no
corroborative
evidence
of
liver
toxicity
histologically.
Hematology
and
clinical
chemistries
were
not
affected.
There
were
no
treatment­
related
neurological
findings
in
males
and
females.
References:
MRID
45257701.
Jonker,
D.
(
1991)
Subchronic
(
90­
Day)
Dietary
Toxicity
Study
with
Acetyl
Tributyl
Citrate
in
Rats:
Lab
Project
Number:
ATBC/
TEC
51147­
10.
Unpublished
study
prepared
by
TNO
Nutrition
and
Food
Research.
352
p.

MRID
45221211.
Jonker,
I.
(
1991)
Range
Finding
Study
(
14­
Day)
Dietary
with
Acetyl
Tributyl
Citrate
in
Rats:
Lab
Project
Number:
ATBC/
TEC
51147­
12.
Unpublished
study
prepared
by
TNO
Nutrition
and
Food
Research.
78
p.
Reliability:
High.
Guideline
method
was
used.

Chronic
Oral
Toxicity
­
Rat
Species/
Strain:
Rat/
Sherman
Conclusion:
NOAEL

20,000
ppm
(
1000
mg/
kg/
day).
LOAEL
was
not
established.
Method:
Acetyl
tributyl
citrate
(
99.4%
pure)
was
administered
to
20
rats/
sex/
dose
at
concentrations
of
0,
200,
2000
or
20,000
ppm
for
two
years.
Body
weights
and
clinical
signs
were
recorded
but
frequency
was
not
given.
There
was
slight
decrease
in
body
weights
during
5
to
15
weeks
in
all
groups,
however,
the
decreases
were
equivocal.
GLP:
Yes
Test
Substance:
Acetyl
tributyl
citrate
Results:
No
systemic
toxicity
was
observed
up
to
20,000
ppm
(
1000
mg/
kg/
day).
(
HDT)
Reference
:
MRID
45259501.
Soeler,
A.
et
al.
(
2000)
Experiments
on
the
Chronic
Toxicity
of
Acetyl
Tributyl
Citrate:
Lab
Project
Number:
ACTB/
TEC
51147­
16.
Unpublished
study
prepared
by
Harvard
School
of
Public
Health
and
Medical
School.
19
p.
Reliability:
University­
conducted
study
provides
sufficient
information
when
considered
with
other
information.
Page
36
of
48
Chronic
Oral
Toxicity
­
Dog
Species/
Strain:
Dog/
Mongrel
Conclusion:
NOAEL

140
mg/
kg/
day.
LOAEL
was
not
established.
Method:
Acetyl
tributyl
citrate
(
99.4%
pure)
was
administered
in
gelatin
capsule
orally
to
2
dogs
at
a
dosages
of
0
or
140
mg/
kg/
day
for
two
years.
Dogs
were
examined
for
clinical
signs
toxicity
daily
and
body
weights
weekly.
Hematological
parameters
(
hematocrit,
hemoglobin,
sedimentation
rate,
red
and
white
cell
counts,
and
differential
white
cell
counts)
were
determined
at
6,
11,
17,
20
and
24
months.
Urinalyses
was
performed
for
protein,
sugar,
and
sediment.
Treatment
with
acetyl
tributyl
citrate
at
140
mg/
kg/
day
did
not
elicit
any
adverse
effects
on
clinical
signs,
body
weights,
hematology
and
urinalyses
parameters.
GLP:
Yes
Test
Substance:
Acetyl
tributyl
citrate
Results:
No
systemic
toxicity
was
observed
up
to
140
mg/
kg/
day.
Reference:
MRID
45259501.
Soeler,
A.
et
al.
(
2000)
Experiments
on
the
Chronic
Toxicity
of
Acetyl
Tributyl
Citrate:
Lab
Project
Number:
ACTB/
TEC
51147­
16.
Unpublished
study
prepared
by
Harvard
School
of
Public
Health
and
Medical
School.
19
p.
Reliability:
University­
conducted
study
provides
sufficient
information
when
considered
with
other
information
Reproductive
Toxicity
Species/
Strain:
Rat/
Sprague
Dawley
Endpoint:
NOAEL
(
parental):
100
mg/
kg/
day
LOAEL
(
parental):
300
mg/
kg/
day,
based
on
decreased
body
weights
and
water
consumption
NOAEL
(
reproductive):
1,000
mg/
kg/
day
LOAEL
(
reproductive):
not
observed
NOAEL
(
offspring):
100
mg/
kg/
day
LOAEL
(
offspring):
300
mg/
kg/
day,
based
on
increased
pup
mortality
and
decreased
pup
weights
Method:
Acetyl
tributyl
citrate
(
purity
not
provided)
was
administered
in
diet
to
30
rats/
sex/
dose
at
nominal
dose
levels
of
0,
100,
300
or
1,000
mg/
kg/
day.
The
P
(
parental)
animals
were
given
test
diet
for
3
(
females)
or
11
(
males)
weeks
prior
to
mating
to
produce
the
F1
(
first
generation)
litters.
After
weaning,
the
selected
F1
animals
were
given
the
same
concentration
test
diet
as
P
dams,
for
10
weeks
prior
to
mating,
which
produced
the
F2
(
second
generation)
generation
progeny.
The
animals
were
checked
for
clinical
signs
of
toxicity
and
mortality
daily
and
detailed
clinical
examinations
weekly.
All
P
males
were
weighed
pre­
treatment,
3
days
following
initiation
of
treatment
and
weekly
thereafter
until
necropsy.
All
P
females
were
weighed
pretreatment,
3
days
following
treatment
initiation,
weekly
throughout
premating
and
mating,
daily
during
gestation
and
weekly
during
lactation.
All
F1
males
were
weighed
weekly
from
weaning
until
termination.
All
F1
females
were
weighed
weekly
from
weaning
to
mating,
daily
during
gestation,
on
LDs
4,
7,
and
14,
and
weekly
thereafter
until
termination.
Food
and
water
consumption
were
measured
between
weighing
intervals
excepting
during
mating.
Litters
were
examined
for
survival
and
abnormalities
(
external
malformations)
on
LDs
Page
37
of
48
1,
4,
7,
10,
14,
17
and
21.
Pups
were
weighed
on
PNDs
1,
4,
7,
14,
and
21.
At
sacrifice,
gross
examinations
of
the
abdominal
cavities
were
conducted,
multiple
organs
were
preserved
in
buffered
formalin
and
examined
microscopically.
The
following
indices
were
calculated:
­
fertility
index
­
offspring
viability
index
at
days
4
and
21
­
sex
ratio
­
mortality
GLP:
Unknown
Test
Substance:
Acetyl
tributyl
citrate,
purity
not
known
Results:
When
compared
to
concurrent
controls,
no
treatment­
related
changes
were
observed
in
the
following
parameters:
mortality,
clinical
signs,
food
consumption,
and
gross
pathology
in
the
P
or
F1
adults;
litter
size,
number
of
live
pups,
sex
ratios,
clinical
signs,
gross
pathology,
and
histopathology
in
the
F1
and
F2
offspring.
Reproductive
function
and
organ
weights
were
not
evaluated
in
the
parental
animals.
Developmental
landmarks
and
organ
weights
were
not
evaluated
in
the
F1
or
F2
offspring.
Systemic
toxicity
was
observed
at
300
mg/
kg/
day
characterized
by
decreased
body
weights
and
water
consumption.
The
parental
toxicity
LOAEL
was
300
mg/
kg/
day
and
the
NOAEL
was
100
mg/
kg/
day.
No
adverse
reproductive
performance
was
observed
at
any
dose.
Based
on
the
available
observations,
the
reproductive
toxicity
NOAEL
was
1000
mg/
kg/
day,
LOAEL
was
not
observed.
Dose­
related
increased
pup
mortality
was
observed
in
the
F2
generation;
6,
4,
13,
and
19
in
the
control,
100,
300,
and
1,000
mg/
kg/
day
dose
groups,
respectively.
Mortality
significantly
increased
(
250%)
in
high­
dose
F2
pups
during
days
7
­
21.
Pup
weights
significantly
decreased
(
7%)
in
F2
generation
on
PND
21.
Pup
body
weights
decreased
significantly
in
the
1000
mg/
kg/
day
F1
pups
on
PND
1
(
9%),
4
(
7%),
and
21
(
5%),
and
in
F2
pups
on
PND
1
(
9%),
4
(
9%),
14
(
10%),
and
21
(
12%).
The
offspring
NOAEL
is
100
mg/
kg/
day.
The
offspring
toxicity
LOAEL
is
300
mg/
kg/
day
based
on
increased
pup
mortality
and
decreased
pup
weight.
Reference:
MRID
45257702.
Robbins,
M.
(
1994)
A
Two
Generation
Reproduction
Study
with
Acetyl
Tributyl
Citrate
in
Rats:
Lab
Project
Number:
ATBE/
TEC
51147­
13.
Unpublished
study
prepared
by
BIBRA
Toxicology
International.
384
p.
Reliability:
High.
Guideline
method
was
used;
study
less
than
10
years
old;
however,
lacked
the
purity
information.
It
is
noted
that
several
critical
evaluations
were
not
made.

In
vitro
Cytotoxicity
Species/
Strain:
Rat/
Sprague­
Dawley
Conclusion:
ATBC
at
1
mg%
for
4
hours
was
not
cytotoxic
to
mammalian
cells.
Method:
Primary
rat
hepatocytes
were
exposed
to
ATBC
(
purity
unknown),
in
DMSO,
at
concentrations
of
0.01,
0.05,
0.1,
or
1
mg%
for
4
hours.
Cell
cultures
were
also
exposed
to
ATBC
metabolite
tributyl
citrate
(
0.01,
0.05,
0.1
or
1
mg%)
and
n­
butanol
(
100,
200,
or
400
mg%).
GLP:
Unknown
Test
Substance:
ATBC,
purity
unknown
Results:
Toxicity,
as
indicated
by
elavated
lactate
dehydrogenase
activities
was
not
observed.
Significant
toxicity
was
observed
with
tributyl
citrate.
Page
38
of
48
Reference:
MRID
45221203.
Acosta,
D.
(
1991)
In
Vitro
Cytotoxicity
of
n­
Butanol,
Acetyl
Tributyl
Citrate,
and
Tributyl
Citrate
in
Primary
Cultures
of
Rat
Hepatocytes:
Lab
Project
Number:
ATBC/
TEC
51147­
3.
Unpublished
study
prepared
by
The
University
of
Texas.
17
p.
Reliability:
University­
conducted
study
provides
sufficient
information
when
considered
with
other
information
Gene
Mutation
Species/
Strain:
Bacteria/
Salmonella
typhimurium
­
reverse
mutation
Conclusions:
Not
mutagenic
Method:
Histadine
requiring
mutagenic
strains
of
salmonella
typhimurium
strains
were
exposed
to
ATBC
in
dimethylsulfoxide
at
concentrations
of
50,
158,
500,
1580
or
5000

g/
plate
and
reverse
mutations
were
determined
after
48
hours
incubation
at
37

C,
both
in
the
presence
and
absence
of
S9
derived
from
Aroclor
124­
induced
rat
and/
or
hamster
induced
livers.
GLP:
Yes
Test
Substance:
Acetyl
tributyl
citrate,
98.55%
pure
Results:
No
evidence
of
mutagenicity
(
reverse
mutation)
was
observed
in
strains
TA98,
TA100,
TA1537,
and
TA1538.
Slight
precipitation
was
observed
at
doses

1000

g/
plate
both
in
the
presence
and
absence
of
S9
metabolic
activation.
Positive
controls
exhibited
appropriate
response.
Reference:
MRID
45221207.
Bollapudi,
B.;
Linscombe,
V.
(
1988)
Evaluation
of
Acetyl
Tributyl
Citrate
in
the
Ames
Salmonella/
Microsome
Bacterial
Mutagenicity
Assay:
Lab
Project
Number:
ATBC/
TEC
511147­
7.
Unpublished
study
prepared
by
The
Dow
Chemical
Company.
29
p.
Reliability:
High.
Guideline
method
was
used.

Species/
Strain:
Bacteria/
Salmonella
typhimurium
­
reverse
mutation
Conclusions:
Not
mutagenic
Method:
In
a
plate
incorporation
assay,
histadine
requiring
mutagenic
salmonella
typhimurium
strains
TA98,
TA100,
TA1537,
and
TA1538
were
exposed
to
ATBC
in
dimethylsulfoxide
at
concentrations
of
333,
1000,
3333,
6667,
or
10,000

g/
plate
and
reverse
mutations
were
determined
after
48
hours
incubation
at
37

C,
both
in
the
presence
and
absence
of
S9
derived
from
Aroclor
124­
induced
rat
and/
or
hamster
induced
livers.
Results:
No
evidence
of
mutagenicity
(
reverse
mutation)
was
observed
in
strains
TA98,
TA100,
TA1537,
and
TA1538.
There
was
slight
precipitation
was
observed
at
doses

3333

g/
plate
both
in
the
presence
and
absence
of
S9
metabolic
activation.
Positive
controls
exhibited
appropriate
response.
Reference:
MRID
45221208.
San,
R.;
Wagner,
V.
(
1991)
Salmonella/
Mammalian­
Microsome
Plate
Incorporation
Mutagenicity
Assay
(
Ames
Test):
Lab
Project
Number:
ATBC/
TEC
51147­
8.
Unpublished
study
prepared
by
Microbiological
Associates,
Inc.
47
p.
Reliability:
High.
Guideline
method
was
used;
however,
lacked
the
purity
information.

Species/
Strain:
Mammalian/
Chinese
Hamster
Ovary
(
CHO)
Conclusions:
Did
not
induce
mutant
colonies.
Method:
In
this
forward
mutation
assay,
CHO
were
exposed
to
ATBC
in
DMSO
at
concentrations
of
25,
50,
100,
200,
or
400

g/
mL
with
and
without
S9
activation
for
4
hours
and
forward
mutations
were
evaluated
following
Page
39
of
48
incubation
in
the
medium
containing
the
selective
agent,
6­
thioguanine.
GLP:
Yes
Test
Substance:
Acetyl
tributyl
citrate,
99.02%
pure.
Results:
Cytotoxicity
was
observed
in
the
absence
of
S9
at

50

g/
mL
in
the
concurrent
toxicity
plates;
however,
in
the
mutagenicity
plates

50%
of
the
cells
survived.
There
were
no
treatment­
related
increases
in
mutant
frequency
observed
at
any
dose.
The
positive
controls
produced
appropriate
response.
Reference:
MRID
45221210.
Dow
Chemical
Company
(
1991)
Evaluation
of
Acetyl
Tributyl
Citrate
in
the
Chinese
Hamster
Ovary
Cell/
Hypoxanthine­
Guanine­
Phosphoribosyl
Transferase
(
CHO/
HGPRT)
Forward
Mutation
Assay:
Lab
Project
Number:
ATBC/
TEC
51147­
11.
Unpublished
study.
31
p.
Reliability:
High.
Guideline
method
was
used.

Species/
Strain:
Mammalian/
mouse
lymphoma
Conclusions:
No
evidence
forward
mutations
over
background
in
the
presence
or
absence
of
S9­
activation.
Method:
In
this
in
vitro
assay,
mouse
lymphoma
cells
(
L5178Y
TK
+/­
locus)
were
exposed
to
ATBC
in
DMSO
at
concentrations
of
10,
70,
150,
230,
or
310

g/
mL
without
S9­
activation
and
200,
270,
340,
410,
480,
or
550

g/
mL
with
S9­
activation
(
duration
of
exposure
not
provided).
GLP:
Yes
Test
Substance:
ATBC,
purity
not
specified.
Results:
Cytotoxicity
was
observed
at
230

g/
mL
­
S9
and
480

g/
mL
+
S9­
activation.
No
marked
increase
in
the
mutant
frequencies
were
observed
with
or
without
S9­
activation
over
background.
Positive
controls
produced
appropriate
response.
Reference:
MRID
45221209.
Bigger,
C.;
Harbell,
J.
(
1991)
Mouse
Lymphoma
Assay
(
L5178YTK+/­)
Acetyl
Tributyl
Citrate:
Lab
Project
Number:
ATBC/
TEC
51147­
9.
Unpublished
study
prepared
by
Microbiological
Associates,
Inc.
22
p.
Reliability:
High.
Guideline
method
was
used;
however,
lacked
the
purity
information.

Cytogenetics
Species/
Strain:
Rat/
Lymphocytes
Conclusions:
Did
not
induce
chromosomal
aberrations
Method:
In
this
in
vitro
cytogenetics
assay,
rat
lymphocytes
were
exposed
to
ATBC
in
DMSO
at
concentrations
of
0,
40,
133,
or
400

g/
mL
with
or
without
S9­
activation
for
4
hours.
GLP:
Yes
Test
Substance:
ATBC,
99.02%
pure
Results:
ATBC
was
tested
up
to
the
limit
of
solubility,
a
slight
precipitate
was
observed
at

133
(­
S9)
and
400
(+
S9)

g/
mL.
At
400

g/
mL
mitotic
indices
were
reduced
66%
at
24
hours
or
74%
at
48
hours
(­
S9)
and
0%
at
24
hours
or
100%
at
48
hours
(+
S9).
No
statistically
significant
increases
in
aberration
frequency
were
observed
at
any
dose
at
24
or
48
hours
with
or
without
S9­
activation.
Positive
controls
induced
appropriate
response.
Reference:
MRID
45221206.
Dow
Chemical
Company
(
1991)
Evaluation
of
Acetyl
Tributyl
Citrate
in
an
In
Vitro
Chromosomal
Aberration
Assay
Utilizing
Page
40
of
48
Rat
Lymphocytes:
Lab
Project
Number:
ATBC/
TEC
51147­
6.
Unpublished
study.
26
p.
Reliability:
High.
Guideline
method
was
used.

Species/
Strain:
Rat/
Sprague
Dawley
Conclusions:
Not
cytotoxic
to
mammalian
cells.
Method:
Primary
rat
hepatocytes
from
8­
10
day
old
rats
were
exposed
ATBC
in
DMSO
at
concentrations
of
0.01,
0.05,
0.1,
or
1
mg%
for
4
hours.
In
addition,
the
ATBC
metabolites,
tributyl
citrate
(
TBC)
and
n­
butanol
were
tested
at
concentrations
of
0.01,
0.05,
0.1,
or
1
mg%
and
100,
200,
or
400
mg%,
respectively.
GLP:
No
Test
Substance:
ATBC,
purity
not
provided.
Results:
No
significant
cytotoxicity,
as
indicated
by
elevated
lactate
dehydrogenase
activities
in
the
culture
medium
was
observed
at
any
dose
levels
tested
for
ATBC
or
its
principal
metabolites
(
TBC
and
n­
butanol).
Reference:
MRID
45221203.
Acosta,
D.
(
1991)
In
Vitro
Cytotoxicity
of
n­
Butanol,
Acetyl
Tributyl
Citrate,
and
Tributyl
Citrate
in
Primary
Cultures
of
Rat
Hepatocytes:
Lab
Project
Number:
ATBC/
TEC
51147­
3.
Unpublished
study
prepared
by
The
University
of
Texas.
17
p.
Reliability:
University­
conducted
study
provides
sufficient
information
when
considered
with
other
information
Metabolism
Species/
Strain:
Rat/
Sprague
Dawley
Conclusions:
ATBC
was
readily
absorbed
and
rapidly
excreted
in
urine
and
feces
within
48
hours.
Method:
4
­
5
male
rats
were
dosed
with
a
single
oral
of
70
mg/
kg
(
14C)­
ATBC
(
100%
radiochemical
purity)
and
mass
balance,
metabolic
profile,
and
blood
kinetics
were
evaluated.
GLP:
Yes
Test
Substance:
ATBC,
100%
radiochemical
purity
Results:
The
total
recovery
of
radioactivity
was
99.94%.
Elimination
of
radioactivity
occurred
mostly
within
24
hours
of
dosing
(
89.2%
dose)
and
was
essentially
complete
within
48
hours
(
99.26%
dose).
Elimination
occurred
predominantly
in
the
urine,
but
a
substantial
amount
was
also
excreted
in
the
feces
(
32%).
Very
little
radiation
was
expired
as
CO
2
(
2.2%),
and
none
was
expired
as
volatile
organics.
The
half­
times
were
as
follows:
KA
=
1.0
hour,
 
=
3.4
hours,
and
 
=
39
hours.
Tissue
distribution
was
only
quantified
at
48
hours
post­
dose
by
which
time
excretion
was
essentially
complete.
Concentrations
(%
dose/
g)
of
radioactivity
were
as
follows:
the
GI
tract
(
with
contents;
0.008),
the
liver
and
perirenal
fat
(
0.005
each),
kidney
(
0.003),
skin
(
0.002),
and
blood
and
carcass
(
0.001
each).
Quantitative
RP­
HPLC
analyses
isolated
9
metabolites
in
the
urine
of
which
2
were
identified.
The
primary
metabolite
was
monobutyl
citrate
(
29.44%
dose).
The
other
identified
metabolite
was
dibutyl
citrate
(
0.36%
dose).
Parent
was
not
detected
in
the
urine,
and
all
metabolites
were
more
polar
than
the
parent.
The
seven
unknown
urinary
metabolites
each
accounted
for
0.7­
10.6%
of
the
dose
with
three
unknowns
accounting
for
5.0,
7.0,
and
10.6%
of
the
dose.
GC/
MS
Page
41
of
48
analysis
also
detected
the
presence
of
the
following
metabolites:
acetyl
citrate,
monobutyl
citrate,
acetyl
monobutyl
citrate,
dibutyl
citrate,
and
acetyl
dibutyl
citrate.
However,
no
quantitative
data
were
provided
from
GC/
MS.
Acid
hydrolysis
resulted
in
the
same
qualitative
peak
profile,
but
most
of
the
radioactivity
(
59%)
was
eluted
in
a
broad
peak
occurring
at
4.5­
8
minutes.
Base
hydrolysis
eliminated
peak
separation,
and
the
majority
of
the
radioactivity
(
94%)
eluted
in
a
broad
peak
occurring
at
4.5­
8
minutes.
Quantitative
RP­
HPLC
analyses
isolated
3
metabolites
in
the
ethyl
acetate
extract
of
feces
and
up
to
2
more
metabolites
in
the
acidic
ethyl
acetate
extract
of
feces.
None
of
the
metabolites
were
identified.
The
parent
was
isolated
in
the
feces
(
5.17%
dose).
Unanalyzed
fractions
of
urine,
feces,
and
CO
2
contained
less
than
5%
dose,
each.
A
figure
of
the
proposed
metabolic
pathway
was
not
presented.
Reference:
MRID
45221205.
Dow
Chemical
Company
(
1992)
Metabolism
and
Disposition
of
Acetyl
Tributyl
Citrate
in
Male
Sprague
Dawley
Rats:
Lab
Project
Number:
ATBC/
TEC
51147­
5.
Unpublished
study.
62
p.
Reliability:
Good.
Guideline
method
was
not
used;
however,
study
provides
useful
information
Species/
Strain:
Human
serum
and
rat
liver
homogenates
Conclusion:
ATBC
was
hydrolyzed
in
both
human
and
rat
liver
homogenates
resulting
in
n­
butanol
and
tributyl
citrate
(
TBC),
however,
in
human
serum
the
halflife
was
7
hours
vs
30
minutes
in
rat.
Method:
ATBC
(
10.9
µ
M)
in
dimethylsulphoxide
was
diluted
with
serum
to
155
nmole/
mL
and
liver
homogenate
to
132
nmole/
ml.
Samples
containing
1­
butanol
(
150
nmole/
ml)
in
serum
and
liver
homogenate
were
also
prepared.
The
samples
were
incubated
at
37oC
with
magnetic
stirring
and
duplicate
1
ml
samples
were
collected
at
3,
15,
and
30
minutes,
and
1,
2,
4,
6,
24,
and
46
hours.
The
samples
were
acidified
within
1
minute
to
inhibit
the
hydrolysis
of
ATBC.
One
of
the
duplicate
samples
and
the
samples
fortified
with
n­
butanol
were
analyzed
by
head­
space
capillary
gas
chromatography.
The
other
duplicate
samples
were
analyzed
by
capillary
gas
chromatography.
GLP:
Yes
Test
Substance:
ATBC,
purity
not
reported
Results:
In
human
serum,
an
initial
half­
life
of
ATBC
was
approximately
7
hours.
TBC
was
detected
after
one
hour.
Hydrolysis
of
ATBC
resulted
in
the
formation
of
n­
butanol
and
was
essentially
complete
after
24
hours.
In
serum,
n­
butanol
was
essentially
stable
(

29%
after
46
hours).
In
rat
liver
homogenate,
ATBC
half­
life
was
less
than
30
minutes.
TBC
was
detected
after
3
minutes
of
incubation,
but
not
in
longer
incubations
suggesting
that
ATBC
is
quickly
hydrolyzed.
Hydrolysis
of
ATBC
resulted
in
the
formation
of
n­
butanol
and
was
essentially
complete
in
1
hour.
Reference:
MRID
45221202.
Edlund,
P.;
Ostelius,
J.
(
1991)
In
Vitro
Hydrolysis
of
Acetyl
Tributyl
Citrate
in
Human
Serum
and
Rat
Liver
Homogenates:
Lab
Project
Number:
ATBC/
TEC
51147­
2.
Unpublished
study
prepared
by
Oratech.
23
p.
Reliability:
High.
It
is
a
non­
guideline
study,
but
the
information
is
essential
for
understanding
the
metabolism
of
ATBC.
It
satisfies
the
purpose
fors
which
it
was
conducted:
to
demonstrate
that
human
serum
and
rat
liver
homogenates
are
capable
of
metabolizing
acetyl
tributyl
citrate
resulting
in
n­
butanol
and
tributyl
citrate
as
intermediate
products.
Page
42
of
48
Species:
Human
serum
and
rat
liver
homogenates
Conclusion:
Human
serum
and
rat
liver
homogenates
metabolize
ATBC
and
TBC
and
that
TBC
metabolism
is
relatively
fast.
Butanol
was
observed
as
a
metabolite
of
ATBC
and
TBC.
Method:
ATBC
(
100
µ
g
[
248
nmoles]/
mL)
,
TBC
(
100
µ
g
[
252
nmoles]/
mL)
and
butanol
(
14.8
µ
g
[
200
nmoles]/
mL)
in
DMSO
were
added
to
aliquots
of
human
serum
and
liver
homogenates
and
were
incubated
in
a
circulating
water
bath
at
37oC.
Samples
were
collected
for
metabolite
analysis
from
serum
at
0
and
20
minutes
and
1,
2,
4,
6,
11,
24,
and
48
hours;
and
from
liver
homogenate
at
0,
15,
and
30
minutes
and
1,
2,
4,
and
9
hours.
The
concentrations
of
ATBC,
TBC
and
butanol
were
determined
using
GC.
GLP:
Yes
Test
Substance:
ATBC,
TBC,
and
butanol
of
highest
purity
(
unspecified)
Results:
In
human
serum,
ATBC
incubations
demonstrated
a
linear
decline
over
a
48­
hour
period,
at
which
time
only
25%
of
the
starting
material
remained.
The
half­
life
was
32
hours.
Only
traces
of
TBC
were
detected,
which
was
consistent
with
a
rapid
metabolism
of
TBC.
TBC
incubations
demonstrated
an
exponential
decline
with
almost
complete
conversion
shown
in
the
24­
hour
sample.
The
half­
life
was
4
hours.
In
the
liver
homogenate,
ATBC
incubations
demonstrated
a
linear
decline
in
the
first
hour
with
almost
complete
conversion
.
The
half­
life
was
10
minutes.
No
trace
of
TBC
was
detected,
which
was
consistent
with
a
rapid
metabolism
of
TBC.
TBC
incubations
demonstrated
complete
conversion
within
15
minutes.
The
half­
life
was
estimated
as
seconds.
Reference:
MRID
45221204.
Davis,
P.
(
1991)
Metabolism
of
Acetyl
Tributyl
Citrate
(
ATBC)
and
Tributyl
Citrate
(
TBC)
in
Human
Serum
and
Rat
Liver
Homogenates:
Lab
Project
Number:
ATBC/
TEC
51147­
4.
Unpublished
study
prepared
by
The
University
of
Texas.
40
p.
Reliability:
High.
It
is
a
non­
guideline
study,
but
the
information
is
essential
for
understanding
the
metabolism
of
ATBC.
It
satisfies
the
purpose
for
which
it
is
conducted:
to
demonstrate
that
human
serum
and
rat
liver
homogenates
are
capable
of
metabolizing
acetyl
tributyl
citrate
and
its
metabolite
tributyl
citrate
and
that
n­
butanol
is
a
metabolite
of
both.

10.
Toxicity
of
Triethyl
Citrate
(
TEC)

Primary
Eye
Irritation
Species/
Strain:
Rabbits/
Albino
Conclusions:
TEC
induced
ocular
irritation,
characterized
by
slight
or
mederate
erythema
in
one
animal
for
up
to
3
hours
and
irritation
subsided
by
24
hours
post­
instillation.
Not
a
severe
ocular
irritant.
Toxicity
Category
IV
based
on
the
degree
of
irritation
which
subsided
from
all
treated
eyes
by
24
hours.
Method:
0.1
ml
TEC
(
purity
unknown)
was
instilled
in
the
left
conjunctival
sac
of
3
male
albino
rabbits
and
observed
for
72
hours
post­
dosing
for
eye
irritation.
GLP:
Yes
Test
Substance:
TEC,
purity
unknown
Results:
Moderate
erythema
was
observed
in
1/
3
rabbits
for
up
to
3
hours
and
was
cleared
by
24
hours.
Reference:
MRID
45221213.
Chas.
Pfizer
(
1975)
Eye
and
Dermal
Irritation
of
Page
43
of
48
Citroflex
A2
(
Triethylcitrate)
and
Citroflex
A4:
Lab
Project
Number:
ATBC/
TEC
51147­
15.
Unpublished
study.
5
p.
Reliability:
Provides
sufficient
information
for
regulatory
purposes.

Primary
Dermal
Irritation
Species/
Strain:
Rabbits/
Albino
Conclusions:
TEC
did
not
induce
dermal
irritation.
Toxicity
Category
IV.
Method:
1
ml
TEC
(
purity
unknown)
was
applied
to
abdominal
skin,
daily,
for
4
days.
Animals
were
observed
for
dermal
irritation
for
36
hours
post­
last
application.
In
addition,
two
3
week
dermal
studies
in
rabbits,
one
with
intact
skin
and
another
with
abraded
skin
were
also
performed.
GLP:
Yes
Test
Substance:
TEC,
purity
unknown
Results:
No
dermal
irritation.
Reference:
MRID
45221213.
Chas.
Pfizer
(
1975)
Eye
and
Dermal
Irritation
of
Citroflex
A2
(
Triethylcitrate)
and
Citroflex
A4:
Lab
Project
Number:
ATBC/
TEC
51147­
15.
Unpublished
study.
5
p.
Reliability:
Provides
sufficient
information
for
regulatory
purposes.

Dermal
Sensitization
Species/
Strain:
Guinea
Pig
Conclusions:
TEC
is
strong
dermal
sensitizer.
Method:
Maximization
method
was
employed
to
evaluate
the
sensitization
potential
of
TEC
GLP:
Yes
Test
Substance:
TEC,
purity
unknown
Results:
9/
9
animals
showed
positive
signs
of
sensitization,
at
both
24
and
48
hour
observations
in
the
first
and
second
challenges.
Barely
perceptible
erythema
was
observed
during
the
first
challenge
phase
(
1/
4)
in
the
controls.
No
dermal
irritation
was
observed
in
any
untreated
controls.
Reference:
MRID
45221220
Philp,
J.
(
1976)
Sensitization
Potential
of
Citroflex
A2,
Citroflex
A4
and
Citroflex
2
in
Guinea
Pigs:
Lab
Project
Number:
ATBC/
TEC
51147­
25.
Unpublished
study
prepared
by
Unilever
Research
Laboratory.
40
p.
Reliability:
High
­
Guideline
method
was
used.

Human
Sensitization
Species:
Human
volunteers
Conclusions:
TEC
is
not
a
dermal
sensitizer
to
humans
Methods:
Human
volunteers
were
applied
with
Webril
patch
moistened
with
0.4
mL
of
test
substance
to
the
upper
arm
for
24
hours
followed
by
a
24
or
48
hour
recovery
period
according
to
the
method
of
Draize.
Nine
induction
treatments
followed
by
single
challenge
treatment
were
performed.
Test
sites
were
observed
for
dermal
irritation
immediately
prior
to
patch
application
at
the
second
through
ninth
visits
and
following
the
tenth
visit.
GLP:
Yes
Test
Substance:
TEC,
unknown
purity
Results:
No
evidence
of
dermal
irritation
was
observed
following
any
induction
Page
44
of
48
treatment
or
the
challenge
treatment.
Reference:
MRID
45221201
Guillaume,
R.
(
1978)
Repeated
Insult
Patch
Test:
Acetyl
Tributyl
Citrate
(
in
Humans):
Lab
Project
Number:
ATBC/
TEC
51147­
1.
Unpublished
study
prepared
by
Hill
Top
Research.
24
p.
Reliability:
High.
Tested
in
the
population
of
concern.
It
satisfies
the
purpose
for
which
it
was
intended:
to
evaluate
the
irritative
properties
of
TEC
and
to
determine
if
hyperactivity
to
TEC
would
occur
following
repeated
application
in
humans.

Chronic
Oral
Toxicity
­
Rat
Species/
Strain:
Rat/
Sprague
Dawley
Conclusions:
Inconclusive
for
lack
of
details
Method:
TEC
was
administered
in
diet
at
concentrations
of
0,
0.33,
1.0,
or
3.0%
(
0,
30,
200,
or
600
mg/
kg/
day)
to
15
rats/
sex/
dose
for
104
weeks.
Body
weights
were
recorded
weekly
for
12
weeks
then
every
4
weeks
for
remainder
of
the
study.
Food
consumption
was
recorded
for
12
weeks.
Blood
and
urine
parameters
were
evaluated,
however,
intervals
not
specified.
On
study
weeks
6,
12,
55,
and/
or
91
to
104,
2­
4
rats/
sex/
dose
were
sacrificed
and
their
kidneys,
liver,
spleen,
lung,
heart,
stomach,
small
intestine,
ovaries,
testes
and/
or
adrenals
were
examined
microscopically.
GLP:
Unknown
Test
Substance:
TEC,
unknown
purity
Results:
No
adverse
effects
of
hematologic,
urinalysis,
survival,
gross
or
histopathological
parameters
were
effected
due
to
treatment.
In
males,
at
600
mg/
kg/
day
decreased
body
weights
and
food
consumption
were
observed.
Reference:
MRID
45221214.
Harrison,
J.
(
1954)
Triethyl
Citrate,
Life
Time
Study
on
Rats:
Lab
Project
Number:
ATBC/
TEC
51147­
17.
Unpublished
study
prepared
by
LaWall
and
Harrison.
14
p.
Reliability:
Low
given
that
this
is
a
1954
study,
the
lack
of
details,
and
the
unknown
TEC
purity
Range­
Finding
Oral
Toxicity
­
Dog
Species/
Strain:
Dog/
beagle
Conclusions:
Liver
toxicity
was
observed
at
2.5
to
3.5
mL/
kg
(

2.5
to
3.5
g/
kg).
No
effects
were
observed
at
0.25
mL/
kg
(
250
mg/
kg).
Method:
In
one
range­
finding
study,
dogs
were
dosed
with
TEC
in
the
diet
at
concentrations
of
0,
0.05
and
0.25
mL/
kg
for
up
to
6
months.
In
the
second
study,
dosing
was
increased
to
2.5
to
3.5
mL/
kg
for
7
to
12
weeks.
GLP:
No
Test
Substance:
TEC,
99.1
­
99.6%
pure
Results:
No
treatment­
related
findings
were
observed
in
mortality,
clinical
signs,
body
weights,
food
consumption,
organ
weights
and
microscopic
changes
up
to
0.05
to
0.25
mL/
kg.
Urinalysis
parameters
(
sugar
and
protein)
and
clinical
chemistry
parameters
(
non­
protein
nitrogen,
glucose
and
serum
calcium)
were
also
unaffected
by
treatment.
In
the
second
range­
finding
study,
at
doses
of
2.5
to
3.5
mL/
kg
caused
severe
liver
damage,
however
the
findings
were
not
described.
Hematological
parameters
(
specific
parameters
not
stated)
indicated
anemia.
No
treatment­
related
findings
were
observed
in
body
weights.
Urinalysis
indicated
the
presence
of
a
Page
45
of
48
reducing
substance
in
the
urine
of
the
one
dog
dosed
at
3.5
mL/
kg.
Clinical
chemistry
parameters
(
non­
protein
nitrogen,
sugar,
serum
calcium
and
several
indices
of
liver
damage)
were
unaffected
by
treatment.
Reference:
MRID
45221219.
Hodge,
H.
(
1956)
Chronic
Oral
Toxicity
Studies
of
Triethyl
Citrate
in
Dogs:
Lab
Project
Number:
ATBC/
TEC
51147­
24.
Unpublished
study
prepared
by
University
of
Rochester
School
of
Medicine
and
Dentistry.
12
p.
Reliability:
Low
given
that
this
is
a
1956
study
and
the
unknown
TEC
purity
Gene
Mutation
Species/
Strain:
Bacteria/
Salmonella
and
Saccharomyces
Conclusion:
TEC
is
not
considered
to
be
mutagenic
in
S.
typhimurium
when
tested
up
to
1.6%
(
v/
v)
or
in
Saccharomyces
cerevisiae
when
tested
up
to
1.7%
(
v/
v)
with
or
without
S9­
activation.
Method:
Histadine
requiring
mutagenic
strains
of
salmonella
typhimurium
strains
TA1535,
TA1537,
and
TA1538
and
adenine­
and
tryptophan­
deficient
Saccharomyces
cerevisiae
strain
D4
were
exposed
to
TEC
in
dimethylsulfoxide
at
concentrations
of
0.4,
0.8,
or
1.6%
(
v/
v)
(
salmonella
strains)
and
0.425,
0.85,
or
1.7%
(
Saccharomyces)
in
the
presence
and
absence
of
S9­
activation,
and
reversion
to
prototrophy
determined
after
48
or
72
hours
incubation
at
37

C
(
Salmonella)
or
30
hours
for
3
­
5
days
(
Saccharomyces).
The
suspension
test
was
performed
using
the
Salmonella
and
Saccharomyces
strains
and
the
standard
plate
incorporation
method
was
performed
using
Salmonella
strains
only.
No
precipitation
or
cytotoxicity
was
observed
at
any
dose
level
in
any
strain
in
either
test.
GLP:
No
Test
Substance:
TEC,
unknown
purity
Results:
No
significant
increases
in
the
number
of
revertants/
plate
or
mutation
frequency
were
observed
in
any
bacterial
or
yeast
strain
at
any
dose
level
of
TEC
in
the
presence
or
absence
of
S9­
activation,
compared
to
vehicle
controls.
Reference:
MRID
45221217.
Brusick,
D.
(
1976)
Mutagenic
Evaluation
of
Triethyl
Citrate:
Lab
Project
Number:
ATBC/
TEC
51147­
21.
Unpublished
study
prepared
by
Litton
Bionetics,
Inc.
44
p.
Reliability:
Provides
sufficient
information
for
regulatory
purposes.

Species/
Strain:
Mouse
fibroblasts
Conclusions:
Time
and
concentration
of
TEC
had
affect
on
cell
death
and
ultrastructural
changes.
Method:
Mosue
fibroblasts
eight
hours
into
anaphase
in
cell
suspension
were
exposed
to
7.9,
9,
12,
24,
and
48
mM
TEC.
Cultures
were
studied
with
an
inverted
phase
contrast
microscope,
chiefly
with
a
100X
oil
immersion
phase
contrast
objective
while
the
cultures
were
maintained
at
35

C.
Images
were
recorded
with
both
a
movie
camera
and
a
35mm
camera.
Time
lapse
microphotography
was
conducted
for
4
hours
after
TEC
administration
with
exposures
taken
every
3.6
seconds.
GLP:
Unknown
Test
Substance:
TEC,
unknown
purity
Results:
The
ID
50
is
6
mM
and
the
ID
100
is
12
mM
for
the
72
hour
cultures.
At
all
concentrations,
the
plasma
membrane
retracted
resulting
in
a
decreased
Page
46
of
48
cellular
cross
sectional
area
within
two
to
three
minutes
at
the
lower
concentrations
and
seconds
at
the
higher
concentrations.
Simultaneously,
cytoplasmic
particle
movement
slowed
(
cytoplasmic
gelation)
and
this
effect
appeared
to
be
dose­
dependent.
At
7.9,
9
and
12
mM
TEC,
mitochondrial
swelling
was
observed,
which
would
presumably
interfere
with
ATP
production
and
thereby
inhibit
growth.
At
12,
24,
and
48
mM
TEC,
the
optical
density
of
the
nuclear
membrane
increased
(
presumably
due
to
precipitated
proteins)
within
1.5­
3.5
hours
(
onset
dependent
on
dose).
At
48
mM
TEC,
plasma
membrane
retraction
was
followed
by
the
appearance
of
superficial
vacuoles
at
two
hours,
and
with
lysis
following
within
minutes.
Immediately
prior
to
lysis,
all
cellular
movement
ceased.
At
12
and
24
mM
TEC,
cells
also
had
superficial
vacuoles
and
lysis
occurred
within
24
hours.
Reference:
MRID
45221215.
Jones,
A.
et
al.
(
2000)
Mechanistic
Toxicology
of
Triethyl
Citrate
in
Cultured
Mammalian
Cells
by
Cinematography:
Lab
Project
Number:
ATBC/
TEC
51147­
19.
Unpublished
study
prepared
by
The
University
of
Texas.
28
p.
Reliability:
Recently
conducted,
provides
sufficient
information
for
regulatory
purposes.

Species/
Strain:
Mouse
fibroblasts
Conclusion:
Inconclusive
Method:
Mouse
fibroblast
cells
in
static
tube
culture
were
exposed
to
6,
9,
and
12
mM
TEC
for
1.5,
48,
and
78
hours.
The
cells
were
then
pulsed
with
14Clabeled
purine
and
pyrimidine
dissolved
in
sterile
deionized
water
(
0.15

Ci/
mL).
The
cells
were
incubated
for
an
hour
before
liquid
scintillation
and
U.
V.
spectrophotometric
analyses.
GLP:
Unknown
Test
Substance:
TEC,
unknown
purity
Results:
At
1.5
hours,
uridine,
thymidine,
and
adenine
were
decreased
significantly
at
all
doses,
except
thymidine
was
not
decreased
by
exposure
to
6
mM
TEC.
At
48
hours,
thymidine
and
adenine
was
decreased
significantly
at
9
and
12
mM
TEC.
At
78
hours,
only
adenine
was
decreased
significantly
at
12
mM
TEC.
Adenine
uptake
levels
remained
significantly
lower
than
thymidine
and
uridine
uptake
at
all
doses
and
did
not
recover
to
normal
values
within
78
hours.
Uridine
uptake
increased
significantly
over
adenine
and
thymidine
at
48
and
78
hours
at
9
and
12
mM
TEC.
The
U.
V.
spectrophotometric
data
substantiated
the
liquid
scintillation
data,
indicating
an
overall
increase
in
uridine
content
when
compared
to
the
other
purines
and
pyrimidines.
Thus,
only
exposure
to
9
and
12
mM
TEC
resulted
in
significant
effects
on
cellular
utilization
of
the
test
precursors
(
except
at
1.5
hours).
This
study
indicated
that
DNA
content
of
the
cell
does
not
increase
sufficiently
to
support
mitosis
at
9
and
12
mM
TEC
under
the
conditions
of
this
study.
Reference:
MRID
45221216.
Golaz,
M.
et
al.
(
2000)
Mechanistic
Toxicology
of
Triethyl
Citrate
in
Mouse
Fibroblast
Cells
by
Liquid
Scintillation
Techniques:
Lab
Project
Number:
ATBC/
TEC
51147­
20.
Unpublished
study
prepared
by
The
University
of
Texas.
25
p.
Reliability:
Recently
conducted,
provides
sufficient
information
for
regulatory
purposes.
Page
47
of
48
Appendix
3
Re­
Evaluation
of
ATBC
Multigeneration
Reproduction
Study
(
MRID
45257702)

According
to
the
Data
Evaluation
Record
(
DER),
ATBC
was
administered
in
the
diet
of
rats
to
achieve
nominal
dose
levels
of
0,
100,
300
or
1000
mg/
kg
body
weight
during
the
two
generations
of
the
study.
The
results
of
the
Agency
review
and
evaluation
of
that
study
(
performed
in
2002)
are
given
below:

2­
generation
reproductive
(
rat)
(
in
the
diet)

dose
levels:
(
0,
100,
300,
1000
mg/
kg/
day)
Parental
NOAEL
=
100
mg/
kg/
day
LOAEL
=
300
mg/
kg/
day,
based
on
decreased
body
weights
and
water
consumption
Reproductive
NOAEL
is
equal
to
or
greater
than
1000
mg/
kg/
day,
the
highest
dose
tested
(
HDT)
LOAEL
not
determined,
but
would
be
greater
than
1000
mg/
kg/
day
Offspring
NOAEL
=
100
mg/
kg/
day
LOAEL
=
300
mg/
kg/
day,
based
on
increased
pup
mortality
and
decreased
pup
weights
Tables
3­
5
in
the
Agency's
DER
indicated
statistically
significant
changes
in
body
weight,
food
consumption
and
water
consumption.
If
there
are
decreases
in
food
and
water
consumption,
it
is
reasonable
to
expect
a
similar
effect
on
body
weight,
but
in
a
feeding
study,
food
consumption
decreases
could
be
related
to
decreased
palatability
of
the
treated
diet
rather
than
toxicity
of
the
chemical
 
a
possibility
that
should
be
considered
in
the
endpoint
selection
process.
Decreases
in
water
consumption
may
be
related
to
systemic
problems
caused
by
the
test
material
(
e.
g.,
increased
blood
volume
because
of
fluid
retention
which
inhibits
the
thirst
reflex
and
might
account
for
a
body
weight
increase),
but
water
consumption
may
also
vary
for
other
reasons
such
as
a
leaking
water
delivery
system.
Therefore,
consistency
of
response,
dose­
response,
reversibility
of
the
response,
and
effects
on
other
observations
in
the
study
are
important
considerations.

In
this
case,
the
variations
noted
in
these
parameters
were
equal
to
or
less
than
the
coefficient
of
variation
for
these
data
(
standard
deviation
divided
by
the
group
mean
times
100),
and
there
was
almost
no
change
in
response
when
the
dose
level
was
tripled.
The
only
effect
observed
in
both
generations
was
decreased
body
weight
and
food
consumption
in
the
1000
mg/
kg/
day
males.
Because
this
is
a
limit
dose,
the
effects
are
minimal,
and
results
from
the
subchronic
feeding
study
at
the
same
dose
level
indicated
that
male
rats
can
recover
from
the
initial
decrease
in
body
weight
(
see
DER
for
MRID
45257701)
during
treatment,
it
is
reasonable
to
conclude
that
the
1000
mg/
kg
dose
level
approaches
a
minimally
toxic
dose.
This
conclusion
is
further
supported
by
results
from
the
2­
year
feeding
study
in
rats
summarized
in
the
Science
Assessment
(
Table
2,
page
3)
where
the
NOAEL
is
greater
than
or
equal
to
1000
mg/
kg/
day.
Therefore,
it
is
reasonable
to
Page
48
of
48
conclude
that
the
parental
NOAEL
is
also
equal
to
or
greater
than
1000
mg/
kg/
day
for
parental
toxicity
in
the
reproduction
study.

The
number
of
pups
dying
during
lactation
days
7­
21is
of
questionable
toxicological
significance
when
mean
litter
sizes
and
viability
indexes
at
days
7,
14,
and
21
are
not
significantly
different,
and
the
pup
body
weights
follow
a
similar
pattern
to
that
described
above
for
adults.
It
is
unreasonable
to
attribute
the
deaths
to
the
chemical
when
they
occur
only
in
one
of
the
two
generations,
the
pups
do
not
show
other
responses
that
would
likely
be
associated
with
lethality
(
e.
g.,
clinical
signs,
larger
decreases
in
body
weight,
etc).
It
is
also
important
that
other
DERs
where
similar
decreases
in
body
weights
were
noted
did
not
identify
those
effects
as
toxicologically
significant.

There
are
two
options
for
interpreting
these
results.
First
and
most
conservative
would
be
to
call
the
NOEL
at
300
mg/
kg/
day
based
on
the
decreases
in
body
weight
for
both
adults
and
offspring.
Second,
be
consistent
with
the
other
toxicity
studies
and
call
the
NOEL
at
1000
mg/
kg/
day,
and
for
risk
assessment
purposes
simply
compare
the
exposure
estimates
to
acceptable
levels
as
defined
by
other
organizations.
Hopefully,
the
worst
case
pesticidal
exposure
estimates
are
less
than
exposures
used
in
the
other
assessments
from
other
sources,
then
we
can
all
be
on
the
same
page.