DATE:
November
21,
2005
MEMORANDUM
SUBJECT:
TRIETHYLENE
GLYCOL
­
Revised
Report
of
the
Antimicrobials
Division
Toxicology
Endpoint
Selection
Committee.

FROM:
Timothy
F.
McMahon,
Ph.
D.,
Chair,
ADTC
Michelle
Centra,
Pharmacologist,
Executive
Secretary,
ADTC
Antimicrobials
Division
(
7510C)

TO:
Heather
Garvie,
Chemical
Review
Manager
Ben
Chambliss,
Team
Leader
Mark
Hartman,
Branch
Chief
Regulatory
Management
Branch
II
Antimicrobials
Division
(
7510C)

PC
Codes:
083501
On
February
25,
2003,
the
Antimicrobials
Division
Toxicology
Endpoint
Selection
Committee
(
ADTC)
reviewed
the
available
toxicology
data
for
triethylene
glycol
and
discussed
endpoint
selection
for
use
as
appropriate
in
occupational/
residential
exposure
risk
assessments.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
triethylene
glycol
was
also
evaluated
by
the
committee
in
order
to
meet
the
statutory
requirements
of
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.
In
November
of
2005,
the
ADTC
met
to
discuss
the
impact
of
the
human
studies
rule
on
the
hazard
characterization
of
triethylene
glycol.
This
toxicity
endpoint
document
supercedes
the
ADTC
report
for
triethylene
glycol
dated
May
6,
2003.
2
Committee
Members
in
Attendance
Members
present:
Timothy
F.
McMahon,
Ph.
D.
Stephen
Dapson,
Ph.
D.;
Jonathan
Chen,
Ph.
D.;
Timothy
Leighton;
John
Redden;
Karen
Hamernik,
Ph.
D.,
Michelle
Centra.

Member(
s)
in
absentia:
Roger
Gardner,
Ph.
D.;
Sanyvette
Williams,
D.
V.
M.;
Melba
Morrow,
D.
V.
M.,
Najm
Shamim,
Ph.
D.

DATA
PRESENTATION:
___________________________________
Timothy
F.
McMahon,
Ph.
D.,
Chair
DRAFT
DOCUMENT
PREPARATION:
___________________________________
Timothy
F.
McMahon,
Ph.
D.,
Chair
FINAL
DOCUMENT
PREPARATION:
___________________________________
Michelle
Centra,
Executive
Secretary
3
COMMITTEE
MEMBERS
IN
ATTENDANCE
(
Signature
indicates
concurrence
unless
otherwise
stated)

Stephen
Dapson
Jonathan
Chen
Roger
Gardner
Karen
Hamernik
Tim
McMahon
(
Chair)

Melba
Morrow
John
Redden
Sanyvette
Williams­
Foy
Michelle
Centra
(
Executive
Secretary)

Najm
Shamim
Timothy
Leighton
OTHER
ATTENDEES:
4
I.
INTRODUCTION
Triethylene
glycol
is
produced
commercially
as
a
by­
product
of
ethylene
glycol
production
and
it
is
used
as
a
bacteriostat
(
against
odor­
causing
bacteria)
for
air
sanitization
and
deodorization.
There
are
numerous
active
use
sites
listed
for
triethylene
glycol
that
include:
air
treatment
(
eating
establishments,
hospital,
commercial,
institutional,
household,
bathroom,
transportational
facilities);
medical
premises
and
equipment,
commercial,
institutional
and
industrial
premises
and
equipment;
laundry
equipment;
hard
non­
porous
surface
treatments
(
bathroom
facilities);
automobiles;
air
conditioning
filters,
and
refuse
and
solid
waste
containers.
In
combination
with
other
active
ingredients,
it
is
used
as
a
fungicide,
virucide
and
miticide
for
disinfection
of
hard,
non­
porous
surfaces
and
as
an
insecticide
(
against
lice)
by
direct
application
to
caged
birds.
As
an
inert
ingredient,
triethylene
glycol
facilitates
delivery
of
formulated
pesticide
chemical
products
that
are
used
as
herbicides,
fungicides,
insecticides,
growth
regulators
and
attractants
on
a
wide
variety
of
agricultural
commodities.
Products
contain
triethylene
glycol
in
a
range
of
0.1­
9.15%
a.
i.

II.
PHYSICAL/
CHEMICAL
PROPERTIES
2
FORMULA:
C
6
H
14
O
4
/
HOCH
2
(
CH
2
CH
2
O)
2
CH
2
OH
Active
ingredient:
triethylene
glycol
Color:
hygroscopic
colorless
liquid
Physical
state:
liquid
Flash
point:
165
oC
Vapor
Pressure:
0.15mmHg
at
20
oC;
Boiling
point:
285
oC
Solubility:
Soluble
in
water,
alcohol,
benzene
Molecular
mass:
150.2
Density:
1.1274
g/
cc
III.
HAZARD
IDENTIFICATION
A.
ACUTE
AND
CHRONIC
DIETARY
(
Acute
and
Chronic
Reference
Doses)

At
this
time,
the
product
labels
for
triethylene
glycol
do
not
include
food
contact
uses.
Therefore,
dietary
endpoints
were
not
selected
and
acute
and
chronic
dietary
risk
assessments
are
not
required.

B.
INCIDENTAL
ORAL
EXPOSURE
The
Committee
determined
that
there
were
no
incidental
oral
exposure
scenarios
for
the
uses
of
triethylene
glycol
as
an
air
sanitizer,
and
therefore
incidental
oral
toxicity
endpoints
were
not
selected
at
this
time.
5
C.
OCCUPATIONAL
/
RESIDENTIAL
EXPOSURE
1.
DERMAL
ABSORPTION
No
studies
have
been
reported
dealing
with
the
skin
absorption
of
triethylene
glycol.
Although
it
is
possible
that
under
conditions
of
very
severe
prolonged
exposures
to
this
chemical,
absorption
through
the
skin
can
occur,
it
is
doubtful
any
appreciable
systemic/
dermal
injury
would
occur
because
triethylene
glycol
has
(
1)
a
low
order
of
dermal
irritancy,
(
2)
is
not
a
dermal
sensitizer,
and
(
3)
showed
no
evidence
of
dermal
or
systemic
toxicity
following
repeated
dermal
applications
of
2ml
(
approximately
600
mg/
kg)
triethylene
glycol
applied
to
the
skin
of
rabbits
in
a
21­
day
dermal
toxicity
study.

2.
DERMAL
EXPOSURE
SCENARIOS
(
All
Durations)

The
dermal
route
of
exposure
is
not
considered
a
major
route
of
exposure
for
triethylene
glycol
as
an
air
sanitizer.
The
chemical
is
shown
to
be
a
non
­
sensitizer
and
of
low
dermal
irritancy.
In
a
21­
day
dermal
toxicity
study,
there
was
no
evidence
of
dermal
or
systemic
toxicity
from
repeated
dermal
applications
of
2ml
(
approximately
600
mg/
kg)
triethylene
glycol
applied
to
the
skin
of
rabbits.
Therefore,
toxicological
endpoints
for
dermal
exposure
scenarios
were
not
selected
by
the
Committee.

3.
INHALATION
EXPOSURE
SCENARIOS
(
All
Durations)

Repeat­
dose
inhalation
toxicities
studies
conducted
with
triethylene
glycol
were
submitted
to
the
Agency's
Office
of
Pesticide
Programs
and
Toxic
Substances.
This
is
an
important
route
of
exposure
to
characterize
hazard,
as
this
chemical
is
used
as
an
air
sanitizer.
Although
the
following
studies
were
not
conducted
according
to
the
OPPTS
870
Harmonized
Test
Guidelines,
they
do
provide
information
that
is
adequate
to
characterize
the
toxicity
from
repeat­
dose
inhalation
exposure
to
triethylene
glycol.

Sprague­
Dawley
rats
exposed
(
whole
body)
to
triethylene
glycol
in
an
aerosol
inhalation
study
at
concentrations
of
494,
2011,
or
4842
mg/
m3
(
0.5,
2.0,
or
5.0
mg/
L/
day),
for
six
hours
a
day,
nine
times
over
a
two­
week
period
showed
the
following
toxicities
at
the
highest
concentration
level
tested:
ataxia,
prostration,
unkept
fur,
labored
respiration
(
males
only),
ocular
discharge,
swollen
periocular
tissue,
perinasal
and
perioral
encrustation,
blepharospasm
and
reduced
body
weight
Necropies
revealed
hyperinflation
of
the
lungs,
ocular
opacity,
congestion
and
hemorrhage
in
many
organs
and
tissues
(
pituitary
gland,
brain,
nasal
mucosa,
kidney,
thymus
and
lungs).
All
of
the
rats
in
the
high
dose
group
died
or
were
sacrificed
moribund
by
day
5
of
the
study.
Clinical
signs
of
toxicity
observed
at
the
lowand
mid­
dose
of
0.5
and
2.0
mg/
L/
day,
respectively,
were
limited
to
swollen
periocular
tissues
and
perinasal
encrustations.
Treatment­
related
changes
in
organ
weights
in
mid­
dose
males
included
an
increase
in
liver
and
kidney
weights
relative
to
body
weight;
mid­
dose
females
showed
increases
in
absolute
and
relative
(
to
body
and
brain
weights)
liver
and
kidney
weights.
Statistically
significant
clinical
chemistry
findings
for
males
treated
with
2.0
mg/
L/
day
triethylene
glycol
included
an
increase
in
ALT
activity
and
a
decrease
in
serum
creatinine
levels.
Mid­
dose
females
showed
increases
in
urea
nitrogen,
inorganic
phosphorus,
ALT
and
ALK
activity,
and
decreases
in
glucose,
creatinine,
and
chloride.
However,
the
changes
in
organ
weights
and
clinical
chemistry
findings
were
not
correlated
with
any
histopathological
observations.
6
Rats
exposed
to
the
test
material
via
a
whole­
body
inhalation
protocol
are
also
receiving
the
chemical
via
the
oral
and
dermal
routes.
These
additional
routes
of
exposure
may
have
increased
the
total
dose
received
and
contributed
to
the
toxicities
observed
in
the
whole­
body
exposure
inhalation
study.
Therefore,
a
second
study
was
conducted
using
a
nose­
only
exposure
for
6
hours
a
day,
9
consecutive
days.
In
this
second
inhalation
toxicity
study,
mean
exposure
concentrations
of
102,
517,
or
1036
mg/
m3
(
approximately
0.1,
0.5,
1.0
mg/
L/
day)
triethylene
glycol
produced
no
treatment­
related
toxicities
at
any
dose
tested.

Monkeys
exposed
by
inhalation
to
approximately
1
ppm
vapor
from
two
weeks
to
13
months
(
approximately
0.5
to
1
ppm)
showed
no
adverse
reactions
or
histopathological
changes
suggestive
of
toxicity
from
prolonged
exposure
to
triethylene
glycol.

Review
of
these
data
show
that
triethylene
glycol
is
of
low
toxicity
by
the
inhalation
route
of
exposure.
Toxicities
are
only
observed
at
doses
that
far
exceed
the
testing
limits
established
for
repeat
exposure
studies.
Therefore,
toxicological
endpoints
for
inhalation
exposure
scenarios
were
not
selected
by
the
Committee.

4.
RECOMMENDATION
OF
MARGINS
OF
EXPOSURE
Margins
of
exposure
were
not
established
for
triethylene
glycol
because
there
were
no
toxicological
endpoints
of
concern
identified.

5.
AGGREGATE
EXPOSURE
RISK
ASSESSMENTS
The
ADTC
did
not
identify
toxicological
endpoints
of
concern
for
the
active
(
air
sanitization)
and
the
inert
(
agricultural
commodities)
uses
of
triethylene
glycol.
Therefore,
aggregate
risk
assessments
are
not
required.

IV.
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
Published
literature
sources
examining
the
chronic
toxicity
and
carcinogenic
potential
of
triethylene
glycol
have
shown
the
chemical
to
be
negative
in
rodent
species.

In
a
12
month
study,
monkeys
receiving
triethylene
glycol
(
0.25
mL
to
0.5
mL)
orally
in
egg
nog
(
approximately
50
to
100
times
the
quantity
an
animal
could
absorb
by
breathing
air
saturated
with
glycol)
were
without
any
adverse
effects
in
physiological
functions
or
organ
histopathology.

Triethylene
glycol
administered
in
feed
at
levels
of
0,
1,
2
or
4%
to
Osborn­
Mendel
rats
for
2
years
showed
that
the
body
weight
gains,
hematological
parameters
and
clinical
chemistries
were
not
affected
by
treatment.
The
dosages
tested
in
rats
are
equivalent
to
as
much
as
3
to
4
g/
kg/
day
which
are
well
above
the
limit
dose
of
1
g/
kg/
day
(
1000
mg/
kg/
day)
for
testing
pesticides
via
the
oral
route
in
subchronic
and
chronic
toxicity
studies.
Under
the
conditions
of
this
study,
triethylene
glycol
was
not
carcinogenic
in
rats.
7
V.
MUTAGENICITY
Triethylene
glycol
was
tested
for
mutagenic
or
genotoxic
potential
and
found
to
be
negative
in
a
battery
of
studies:
a
bacterial
gene
mutation
assay
using
Salmonela
typhimurium,
an
in
vitro
Chinese
hamster
ovary
(
CHO)
mutation
assay,
an
in
vitro
Chinese
hamster
ovary
(
CHO)
chromosomal
aberration
assay
and
an
in
vitro
sister
chromatid
exchange
assay.

VI.
FQPA
CONSIDERATIONS
A.
ADEQUACY
OF
THE
TOXICITY
DATA
BASE
The
available
toxicity
studies
conducted
with
triethylene
glycol
are
from
published
sources
or
from
studies
submitted
to
the
Office
of
Toxic
Substances
and
do
not
report
all
the
data
that
are
normally
reported
under
the
OPPTS
870
Harmonized
Test
Guidelines.
However,
it
is
apparent
that
the
toxicities
observed
in
these
studies
are
consistently
manifested
only
at
doses
of
triethylene
glycol
that
exceed
the
established
limit
doses
for
animal
studies
and
are
of
a
non­
specific
nature.
Therefore,
there
is
no
concern
for
the
developmental
or
reproductive
toxicity
of
triethylene
glycol.

B.
EVIDENCE
OF
NEUROTOXICITY
From
the
available
repeat
dose
toxicity
studies,
there
was
no
evidence
of
neurotoxicity
of
triethylene
glycol.
However,
the
existing
toxicology
data
do
not
fully
characterize
repeated
dose
neurotoxicity.
Neurotoxicity
testing
could
be
required
if
additional
data
are
needed
to
support
new
uses
of
triethylene
glycol.

C.
DEVELOPMENTAL
&
REPRODUCTIVE
TOXICITY
(
1)
Developmental
Toxicity
In
a
published
study,
triethylene
glycol
did
not
appear
to
cause
any
developmental
effects
in
rats
at
a
dose
of
2.25
g/
kg/
day.
However,
the
subcutaneous
route
of
administration
is
not
an
acceptable
route
of
exposure
for
determining
the
potential
prenatal
developmental
toxicity
of
triethylene
glycol.

In
a
second
study,
pregnant
Sprague­
Dawley
rats
were
administered
triethylene
glycol
by
gavage
on
gestation
days
6
through
15
at
dose
levels
of
0,
1.0,
5.6,
and
11.27
g/
kg/
day.
There
were
no
effects
on
maternal
mortality
and
there
were
no
abortions.
Clinical
toxicity
was
observed
in
maternal
rats
at
the
high
dose
and
consisted
of
audible
respiration,
periocular
encrustation,
and
perioral
wetness.
Decreased
body
weight
and
food
consumption
was
observed
in
maternal
rats
at
the
5.6
g/
kg/
day
dose.
No
effects
were
observed
at
the
1.0
g/
kg/
day
dose.
In
offspring,
mean
fetal
body
weight
was
decreased
at
the
11.27
g/
kg/
day
dose
level,
however,
there
were
no
treatment­
related
increases
in
external,
visceral,
or
skeletal
malformations.
8
In
this
same
study,
triethylene
glycol
was
administered
orally
at
doses
of
0,
0.5,
5.6,
and
11.27
g/
kg/
day
in
timed
pregnant
CD­
1
mice
from
gestation
Days
6
through
15.
There
were
no
treatment
related
maternal
deaths
and
no
abortions.
Hyperactivity
and
rapid
respiration
were
observed
at
the
highest
dose
level.
No
effects
were
observed
on
maternal
weight
gain
or
food
consumption
at
any
dose
level.
Pregnancy
outcome
was
unaffected
at
any
dose
level
tested.
There
were
no
treatment­
related
effects
on
external
or
visceral
malformations
in
offspring.
Some
evidence
of
delayed
ossification
was
observed
only
at
the
high
dose
level
of
11.27
g/
kg/
day.

(
2)
Reproductive
Toxicity
Published
literature
examined
the
effect
of
triethylene
glycol
on
reproduction
in
Swiss
CD­
1
mice.
Doses
of
0,
0.3,
1.5,
and
3%
triethylene
glycol
were
administered
in
drinking
water
using
a
continuous
breeding
protocol.
No
effects
on
reproductive
function
were
observed
at
any
dose
level
tested.
Although
reduced
pup
weight
was
observed
in
the
mid
and
high­
dose
(
1.5%
and
3%
triethylene
glycol,
approximate
equivalent
doses
of
3390
mg/
kg/
day
and
6780
mg/
kg/
day,
respectively)
treated
mice,
this
effect
occurred
at
doses
in
excess
of
the
established
testing
limit
doses
(
1000
mg/
kg/
day)
for
this
type
of
study.

In
a
second
study
submitted
to
the
Agency,
rats
were
exposed
via
inhalation
to
an
atmosphere
saturated
with
triethylene
glycol
(
approx.
1
ppm)
for
12­
18
months
with
no
adverse
reproductive
effects
noted.

The
ADTC
concluded
that
the
toxicity
observed
from
these
data
were
not
significant
and
were
apparent
only
at
doses
of
triethylene
glycol
in
excess
of
limit
doses
for
animal
studies.
Therefore,
there
is
no
concern
for
reproductive
toxicity
of
this
chemical.

D.
DETERMINATION
OF
SUSCEPTIBILITY
The
ADTC
concluded
from
the
available
animal
data
that
there
is
no
evidence
of
increased
susceptibility
to
fetuses
or
offspring
following
exposure
to
triethylene
glycol.
As
there
are
no
active
food
uses
registered
by
the
Agency
for
triethylene
glycol,
the
ADTC
recommended
that
the
special
hazard­
based
safety
factor
under
the
FQPA
be
reduced
to
1x.
This
issue
can
be
revisited
if
direct
or
indirect
food
uses
for
triethylene
glycol
become
active
in
the
future.

E.
DETERMINATION
OF
THE
NEED
FOR
A
DEVELOPMENTAL
NEUROTOXICITY
STUDY
The
ADTC
has
not
identified
a
basis
for
requesting
a
developmental
neurotoxicity
study
at
this
time.

F.
DATABASE
UNCERTAINTY
FACTOR
No
additional
database
uncertainty
factor
is
needed
at
this
time
for
triethylene
glycol.

VII.
HAZARD
CHARACTERIZATION
9
The
hazard
of
triethylene
glycol
is
characterized
by
reports
in
the
open
scientific
literature,
submitted
by
the
CSMA
Glycol
Joint
Venture
in
response
to
Phase
IV
under
FIFRA.
The
acute
oral
and
dermal
toxicity
of
the
chemical
appears
to
be
low,
with
reported
oral
LD
50
values
ranging
from
15­
22
g/
kg
compiled
from
monographs
and
review
articles.
The
data
available
on
acute
dermal
toxicity
were
insufficient
to
establish
a
dermal
LD
50
,
but
the
data
requirement
was
waived
based
on
the
low
order
of
toxicity
observed
in
other
studies
with
triethylene
glycol.
Data
on
inhalation
toxicity
showed
a
maximum
tolerated
level
of
800
mg/
m3
in
rats,
but
intratracheal
instillation
of
0.25
cc
undiluted
chemical
caused
marked
pulmonary
irritation,
edema,
and
later,
fibrosis
and
abcess
formation
in
these
animals
(
intratracheal
instillation
is
not
an
accepted
route
of
administration
for
the
Agency's
toxicity
testing
guidelines).
Published
literature
data
on
the
skin
and
eye
irritation
as
well
as
skin
sensitization
showed
triethylene
glycol
to
be
non­
irritating
to
the
skin
and
eye
(
when
tested
at
the
limit
doses
established
by
the
Agency
for
acute
toxicity
testing)
and
not
a
dermal
sensitizer.
1­
6
Repeated
oral
dosing
studies
of
triethylene
glycol
toxicity
showed
in
general
that
the
chemical
was
without
any
adverse
effects.
Only
one
study,
a
90­
day
oral
toxicity
study
in
rats
used
more
than
one
dose
level
and
reported
the
doses
in
mg/
kg.
In
this
study,
oral
doses
of
748,
1522,
or
3849
mg/
kg/
day
(
males),
and
848,
1699,
or
4360
mg/
kg
(
females)
were
administered
in
the
diet.
Significant
effects
were
noted
at
the
high
dose
in
male
and
female
rats,
including
decreases
in
body
weight,
slight
decreases
in
hemoglobin
and
hematocrit,
slight
increase
in
mean
corpuscular
volume,
and
increased
kidney
and
brain
weight.
As
noted,
however,
these
effects
were
seen
at
doses
in
excess
of
the
Agency's
limit
dose
(
1000
mg/
kg/
day)
for
repeated
oral
toxicity
testing.
7,
8
Repeated
dose
inhalation
toxicity
studies
conducted
with
triethylene
glycol
show
the
chemical
to
be
without
adverse
effects
in
experimental
animals
at
doses
up
to
an
exceeding
the
limit
dose
(
1
mg/
L).
Therefore
there
are
no
inhalation
toxicity
concerns
for
the
chemical.
9,10,11
Published
literature
sources
examining
the
chronic
toxicity
and
carcinogenic
potential
of
triethylene
glycol
have
shown
the
chemical
to
be
negative
in
rodent
species.
11,12,13,
14
Triethylene
glycol
was
tested
for
mutagenic
or
genotoxic
potential
and
found
to
be
negative
in
a
battery
of
studies:
a
bacterial
gene
mutation
assay
using
Salmonela
typhimurium,
an
in
vitro
Chinese
hamster
ovary
(
CHO)
mutation
assay,
an
in
vitro
Chinese
hamster
ovary
(
CHO)
chromosomal
aberration
assay
and
an
in
vitro
sister
chromatid
exchange
assay.
15
­
18
Following
oral
dosing,
the
rat
and
rabbit
excreted
most
of
the
triethylene
glycol
in
both
unchanged
and/
or
oxidized
forms
(
mono­
and
dicarboxylic
acid
derivatives
of
triethylene
glycol).
In
rabbits
dosed
with
200
or
2000
mg/
kg
triethylene
glycol
respectively
excreted
34.3%
or
28%,
of
the
administered
dose
in
the
urine
as
unchanged
triethylene
glycol
and
35.2%
as
a
hydroxyacid
form
of
this
chemical.
In
the
studies
with
rats,
little
if
any
C14­
oxalate
or
C14­
triethylene
glycol
in
conjugated
form
was
found
in
the
urine.
Trace
amounts
of
orally
administered
14C
triethylene
glycol
were
excreted
in
expired
air
as
carbon
dioxide
(<
1%)
and
in
detectable
amounts
in
feces
(
2
to
5
%).
The
total
elimination
of
radioactivity
(
urine,
feces
and
CO
2
)
during
the
five
day
period
following
an
oral
dose
of
labeled
compound
(
22.5
mg)
ranged
from
91
to
98%.
The
majority
of
the
radioactivity
appeared
in
the
urine.
19
Developmental
toxicity
testing
of
triethylene
glycol
showed
unremarkable
effects.
Studies
in
rats
and
10
mice
tested
the
chemical
at
very
high
dose
levels
(
11.27
g/
kg/
day,
4.4
g/
kg/
day,
and
2.25
g/
kg/
day)
without
developmental
effects.
Sprague­
Dawley
rats
were
administered
triethylene
glycol
by
gavage
on
gestation
days
6
through
15
at
dose
levels
of
0,
1.0,
5.6,
and
11.27
g/
kg/
day.
There
were
no
effects
on
maternal
mortality
and
there
were
no
abortions.
Clinical
toxicity
was
observed
in
maternal
rats
at
the
high
dose
and
consisted
of
audible
respiration,
periocular
encrustation,
and
perioral
wetness.
Decreased
body
weight
and
food
consumption
was
observed
in
maternal
rats
at
the
5.6
g/
kg/
day
dose.
No
effects
were
observed
at
the
1.0
g/
kg/
day
dose.
In
offspring,
mean
fetal
body
weight
was
decreased
at
the
11.27
g/
kg/
day
dose
level,
however,
there
were
no
treatment­
related
increases
in
external,
visceral,
or
skeletal
malformations.
In
this
same
study,
triethylene
glycol
was
administered
orally
at
doses
of
0,
0.5,
5.6,
and
11.27
g/
kg/
day
in
timed
pregnant
CD­
1
mice
from
gestation
Days
6
through
15.
There
were
no
treatment
related
maternal
deaths
and
no
abortions.
Hyperactivity
and
rapid
respiration
were
observed
at
the
highest
dose
level.
No
effects
were
observed
on
maternal
weight
gain
or
food
consumption
at
any
dose
level.
Pregnancy
outcome
was
unaffected
at
any
dose
level
tested.
There
were
no
treatment­
related
effects
on
external
or
visceral
malformations
in
offspring.
Some
evidence
of
delayed
ossification
was
observed
only
at
the
high
dose
level
of
11.27
g/
kg/
day.
20,
21
Published
literature
examined
the
effect
of
triethylene
glycol
on
reproduction
in
Swiss
CD­
1
mice.
Doses
of
0,
0.3,
1.5,
and
3%
were
administered
in
drinking
water
using
a
continuous
breeding
protocol.
No
effects
on
reproductive
function
were
observed
at
any
dose
level
tested
(
up
to
the
high
dose
of
6.78
g/
kg).
Reduced
pup
weight
was
observed
at
the
1.5
and
3%
doses
of
triethylene
glycol.
In
a
study
submitted
to
the
Agency,
rats
were
exposed
to
an
atmosphere
saturated
with
triethylene
glycol
(
approx.
1
ppm)
for
12­
18
months
with
no
adverse
reproductive
effects
noted.
22,
23
VIII.
DATA
GAPS
/
REQUIREMENTS
The
toxicological
database
for
triethylene
glycol
is
currently
comprised
of
published
and
unpublished
studies
either
submitted
to
the
Agency
or
obtained
directly
from
the
published
literature.
These
acceptable
non­
guideline
studies
include:
acute,
subchronic,
developmental,
and
reproductive
toxicity;
carcinogenicity,
mutagenicity,
metabolism/
pharmacokinetics
and
dermal
absorption
studies.
Although
the
available
studies
do
not
meet
the
requirements
of
the
Agency's
OPPTS
harmonized
test
guidelines
published
in
1998,
the
ADTC
concluded
that
the
existing
toxicological
data
base
is
adequate
for
hazard
characterization
of
triethylene
glycol.
Therefore,
the
Agency
has
determined
that
there
are
no
data
gaps
for
the
labelled
non­
food
uses
of
this
chemical
as
an
air
sanitizer
and
deodorizer.
If
a
direct
or
indirect
food­
use
is
sought
in
the
future
for
triethylene
glycol,
the
existing
data
base
would
be
considered
inadequate
and
additional
data
may
be
required
to
support
these
new
uses.
11
IX.
ACUTE
TOXICITY
Acute
Toxicity
Profile
for
Triethylene
Glycol
Guideline
No.
Study
Type
MRID
#(
S).
Results
Toxicity
Category
81­
1
Acute
Oral
42814404
LD
50
=
15­
22
g/
kg
IV
81­
2
Acute
Dermal
42814404
LD
50
not
established
Study
Requirement
Waived
81­
3
Acute
Inhalation
42814404
LC
50
not
assigned
II
(
irritant)

81­
4
Primary
Eye
Irritation
42814404
mild
irritant
III
81­
5
Primary
Skin
Irritation
42814404
slight
irritant
IV
81­
6
Dermal
Sensitization
00104805
non­
sensitizer
N/
A
X.
SUMMARY
OF
TOXICOLOGICAL
DOSE
AND
ENDPOINT
SELECTION
There
were
no
toxicological
endpoints
of
concern
for
triethylene
glycol.
12
XI.
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