United States
Environmental Protection
Agency
Office of Water
Regulations and Standards
Criteria and Standards Division
Washington DC 20460
EPA 440/5-60-048
October 1980
Ambient
Water Quality
Criteria for
Ethylbenzene
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AMBIENT WATER QUALITY CRITERIA FOR
ETHYLBENZENE
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvails, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
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DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document 1s available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
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FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P.L. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all Identifiable effects
on health and welfare which may be expected from the presence of
pollutants 1n any body of water, Including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628).
This document Is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special Interest groups, and Individual scientists. The
criteria contained In this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document 1s also
published 1n satisfaction of paragraph 11 of the Settlement Agreement
1n Natural Resources Defense Council, et. al. vs. Train. 8 ERC 2120
(D.D.C. 1976;, modified, 12 ERC 1833 (D.D.C. 1979).
The term "water quality criteria" 1s used 1n two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The term has
a different prograa Impact 1n each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented 1n this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
303 become enforceable maximum acceptable levels of a pollutant In
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
Incorporation into water quality standards. It is not until their
adoption as part of the State water quality standards that the criteria
become regulatory.
Guidelines to assist the States 1n the modification of criteria
presented 1n this document, 1n the development of •water quality
standards, and In other water-related programs of this Agency, are being
developed by EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
ill
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ACKNOWLEDGEMENTS
Aquatic Life Toxicology:
W111Ian A. Brungs, ERL-Narragansett
U.S. Environmental Protection Agency
John H. Gentile, ERL-Narragansett
U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects:
Richard A. Carchnan (author)
Medical College of Virginia
Steven D. Lutkenhoff (doc. ngr.)
ECAO-CIn
U.S. Environmental Protection Agency
Bonnie Smith (doc. ngr.)
ECAO-C1n
U.S. Environmental Protection Agency
Thomas J. Haley
National Center for Toxlcologlcal
Research
Van Kozak
University of Wisconsin
James Wlthey
Health and Welfare. Canada
John Autlan
University of Tennessee
Karen Blackburn, HERL
U.S. Environmental Protection Agency
Herbert Cornish
University of Michigan
Sherwln Kevy
Children's Hospital Medical Center
V.M. Sadagopa Ramanujam
University of Texas Medical Branch
Patrick Durkln
Syracuse Research Corporation
Technical Support Services Staff: p.J. Relsman, M.A. Garlough, B.L. Zwayer,
P.A. Daunt, K.S. Edwards. T.A. Scandura, A.T. Pressley. C.A. Cooper,
M.M. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks,
B.J. Quesnell, T. Highland, B. Gardiner.
Iv
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TABLE OF CONTENTS
Page
Criteria Summary
Introduction A-l
Aquatic Life Toxicology B-l
Introduction B-l
Effects B-l
Acute Toxldty B-l
Chronic Toxldty B-2
Plant Effects B-2
Miscellaneous B-2
Summary B-2
Criteria B-3
References B-8
Mammalian Toxicology and Human Health Effects C-l
Introduction C-l
Exposure C-2
Ingestlon from Hater C-3
Ingest1on from Food C-3
Inhalation C-5
Dermal C-5
Pharmacok1net1cs C-5
Absorption and Distribution C-5
Metabolism and Excretion C-6
Effects C-13
Acute, Subacute, and Chronic Toxldty C-13
Synergisra and/or Antagonism C-17
Teratogen1c1ty C-17
Mutageniclty and Cardnogenlcity C-17
Criterion Formulation C-19
Existing Guidelines and Standards C-19
Current Levels of Exposure C-19
Special Groups at Risk C-19
Basis and Derivation of Criterion C-21
References C-25
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CRITERIA DOCUMENT
ETHYLBENZENE
CRITERIA
Aouatlc Life
The available data for ethyl benzene Indicate that acute toxldty to
freshwater aouatlc Hfe occurs at concentrations as low as 32,000 wg/1 and
would occur at lower concentrations among species that are more sensitive
than those tested. No definitive data are available concerning the chronic
toxldty of ethyl benzene to sensitive freshwater aouatlc life.
The available data for ethyl benzene Indicate that acute toxldty to
saltwater aauatlc Hfe occurs at concentrations as low as 430 ug/1 and would
occur at lower concentrations among species that are more sensitive than
those tested. No data are available concerning the chronic toxldty of
ethylbenzene to sensitive saltwater aauatlc Hfe.
Human Health
For the protection of human health from the toxic properties of ethyl-
benzene Ingested through water and contaminated aauatlc organisms, the am-
bient water criterion 1s determined to be 1.4 mg/1.
For the protection of human health from the toxic properties of ethyl-
benzene Ingested through contaminated aauatlc organisms alone, the ambient
water criterion 1s determined to be 3.28 mg/1.
vi
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INTRODUCTION
Ethylbenzene (EB) 1s an alkyl-substituted aromatic compound which has a
broad environmental distribution due to Its widespread use 1n a plethora of
commercial products and Its presence 1n various petroleum combustion pro-
cesses. The two primary commercial uses of EB are 1n the plastic and rubber
Industries where 1t 1s utilized as an Initial substrate reactant 1n the
production of styrene (Paul and Soder, 1977). The majority of these com-
mercial sites of production are geographically clustered 1n Texas and Louis-
iana. The amount of EB produced 1n the United States 1n 1975 was approxi-
mately 6 to 7 billion pounds of which about 98 percent was used 1n the manu-
facture of styrenes (Table 1) (U.S. Int. Trade Comm., 1976).
Commercial production of EB currently utilizes a liquid phase FMedel-
Crafts alkylatlon of benzene with ethylene. According to Paul and Soder
(1977), at least 50 percent of the benzene used 1n the United States goes
Into the production of ethylbenzene. Significant quantities of EB are pres-
ent 1n mixed xylenes. These are used as diluents 1n the paint Industry, In
agricultural sprays for Insecticides, and 1n gasoline blends (which may con-
tain as much as 20 percent EB). In light of the large quantities of EB
produced and the diversity of products 1n which 1t 1s used, there exist many
environmental sources for ethylbenzene, e.g., vaporization during solvent
use, pyrolysis of gasoline, and emitted vapors at filling stations.
Ethylbenzene (CgHgt^Hg, molecular weight 106.16) (Figure 1) 1s a
flammable, colorless liquid with a boiling point of 136.25"C and a freezing
point of -95.01"C (Wlndholz, 1976). Its density at 25*C (relative to water
at the same temperature) 1s 0.866 (VMndholz, 1976) and 1t has a specific
gravity of 0.8669 (C1er, 1970). Its vapor pressure 1s 20 mm Hg at 38.6*C
A-l
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TABLE 1
Possible Environmental Sources of Ethylbenzenc*
Source EB Production/annum
Comerdal 6-7 billion pounds
Petroleum Cracking 0.57-0.96 billion pounds
(2-3*-of gasoline (volume) 1s EB)
Residues 1n polystyrene 0.19 billion pounds
Motor vehicle exhaust (and other 0.28 billion pounds
combustion and pyrolysis products)
*Source: U.S. International Trade Commission, 1976.
A-2
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FIGURE 1
Ethylbenzene - Chealcal Structure
CH2 CH3
TABLE 2
Ethylbenzene / Physical Properties*
Molecular weight 106.16
Color colorless
Boiling Point, 760 torr 136.2'C
Freezing Point -95"C
Flashpoint 16*C
Density (g/ml) • 20* C 0.87
Vapor Pressure, torr 20 at 38.6'C
Water Solubility wt. X 0.02**+
Taicen rrom cier (19/0); Gerarae (1963J.
For all practical purposes, EB 1s 'Insoluble1 1n water and due to Its
vapor pressure 1s probably present only 1n the atmosphere.
EB water solublty 161 ppn at 25]C 1n distilled water
111 ppm at 25*C 1n seawater
A-3
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(C1er, 1970). The log of the octanol/water partition coefficient for ethyl-
benzene 1s 3.15 (Tute, 1971). Ethylbenzene 1s slightly soluble (less than
0.1 percent or 866 mg/1) 1n water (Hann and Jensen, 1970), but 1t 1s freely
soluble 1n organic solvents (Table 2) (VMndholz, 1976).
A-4
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REFERENCES
American Hygiene Association. 1957. Ethyl benzene (Phenylethane). Hygiene
guide series. Am. Ind. Hyg. Assoc. Washington, D.C.
C1er, H.E. 1970. Klrk-Othmer Enyclopedla of Chemical Technology. Xylenes
and ethyl benzenes. 2nd ed. Intersdence Pub!., New York. 22: 467.
Gerarde, H.W. 1963. The aromatic hydrocarbons. III. j[n: F.A. Petty,
(ed.), Industrial hygiene and toxicology. John Wiley and Sons, Inc., New
York.
Hann, R.W., Jr. and P.A. Jensen. 1970. Water quality characteristics of
hazardous materials. Environ. Eng. D1v., Texas A and M Univ., College Sta-
tion.
Paul, S.K. and S.L. Soder. 1977. Ethyl benzene-sal lent Statistics. ln_:
Chemical Economics Handbood. Stanford Res. Inst., Menlo Park, California.
Tute, M.S. 1971. Principles and practice of Hansch analysis: A guide to
structure-activity correlation for the medicinal chemist. Adv. Drug Res.
5: 1.
U.S. International Trade Commission. 1976. Synthetic organic chemicals.
U.S. production and sales, Washington, D.C.
Wlndholz, M., (ed.) 1976. The Merck Index. Merck and Co., Rahway, New
Jersey.
A-5
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Aquatic Life Toxicology*
INTRODUCTION
The acute toxlclty data base for ethylbenzene and freshwater organisms
Indicates that there 1s not a large difference 1n sensitivity among the four
tested fish species and that Daphnla magna has similar sensitivity to ethyl-
benzene. Algal assays Indicated that Selenastrum caprlcornutum was much
more resistant.
There was a wide range of acute tox1city among saltwater species repre-
sented by three Invertebrate and two fish species. This range was from 430
to 1,030,000 wg/1.
EFFECTS
Acute Toxldty
An acute test with Daphnla magna (U.S. EPA, 1978) resulted 1n a 48-hour
EC5Q value of 75,000 vg/l (Table 1).
Pickering and Henderson (1966) conducted 96-hour tests with the gold-
fish, fathead minnow, guppy, and blueglll and the |_C50 values ranged from
32,000 to 97,100 yg/1 (Table 1). Two different Investigators' blueglll
LC5Q values, 32,000 and 155,000 yg/1, do not agree well but no explanation
Is available.
Only three tests have been conducted with saltwater Invertebrate spe-
cies, the 96-hour LC5(J for the mysld shrimp was 87,600 ug/l, for the bay
shrimp the LC5(J was 3,700 yg/1, and for the Pacific oyster 1t was
1,030,000 wg/l (Table 1).
*The reader Is referred to the Guidelines for Deriving Water Quality Cri-
teria for the Protection of Aquatic Life and its Uses 1n order to better un-
derstand the following discussion and recommendation. The following tables
contain the appropriate data that were found 1n the literature, and at the
bottom of each table are calculations for deriving various measures of tox-
ldty as described 1n the Guidelines.
B-l
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There Is an extreme, and unexplalnable difference (Table 1) between the
96-hour LC5Q values for the striped bass (430 wg/1) and the sheepshead
minnow (275,000 wg/1). This extreme variability 1n fish and Invertebrate
data suggests possible difficulties 1n testing ethylbenzene 1n saltwater.
Chronic Toxldty
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 wg/1 (Table 2).
Plant Effects
No adverse effects on cell number or chlorophyll £ production of Selena-
strua capHcomutum or Skeletonema costatum were observed at test concentra-
tions as high as 438,000 wg/1 (Table 3).
Miscellaneous
Potera (1975) conducted a variety of 24-hour exposures with the grass
shrimp using static procedures with measured concentrations (Table 4). Tem-
perature (19 and 2CTC), salinity (15 and 25 ppt), and life stage (larval and
adult) were the variables considered. The total range of LC_fl values 1s
10,200 to 17,300 wg/1 which small difference Indicates that these variables
did not have a very great effect. The copepod, NUocra splnlpes. was ex-
posed to ethylbenzene at salinities of 15 and 25 ppt and the 24-hour LCSO
values were both 16,000 ug/l (Table 4).
Summary
Four freshwater fish species have been acutely tested with ethylbenzene
under-static test conditions without measured concentrations. The 96-hour
LC5Q values ranged from 32,000 to 15.000 ug/l. The 48-hour EC50 value
for Daphn-ta magna was 75,000 wg/1 Indicating comparable sensitivity with
fishes. No effects on the embryo and larval stages of the fathead minnow
B-2
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were observed at concentrations as high as 440 ug/1. a concentration about
one-hundredth of the 96-hour LC5Q. No effects were observed on an alga at
concentrations as high as 438,000 vg/1.
The LC50 values for two saltwater fish and three Invertebrate species
varied widely with a range of 430 to 1,030,000 ug/1, no adverse effect on an
alga was observed at concentrations as high as 438,000 ug/1. No chronic
test with any saltwater species has been conducted. The effect of tempera-
ture, salinity, and life stage on the t ox 1 city of ethyl benzene to the grass
shrimp was studied and all LCgo values were within a range of 10,200 to
17,300 ug/1, which results Indicate no significant effect of those variables
on the 24-hour LCg0 values.
CRITERIA
The available data for ethyl benzene Indicate that acute toxldty to
freshwater aquatic life occurs at concentrations as low as 32,000 ug/1 and
would occur at lower concentrations among species that are more sensitive
than those tested. No definitive data are available concerning the chronic
toxldty of ethyl benzene to sensitive freshwater aquatic life.
The available data for ethyl benzene Indicate that acute toxldty to
saltwater aquatic life occurs at concentrations as low as 430 ug/1 and would
occur at lower concentrations among species that are more sensitive than
those tested. No data art available concerning the chronic toxldty of
ethylbenzene to sensitive saltwater aquatic life.
B-3
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Table I. Acute wlees for
Species
Netted*
LOO/GC50
(Ml/I)
Specie* Acute
Value (•o/l)
K49f •TABOO
FRESHWATER SPECIES
Cladoceraa,
Dephala aepna
Goldfish,
Caress 1 us auratus
Fathead Minnow,
PlMaphales proMelas
Fathead Minnow,
PlMaphales proMalas
Guppy,
PoecJIla reticulate
Blueglll,
LepoBls Macrochlnis
Blueylll,
LapoBls Mscrochlrus
Pacific oyster,
Crassostrea qlpas
Bay shrlap,
Crago franc ISCOTUM
Mysld shrlap.
My sloops Is babla
Sheepshead Minnow,
Cyprlnodon varleoatus
Striped bass,
Moron* sexatllls
S, U
s. u
S. U
S. U
s, u
S, U
s. u
s. u
S. M
s, u
s. u
S. M
75,000
94,440
48,510
42,330
97,100
32.000
155.000
SALTWATER
1,030,000
3,700
87,600
273,000
430
75,000
94.440
45.300
97,100
70,400
SPECIES
1,030,000
3,700
87,600
275.000
430
U.S. EPA, 1978
Pickering A Henderson,
1966
Pickering A Henderson,
1966
Pickering A Henderson,
1966
Pickering A Henderson,
1966
Pickering A Henderson,
1966
U.S. EPA, 1978
LaSora. 1974
Benvl 1 le A Korn, 1977
U.S. EPA, 1978
U.S. EPA, 1978
Benvl 1 le A Korn, 1977
• S • static, U • iraeesured. M • Measured
No Final Acute Values are calculable since the • In I
B-4
data base requirements are not eat.
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Table 2. Ckroalc valaaa for atkylbiaiaaa (U^. EPA, l>78)
Ckroalc
LlBlt* Vala*
(M/ll (no/1)
FRESHWATER SPECIES
Fattoad •IMWM. E-L >440
• E-L - Mtryo-larval
No acuta -chronic ratio Is 01 leu lab I*.
B-5
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Table 3. PlMt valaaa for •tftylbaaiana (U.S. EPA, 1971)
3-6
lit
*a«cla« Effact (no/1)
FRESHMTER SPECIES
Alga. Chlorophyll ± >43B.OOO
Salanaatruai caprlconuitua 96-hr EC90
Alga, Call mwbars M36.000
Salani
lanaatrua) caprlcornutuai 96-hr EC90
SALTMATER SPECIES
Alga. Chlorophyll a X43B.OOO
Shalatonaaa coatatua) 96-hr EC90
Alga. Call nuatars MM,000
Skalatonaaa coatatiw 96-hr EC90
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TabU 4. Ottar data for •ttoyl
(Potcra, 197S)
Spaclaa
Nltocra silnlpas
Copapod,
Nltocra splnlpaa
Grass shrlap (adult),
Palaaannatas puglo
Grass shrlap (adult),
Palasannatas puglo
Grass shrlap (adult),
Palaaionataa puglo
Grass shrlap (adult),
Palaaacnatas puglo
Grass shrlap (larva),
PalaasCTiatas puglo
Grass shrlap (larva).
Duration
SAITMATER SPECIES
24 hrs
24 hrs
24 hrs
24 hrs
24 hrs
24 hrs
24 hrs
24 hrs
I«f«ct
LC90
LC90
LC90
LC90
LC50
LC90
LC90
LC30
Raault
(M/D
16,000
16,000
14,900
14,400
17,300
17,300
10.200
10.200
Paliiarinatas puglo
B-7
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REFERENCES
Benvllle, P.E., Jr. and S. Kom. 1977. The acute toxlclty of six monocy-
cllc aromatic crude oil components to striped bass (Morone Saxatnis) and
bay shrimp (Crago franclsconm). Calif. F1sh and Game. 63: 204.
Lefiore, R.S. 1974. The effect of Alaskan crude oil and selected hydrocar-
bon compounds on embryonic development of the Pacific oyster, Crassostrea
glgas. Doctoral Thesis, Ltnlv. Washington.
Pickering, Q.H. and C. Henderson. 1966. Acute toxldty of some Important
petrochemicals to fish. Jour. Hater Pollut. Control Fed. 38: 1419.
Potera, F.T. 1975. The effects of benzene, toluene, and ethylbenzene on
several Important members of the estuarlne ecosystem. Ph.D. dissertation,
Lehlgh Univ.
U.S. EPA. 1978. In-depth studies on health and environmental Impacts of
selected water pollutants. U.S. Environ. Prot. Agency, Contract Ho. 68-01-
4646.
B-8
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Mammalian Toxicology and Human Health Effects
INTRODUCTION
The paucity of information available on the biological effects
of ethylbeniene (EB) in man and other mammalian species is rather
surprising considering the degree of exposure to EB in our environ-
ment. 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
aubcutaneous 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) com-
mercial, e.g., petroleum and petroleum by-products, (2) motor vehi-
cle 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 Value (TLV). The D.S. EPA recommended
carcinogenicity testing for EB in 1976, but test results are not
yet available. Similarly, no data exist for mutagenicity and tera-
togenicity of ethylbenzene. The potential adverse human health
effects following exposure to EB were stated (40 PR 1910.1034) to
be i
1) kidney disease,
EB is not nephrotoxic. Concern is expressed because the
kidney is the primary route of excretion of EB and its
metabolites.
2) liver disease,
EB is not hepatotoxic. Since EB is metabolized by the
liver, concern is expressed for this tissue.
C-l
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3) chronic respiratory disease,
Exacerbation of pulmonary pathology might occur follow-
ing exposure to SB. Individuals with imparied pulaonary
function night be at risk.
4) skin disease,
EB is a defatting agent and may cause dermatitis follow-
ing prolonged exposure. Individuals with pre-existing
skin problems may be more sensitive to EB.
EXPOSURE
Ethylbenzene has a broad environmental distribution due to its
widespread use in a plethora of commercial products and its pres-
ence 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 pro-
duction of styrene (Paul and Soder, 1977). The amount of EB pro-
duced in the United States in 1975 was between 6-7 billion pounds.
Almost all (97 percent) was captively consumed by the producers.
The majority 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 production of ethylbenzene. Sig-
nificant 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
C-2
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•olvent use, pyrolysis of gasoline, and emitted vapors at filling
stations.
Ingestion from Water
In a survey of water contaminants present in the drinking
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 pg/1 concentration. 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 Food
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 aquatic animals to the concentration in the water in
which they live. The steady-state BCFs for a lipid-soluble com-
pound in the tissues of various aquatic animals seem to be propor-
tional to the percent lipid in the tissue. Thus the per capita
C-3
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ingestion of a lipid-soluble chemical can be estimated from the per
capita consumption of fish and shellfish, the weighted average per-
cent lipids of consumed fish and shellfish, and a steady-state BCF
for the chemical.
Data from a recent survey on fish and shellfish consumption in
the United States were analysed by SRI International (U.S. EPA,
1980). These data were used to estimate that the per capita con-
sumption of freshwater and estuarine fish and shellfish in the
United States is 6.5 g/day (Stephan, 1980). In addition, these
data were used with data on the fat content of the edible portion of
the same species to estimate that the weighted average percent
lipids for consumed freshwater and estuarine fish and shellfish is
3.0 percent.
No measured steady-state bioconcentration factor (BCF) is
available for ethylbenxene, but the equation "Log BCF • (0.85
Log P) - 0.70" can be used (Veith, et al. 1979) to estimate the BCF
for aquatic organisms that contain about 7.6 percent lipids (Veith,
1980) from the octanol/water partition coefficient (P). Based on a
measured Log P value of 3.15 (Hansch and Leo, 1979), the steady-
state bioconcentration factor for ethylbenxene is estimated to be
95. An adjustment factor of 3.0/7.6 • 0.395 can be used to adjust
the estimated BCF from the 7.6 percent lipids on which the equation
is based to the 3.0 percent lipids that is the weighted average for
consumed fish and shellfish. Thus, the weighted average bioconcen-
tration factor for ethylbenzene and the edible portion of all
freshwater and estuarine aquatic organisms consumed by Americans is
calculated to be 95 z 0.395 - 37.5.
C-4
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Inhalation
EB probably represents about 10 percent of the total aromatic
compounds detected in the air and roughly one percent of the total
organic 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"6g/hr).
Dermal
No data are available on the dermal exposure of humans to
ethylbenxene.
PHARMACOKINBTICS
Absorption and Distribution
When administered subcutaneously to 40 rats (2.5 ml, 1:1 v/v),
ethylbenxene 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
C-5
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respiratory tract in a number of toxicity studies. Two representa-
tive studies have reported that significant amounts of EB can be
absorbed through the skin. Dutkiewicx and Tyras (1967, L968) have
shown (Table 1) that when human subjects are exposed to EB, there
is a "significant increase in the amount of urinary mandelic acid
excreted" (see Metabolism section). In addition, Smyth, et al.
(1962) reported an LD5Q for EB (via skin application) in rabbits of
17.8 ml/kg.
Dutkiewicx and Tyras (1968) also compared the skin absorption
of several other organic solvents, and they concluded that by com-
parison significantly more EB was absorbed (Table 1).
EB is readily absorbed by inhalation (see Table 2). Symptoma-
tology associated with acute intoxication of EB by this route in-
cludes coordination disorders, narcosis, convulsions, pulmonary
irritation, and conjunctivitis (Ivanov, 1962) (see Effects sec-
tion).
Ingestion of EB has been reported by a number of investigators
to produce a variety of dose-related toxicities in several differ-
ent species (see Effects section). The evidence 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 summarixed in Figure 1. These data
were taken from a series of different studies on rabbits as adapted
from the work of Kiese and Lenk (1974) (Table 3). This proposed
metabolic outline is consistent with reports on the metabolic fate
C-6
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TABLE 1
Skin Absorption of EB in Han*
EB concentration
Rate of Absorption
2
(mg/on ) hour
24-hour nandelic
acid excretion
(% of absorbed dose)
112-156 ng/1
0.11-0.21
4.6
*Sourcei Dutkievics and Tyras, 1968
C-7
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TABLE 2
Human Response to Ethylbenzene Vapors*
Concentration Exposure
mg/1 ppm tine
Response
21.75 5000 Few seconds Intolerable irritation of
nose, eyes and throat.
8.7 2000 Few seconds Severe eye, nose and mucous
membrane irritation.
Lacrimation.
8.7 2000 6 minutes Central nervous system
effects. Dizziness.
4.35 1000 Few seconds Eye irritation.
4.35 1000 Minutes Eye irritation diminishes
0.87 200 Threshold limit.
0.043 10 Few seconds Odor detectable.
*Sourcei Gerarde, 1963
C-8
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6) - oxidation
ethylbenzene phenylacetic acid
-1-oxidation
H^ 1-phenylethanol
L (-)
|r<
\
D (+)
oxidation
V
-oxidation acet°Phenone
•andellc acid
%
p ,hydroxy 1 odon \w_ox1 datl on
* *
*b
conjugated
phenaceturlc
acid
hlppurlc acid
metahydroxyacetophenone
5 ?
u -hydroxyacetophenone
p- hydroxyacetophenone phenyglyoxal
\
conjugation
phenylglyoxyllc
acid
FIGURE 1
Metabolic Pathways of Ethylbenxene
Sources Kieae and Lenk, 1974
C-9
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TABLE 3
EB Metabolites Found in Urine
of Rabbits given 1 gram i.p.*
% of administered EB
phenaceturic acid 10-20
mandelic acid 1-2
p-hydroxyacetophenone 0.13
m-hydroxyacetophenone 0.03
o-hydroxyacetophenone 0.1
hippuric acid 22-41
1-phenylethanol 30% 75% D(+),25% L(-)
*Source: Kiese and Lenk, 1974
Similar data were obtained by El Masry, et al., 1956.
C-10
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of EB in dogs (Nencki, 1878; Nencke and Giacosa, 1880; El Masry, et
al. 1956), cat liver microsomea (McMahon and Sullivan, 1966;
McMahon, et al. 1969), and in man (Bardodej and Bardedjeva, 1970;
Logemann, et al. 1964). The data presented in Table 3 indicate that
the major metabolites of EB are 1-phenylethanol, hippuric acid and
phenaceturic acid.
The study reported in Table 4 is excerpted in a modified form
from Bardodej and Bardedjova (1970). In this study of the metabo-
lism of EB by human volunteers, there are several significant omis-
sions which hamper a clear interpretation of the data. These in-
clude no indication of number, age, or sex of subjects or of their
physical condition prior to EB exposure. The methodologies des-
cribed in the text include spectrophotometry and paper chroma-
tography. These were probably not sensitive enough to detect many
of the metabolites. Indeed, the authors were unable to detect sev-
eral common metabolites of ethylbenzene, including acetophenone,
phenylethyleneglycol, w -hydroxyacetophenone, hippuric acid, and
mercapturic acid. Despite these shortcomings, this study contri-
butes to our understanding of EB metabolism in man. A considerable
amount of EB was absorbed in the respiratory tract; only traces of
EB were expired by the end of the experiment (Table 4). The major
metabolites found in the urine included mandelic and phenyl-
glyoxylic acid, 64 percent and 25 percent respectively, and 1-
phenylethanol, 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 reported fatigue,
C-ll
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TABLE 4
Metabolisa of EB in Man*
EB concentrations in 23,43,46,85
inspired air (ppa)
Duration 8 hours
% of vapor retained 64
in respiratory tract
(arithaw tic average)
Excreted in expired air traces
by the end of the (2-4%)
experiment
retained dose
eliminated in the urine
as mandelic acid 64%
as phenylglyoxlic acid 25%
as 1-phenylethanol 5%
*Source: Bardodej and Bardedjova, 1970
C-12
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Sleepiness, headache, and mild irritation of the eyes and respira-
tory tract.
EFFECTS
Acute, Subacute, and Chronic Toxicity
Gerarde (1963) has reviewed the acute toxicity data in humans
to SB via inhalation; these data are summarized in Table 2.
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 5). 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 5 to
10 percent aqueous solution of gum arable. The total volume admin-
istered 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.
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. Observations were made at three
minutes; one hour; and one, two, and seven days. A 5 percent
flourescein dye solution (water) was used to assess external injury
of the cornea (after three minutes). EB produced a slight con-
junct! val irritation but did not produce any injury to the cornea.
Wolf, et al. (1956) administered EB via the oral route to ten
white rats for approximately six months. They received daily sin-
gle doses 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 for this study included 20 white
C-13
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TABLE 5
Acute ToxicIty of Ethylbenxene*
Route of
Administration
oral
oral
•kin
inhalation
SP.C1..
rat
rat
rabbit
rat
both
male
male
female
No. of
Animals
57
5
4
6
^50
3.5 gm/kga
5.46 ml/kgb
17.8 ml kgb
4000 ppsi x 4 hrs.b
*Sourcea:
"wolf, et al. 1956
bSmyth, et al. 1962
C-14
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rats that received 2.5 ml olive oil emulsified in gum arabic. The
findings (Table 6) 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 narrow counts of nucleated cells.
Wolf, et al. (1956) also evaluated the ability of EB to pro-
duce injury to the skin (rabbit). EB was tested undiluted, 10 to 20
applications to the ear and onto the shaved abdomen for two to four
weeks. EB produced moderate "erythemal" edema, superficial necro-
sis, skin blistering, and chapped appearance and exfoliation of
large patches of skin.
The effects of repeated exposures of EB via inhalation are
summarized in Table 6. Matched groups of 10 to 25 rats, 5 to 10
guinea pigs, 1 to 2 rabbits, and 1 to 2 rhesus monkeys were used in
these studies. Exposure in the 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 are primarily only slight
changes in liver and kidney weights.
When acutely exposed to ethylbenzene vapors at concentrations
of 1,000 to 10,000 ppm, guinea pigs developed leukocytesis (Yant,
et al. 1930). Ivanov (1964) reported a study in which rabbits were
subchronically exposed to EB via inhalation. The animals were ex-
po«*d to approximately 230 ppm EB, four hours/day for seven months.
This author reported "changes in blood cholinesterase activity,
C-15
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TABLE 6
Repeated Exposure by Vapor Inhalation to EB in Animals*
Species
rat
guinea
pig
rabbit
rhesus
monkey
Average Vapor
Concentrations
pp» «g/i
2,200
1,250
600
400
1,250
600
400
1,250
600
400
600
400
9.5
5.4
2.6
1.7
5.4
2.6
1.7
5.4
2.6
1.7
2.6
1.7
Sex
male
both
both
both
female
both
both
female
both
both
both
female
7hr.
Exposures
No.
103
138
130
130
138
130
130
138
130
130
130
130
Duratioi
144
214
186
186
214
186
186
214
186
186
186
186
1 Effects**
G++J Lw+r Kw++; Lp+; Kp+
G+j Lw+; Kw+f
Lv+; Kw+
Lw+j Kw+
G+
Lw+
no effect
Tp+
no effect
Lv+) Tp+
no effect
Lp+f Kp+
*Sourcei Wolf, et al. 1956
**G
v
P
L
K
T
growth depression
weight
histopathology
liver
kidney
testes
The intensity of response is noted as follows:
± • questionable
+ • slight
++ - moderate
C-16
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decreased plasma alb main, increased plasma globulins, leukocyte-
sis, reticulocytosis, cellular infiltration and lipid dystrophy in
the liver, dyatrophic changes in the kidney and muscle chronaxia."
Synergism and/or Antagonism
Pertinent data could not be located in the available litera-
ture regarding the possible synergism and/or antagonism of EB with
other substances.
Teratogenicity
Pertinent data could not be located in the available litera-
ture regarding the terotogenic activity of EB.
Mutagenicity and Carcinogenicity
Pertinent data could not be located in the available litera-
ture regarding the mutagenicity of EB, although four common metabo-
lites of EB (d-1-mandelic, phenylglyoxylic, and hippuric acids)
gave negative results in the Ames test using the five tester
strains (Salmona, et al. 1976).
Pertinent data could not be located in the available litera-
ture regarding the carcinogenicity of EB.
Speculation on mutagenic and carcinogenic activities may be
appropriate. Gillete, et al. (1974) have reviewed certain consid-
erations of drug toxicity including those related to possible car-
cinogens. 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
physical/chemical categories of ouitagenic and/or carcinogenic
agents. Although EB metabolites do not show any mutagenic activi-
ty/ styrene, an EB manufacturing product, can undergo metabolism to
C-17
-------
an epoxide Intermediate (Salmona, et al. 1976), which is a possible
carcinogen and which demonstrates a positive mutagenic response in
the Ames test.
C-18
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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/m ) (American Conference of Governmen-
tal Industrial Hygienists (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 8-fold less
than current U.S. TLV standards (ACGIH, 1974).
Current Levels of Exposure
Airt Several investigators have reported that ethylbenzene is
present in the ambient atmosphere at a level of approximately 0.01
ppm. (Altshuller and Beliar, 1963; Lonneman, et al. 1968; Neligan,
et al. 1965).
Wateri Shackelford and Keith (1976) reviewed the literature on
EB contamination and concluded that it was detected in most of the
potable waters tested. No data were reported on the levels of EB in
potable waters.
Food: With the exception of the report by Kinlan, et al.
(1972), EB has not been reported to be present in food.
Industrials 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 petroleum by-
products, e.g., polymerisation workers involved in styrene produc-
tion, may be at risk. In a study of 494 styrene workers, Lilis, et
al. (1978) reported various neurotoxic manifestations. These in-
cluded prenarcotic symptoms, incoordination, dixsiness, headache
C-19
-------
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
ntnber of different precursors, by-products, and end products. In
this particular study, toxic effects were reported, but there was a
general lack of symptoas 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) report-
ed on the relationship between styrene exposure and symptoms of
central nervous system dysfunction in 98 occupationally 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 paychomotor performance.
A National Institute for Occupational Safety and Health
(NIOSH) report by Rivera and Rostand (1975) on worker exposure to
various lacquer constituents (including EB in a baseball bat manu-
facturing 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 occu-
pational situation again illustrates the fact that these workers
were exposed to more than one chemical in addition to EB.
C-20
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Cigarettes contain 7 to 20 x 10"6g of EB per cigarette (John-
atone, et al. 1962). Conkle, et al. 1975 have reported that moder-
ate cigarette smokers expired up to 14 x 10 ~6 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 includei (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 Criteria
The threshold limit value (TLV) of 435 mg/m3 (100 ppm) EB
represents what is believed to be a maximal concentration 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
(ACGIH, 1977). To the TLV, Stokinger and Woodward (1958) apply
terms expressing respiratory volume during an eight hour period
(assumed to be 10 m3) and a respiratory absorption coefficient
appropriate to the substance under consideration. In addition, the
five-day-per-week occupational exposure is often converted to a
seven-day-per-week equivalent in keeping with the more continuous
pattern of exposure to drinking water.
According to the model, the amount of ethylbenxene that may be
absorbed without effect can be calculated as follows:
435 mg/m3 I 10 n3 I 0.5* 15/7 week • 1555 mq/day
(TLV) Respiratory Respiratory Proportion Maximum
Intake Absorption of week Noninjurious
Term Coefficient Exposed Intake
C-21
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A. safety factor of 1000 is used since no long-term or acute inges-
tion human data are available, and there is very little information
from experimental animals (National Academy of Sciences (HAS),
1977). Thus, 1555 mg/day divided by 1000 • an allowable daily
intake (ADI) of 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 6.5 grams of fish/shellfish per day, a bio-
concentration factor of 37.5 for fish and 50 percent absorption.
(x) (2 + 37.5 (0.0065)) 0.8* 1.6 mg/day
Upper Oral Gastrointestinal Maximum
Intake Intake Absorption Noninjurious
Limit Term Coefficient Intake
Solving for x, the value derived is 0.89 mg/1. According to Stok-
inger and Woodward (1958),
This derived value represents 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 considerations because
acceptable limits for these may be below the estimated
health limit.
It should also be noted that the basis for the above recom-
mended limit, the TLV for EB, is the prevention of irritation,
rather than chronic effects (ACGIH, 1977). Should chronic effects
data become available, both TLVs and recommendations based on them
will warrant reconsideration.
*Given the chemical and physical properties of ethylbenzene, these*
absorption coefficients seem reasonable. They are recognized to be
somewhat judgemental due to the limited data; however, their ef-
fect on the final criteria is minimal.
C-22
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A second approach in calculating an allowable daily intake
(ADI) level of EB in humans involves the use of the no-observable-
adverse-effect level (NOAEL) in the six month toxicity study by
Wolf, et al. (1956). Table 6 indicates that 136.0 mg/kg/day of EB
produced no observable effects following oral administration in
rats. A 70 kg man could then ingest 9,520 rag of EB/day. Using a
safety factor of 1,000 {HAS, 1977), this daily intake would be
reduced to 9.5 mg of EB/day. Using the same equation as above,
assuming 2 liters of water and 6.5 g of fish ingested per day the
equation becomes:
I (2 + 0.0065 x 37.5) • 0.5 - 9.5
1.12 Z • 9.5
I - 8.5 mg/1
Therefore, using two different endpoints a criterion of 1.4 mg/1 or
8.5 mg/1 was calculated. Although both criteria are defensible,
the criterion based on the TLV is recommended for two reasons.
First, the animal toxicity study involved an exposure period of
only six months. Secondly, the TLV represents a body of human
experience with the chemical which is apparently protective. It
should be noted that the criteria are not substantially different.
The assumptions used to derive the Acceptable Daily Intake
(ADI) were based on the TLV for EB. Several of these assumptions
can be supported further by published datat (1) Although the TLV
of 435 mg/m was based on irritation, Bardodej and Bardedjova
(1970) reported a NOEL of 370 mg/m , with higher levels causing
fatigue, sleepiness, and headache, in addition to eye and res-
piratory tract irritation; (2) although a 50 percent inhalation
C-23
-------
absorption factor was used, Bordodej and Bardedjova (1970) reported
that 64 percent of the EB vapor was retained (absorbed) in the
respiratory tract; (3) the Wolf, et al. (1956) dosing study, upon
which a no-effect dose level for EB-contarninated water is based,
was carried out with ethylbenzene dissolved in olive oil. It has
been demonstrated (Withey, 1976a,b) that the rate and extent of
uptake fron the G.I. tract of lipid soluble compounds is greatly
reduced when solutions in vegetable oil rather than water are used;
(4) a safety factor of 1,000 was used since no chronic toxicity
studies or reports on the teratogenicity, mutagenicity or carcino-
gen icity of EB are available; and (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 excre-
tion of EB. Extensive animal data are necessary before a defini-
tive value can be determined. It is to be stressed that this cri-
terion is based on inadequate chronic effects data and should be
re-evaluated upon completion of chronic oral toxicity studies.
In Bunaary, based on a threshold limit value and an uncertain-
ty factor of 1,000, the criterion level for ethylbenzene correspond-
ing to the calculated acceptable daily intake of 1.6 mg/day is 1.4
mg/1. Drinking water contributes 89 percent of the assumed expo-
sure, while eating contaminated fish products accounts for 11 per-
cent. The criterion level can alternatively be expressed as 3.28
mg/1 if exposure is assumed to be from the consumption of fish and
shellfish products alone.
C-24
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C-25
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