DIETHYL PHTHALATE
CAS number: 84-66-2
Synonyms: 1,2-Benzenedicarboxylic acid diethyl ester; DEP; Ethyl phthalate; Phthalic acid,
diethyl ester
Molecular formula: C12H14O4
Structural formula:
TLV–TWA, 5 mg/m3
A4—Not Classifiable as a Human Carcinogen
Summary
A TLV–TWA of 5 mg/m3 is recommended for
occupational exposure to diethyl phthalate (DEP) to
minimize the potential for nasal and throat irritation.
Published data from animal experimentation indicate
that the toxicity of diethyl phthalate is of a low order.
Although occupational exposures to mixtures of
phthalate plasticizers have been associated with
polyneuritis and vestibular dysfunction, concomitant
exposure to the human neurotoxin tri-o-cresyl
phosphate (TOCP) precludes drawing any cause-
and-effect relationship. In addition, scientifically
defensible indicators of central or peripheral
neuropathy in animal studies are not available. The
absence of equivocal evidence of carcinogenicity
from animal bioassays provide the basis for an A4,
Not Classifiable as a Human Carcinogen,
designation. Sufficient data were not available to
recommend Skin or SEN notations or a TLV–STEL.
Chemical and Physical Properties
DEP is the aromatic diester of phthalic
anhydride and ethanol. It is a stable, colorless,
odorless, oily liquid with a bitter taste. Chemical and
physical properties include:(1–4)
Molecular weight: 222.23
Specific gravity: 1.232 at 14°C
Freezing point: –40.5°C
Boiling point: 298°C
Vapor pressure: 0.05 torr at 70°C; 14 torr at
163°C; 30 torr at 182°C
Flash point: 163°C, open cup
Solubility: soluble in water to 1 ppm at 25°C;(5)
only partly miscible in aliphatic solvents;
miscible with alcohols, ketones, esters, and
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aromatic hydrocarbons
Conversion factors at 25°C and 760 torr:
1 ppm = 9.09 mg/m3; 1 mg/m3 = 0.11 ppm
Major Uses
DEP is used in plastic packaging, is present in
toiletries and cosmetics ranging from 0.1% to 50%,(6)
in dental impression materials, and in adhesives,
plasticizers, and lubricants in food and pharmaceu-
tical packaging. DEP is used as a solvent for cellu-
lose acetate and nitro cellulose in manufacturing
varnishes and dopes, for denaturing alcohol, as a
mosquito repellant, and as a plasticizer in solid
product propellants.(4) In 1991, the approximate
annual production in the United States was 22
million lbs.(6) In 1990, the National Institute for
Occupational Safety and Health(7) estimated 239,000
U.S. workers are potentially exposed each day to
DEP and DEP-containing materials.
Animal Studies
The toxicology of DEP has been reviewed,(3,4,6)
and only those data relevant to the TLV are cited
here.
Acute
The acute toxicity of DEP for laboratory animals
by most routes of administration is very low,
bordering on "relatively harmless."(8) The oral rat
LD50 is reported to range between 9.5 and 31 g/kg
body weight.(9) The intraperitoneal LD50 is given as
6.3 g/kg for the rat(10) and 2.8 g/kg for the mouse.(11)
The only changes noted in rabbits given an
intravenous injection of 100 mg/kg were transient
hypotension and transient reduction in respiratory
rate.(11) Sax and Lewis(1) state that DEP is an irritant
Diethyl Phthalate – 1
to the eye and mucous membranes.
Serum triglycerides in male F344 rats fed 2%
DEP for 3 weeks were significantly reduced
compared to concurrent controls, an effect that
developed as a consequence of the weak hepatic
peroxisome proliferation induced by oral DEP.(12)
Subchronic
The no-observed-effect levels (NOELs) of DEP
determined from 6-week feeding studies were 2.5
g/kg/day for the rat and 1.25 g/kg/day for the dog;(9)
for one or more years of feeding, NOELs were 1.25
g/kg/day for the rat and 625 mg/kg/day for the dog.(9)
There were neither any specific lesions attributable
to DEP nor unusual incidence of tumors.
Topical application to shaved dorsal skin of male
and female B6C3F1 mice of up to 123 μg/mouse, 5
days/week for 4 weeks failed to elicit any sign of
dermatotoxicity. There were no consistent changes
in weight gain, food consumption, or organ weights.
Similar studies where mice received 43 or 123
μg/day, 5 days/week for 32 weeks produced
reductions of 10% to 19% in body weight gain
relative to controls.(13)
Chronic/Carcinogenicity
(14)
A feeding study with male and female rats
given 0.5% to 5% DEP for 2 years found only
reduced body weight gain in the high-dose animals.
No adverse effects could be detected in dogs fed up
to 2.5% DEP for up to 1 year.(14) DEP is considered
a weak peroxisome proliferator in rats, being about
one-quarter as potent in this regard as diethylhexyl
phthalate.(15)
When groups of 60 male and 60 female B6C3F1
mice were given topical DEP at up to 37 μg/mouse,
5 days/week for 2 years, there was no evidence of
skin or systemic toxicity,(13) but there was a dose-
related trend in the incidence of hepatic adenoma/
carcinoma. Among male and female F344/N rats
given topical DEP at up to 370 μg/animal, 5 days/
week for 2 years, there was no sign of toxicity at the
site of application nor evidence of systemic toxic-
ity.(13) Based on these results, the U.S. National Tox-
icology Program (NTP)(13) concluded there was
equivocal evidence of carcinogenic activity in mice
and no evidence of carcinogenic activity of DEP in
rats.
A 1-year study was also conducted by the NTP(13)
to evaluate the potential of DEP, applied dermally
to the clipped backs of Swiss CD-1 mice, to initiate
tumorigenesis when followed by dermal application of
a known skin tumor promotor, 12-o-tetradecanoyl-
phorbol-13-acetate (TPA) or to promote tumorigen-
esis following application of a known skin tumor
initiator, 7,12-dimethylbenzanthra-cene (DMBA).
Based on the incidence of skin neoplasms and the
number of skin neoplasms, there was no evidence
that DEP was able to initiate skin carcinogenesis
when chronically promoted by TPA or that DEP was
2 – Diethyl Phthalate
able to promote skin carcinogen-esis in the skin of
mice previously initiated with DMBA.(13)
Reproductive/Developmental
Oral administration of up to 1600 mg/kg/day of
DEP to rats failed to influence testicular or accessory
gland weight, histopathologic parameters, or func-
tional status.(16,17) Repeated daily oral dosing with up
to 4500 mg/kg/day throughout organogenesis in
mice failed to elicit either maternal or developmental
toxicity.(18) Even though the radiocarbon of [14C]-DEP
crossed the rodent placenta,(19) DEP was not
teratogenic in rats even after intraperitoneal
injections of up to 2 g/kg(10) or feeding up to 5%
throughout organogenesis.(20)
In a continuous breeding study, mice were fed
DEP at dietary concentrations ranging from 0.25% to
2.5%.(21) DEP caused decreased body weight gain
but did not affect reproduction. The fertility of the first
generation was not affected; however, DEP was
associated with decreased litter size in the second
generation.
Genotoxicity Studies
DEP was without mutagenic activity in
Salmonella typhimurium tester strains TA98, TA100,
TA1535, TA1537, TA1538, or TA2637 in the
presence of rat hepatic enzymes; however, this
compound gave mixed results in the absence of
exogenous bioactivation enzymes.(22–28) DEP was
not mutagenic in cultured Chinese hamster
pulmonary fibroblasts at up to 2 ppm.(29)
Pharmacokinetic/Metabolism Studies
DEP is absorbed from the gut with peak
circulating concentrations achieved at 1 hour in
rodents.(19) The parent compound is de-esterified in
the gut and liver(30) and eliminated in urine principally
as the monoester phthalate, along with small
amounts of the free dicarboxylic acid.(31)
A single topical application of [14C]-DEP at 5 to 8
mg/cm2 found only very limited systemic uptake in
rats. Small amounts (0.03% to 0.14% of applied
dose) were detected in fat, muscle, and skin with
less than 0.5% in blood, brain, lung, and other
tissue. After 1 week of continuous contact, about
60% of the DEP applied to skin was absorbed.(32)
Using in vitro preparations of rat, baboon, and
human tissues, Lake et al.(30) demonstrated that
DEP was hydrolyzed to the monoester. Further
hydrolysis of the monoester and its conjugation with
glucuronic acid are consistent with the biotransfor-
mation pathways for related phthalates.(33)
Human Studies
Exposure to the heated vapor of DEP may
produce some transient irritation of the nose and
throat, but no reports have been identified regarding
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cumulative adverse health effects from occupational
use of DEP alone.(2) DEP has been detected in
human semen,(34) perhaps as a result of its
widespread use in plastic packaging.
A study by Milkov et al.(35) investigated workers
in the artificial leather industry in Russia in which a
number of phthalate plasticizers were used,
predominately butyl phthalate and the higher alkyl
phthalates. Dioctyl phthalate, diisooctyl phthalate,
and benzyl butyl phthalate were also used in some
formulations along with small amounts of some
sebacates and adipates. DEP was not specifically
identified. Tri-o-cresyl phosphate (TOCP) was a
component of materials produced at 10% to 20% of
the work stations. Of 147 workers, 87 were females
and 60 were males and 75% were 40 years old or
less. The duration of employment ranged from 0.5
year to 19 years. Ambient air concentrations for the
plasticizers (mixed esters) varied from 1.7 to 66
mg/m3.(35)
The most frequent complaints from these
workers were pain, numbness, and spasms in the
upper and lower extremities.(35) These complaints
were related to the duration of exposure and usually
began after the 6th to 7th year of work. Pain and
numbness were first noted at rest, frequently at
night. This was followed by objective evidence of
weakness in the upper and lower extremities.
Extensive neurological studies revealed polyneuritis
in 47 persons (32%), while 49.6% of the workers
were classified as essentially healthy. Eighty-one
persons were evaluated for disturbance of the
vestibular function, and 78% showed depression of
vestibular receptors, but the significance of this
observation is not known. This was said to be the
worker's first evidence of neurosomatic dysfunction
as was a lowering of the excitability threshold level
for the olfactory receptors. The concomitant
presence at the worksite of TOCP, a potent, known
cause of human peripheral neuropathy, precludes
any association between DEP occupational
exposures and DEP effects on the human nervous
system.(35)
TLV Recommendation
Acute animal toxicity of DEP is of a low order.(7–
11)
Exposure of workers to the heated vapor of DEP
may cause transient irritation of the nose and
throat.(2) While occupational exposures to mixtures
of phthalate plasticizers have been associated with
polyneuritis and vestibular dysfunction,(35)
concomitant exposure to the human neurotoxin
TOCP in that cohort precludes drawing any cause-
and-effect relation here. Since there has been no
scientifically defensible indication of central or
peripheral neuropathy in animal bioassays,(3,4,12) or
in occupational cohorts, the ACGIH concluded that
DEP exposure under current workplace conditions
should not present a neurotoxic hazard.
To minimize the potential for respiratory
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irritation, a TLV–TWA of 5 mg/m3 is recommended
for exposure to DEP, equivalent to that
recommended for di(2-ethylhexyl) phthalate (DEHP)
(see Documentation for DEHP).
Given that lifetime bioassays in rodents provided
no or equivocal evidence of carcinogenicity, the A4,
Not Classifiable as a Human Carcinogen,
designation is assigned.
Sufficient data were not available to recommend
Skin or SEN notations or a TLV–STEL. The reader is
expected to be familiar with the section on Excursion
Limits in the "Introduction to the Chemical
Substance TLVs" found in the current edition of the
Documentation of the TLVs and BEIs for the
guidance and control of excursions above the TLV–
TWA, even when the 8-hour TWA is within the
recommended limit.
Historical TLVs
1973: Proposed: TLV–TWA, 5 mg/m3
3
1975–present: TLV–TWA, 5 mg/m
1976–1986: TLV–STEL, 10 mg/m3
1987: TLV–STEL deleted
1998: Proposed: A4, Not Classifiable as a Human
Carcinogen
1999: A4
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