Document ID: EPA-HQ-OPP-2005-0250-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-03-22T05:00Z

DATE:
October
11,
2005
MEMORANDUM
SUBJECT:
TRIETHYLENE
GLYCOL:
Revised
Toxicology
Chapter
in
Support
of
Issuance
of
the
Reregistration
Eligibility
Decision
(
RED)
Document.
PC
Code:
083501
Reregistration
Case
Number:
3145.
CAS
Registry
Number:
112­
27­
6.
DP#:
325786
FROM:
Michelle
M.
Centra,
Pharmacologist
Regulatory
Management
Branch
II
Antimicrobials
Division
(
7510C)

THRU:
Timothy
F.
McMahon,
Ph.
D.
Division
Senior
Toxicologist
Antimicrobials
Division
(
7510C)

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

Attached
is
the
revised
Triethylene
Glycol
toxicology
chapter
for
incorporation
into
the
risk
assessment
document
and
the
Reregistration
Eligibility
Decision
(
RED)
document.

Supporting
documentation
used
to
generate
the
toxicology
chapter
are
listed
below:

1.
TRIETHYLENE
GLYCOL
­
Revised
Report
of
the
Antimicrobials
Division
Toxicology
Endpoint
Selection
Committee
(
Memorandum:
T.
McMahon,
11/
21/
05).
2
2.
EPA
ID#
083501:
Triethylene
glycol.
Review
of
Phase
IV
Response
Submissions
in
Support
of
FIFRA
88.
(
Memorandum:
G.
Reddy,
12/
12/
93).

3.
TRIETHYLENE
GLYCOL:
Antimicrobials
Division
Review
of
Toxicity
Studies
Submitted
to
the
Agency's
Office
of
Pollution,
Prevention
and
Toxics.
PC
Code:
083501.
Reregistration
Case
Number:
3145.
CAS
Registry
Number:
112­
27­
6.
DP#:
305169
(
Memorandum:
M.
Centra,
10/
11/
05).
3
TRIETHYLENE
GLYCOL
PC
Code:
083501
Revised
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
(
RED)
Document
Antimicrobials
Division
Office
of
Pesticide
Programs
U.
S.
Environmental
Protection
Agency
Prepared
by:
Michelle
M.
Centra,
Pharmacologist
Revised
Date:
October
11,
2005
4
INTRODUCTION
The
active
ingredient,
triethylene
glycol,
was
first
registered
by
the
FDA
for
use
in
hospitals
as
an
air
disinfectant
on
August
3,
1948
(
James
Varley
&
Sons'
Glyco
Mist,
EPA
Reg.
No.
421­
21).
As
an
active
ingredient,
triethylene
glycol
is
formulated
primarily
as
a
pressurized
liquid
and
is
used
in
two
types
of
applications:
air
sanitizers/
hospital
disinfectants,
and
pest
(
mites
and
red
lice)
control
on
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.

The
majority
of
the
producers
of
triethylene
glycol
formulated
pesticide
products
are
represented
by
a
consortium
called
the
CSPA
(
Consumer
Specialty
Products
Association)
Glycols
Joint
Venture
(
formerly
known
as
the
CMSA
Glycol
Joint
Venture).
The
member
companies
currently
represented
by
this
consortium
are:
Amrep,
Inc.,
Medo
Industries,
Inc.,
S.
C.
Johnson
&
Son,
and
Waterbury
Companies,
Incl.

In
1997,
the
Office
of
Pesticide
Programs,
Health
Effects
Division
conducted
an
evaluation
of
the
toxicity
of
the
active
ingredient,
triethylene
glycol
as
required
by
law
under
FIFRA
for
the
reregistration
of
pesticidal
chemicals.

The
triethylene
glycol
mammalian
toxicity
database
consists
of
published
literature
studies
and
monographs
submitted
by
the
Glycols
Joint
Venture
consortium
as
a
result
of
the
Phase
IV
review
of
triethylene
glycol
for
reregistration
under
FIFRA.
These
submitted
data
were
reviewed
by
the
Agency
and
classified
as
acceptable
or
waived
as
indicated
below
in
Table
2.
At
that
time,
these
data
were
determined
to
satisfy
the
Subdivision
F
guideline
test
guideline
requirements
and
no
additional
data
requirements
were
identified
for
the
non­
food
use
of
triethylene
glycol.
1
Table
2.
Data
Requirements
for
Non­
Food
Use
of
Triethylene
Glycol
(
1997)

Guideline
Number
Study
Type
Required
Satisfied
§
81­
1
Acute
Oral
­
Rat
Yes
Yes
§
81­
2
Acute
Dermal
­
Rabbit
Yes
Waived
§
81­
3
Acute
Inhalation
­
Rat
Yes
Yes
§
81­
4
Primary
Eye
Irritation
Yes
Yes
§
81­
5
Primary
Dermal
Irritation
Yes
Yes
§
81­
6
Skin
Sensitization
Yes
Yes
§
82­
1a
Subchronic
Oral
­
Rodent
No
No
§
82­
1b
Subchronic
Oral
­
Non
Rodent
Yes
Yes
Table
2.
Data
Requirements
for
Non­
Food
Use
of
Triethylene
Glycol
(
1997)

5
§
82­
2
21­
Day
Dermal
Yes
Yes
§
82­
4
90­
Day
Inhalation
Yes
Yes
§
83­
3a
Developmental
Toxicity
­
Rodent
Yes
Yes
§
83­
3b
Developmental
Toxicity
­
Non
Rodent
Yes
Yes
§
83­
4
Reproductive
Toxicity
­
Rodent
Yes
Yes
§
83­
1b
Chronic
Toxicity
­
Non
Rodent
Yes
Yes
§
83­
1a
Carcinogenicity
­
Rodent
Yes
Yes
§
84­
2
Gene
Mutation
­
Ames
Yes
Waiveda
§
84­
2
Cytogenetics
­
Structural
Chromosomal
Aberration
Yes
Waiveda
§
85­
1
General
Metabolism
Yes
Yes
aThe
data
waivers
granted
by
the
Agency
in
1997
for
the
triethylene
glycol
mutagenicity
assays
are
no
longer
applicable
to
this
chemical.
Several
mutagenicity
assays
submitted
to
the
Agency's
Office
of
Toxic
Substances
were
reviewed
by
OPP's
Antimicrobials
Division
and
determined
to
be
acceptable/
non­
guideline
studies.
These
four
mutagenicity
studies
have
been
incorporated
into
the
toxicity
data
base
for
triethylene
glycol.

HAZARD
PROFILE
Acute
Toxicity
Published
literature
studies
submitted
by
the
Glycols
Joint
Venture
consortium
show
low
toxicity
(
Toxicity
Categories
III
and
IV)
following
acute
exposures
(
Table
3).
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.
2­
5
Triethylene
glycol
was
evaluated
for
acute
inhalation
toxicity
in
male
and
female
Sprague­
Dawley
albino
rats
in
a
study
submitted
to
the
Agency's
Office
of
Toxic
Substances.
A
review
of
this
study
by
the
Antimicrobials
Division
established
a
four
hour
LC
50
greater
than
5.2
mg/
L,
and
6
places
acute
inhalation
in
Toxicity
Category
IV.
Based
on
these
results,
this
study
was
determined
to
be
adequate
for
regulatory
purposes
and
it
now
replaces
the
earlier
submitted
acute
inhalation
information.
6
Table
3.
Acute
Toxicity
Profile
of
Triethylene
Glycol
Guideline
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
Oral
­
Rat
42814404
LD50
=
15­
22
g/
kg
IV
870.1200
Acute
Dermal
­
Rabbit
42814404
LD50
not
determined
Study
requirement
waived
870.1300
Acute
Inhalation
­
Rat
OTS0527779­
2
LC50
>
5.2
mg/
L
IV
870.2400
Acute
Eye
Irritation
­
Rat
42814404
mild
irritant
III
870.2500
Acute
Skin
Irritation
­
Rabbit
42814404
slight
irritant
IV
870.2600
Skin
Sensitization
42814404
non­
sensitizer
N/
A
N/
A
=
Not
applicable
Subchronic
Toxicity
Repeat
oral
dosing
studies
conducted
in
rats
to
determine
triethylene
glycol
toxicity
showed
in
general,
that
the
chemical
was
either
without
any
adverse
effects
or
produced
toxicities
only
at
doses
at
or
greater
than
the
limit
doses
established
for
EPA
guideline
test
requirements.
Triethylene
glycol
administered
in
the
drinking
water
to
rats
at
concentrations
of
3%
and
5%
by
volume
for
30
days
showed
signs
of
toxicity
(
weight
loss,
alopecia
and
poor
grooming)
at
the
lower
concentration
with
one
animal
dying
on
day
25
of
the
study.
All
rats
in
the
3%
test
group
survived
to
study
completion
with
no
signs
of
toxicities.
7
In
a
14­
day
oral
toxicity
study,
Fischer
344
rats
receiving
triethylene
glycol
in
the
feed
(
doses
equivalent
to
1132,
2311,
or
3916
mg/
kg/
day
for
males
and
1177,
2411,
or
6209
mg/
kg/
day
for
females
)
showed
only
changes
in
urinalysis
(
increased
urine
volume,
decreased
urine
pH,
and
decreased
urine
triple
phosphate
crystals)
at
the
highest
respective
doses
tested
in
male
and
female
rats.
8
In
a
third
oral
toxicity
study
conducted
for
90­
days
in
rats,
triethylene
glycol
was
administered
in
the
diet
at
doses
of
748,
1522,
or
3849
mg/
kg/
day
(
males),
and
848,
1699,
or
4360
mg/
kg
(
females).
Although
toxicities
were
noted
at
the
high
dose
in
male
and
female
rats
(
decreases
in
body
weight,
slight
decreases
in
hemoglobin
and
hematocrit,
slight
increases
in
mean
corpuscular
volume,
and
increased
relative
kidney
and
brain
weights),
these
effects
were
noted
at
dose
levels
that
exceed
the
established
limit
dose
of
1000
mg/
kg/
day
for
such
studies.
9
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.
These
results
are
supported
by
triethylene
glycols'
low
dermal
irritancy
a
negative
response
as
a
skin
sensitizer.
10­
11
7
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
low­
and
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.
13
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.
12
Monkeys
exposed
by
inhalation
to
approximately
1
ppm
vapor
from
two
weeks
to
13
months
and
human
volunteers
exposed
to
air
saturated
with
vapor
(
approximately
0.5
to
1
ppm)
showed
no
adverse
reactions
or
histopathological
changes
suggestive
of
toxicity
from
prolonged
exposure
to
triethylene
glycol.
14
Dogs
given
daily
intravenous
injections
(
0.1
or
0.5
ml/
kg)
of
triethylene
glycol
for
four
weeks
showed
no
mortality
or
toxicity
with
the
exception
of
flattened
epithelial
cells
in
the
urine
and
phlebitis
at
the
site
of
injection.
15
Chronic
Toxicity
and
Carcinogenicity
Published
literature
sources
examining
the
chronic
toxicity
and
carcinogenic
potential
of
triethylene
glycol
have
shown
the
chemical
to
be
non
toxic/
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
8
with
glycol)
were
without
any
adverse
effects
in
physiological
functions
or
organ
histopathology.
14
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.
Under
the
conditions
of
this
study,
triethylene
glycol
was
not
carcinogenic
in
rats.
The
dosages
tested
in
rats
are
equivalent
to
as
much
as
3
to
4
g/
kg/
day
which
are
well
above
the
upper
limit
dose
of
1
g/
kg/
day
(
1000
mg/
kg/
day)
for
testing
pesticides
via
the
oral
route
in
subchronic
and
chronic
toxicity
studies.
16
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.
17­
20
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,
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
skin
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.

Metabolism
and
Excretion
The
fate
of
14C­
labeled
triethylene
glycol
in
rats
and
of
unlabeled
material
in
rabbits
was
recently
studied.
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.
21
Developmental
and
Reproductive
Toxicity
9
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
at
the
high
dose
level.
22
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,
but
there
were
no
treatmentrelated
increases
in
external,
visceral,
or
skeletal
malformations.
23
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)
including
sperm
concentration,
morphology,
and
motility.
Reduced
pup
weight
was
observed
at
the
1.5
and
3%
doses
of
triethylene
glycol.
24­
25
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.
14,26
The
available
developmental
and
reproductive
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
toxicity
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.

Neurotoxicity
From
the
available
repeat
dose
toxicity
studies,
there
was
no
evidence
of
neurotoxicity
of
triethylene
glycol,
however,
the
toxicology
data
are
inadequate
to
characterize
repeated
dose
toxicity.
Therefore,
neurotoxicity
testing
could
be
required
if
additional
data
are
needed
for
future
uses
of
triethylene
glycol.
10
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