ETHYLBENZENE
Ambient Water Quality Criteria
Criteria and Standards Division
Office of Waters-Planning and Standards
U.S. Environmental Protection Agency
Washington, D.C.
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CRITERION DOCUMENT
ETHYLBENZENE
CRITERIA
Aquatic Life
For freshwater aquatic life, no criterion for ethylbenzene
can be derived using the Guidelines, and there are insufficient
data to estimate a criterion using other procedures.
For saltwater aquatic life, no criterion for ethylbenzene
can be derived using the Guidelines, and there are insufficient
data to estimate a criterion using other procedures. v
Human Health
For the protection of human health from the toxic properti3S
of ethylbenzene ingested through water and contaminated aquatic
organisms, the ambient water quality criterion is 1.1 mq/1.
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Introduction
Ethylbenzene (EB) is an alkyl substituted aromatic
compound which has a broad environmental distribution due
to its widespread use in a plethora of commercial products
and its presence in various petroleum combustion processes.
The two primary commercial uses of EB are in the plastic
and rubber industries where it is utilized as an initial
substrate reactant in the production of styrene (Paul and
Soder, 1977). The majority of these commercial sites of
production are geographically clustered in Texas and Louisiana,
The amount of EB produced in the United States in 1976 was
approximately 6 to 7 billion pounds of which about 98 percent
was used in the manufacture of styrenes (U.S. Int. Trade
Comm. 1976).
Commercial production of EB currently utilizes a liquid
phase Friedel-Crafts alkylation of benzene with ethylene.
According to Paul and Soder (1977), at least 50 percent
of the benzene used in the United States goes into the produc-
tion of ethylbenzene. Significant quantities of EB are
present in mixed xylenes. These are used as diluents in
the paint industry, in agricultural sprays for insecticides
and in gasoline blends (which may contain as much as 20
percent EB). In light of the large quantities of EB produced
and the diversity of products in which it is fo'und," there
exist many environmental sources for ethylbenzene, e.g.,
vaporization during solvent use, pyrolysis of gasoline and
emitted vapors at filling stations.
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Ehtylbenzene (CgH5C2H5,*molecular weight 106.16) is
a flammable, colorless liquid with a boiling point of 136.25° C
and a freezing point of -95.01°C (Windholz, 1976). Its
density at 25° C (relative to water at the same temperature)
ia 0.866 (Windholz, 1976) and it has a specific gravity
of 0.8669 (Cier, 1970). Vapor pressures range from 7 to
15.3 mm Hg at 20° C (Am. Hyg. Assoc., 1957) to 20 mm Hg
at,38.6° C (Cier, 1970). Ethylbenzene is slightly soluble
(less than 0.1 percent or 866 mgl) in water (Hann and Jensen,
1970), but it is freely soluble in organic solvents (Windholz,
1976) .
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REFERENCES
American Hygiene Association. 1957. Ethylbenzene (Phenyl-
ethane). Hygiene guide series. Am. Ind. Hyg. Assoc. Washington,
D.C.
Cier, H.E. 1970. Kirk-Othmer Encyclopedia of Chemical Tech-
nology. Xylenes and ethylbenzenes. 2nd ed. Interscience
Publ., New York 22: 467.
i
Hann, R.W. Jr., and P.A. Jensen. 1970. Water quality char-
acteristics of hazardous materials. Environ. Eng. Div.,
Texas A and M University, College Station.
Paul, S.K., and S.L. Soder. 1977. Ethylbenzene-salient
statistics. Ir\ Chemical economics handbook. Stanford Research
Institute, Menlo Park, Calif.
U.S. International Trade Commission. 1976. Synthetic
organic chemicals. U.S. production and sales, Washington,
D.C.
Windholz, M. ed. 1976. The Merck Index. Merck and Co.,
Rahway, N.J.
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AQUATIC LIFE TOXICOLOGY*
FRESHWATER ORGANISMS
Introduction
The acute toxicity data base for ethylbenzene and freshwater
organisms indicates that there is not a large difference in sen-
sitivity of the four tested fish species and that Daphnia magna
is similarly sensitive to ethylbenzene. Algal assays indicated
that Selenastrum capricornutum was much more resistant. Acute
Toxicity
Pickering and Henderson (1966) conducted 96-hour tests with
the goldfish, fathead minnow, guppy, and bluegill and the unad-
justed LC50 values ranged from 32,000 to 97,100 ug/1 (Table 1).
The two bluegill LC50 values, 32,000 and 155,000 ug/1/ do not
agree well but no explanation is available. After adjustment for
test procedures and species sensitivity, the Final Fish Acute
Value based on these data is 10,000 ug/1.
*The reader is referred to the Guidelines for Deriving Water
Quality Criteria for the Protection of Aquatic Life [43 FR 21506
(May 18, 1978) and 43 FR 29028 (July 5, 1978)] in order to better
understand the following discussion and recommendation. The fol-
lowing tables contain the appropriate data that were found in the
literature, and at the bottom of each table are the calculations
for deriving various measures of toxicity as described in the
Guidelines.
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An acute test with Daphnia magna (U.S. EPA, 1978) resulted
in an unadjusted 48-hour EC50 value of 75,000 ug/1 (Table 2).
The Final Invertebrate Acute Value is 3,000 ug/1 and this also
becomes the Final Acute Value since the comparable concentration
for fish is higher.
Chronic Toxicity
The embryo and larval stages of the fathead minnow have been
exposed to ethylbenzene (U.S. EPA, 1978) and no adverse effects
were observed at the highest test concentration, 440 ug/1 (Table
3). This datum results in a Final Fish Chronic Value greater
than 33 ug/1.
Plant Effects
No adverse effects on cell number or chlorophyll £ produc-
tion of Selenastrum capricornutum were observed at test concen-
trations as high as 438,000 ug/1 (Table 4).
Residues
No measured steady-state bioconcentration factor (BCF) is
available for ethylbenzene. A BCF can be estimated using the
octanol-water partition coefficient of 1,400. This coefficient
is used to derive an estimated BCF of 150 for aquatic organisms
that contain about 8 percent lipids. If it is known that the
diet of the wildlife of concern contains a significantly dif-
ferent lipid content, an appropriate adjustment in the estimated
BCF should be made.
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CRITERION FORMULATION
Freshwater Aquatic-Life
Summary of Available Data
The concentrations below have been rounded to two significant
figures.
Final Fish Acute Value = 10,000 ug/1
Final Invertebrate Acute Value = 3,000 ug/1
Final Acute Value = 3,000 ug/1
Final Fish Chronic Value = greater than 33 ug/1
Final Invertebrate Chronic Value = not available
Final Plant Value = greater than 440,000 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = greater than 33 ug/1
0.44 x Final Acute Value = 1,300 ug/1
No freshwater criterion can be derived for ethylbenzene using
the Guidelines because no Final Chronic Value for either fish or
invertebrate species or a good substitute for either value is
available, and there are insufficient data to estimate a criterion
using other procedures.
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Table 1. Freshwater fish acute values for ethylbenzene
Adjusted
Bioassay Teat
Oraanian Method* Cone.**
Goldfish, S U
Carasalns auratus
Fathead minnow, S U
Pimephales promelaa
Fathead minnow. S U
t imephalea promelaa
Guppy. S U
foecilia retlculatus
Bluegill. S U
Lopomis macrochiruB
m Bluegill, S U
1 Lepomis macrochirua
rfk
Time
(hra)
96
96
96
96
96
96
LC50
94,440
48.510
42,330
97,100
32,000
155,000
LC50
fuq/1)
51.630
26.520
23.140
53.080
17,490
84,700
_ Deference
Pickering
1966
Pickering
1966
Pickering
1966
Pickering
1966
Pickering
1966
U.S. EPA.
& Henderson,
& Henderson,
f< Henderson,
& Henderson,
& Henderson,
1978
* S = static
A* U = unmeasured
Geometric mean of adjusted values- 40,200 iig/1
- 10.000 Mg/i
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CO
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en
Tdble 2. Freshwater invertebrate acute values for ethylbenzene (U.S. EPA, 1978)
Adjusted
bicdssay Ttet rime LC50 I.CbO
III b
Cladoceran. S U 48 75,000 64,000
Daphnia magna
* S = static
** u » unmeasured
Geometric mean of adjusted values - 64,000 pg/1 s = 3,000 pg/1
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Organism
Table 3-. Freshwater fish chronic values for elhylbenzene (U.S. EPA, 1978)
Chronic
Limits Value
Test* 440 >220
* E-L " embryo-larva
>220
Geometric mean of chronic values =• >220 pg/1 ~T~J ">33 Me/'1
Lowest chronic value *• >220 [ig/1
03
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03
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Table 4. Freshwater plant effects for eLhylbenzene (U.S. EPA, 1978)
•Organism
Effect
Concentration
Alga,
Selenastrum
capricprnutum
Alga.
Selenastrum
capricornutum
EC50 96-hr
chlorophyll a
EC50 96-hr
cell numbers
>438,000
>438,000
Lowest plant value » >A38.000
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SALTWATER ORGANISMS
Introduction
The sheepshead minnow, a mysid shrimp, Mysidopsis bahia, and
an aiga, Skeletonema costatum, have been acutely exposed to ethyl-
benzene and the lowest 50 percent effect concentration was 87,600
ug/1.
Acute Toxicity
The unadjusted 96-hour LC50 for the sheepshead minnow is
275?000 ug/1 (Table 5) and after adjustment of this concentration
for test methods arid species sensitivity the Final Fish Acute
Value of 41,000 ug/1 is obtained.
As with fish, only one test has been conducted with a salt-
water invertebrate species. The Final Invertebrate Acute Value
derived from the 96-hour LC50 for the mysid shrimp (87,600 ug/1)
is 1,500 ug/1 (Table 2). Since this concentration is lower than
the equivalent value for fish, it also becomes the Final Acute
Value.
Chronic Toxicity
No chronic tests have been conducted with saltwater organisms
and ethylbenzene.
Residues
No measured steady-state bioconcentration factor (BCF) is
available for ethylbenzene. A BCF can be estimated using the
octanol-water partition coefficient of 1,400."This coefficient
is used to derive an estimated BCF of 150 for aquatic organisms
o
that contain about 8 percent lipids. If it is known that the diet
of the wildlife of concern contains a significantly different
lipid content, an appropriate adjustment in the estimated BCF
should be made.
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CRITERION FORMULATION
Saltwater Aquatic-Life
Summary of Available Data
The concentrations below have been rounded to two significant
figures.
Final Fish Acute Value = 41,000 ug/1
Final Invertebrate Acute Value = 1,500 ug/1
Final Acute Value = 1,500 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = greater than 440,000 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = greater than 440,000 ug/1
0.44 x Final Acute Value = 660 ug/1
No saltwater criterion can be derived for ethylbenzene using
the Guidelines because no Final Chronic Value for either fish or
invertebrate species or a good substitute for either value is
available, and there are insufficient data to estimate a criterion
using other procedures.
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Table 5i Marine fish acute values for ethylben/ene (U.S. EPA, 1978)
Adjusted
Bioaaaay Test Tine LC50 LC60
M££b££*_ gone,** thra) (uq/ll tug/1)
Sheupihead minnow, S U 96 275,000 150.3A3
Cyprinodon varieRatus
* S =• static
*- U = unmeasured
Geometric mean of adjusted values- 150,343 ug/1 150,343 _ ^1(000
J • /
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00
I
Table 6< Marine invertebrate acute values for ethylbenzene (U.S. EPA, 1978)
Hysid shri-np.
Hystdopsia bahia
Bioasaay Teat Time
Method* Cone."*
96
Adjusted
LC50 LC60
tuq/U
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CD
h-
N>
Table 7- Marine plant effects for echylbenzene (U.S. EPA, 1978)
•
Concentration
Organism Effect (ut',/1)
Alga. EC50 96-hr >A38,000
Skeletoncma coatatum chlorophyll a
Alga, EC50 96-hr >438,000
Skeletonema coatatum cell numbers
Lowest plant value = >A38.000
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ETHYLBENZENE
REFERENCES
Pickering, Q.H., and C. Henderson. 1966. Acute toxicity
of some important petrochemicals to fish. Jour. Water Follut.
Control Fed. 38: 1419.
U.S. EPA. 1978. In-depth studies on health and environmental
impacts of selected water pollutants. U.S. Environ. Prot.
Agency, Contract No. 68-01-4646.
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Mammalian Toxicology and Human Health Effects
Summary
The paucity of information available on the biological
effects of ethylbenzene(EB) in man and other mammalian species
is rather surprising considering the degree of exposure
to EB in our environment. EB is present in drinking waters
and in the atmosphere. It has been shown to persist in man
for days after exposure (Wolff, et al. 1977). It is present
in the respiratory tract (Conkle, et al. 1975) , umbilical
cord and maternal blood (Dowty, et al. 1976) and subcutaneous
fat (Wolff, et al. 1977) of exposed humans. There is little
reason to suspect that the current sources of EB in our
environment will be abated. The sources of EB include:
(1) commercial - e.g., petroleum and petroleum by-products;
(2) motor vehicle exhaust, and (3) cigarette smoke. These
appear to be integral parts of our society. In man and
in animals, EB is an irritant of mucous membranes. It is
this response which forms the basis for the current Threshold
Limit Values (TLV's). The EPA proposed to evaluate the
carcinogenic potential of EB in 1976, but test results are
not yet available. Similarly, no data exist for mutagenicity
and teratogenicity of ethylbenzene. The potential adverse
human health effects following exposure to EB were stated
(40 PR 1910.1034) to be:
"1) kidney disease,
2) liver disease,
3) chronic respiratory disease,
4) skin disease.
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1) EB is not nephrotoxic. Concern is expressed because
the kidney is the primary route of excretion of EB and its
metabolites.
2) EB is not hepatotoxic. Since EB is metabolized
by the liver, concern is expressed for this tissue.
3) Exacerbation of pulmonary pathology might occur
following exposure to EB. Individuals with impaired
pulmonary function might be at risk.
4) EB is a defatting agent and may cause dermatitis
following prolonged exposure. Individuals with pre-
existing skin problems may be more sensitive to EB."
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EXPOSURE
Introduction
Ethylbenzene has a broad environmental distribution
due to its widespread use in a plethora of commercial products
and its presence in various petroleum combustion processes.
The two primary commercial uses of EB are in the plastic
and rubber industries where it is utilized as an initial
substrate reactant in the production of styrene (Paul and
Soder, 1977). The amount of EB produced in the United
States in 1976 was 7.2 x 109lbs (Table 1). Almost all (97
percent) was captively consumed by the producers. The major-
ity of these commercial sites are geographically clustered
in Texas and Louisiana.
Commercial production of EB currently utilizes a liquid
phase Friedel-Crafts alkylation of benzene with ethylene.
According to Paul and Soder (1977), at least 50 percent
of the benzene used in the United States goes into the produc-
tion of ethylbenzene. Significant quantities of EB are
present in mixed xylenes. These are used as diluents in
the paint industry, in agricultural sprays for insecticides
and in gasoline blends (which may contain as much as 20
percent EB). In light of the large quantities of EB produced
and the diversity of products in which it is found, there
exist many environmental sources for ethylbenzene, e.g.,
vaporization during solvent use, pyrolysis of gasoline and
emitted vapors at filling stations.
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Ethylbenzene - Chemical Structure
TABLE 1
Possible Environmental Sources of Ethylbenzene
*U.S. International Trade Commission 1976.
Source
Commercial
Petroleum Cracking
(2-3% of gasoline (volume) is EB)
EB production/annum
6-7 billion pounds
0.57-0.96 billion
pounds
Residues in polystyrene
Motor vehicle exhaust (and other
combustion and pyrolysis products)
0.19 billion pounds
0.28 billion pounds
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TABLE 2
Ethylbenzene / Physical Properties3
Molecular weight 106.17
Color colorless
Boiling Point, 760 torr 136.2 C
Freezing Point -95° C
Flashpoint 16° C
Density (gm/ml) @ 20° C 0.87
Vapor Pressure, torr 20 at 38.6° C
Water Solubility wt. % 0.02bc
aTaken from Cier (1970); Gerarde (1963).
For all practical purposes, EB is 'insoluble1 in water
and due to its vapor pressure is probably present only in
the atmosphere.
CEB water solubility 161 ppm at 25° C in distilled water
111 ppm at 25° C in seawater
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Ingestion from Water
In a survey of water contaminants present in the drink-
ing water of ten cities in the United States, ethylbenzene
(EB) was detected but not quantified in six of ten samples
(U.S. EPA, 1975). This report indicated that alkylated
benzenes were present in U.S. drinking water at 10~ g/1.
A broad distribution was estimated in a document prepared
for the U.S. EPA by Shackelford and Keith (1976); EB was present
in finished drinking water in the United States, the United
Kingdom and Switzerland. EB was also found in river water,
chemical plant effluents, raw water, textile plant effluents
and well water at 15 ppb (Burnham, et al. 1972).
Ingestion From Foods
The only report in the literature indicating the presence
of ethylbenzene in food is that of Kinlin, et al. (1972),
wherein they reported the presence of 227 organic compounds
including EB in roasted filbert nuts (no quantitative data
given).
Styrene food packaging techniques represent another
possible source of EB contamination in food products. Though
styrene has been detected in certain food products, the
presence of EB in these products has not been reported.
A bioconcentration factor (BCF) relates the concentration
of a chemical in water to the concentration in aquatic organisms,
but BCF's are not available for the edible portions of all
four major groups of aquatic organisms consumed in the United
States. Since data indicate that the BCF for lipid-soluble
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compounds is proportional to percent lipids, BCF's can be
adjusted to edible portions using data on percent lipids
and the amounts of various species consumed by Americans.
A recent survey on fish and shellfish consumption in the
United States (Cordle, et al. 1978) found that the per capita
consumption is 18.7 g/day. From the data on the nineteen
major species identified in the survey and data on the fat
content of the edible portion of these species (Sidwell,
et al. 1974), the relative consumption of the four ma3or
groups and the weighted average percent lipids for each
group can be calculated:
Consumption Weighted Average
Group (Percent) Percent Lipids
Freshwater fishes 12 4.8
Saltwater fishes 61 2.3
Saltwater molluscs 9 1.2
Saltwater decapods 18 1.2
Using the percentages for consumption and lipids for each
of these groups, the weighted average percent lipids is
2.3 for consumed fish and shellfish.
No measured steady-state bioconcentration factor (BCF)
is available for ethylbenzene, but the equation "Log BCF
=0.76 Log P - 0.23" can be used (Veith, et al. Manuscript)
to estimate the BCF for aquatic organisms that contain about
eight percent lipids from the octanol-water partition coef-
ficient (P). Based on an octanol-water partition coefficient
of 1,400, the steady-state bioconcentration factor for ethyl-
benzene is estimated to be 145. An adjustment factor of
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2.3/8.0 = 0.2875 can be used to adjust the estimated BCF
from the 8.0 percent lipids on which the equation is based
to the 2.3 percent lipids that is the weighted average for
consumed fish and shellfish. Thus, the weighted average
bioconcentration factor for ethylbenzene and the edible
portion of all aquatic organimsm consumed by Americans is
calculated to be 145 x 0.2875 = 42.
Inhalation
EB probably represents about 10 percent of the total
aromatic compounds detected in the air, and roughly one
percent of the total carbon compounds detected. Altshuller
and Bellar (1963) detected 0.01 ppm EB in the air around
Los Angeles, California. Lonneman, et al. in 1968 detected
EB in the air around Los Angeles at a level of 0.006 ppm.
Neligan, et al. (1965) surveyed five different sites in
California. EB levels averaged 0.01 ppm. These authors
have suggested that commercial sources and motor vehicles
are the major contributors to EB in the atmosphere.
EB is present in cigarette smoke. Conkle, et al. (1975)
measured trace quantities of EB in the expired air of eight
male subjects with a range of 23 to 47 years of age, median
age 38. Using gas chromatography techniques they detected
EB in five of eight subjects with the smokers in this group
having the highest levels of EB (0.78 to 14 x 10 g/hr).
Dermal
No data are available on the exposure of humans to
ethylbenzene.
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PHARMACOKINETICS
Absorption and Distribution
When administered subcutaneously to 40 rats (2.5 ml,
1:1 v/v), ethylbenzene was detected in the blood within
2 hours and the levels of EB (10-15 ppm in blood) were
maintained for at least 16 hours (Gerarde, 1959).
Although little quantitive data on the absorption of
EB is available absorption has been demonstrated via the
skin and respiratory tract in a number of toxicity studies.
Two representative studies have reported that significant
amounts of EB can be absorbed through the skin. Dutkiewicz
and Tyras (1967, 1968) have shown (Table 3) that when human
subjects are exposed to EB, there is a "significant increase
in the amount of urinary mandelic acid excreted" (see Metabo-
lism section). In addition, Smyth, et al. (1962) reported
an LD50 for EB (via skin application) in rabbits of 17.8
ml/kg.
TABLE 3
Skin Absorption of EB in Man
(Dutkiewicz and Tyras, 1968)
24-hour mandelic
Rate of Absorption acid excretion
9
EB concentration (mg/cm-) hour (% of absorbed dose)
112-156 mg/1 0.11-0.21 4.6
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Dutkiewicz and Tyras (1968) also compared the skin
absorption of several other organic solvents, and they con-
cluded that by comparison significantly more EB was absorbed
(Table 3).
EB is readily absorbed by inhalation (see Table 6).
Symptomatology associated with acute intoxication of EB
by this route includes coordination disorders, narcosis,
convulsions, pulmonary irritation, and conjunctivitis (Ivanov,
1962) (see Effects section).
Ingestion of EB has been reported by a number of investi-
gators to produce a variety of dose related toxicities in
several different species (see Effects section). The evi-
dence presented above indicates that EB can be absorbed
via several different routes of administration, producing
systemic effects in various species of animals including man.
Metabolism and Excretion
The metabolism of EB is summarized in Figure 1. These
data were taken from a series of different studies on rabbits
as presented in a modified form from the work of Kiese and
Lenk (1974) (Table 4). This metabolic outline is consistent
with reports on the metabolic fate of EB in dogs (Nencki,
1878; Nencke and Giacosa, 1880; El Masry, et al. 1956),
rat liver microsomes (McMahon and Sullivan, 1966; McMahon,
et al. 1969), and in man (Bardodej and Bardedjeva, 1970;
Logemann, et al. 1964). The data presented in Table 4 indicate
that the major metabolites of EB are 1-phenylethanol, hippuric
acid and phenaceturic acid.
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o
i
6J - oxidation
en, coon
ethylbenzene
phenylacetic acid
-1-oxidation
L (-)
i-phenylethanol
0 (+)
oxidation
\1/
' -oxidation acetophenone
\i/
mandelic acid
conjugated
phenaceturic
acid
hippuric acid
?. vn -hydroxylation /r^ metahydroxyacetophenone
c.c.rt» _—_x. (( )rc-~c' 3
on
P-hydroxylarion\u»_oxidation
\£ *)
conjugation
p-hydroxyacetophenone
-hydroxyacetophenone
o p
c-c
o o
ll II
phenyglyoxal
phenylglyoxylic
acid
Figure 1: Metabolic Pathways of Ethylbenzene
(Based on Kiese and Lenk, 1974)
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TABLE 4
EB Metabolites Found in Urine
of Rabbits given 1 gram i.p.*
phenaceturic acid
raandelic acid
p-hydroxyacetophenone
m-hydroxyacetophenone
o-hydroxyacetophenone
hippuric acid
1-phenylethanol
% of administered EB
10-20
1-2
0.13
0.03
0.1
22-41
30% [75% D( + ) ,25% L(-)J
*These data are abstracted from Figure 1 of the report by
Kiese and Lenk (1974). Similar data were obtained by El Masry,
et al. (1956).
• The study reported in Table 5 is excerpted in a modified
form from Bardodej and Bardedjova (1970) In this study
of the metabolism of EB by human volunteers, there are several
significant omissions which hamper a clear interpretation
of the data. These include no indication of number, age,
or sex of subjects or of their physical condition
prior to EB exposure. The methodologies described in the
text include spectrophotometry and paper chromatography.
These were probably not sensitive enough to detect many
of the metabolites. Indeed, the authors were unable to
detect several common metabolites of ethylbenzene, including
acetophenone,phenylethyleneglycol, w-hydroxyacetophenone,
hippuric acid and mercapturic acid. Despite these shortcom-
ings, this study contributes to our understanding of EB
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TABLE 5
Metabolism of EB in Man*
EB concentrations in
inspired air (ppm)
Duration
% of vapor retained
in respiratory tract
(arithmetic average)
Excreted in expired air
at the end of the
experiment
retained dose
eliminated in the urine
as mandelic acid
as phenylglyoxlic acid
as 1-phenylethanol
23,43,46,85
8 hours
64
traces
(2-4%)
64%
25%
5%
*Based on Bardodej and Bardedjova (1970)
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metabolism in man. A considerable amount of EB was absorbed
in the respiratory tract; only traces of EB were expired
at the end of the experiment (Table 5). The major metabolites
found in the urine included mandelic and phenylglyoxylic
acid, 64 percent and 25 percent respectively, and 1-phenyl-
ethanol, 5 percent. These authors (Bardodej and Bardedjova,
1970) also indicated that if the concentration of EB is
increased above 85 ppm (level not specified), subjects report-
ed fatigue, sleepiness, headache, and mild irritation of the
eyes and respiratory tract.
EFFECTS
Acute, Sub-acute, and Chronic Toxicity
Gerarde (1959) has reviewed the acute toxicity data
in humans to EB via inhalation; these data are summarized
in Table 6.
TABLE 6
Human Response to Ethylbenzene Vapors
(Gerarde, 1959)
Concentration
mg/1 p. p.m.
21.75
8.7
8.7
4.35
4.35
0.87
0.043
5000
2000
2000
1000
1000
200
10
Exposure
time
Few seconds
Few seconds
6 minutes
Few seconds
Minutes
Threshold
Few seconds
Response
Intolerable irritation
of nose, eyes and throat.
Severe eye, nose and
mucous membrane irrita-
tion.
Lacr imation.
Central nervous system
effects. Dizziness.
Eye irritation.
Eye irritation diminishes
limit.
Odor detectable.
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The acute toxicity data on EB in both rat and rabbit
via the oral or dermal route indicate the low toxicity of
this compound (Table 7). In the study by Wolf, et al. (1956)
young adult white rats were intubated via a rubber stomach
tube with either undiluted EB or an olive-oil or corn-oil
solution of EB emulsified with a five to ten percent aqueous
solution of gum arabic. The total volume administered never
exceeded 7 ml. The EB used in these studies was 98 percent
pure (ultraviolet and infrared spectroscopy), BP 136.2°C
with a specific gravity (20°C) = 0.86.
TABLE 7
Acute Toxicity of EB
Route of
Administration
oral
oral
skin
inhalation
Species
rat
rat
rabbit
rat
Sex
both
male
male
female
No. of
Animals
57
5
4
6
LD50
3.5 gm/kg(a)
5.46 ml/kg(b)
17.8 ml kg(b)
4000 ppm x 4 hrs. *
(a) Wolf, et al. (1956)
(b) Smyth, et al. (1962)
These authors (Wolf, et al. 1956) also assessed the
response of administration of EB on the eyes of rabbits.
Two drops of EB were placed on the right eyeball. Observa-
tions were made at three minutes, one hour and one, two
and seven days. A five percent flourescein dye solution
C-15
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(water) was used to assess external injury of the cornea
(after three minutes). EB produced a slight conjunctival
irritation but did not produce any injury to the cornea.
Wolf, et al. (1956) administered EB via the oral route
for approximately six months to ten white rats. They receiv-
ed a daily single dose of EB (98 percent pure) dissolved
in olive-oil, five days/week for six months. The total
daily volume administered did not exceed 2 to 3 ml. Controls
i
for this study included 20 white rats that received 2.5
ml olive-oil emulsified in gum arabic. The findings (Table
8) indicate that repeated oral administration of EB produced
histopathological changes in both the kidney and the liver
at 408 and 680 mg/kg/day. The authors reported that at
these doses of EB no effects on the hematopoietic system
were observed, as indicated by bone marrow counts of nucleat-
ed cells.
TABLE 8
Repeated Oral Dosing of EB
(Wolf, et al. 1956)
Dose (mg/kg/day) No. of Feedings Days of: Exposure Effects
13.6 130 182 No effects
136 130 182 No effects
408 13° 182 Positive.
680 130 182 Findings
aPositive findings: (1) slight increase in liver and kidney
weights; (2) histopathological changes in liver and kidney
which include cloudy swelling of liver parenchymal cells
and of the tubular epithelium in the kidney. No hematopoie-
tic effects were observed.
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Wolf, et al. (1956) also evaluated the ability of EB
to produce injury to the skin (rabbit). EB was tested undi-
luted, 10 to 20 applications to the ear and onto the shaved
abdomen for two to four weeks. EB produced moderate "erythe-
mal" edema, superficial necrosis; chapped appearance and
exfoliation of large patches of skin and skin blistering
were also observed.
The effects of repeated exposures of EB via inhalation
are summarized in Table 9. Matched groups of 10 to 25 rats,
5 to 10 guinea pigs, 1 to 2 rabbits, and 1 to 2 rhesus monk-
eys were used in these studies. Exposure in chambers was
for seven to eight hours daily, five days/week. These authors
(Wolf, et al. 1956) concluded that a no effect concentration
of EB is 200 ppm (rat, guinea pig, rabbit). Effects with
EB were observed at doses equal to or greater than 400 ppm;
these effects include primarily changes (slight) in liver
and kidney weights.
When acutely exposed to ethylbenzene vapors at concentra-
tions of 1,000 to 10,000 ppm, guinea pigs developed leukocyto-
sis (Yant, et al. 1930). Ivanov (1964) reported a study
in which rabbits were subchronically exposed to EB via inhala-
tion. The animals were exposed to approximately 230 ppm
EB, four hours/day for seven months. This author reported
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TABLE 9
Repeated Exposure by Vapor Inhalation to EB in Animals*
Species
Average Vapor
Concentrations
ppm rag/1
Sex
7hr.
Exposures
No.
Duration
Days
Effects
rat
o
i
M
00
2200
1250
600
9.5
male
5.4
both
2.6
both
103
144
138
214
130
186
guinea
pig
rabbit
rhesus
monkey
_400
1250
600
400
1250
600
_400
~ 600
400
*Modif led
1.7
5.4
2.6
1.7
5.4
2.6
1.7
2.6
1.7
from
both
male
both
both
male
both
both
Wolf, et al.
130
138
130
130
138
130
130
130
130
(1956)
186
214
186
186
214
186
186
186
186
moderate growth depression,
slight and moderate increase of
liver and kidney weights (respectively)
and slight histopathological
changes in liver and kidney
questionable growth depression,
slight and moderate increase
in liver and kidney weights
(respectively) and slight histo-
pathological changes in liver
and kidney
slight change in liver and kidney
weights
slight change in liver and kidney weights
moderate growth depression
slight liver weight change
no effect
not reported
slight testicular histopathology
no effect
slight testicular histopathology; slight
change in liver weight
no effect
-------
"changes in blood cholinesterase activity, decreased plasma
albumin, increased plasma globulins, leukocytosis, reticulocy-
tosis, cellular infiltration and lipid dystrophy in the
liver, dystrophic changes in the kidney and muscle chronaxia.
Synergism and/or Antagonism
No published information is available on the possible
synergism and/or antagonism of EB with other substances.
Teratogenicity
No reports on the teratogenic activity of EB are avail-
able.
Mutagenicity
There are no available data on the mutagenicity of
EB, though four common metabolites of EB (D and L mandelic,
phenylglyoxylic, and hippuric acids) gave negative results
in the Ames test using the five tester strains (Salmona,
et al. 1976).
Carcinogenicity
There is no available information on the carcinogeni-
city of EB.
Possibility of Mutagenic and /or Carcinogenic Activity of EB
As mentioned above, there are no data on the mutagenic
and/or carcinogenic potential of EB. However, speculation
on such a possibility may be appropriate. Gillete, et al.
(1974) have reviewed certain considerations of drug toxicity
including those related to possible carcinogens. EB or
its known metabolites in man and in animals (Bardodej and
Bardedjova, 1970; Kiese and Lenk, 1973, 1974; McMahon and
Sullivan, 1966) do not fit into any of the presently known
C-19
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physical/chemical categories of mutagenic and/or carcinogenic
agents. Although EB metabolites do not show any mutagenic
activity, styrene, an EB manufacturing product, can undergo
metabolism to an epoxide intermediate (Salmona, et al. 1976) ,
which is a possible carcinogen and which demonstrates a
positive mutagenic response in the Ames test.
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CRITERION FORMULATION
Existing Guidelines and Standards
The U.S. Occupational Standard for "permissable exposure
has been set at 100 ppm (435 mg/ra3) (ACGIH, 1974 1977; U.S.
EPA, 1976; 40 FR 1910.1034). At this level of exposure
eye irritation is minimal. The Soviet standards (TLV) for
EB are approximately eight-fold less than current U.S. TLV
standards (ACGIH, 1974).
Current Levels of Exposure
Air: Several investigators have reported that ethylben-
zene is present in the ambient atmosphere at a level of
approximately 0.01 ppm. (Altshuller and Bellar, 1963; Lonne-
man, et al. 1968; Neligan, et al. 1965).
Water: Shackelford and Keith (1976) reviewed the litera-
ture on EB contamination and concluded that it was found
in most of the potable waters tested. No data were reported
on the levels of EB in potable waters.
Food: Except for the report by Kinlan, et al. (1972),
EB has not been reported to be present in food.
Industrial: EB can be found in a number of volatile
compounds with widespread industrial use (including gasoline
and solvents).
Special Groups at Risk
Those individuals who are involved in the use of petro-
leum by-products e.g., polymerization workers involved in
styrene production, may be at risk. In a study of 494 sty-
rene workers, Lilis, et al. (1978) reported various neuro-
toxic manifestations. These included prenarcotic symptoms,
C-21
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incoordination, dizziness, headache and nausea (13 percent
of worker group) and a decrease in a radial and peroneal
nerve conduction velocity (19 percent of workers). In
50 percent of the workers, distal hypoasthesia involving
the lower limbs was observed. It is difficult to assess
occupational reports evaluating such a situation since these
workers are exposed to a number of different precursors,
by-products and end products. In this particular study,
toxic effects were reported but there was a general lack
of symptoms among workers who were exposed for many years,
suggesting that the risk of severe neurologic deficiencies
may be minimal. Recently, however, Harkonen, et al. (1978)
reported on the relationship between styrene exposure and
symptoms of central nervous system dysfunction in 98 occupa-
tionally exposed workers. Urinary mandelic acid concentration
was used as an index of exposure intensity. Although no
exposure-response relationship was observed between symptoms
of ill health and urinary mandelic acid concentration, the
exposed group expressed significantly more symptoms than
the unexposed group. Symptoms included abnormal electro-
encephalograms, and impaired psychological functions such
as visuomotor accuracy and psychomotor performance.
A NIOSH report by Rivera and Rostand (1975) on worker
exposure to various lacquer constituents including EB in
a baseball bat manufacturing facility concluded that no
health hazard existed with the exception of mucous membrane
irritation and the potential for contact dermatitis under
the conditions at the plant. This occupational situation
C-22
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again illustrates the fact that these workers were exposed
to more than one chemical in addition to EB.
Cigarettes contain 7 to 20 x 10 g of EB per cigarette
(Johnstone, et al. 1962). Conkle, et al. 1975 have reported
that moderate cigarette smokers expired up to 14 x 10 g/hr
of EB (during an eight hour measurement).
Groups of individuals who are exposed to EB to the
greatest extent and could represent potential pools for
the expression of EB toxicity include: 1) individuals in
commercial situations where petroleum products or by-products
are manufactured (e.g./ rubber or plastics industry); 2)
individuals residing in areas with high atmospheric smog
generated by motor vehicle emissions.
Basis and Derivation of Criterion
The threshold limit value (TLV) of 435 mg/m3 (100
ppm) EB represents what is believed to be a maximal concentra-
tion to which a worker may be exposed for eight hours per
day, five days per week over his working lifetime without
hazard to health or well-being (Amer. Conf. Gov't. Ind.
Hyg., 1977). To the TLV, Stokinger and Woodward (1958)
apply terms expressing respiratory volume during an eight
hour period (assumed to be 10 m ) and a respiratory absorp-
tion coefficient appropriate to the substance under considera-
tion. In addition, the five-day-per-week occupational expo-
sure is often converted to a seven-day-per-week equivalent
in keeping with the more continuous pattern of exposure
to drinking water.
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According to the model, the amount of ethylbenzene
that may be taken into the bloodstream and presumed to be
noninjurious and which, hence, may be taken in water each
day is:
435 mg/m3 X 10 m3 X 0.5 X 5/7 week =1555 mg/day
(TLV) Respiratory Respiratory Proportion Maximum
Intake Absorption of week Noninjurious
Term Coefficient Exposed Intake
A safety factor of 1000 is used since no long-term or acute
human data are available, and there is very little informa-
tion from experimental animals (Natl. Acad. Sci., 1977).
Thus, 1555 mg/day divided by 1000= 1.555 or 1.6 mg/day.
To calculate an acceptable amount of EB in ambient
water, the methodology assumes a maximal daily intake of
2 liters of water per day, the consumption of 18.7 grams
of fish/shell-fish per day, a bioconcentration factor of
42 for fish and 50 percent absorption.
(x) (2 + 42 (0.0187)) 0.5 = 1.6 mg/day
Upper Oral Gastrointestinal Maximum
Intake Intake Absorption Noninjurious
Limit — Term Coefficient Intake
Solving for x, the value derived is 1.1 mg/1. According
to Stokinger and Woodward (1958), "This derived value repre-
sents an approximate limiting concentration for a healthy
adult population; it is only a first approximation in the
development of a tentative water quality criterion....several
adjustments in this value may be necessary...Other factors,
such as taste, odor and color may outweigh health considera-
tions because acceptable limits for these may be below the
C-24
-------
estimated health limit."
It should also be noted that the basis for the above
recommended limit, the TLV for EB, is the avoidance of irrita-
tion, rather than chronic effects (Am. Conf. Ind. Hyg.,
1977). Should chronic effects data become available, both
TLV's and recommendations based on them will warrant reconsid-
eration.
A second approach to calculating a maximum noninjurious
level of EB in humans involves the use of the no observable
adverse effect level in the six month toxicity study by
Wolf, et al. 1956. Table 8 indicates that 136.0 mg/kg/day
of EB produced no observable effects following oral adminis-
tration in rats. A 70 kg man could then ingest 9,520 mg
of EB/day. Using a safety factor of 10 (Natl. Acad. Sci.,
1977), this daily intake would be reduced to 9.5 mg/EB/day.
Using the same equation as above, assuming 2 liters of water
and 18.7g of fish ingested per day the equation becomes:
X (2 + 0.0187 x 42) * 0.5 = 9.5
1.39 X = 9.5
X = 6.8 mg/1
Therefore, using two different endpoints a criterion of
1.1 mg/1 or 6.8 mg/1 was calculated. The lower level will
be selected for the protection of public health.
It should be stated at this point that several important
assumptions were made in order to arrive at the Acceptable
Daily Intake (ADI). These include the facts that 1) the
TLV for EB was arrived at based on irritation; 2) no published
data exist on the percentage of EB absorbed; 3) the Wolf,
C-25
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et al. (1956) dosing study, upon which a no-effect dose
level for EB-contaminated water is based, was carried out
with ethylbenzene dissolved in olive oil. It has been demon-
strated (Withey, 1976a,b) that the rate and extent of uptake
from the G.I. tract of lipid soluble compounds is greatly
reduced when solutions in vegetable oil rather than water
are used; 4) 10 safety factor was used since no chronic
toxicity studies or reports on the teratogenicity, mutagenicity
or carcinogenicity of EB are available; 5) extrapolating
the dose effects from rat to man based on the no-effect
data of Wolf, et al. (1956) assumes, in part, equal absorption,
distribution and excretion of EB. Extensive animal data
are necessary before a definitive value can be determined.
It is to be stressed that this criterion is based on inadequate
chronic effects data and should be re-evaluated upon completion
of chronic oral toxicity studies.
In summary, based on a threshold limit value, and an
uncertainty factor of 1000, the criterion level for ethyl-
benzene corresponding to the calculated acceptable daily
intake of 1.6 mg/day, is 1.1 mg/1. Drinking water contributes
72 percent of the assumed exposure while eating contaminated
fish products accounts for 28 percent. The criterion level
can alternatively be expressed as 2.0 mg/1 if exposure is
assumed to be from the consumption of fish and shellfish
products alone.
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