FINAL REPORT

MONOGRAPH ON HUMAN EXPOSURE TO

CHEMICALS IN THE WORKPLACE:
ETHYLENE OXIDE
Prepared by:
Center for Chemical Hazard Assessment
Syracuse Research Corporation
Syracuse, NY 13210
Prepared for:
Division of Cancer Etiology
National Cancer Institute
Bethesda, MD 20205
Contract N01-CP-26002-03
July, 1985
REPRODUCED BY
NATlONAL TECHNICAL
INFORMATION SERVICE
u.s. DEPARTMENT OF COMMERCE
SPRINGFIELD. VA. 22161
PB86143559
1111111111111111111111111111111111111111111111111111111
SRC-TR-84-668
Page Intentionally Left Blank
PREFACE
This report presents a summary and evaluation of information relevant to
an occupational hazard assessment of ethylene oxide. Pertinent toxicologic
data were located through on-line and manual literature searches fer the
period extending back approximately ten years from 1984. No attempt was made
to exhaustively review the toxicologic literature; where apropriate the reader
is referred to comprehensive reviews on this topic. Special attention in this
report was focused on summarizing the available information regarding the
carcinogenic potential of ethylene oxide.
Information concerning production uses and worker exposure potential was
identified from handbook sources as well as on-line searches of bibliographic
and numeric data bases. Data regarding actual or estimated levels of exposure
in the workplace were considered especially important. In particular, an
attempt was made whenever possible to relate exposure concentrations with
specific job categories and specific industries or chemical uses. Tne
objective in deriVing such relationships is to assist in the identification of
groups of workers or occupations that warrant further epidemiologic
investigation.
For many occupations and industries, quantitative worker exposure
information is not available andlor cannot be. estimated from the existing
pUblished data. Such a finding represents an important conclusion in this
report, and indicates the need to develop industrial hygiene information prior
to initiation of occupational health studies. In lieu of documentation on
levels of worker exposure, this report discusses the available surrogates that
ii
may serve as indirect indicators of exposure magnitude, such as vapor
odor threshold, nature of industrial process, etc.
The Syracuse Research Corporation was responsible for preparation of
report under contract N01-CP-26002-03 with the National Cancer Institute.
Principal authors of the report are as follows:
Joseph Santodonato, Ph.D., CIH (Project Director)
Stephen Bosch, B.S.
William Meylan, B.S.
John Becker, M.S.
Michael Neal, Ph.D.
Any opinions expressed in this report are those of the contractor and not
necessarily the National Cancer Institute.
iii
TABLE OF CONTENTS
FBEFACE. . ili
LIST OF TABLES.......................................................... ,tV
LIST OF FIGURES.........................................................
1.
2.
3.
CHEMICAL AND PHYSICAL PROPERTIES
PRODUCTION AND USE
2. 1. PRODUCTION
2.2. USE...........
EXTENT OF OCCUPATIONAL EXPOSURE
3.1. PREDICTED EXPOSURE TO ETHYLENE OXIDE BY UNIFORM TASK CATEGORY.
3.2. DETERMINATION OF SPECIFIC JOBS OR OPERATIONS WITHIN INDUSTRIAL
SECTORS WITH POTENTIAL FOR ETHYLENE OXIDE EXPOSURE
iii If'\.
i-el,

3.2.1.
3.2.2.
3.2.3.
Ethylene Oxide Production
Sterilization of Medical Properties by the Manufacturer.
Sterilization of Medical Products in Health Care
Facilities.........
Sterilization of Other Commodities by the Manufacturer
Other Operations Using Ethylene Oxide as a Sterilant
4.
5.
6.
8.
3.3. EXTENT OF OCCUPATIONAL EXPOSURE
PHARmcOKINETICS...............................
4. 1. ABSORPTIONo
4.2. DISTRIBUTION...........
4- ., 3. l-tETABOLISM
4:. -_11:. -_ - -
BIOLOGICAL DATA RELEVANT TO CARCINOGENESIS
5.1. ANIMAL CARCINOGENICITy
5 .2. MOTAGENICITY
EPIDEMIOLOGICAL STUDIES
SUMi1ARY AND CONCLUSIONS _. '
REFERENCES. _ _
iv
T-t

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LIST OF TABLES
No. Title ~
1-1 Physical Properties of Ethylene Oxide............................ ~ i
2-1 United States Production and Sales of Ethylene Oxide............. 2-2
2-2
2-3
2-4
2-5
3-1
3-2
3-3
United States Producers of Ethylene Oxide
Ethylene Oxide Consumption Patterns in the United States
Ethylene Oxide Consumption for Derivation in 1982
Users and Use Sites of Ethylene Oxide
Reported and Predicted Exposure to Ethylene Oxide by Uniform Task
Category/Industrial Sector
Number of Workers Exposed to Ethylene Oxide by Industry Sector
Summary of Exposure Information From Epidemiology Studies
v
2-"'":'
2.
-...0
".,
3-7
3-8
Page Intentionally Left Blank
No.
2-1
2-2
LIST OF FIGURES
Title
Chlorohydrin process for manufacturing ethylene oxide
Direct-oxidation process for manufacturing ethylene oxide
VI
Page Intentionally Left Blank
1. CHEMICAL AND PHYSICAL PROPERTIES
Et.hylene oxide (oxirane, dimethylene oxide, 1,2-epoxy-ethane, ETC) is a
colorless gas with an ether-like odor that condenses at low temperatures (1Q
c
C)
to a mobile liquid. It is miscibIe in all proportions with water, alcoha1.,
etper, and most organic solvents (Cawse et al., 1980). The physical properties
of ethylene oxide are summarized .inTable 1-1.
Ethylene oxide is a highly reactive molecule; industrially, it is primarily
a chemical intermediate for a wide variety of compounds (Cawse et al., 19SQ;
Schultze, 1965). Most reactions involve the opening of' the three-membered rirls;.
Ethylene oxide reacts with compounds having an active hydrogen such as
and amines; also, ethylene oxide will polymerize. It is considered a potential
environmental pollutant; in the atmosphere, it reacts in the normal
photochemical cycle to form smog (Cawse et al., 1980). Ethylene o%ide
thermodynamically unstable, decomposing exothermically at >500
c
C in the
of a catalyst to methane, carbon monoxide, ethane, hydrogen and carbcc.
vapors of ethylene oxide are flammable and explosive.
Commercially, ethylene oxide is sold only as a high-purity chemical.
purity is so high (>99.95S) that no specific impurities are listed in
ssc shown belcrw" (Cawsa e.t- 1 }:
a,cidity
aldehydes
water

suspended matter
color
acetylene
0.002 max as acetic acid
max as acetaldehyde
0.03 wt,. max
0.005 g"OO m! max
SUbstantially free
10 Pt-Co, max
none
1-1
2. PRODUCTION AND USE
2.1. PRODUCTION
Ethylene oxide was first commercially produced in the United States in 19211
(IARC, 1976); production reached 16 million pounds by 1930 and 110 million pounds3
by 1940 (Schultze, 1965). United States workers have, therefore, b.een:
potentially exposed to this chemical for >60 years.
Annual production and sales figures for ethylene oxide are listed in
2-1, which states that sales total only of production, indicating that
production is captively consumed. In fact, most ethylene oxide productiont
continues to be consumed at the plant site, chiefly for ethylene glycol.
synthesis, which accounts tor nearly two-thirds of production (Chemical anc11
Engineering News, 1983). Historically, for the period 1970-1980, demand fOl!'
ethylene oxide grew at a rate of per year (CHR, 1981); demand is expected
show 11t tle significant change through 1984 (Chemical and Engineering News,
1983). In foreign trade, exports were probably <10 million pounds, and import$
<50.million pounds during 1983 (Chemical apd Engineering News, 1983).
Ethylene oxide is produced commercially by two basic routes, the
chlorohydrin and the direct oxidation processes (Cawse et al., 1980). The
process is older and involves the reaction of ethylene with hypochlorous
followed by dehydrochlorination of the resulting chlorohydrin with lime
produce ethylene oxide and calcium chloride. Figure 2-1 depicts the chlorohydrm
In 1955, the chlorohydrin process accounted for of the
States ethylene oxide production, but advantages of the direct oxidaticm.
technology reduced this percentage to in 1978. Dow Chemical's Freeport,
facility is the only United States plant using this chlorohydrin technology.
The direct oxidation process completely dominates the ethylene oxide
today (cawse et al., 1980). The. fundamental reaction 1s the catalytic oxidatlQft
1- J,
TAELE 1-1
Physical Properties of Ethylene Oxide-
------------------------ --------
Property
CAS Eegistry Number
Chemical structure
Empirical formula
Boiling point (CC, 760 mm Hg)
Freezing point (CC)
Vapor Pressure (at OCC, mm Hg)
(at 20
c
C, mm Hg)
(at 30
c
C, mm Hg)
Density (kg/t at 20
C
C)
Viscosity (cP atOCC)
Refractive index (n7/D)
Flash point (tag open cup, CC)
Explosive limits in air, vol%
upper
lower
Critical temperature (CC)
Dielectric constant (at OCC)
factors
Source: Cawse et al., 1980; Verschueren, 1983
;l-I
Value
------------
75-21-8
/Q\
CH
2
-CH
2

10.14
-112.5

1094
1558
0.8697
0.325
1.3597
<18
lOa
3
195.8
13.71
1 mg/m
3
=
1 ppm =1.83 mg/m.J
TABLE 2-1
United States Production and Sales of Ethylene Oxide.
-----------------------,----
Year
Millions of Pounds
Production Sales
--------------------------------------------------------------
1983
1982
1981
1980
1979
1978
1977
1976
1975
1974
1973
1972
1971
1970
1969
1968
1967
1966
1965
1964
1963
1962
1961
1960
1955
1950
1940
1930
5200 NR
4987 379
4937 344
5220 531
5665 560
5012 525
4364 549
4184 439
4467 409
4200 457
4200 501
4250 454
3740 391
3990 411
3525 438
2805 394
2410 302
2410 304
2190 256
2163 198
1889 170
1595 157
1329 128"
13'7'9- 123
876 128
454 NR
110 NR
16 NR
------
--
.Source: USITC, annual; USTC, annual; Chemical and Engineering News,
1983; Schultze, 1965
Nft = Not. reported
2-2
Copyright@ 1965, John Wiley &Sons, Inc.
Reprinted by permission of John Wiley &Sons, Inc.
........
1:!lt1l.1e todf
Il:rohbara
ChflWMydfln
..-.nr lIItd
eondantIr Hydrolv"'
flit"......Ida
diltillatlon
IV"-
I
.1'

FCV
I
.1'
3
, R.,....
'hylene
OIlHb '0
.'or.
Ii LeV
B
tn
.t
i\:
I
Mllfe 01 lime
R8llVejIe
hy....,,11
Chlorlfll

mmt
N

W
Wa'. -,.,-e-t-I
Wa....
c.,cimn
th'OIhla
and tome
""y'a",
Ili"II01;d.
Chlorln....
hydroc8fbon
by - prodllC:tI
t,. t8GOllllry
"nit
Flg'ln, 2 I. G.b.lOI'ohydrln pI'oce ss foI' manufaetu:ring \ethylene oxj.de (Schultze, 19
6
5) \
of ethylene with oxygen over a silver-based catalyst to yield ethylene
Direct oxidation processes are divided into two categories depending on
source of the oxidizing agent: the air-based process and the oxygen-has::ed.
process. In the first process, air, or air enriched with oxygen, 1s fed dir-ectly'
to the system. In the second, a high purity oxygen stream (>95 IDol %) froID aml ait"
unit is employed as the source of the oxidizing agent.
outlines the general direct oxidation process. Table 2..2 lists the e:umcenrtt
United States producers of ethylene oxide along with their locatic:m::! am:!!
capacities.
2.2. USE
More than 98% of the total production of ethylene oxide is convertea to
derivatives (Cawse et al., 1980); a more exact figure for derivative use DJa'
99.8%. The consumption pattern of ethylene oxide in the United States ia
in Table 2-3. Table 2..4 shows the 1982 production of some ethylene oE:.de:
derivatives and the corresponding amount of ethylene oxide needed
production.
derivatives.
Table 2..5 identifies the major users and use sites for
A general description of the various uses of ethylene oxide is
below.
-
Ethylene Glycol: By far, the largest single use of ethylene oxide is- in:,
synthesis of ethylene glycol. Ethylene glycol is used to make polyester
and film and in automobile antifreeze (Cawse et al., 1980).
1>1-, Tr.i-, Tetra- and Polyethylene Glyool: Diethylene, triethyl..etIe ami
tetraethylene glyool are obtained mainly as by-products of ethylene gIy-en!
Diethylene glyool is used to make polyurethane and polyest,&.l'
resins, morpholine, textile agents, 1n gas dehydration, in solvent
and 1n antifreeze blending (CMR, 1979), while triethylene glyoolis used in
2-4
I\)

Main,
reactor
Compressor

absor,Mr
Pur...
fIIl1Ctor
RecVc'e wator
Ethvlene oKide lolution
Pufll
worMr OMorber Stripper
Steom
neflner
EthVlene
oKidll
Fli',de 2. ui"ecl' ())(LL,tiol\ fill r.<\l\I'l\rfac.lurlll
"
,'ihyli.:'I1L (j)(k,l<: ("indi", I 1965)
TABLE 2-2
United States Producers of Ethylene OXide
------------- -------------- -----
Producer Location
Annual Capacity
(Millions of Pounds)
-------------------------------------------------------
BASF Wyandotte Corp.
Celanese Corp.
Dow Chemical
Eastman Kodak
ICI Americas
Inter North (Northern Petrochem)
Olin Corp.
PD GlycolC
PPG Industries
Shell Chemical
Sun Olin Chem.
Texaco
Union Carbide
Geismar, LA
Clear Lake, TX
Freeport, TX
Plaquemine, LA
Longview, TX
Bayport, TX
Morris, IL
Brandenburg, II
Beaumont, TX
Beaumont, TX
Geismar, LA
Claymont, DE
Port Neches, TX
Penuelas, PR
Seadrift, TX
Taft, LA
Total
480
450
280
b
450
190
500
230
110
455
155
700
100
700
630
1000
1325
7755
------------------------------------------------------------------------
aSource: SRI, 1983
bTo be increased to 850 million pounds
t! ~ ~ .
-Joint venture of PPG Ind. and D u ~ o n t
2-6
TABLE 2-3
Ethylene Oxide Consumption Patterns in the United States
Derivative Year
Ethylene 81ycol
Surfactants
Glycol ethers
Ethanolamines
Miscellaneous (includes
higher glycols, urethane
polyols, exports)
Percent
1981
b
1978
c
1975
d
62 62 60 60
12 12 11 11
7 6 7 7
7 5 7 6.5
12 15 16 16. 5
Derivative
Ethylene glycol
Non-ionic surfactants
Glycol ethers
Diethylene glycol
. Ethanolamines
Triethylene glycol
Polyethylene glycol
Exports
Miscellaneous
a
Source::CHR,
b .
Source: CMR, 1981
CHE, 1978
CME, 1975
e
Source: Lawler, 1977
Year
63
11
6
5
5
2
2
TABLE 2-11
Ethylene Oxide Consumption for Derivatives 1n 1982
---------------.............
Derivative
Millions of Pounds
Ethylene
Oxide
1982 Production
a
consumption
b
Percentage

Glycols:
Ethylene glycol
Diethylene glycol
glycol
?olyethylene glycol
glycol
Ethanolamines:
Monoethanolamine
Diethanolamine
Triethanolamine
Glycol Ethers:
Ethylene - monoethyl ether
- monomethyl ether
- monobutyl ether
Diethylene glycol - monoethyl ether
- monomethyl ether
- monobuty1 ether
Triethylene glycol - monoethyl ether
- monomethy1 ether
- monobutyl ether
11309
394
95
73
17
150
145
120
178
89
217
28
28
118
20
22
6
3232
331
86
80
16
3745
113
128
112
353
96
52
89
19
21
28
16
18
4
34-3--
64.8
6.6
1.1
1.6
0.3
75.0
2.3
2.6
2.3
7.2
---------------------------_.-, -------
&uSITC, 1983
b
Calculated trom conversion factors from Blackford, 1976
caased upon an ethylene oxide production of 4987 million pounds in 1982 (USITC, 1983)
2-8
tABLE 2-5
Users and Use Sites of Ethylene Oxide
------------- ---- . ---------_....,--------------------------------------------------------------------------------
Producer
"
Looation
Ethylene Glycol
Glycol Ethers
Diethylene
Glycol
Ethanol Triethylene
Amines Glycol
Polyethylene Polyether
Glycol Polyols
Anco
BASF Wyandotte
carpenter Chem.
Celanese Chem.
Dow Chemical
Eastman Kodak
"oadag Chemical
ICI Americas .
3M
Mobay Chem.
I\)
I
Northern Petroohem.
011n Corp.
Pelron Corp.
PPG Industriea
Shell Chem.
Texaco Chem.
Union Carbide
\tIitco Chem.
-----_....----------------------------------------------------------------------------------
,'.
Channelview, TX X
Wyandotte. HI X
Ge1l'Jmar, LA 1 1 X
Washington, NJ X X
Spartanburg, SC X
Bayport, TX X
Clear Lake, TI X X X
Freeport, TX X X X X X
Plaquemine, LA X X X 1 X
Midland. HI X
Longview, TI 1 X X X
Skokie, IL X
Bayport, TI 1 1 X 1 1
Decatur, AL X
Cedar Bayou. TI X
New Martinsville, WV X
Morris, IL X 1
Lake Charles, LA X
Brandenburg, KY X X X X X
Lyons, IL X
. Beaumont, TI X X X X
Circleville, OU X
Geismar, LA X X 1 X
Port Neohes, 11 1 1 1 X 1 X X
Seadri rt, TX X 1 X X
Taft, LA X X X X
Penuelas, PO X X X X
Texas City, TX X
Institute and S.
Charleston, WV X
Chicago, IL X
_____________ ,u__ __ __ __ __ _
Sftt e 1903
,r '"' CI\(: , tell I 19 .wmchcet'\
dehydration, as a solvent, as a humectant, and in the synthesis of vinyl
plasticizer, polyester resins and polyols (CMR, 1982). Tetraethylene glycol
uses include extractions and solvents (Brown et al., 1980). Polyethylene glycol
uses are similar to those listed above (Hawley, 1981).
Ethanolamines: These are formed by reacting ethylene oxide with ammonia.
and are used in gas conditioning and synthesis of soaps and detergents (Cawse et
a1., 1980).
Glycol Ethers: Glycol ethers are formed by reacting ethylene oxide with
appropriate alcohol, and are used as solvents for lacquers, resins, enamela:,.
epoxy ooatings, water-based ooatings, varnishes and printing inks, and as _
anti-ioing agent in jet fuels. (Cawse et a1., 1980).
Surfaotants: Surfaotants made from ethylene oxide are used as detergent.
(Cahn and Lynn, 1983; Cawse et a1., 1980). Many ethoxylated compounds art
oommeroially produoed as surfaotants, at numerous manufacturing sites. Some ot
the larger manufaoturers making ethylene oxide surfaotants inolude Prooter and
Gamble, Lever Brothers, Henkel Corp., Witco Chemical, GAF Corp., .Stepaa
Chemical, Alcolao, Diamond Shamrook, Hodag Chemical, ICI Amerioas, Milliken
Company, Rohm and Haas, Texaoo, Union Carbide, Emery and BASF Wyandotte
1983)
Misoellaneous Applioations: Ethylene oxide is oonsumed in the synthesis ot
many oommercial ohemioals. The largest amount in the misoellaneous group goes
into the produotion of polyether polyols for flexible polyurethane foams. Ia
1975, :75 million pounds of ethylene oxide were oonsumed in these polyols
(Blaokford, 1976). Tbe major manufacturers of these polyols are shown in Table
2-5.
Approximately 13-18 million pounds of ethylene oxide are used annually to
make the medicinals oholine and oholine chloride (Blackford, 1976). Manutac.
turers inolUde Diamond Shamrook, IMC Chemioal and Syntex Corp. (SRI, 1983).
2-10
Approximately 10 million pounds of ethylene oxide are used annually in the
manufacture of hydroxyethyl starch, which is a semi-synthetic gum used in textile
sizing and adhesives (Elackford, 1976). Bydroxyethyl cellUlose is produced by
reacting cellulose with ethylene oxide. In 1975, 20 million pounds of ethylene
oxide were used to make these adhesive additives (Elackford, 1976). Hydroxyethyl
starch is made by. Nabisco in Clinton, lA, while hydroxyethyl cellulose is made by
Union Carbide and Hercules, Inc. (SBI, 1983).
Arylethanolamines are made by reacting ethylene oxide with either aniline
or aniline derivatives. It is estimated that 3 million pounds of ethylene oxide
were used for arylethanolamines in (Elackford, 1976). They are used as
intermediates for monoazo dyestuffs.
Acetal copolymer resins are produced by catalytically copolymerizing 1,3,5-
trioxane with a cyclic ether having at least two adjacent carbon atoms (e.g.,
ethylence o%ide). Ethylene oxide consumption for these resins is believed to have
amounted to =2-3 million pounds per year from 1972-1975. Acetal copolymer resins
are made by Celanese Plastics at Eishop, TX, under the trade name Celcon
(Blackford, 1976).
Poly(ethylene oxide) resins are produced by Union Carbide under the trade
namePolyox (Eraun and DeLong, 1982). Plant capacity for poly(ethylene oxide) is
<20 million pounds
Ethylene carbonate, made from the reaction of ethylene oxide and carbon
dioxide, used as a (Cavse et al., 1980). It is made by Dow and Texaco
(SEI, 1983).
Ethylene oxide is an e::tcellent fumigant and sterilizing agent (Cawse et a1. ,
1980). H.ixtures of ethylene oxide in carbon dioxide or ethylene oxide
in dichlorcdifluoromethane are commonly used. The 1atter is effect!ve and
nonflammable at ordinary temperatures; therefore, it is recommended for use in
2-11
hospitals. These gas sterilants permit convenient sterilization of delicate
instruments and supplies made of almost any material. A 10% concentration of
ethylene oxide in carbon dioxide effectively kills most insect pests at all life
stages. It is used for fumigation of spices, furs, bedding and transport
equipment. In 1979, Dow Chemical (Kurginski, 1979) estimated that 0.2% of
production (=10 million pounds/year) of ethylene oxide is used as a fumigant.
This is the only identifiable use of ethylene oxide as an end-use product other
than in derivative synthesis.
2-12
3. EXTENT OF OCCUPATIONAL EXPOSURE
3.1. PREDICTED EXPOSURE TO ETHYLENE OXIDE BY UNIFORM TASK CATEGORY
When raw data regarding breathing zone TWA concentrations of ethy!.en:e
oxide were .presented (Hines and Spear, 1984; OSHA, 1983; Joyner, 1964), two
parameters were calculated, the Long Term Average Exposure and the
Probable Average Exposure.. Since occupational exposure estimates
from personal air sampling are best described by a log normal distributiew:
(Esmen, 1979), values for geometric standard deviation are necessary to
for transformation of the data to a normal distribution in order to
a larger number of workplaces. Therefore, when raw data were presented,
geometric mean and geometric standard deviation of the data set
calculated, and used to obtain the Long Term Average Exposures and the
Probable Average Exposures. Table 3-1 presents a summary of measured area and
breathing zone ethylene oxide concentrations, and predicted and
worker exposures to ethylene oxide based on these values. These values are
grouped according to Uniform Task Categories, and allow the cross-industrJ
application of the predicted values for worker exposure.
Estimates of the true long-term average (x) of all standardized exposures
can be calculated as described by Rock (1982), using the equation:
- 2]
x =exp [In (GM) + 0.5 (In (GSD
where GM and GSD are the respective geometric mean and geometric standard
deviation of the exposure measurements. Estimates of the Long Term Average
Exposure in Table 3-1 are based on isolated area ethylene oxide concentra-
tions, mean TWA ethylene oxide exposures or values assumed to be
tive of Task Categories for which no exposure data have been reported.
3-1
TABLE 3-1
'.ported and Exposure to Ethylene Oxide by Unitortl Task Category/Industrial Seotor
W
I
N
Produotion - lnYolYlna direct or
indireot oontaot with ethylene oxlde
durins lts ..nutaoture.
Produotion - lnyolYina dlreat or
indirect oontaot with ethylene oxide
durins ..nuraoture or other ohe.loala.
Produotion - lnyolYina direat or
lndirect oontaot with ethylene oaide
durins aterill.atlon or "'ioal
produota by the ..nuraoturer.
Produotion - lnyolYlns direat or
Indirect oontaot with ethylen. oxide
durins aterillaatlon of rinlahed
apioea and other .laoellaneous
oo.-oditlea.
Uae - lnyolYinc direat or indirect
contaot with ethylene oxlde durins
instru..nt aterillaatlon in health
oare raoUitiea.
Mean 01' Area
Measurellejnh, pp.
(rane;e)
10.25
a
(5-33)b
(5-33)b
11.6 (NI:I_56)b
HR
HR
Hft
a b
0.911a
<3.0 (2,,0-11.5)
Hft
<1I.5
b
,d 1_12}b,d
<1.0
b
,e '<1.0)fl,e
Hft <1_2)1
a b
<11.2 (:<2-51.1)
Mean 8-hour TVA or
Peraonal Sa.plea,
pp. (range)
Hft
b
Hft (0.6-6)b
<111 (6-28)
0.3
b
(NR)
1.8
h
(NO-23)r
<lOb (HR)
HR (0.1-2.0)
HR
<50
b
(NR)
HO
0.611
a
(0.06-3.12)a
(NR) a
0.55 (0.23-0.92)
1I.1
a
(0.116-9.30)a
b a
<1 b(0.21-0.112)
(NR)
<5 (HR)b
NR 0-6)
HR (O_19)b
Long Ter. Averase
Exposure, pp.
(OH, GSO)
NA
<10
0
h
1.1 (0.8,2.11)
<10
0
<100
0.68
a
(0.1111, 2.56)a
0.56
a
(0.52, 1.1I1)a
8.911 (1.93, 5.16)a
Maxi... Probable
Averase Exposure,
pp.
HA
<12.5
0
1.8
h
<12.5
<12.5
0
1.1)a
0.16-
11.11
8
Rererenoe
Joyner, 19611
Rosatedt et aI.,
1919a
Florea, 1983
Oaer, 1919
OSHA, 1983
OsaA, 1983
Ooldsraben and
Zank, 1981
Gor_n and
Horan, 1981
Ooldsraben and
Zank, 1981
Korpela et al.,
1983
Glu8r, 1911
Hines and Spear,
19811
Ooldsraben and
Zank, 1981
He_inki, 1983
OSHA, 1983
Mean, or Area
Measurements, pp.
(range)
.0
TABLE 3-1 (cant.)
Mean O-hour TWA or
Personal SoNples,
ppm (range)
Long Term Average
Exposure, ppm
(OH, 050)
MaxiMUm Probable.
Average Exposure,
PPIII Rererenoe
0.3
b
(un) <10
0
<12.5
0
'lares, 1903
NO (NO-NO) NA UA Oaer, 1978
ND (UO-NO) Nl NA Oaer, 1979
1.11: (0.111-2 .ll)a 2.13
a
(0.99, 3.115)a 3.1l1
a
Joyner, 196"
2.8 (Nn)
h
52.9
h
Florea, 1983
21.1
h
(UD-82) 113.9 <3.1, 17.1) Oaer, 1918
1.0
b
(Nn) <1.0
0
<1.25
0
OSfIA, 1983
u.s
I
u.s
Cleanue - involving direot and
indireot oontaot uith ethylene oxide
during oleaning or produotion and
non-produotion areas.
Maintenanoe - involving dlraot and
indlreot oontaot uith ethylene oxide
during repair and upkeep or ethylene
oxide produotion and handling eQuipaent.
Oualitl Control - direot and indirect
oontaot uith ethylene oxide during
soaplins or produotion strea.a and
analysis.
Quality Control - direot and indirect
oontaot uith ethylene oxide during
inspeotion or goods steriliZed uith
ethylene oxide.
- involvin direct and
indirect oontaot uith ethylene oxide
during tranafer and shipping of
paokaged aaterial. .
lin
un
un
UO
lin
un
UO
NO
Nn (2-150)b
un
UD
".ob(Mn)
".3
h
(IID-8)g
UA
NA h
11.8 (2.19, 6.2")
UA
NA
13.68
h
IIA
Florea, 1983
Oaer, 1978
Caloulated value
bneported value
Retiaated value
dpeak oonoentration above sterilizer door
epeak oonoentration belou aterilizer door
rAn.lytioal deteotion li.it 0.6 pp.
STank oar unloadins
hCaloulated that NO 0.6 ppm limit)
NA II Not IWItHn"l", ,m PI ! "9t, f!IlJlortM'
Estimates of the Maximum Probable Average Exposure in Table 3-1 are based
the assumption (Rock, 1982) that exposure variability for most
workers is characterized by a aSD ranging between 1.2 and 2.5.
3.2. DETERMINATION OF SPECIFIC JOBS OR OPERATIONS WITHIN INDUSTRIAL
WITH POTENTIAL FOR ETHYLENE OXIDE EXPOSURE
3.2.1. Ethylene Oxide Production. Specific job titles in ethylene
3-4
production facilities identified as having at least some ethylene
exposure are:
Maintenance workers (Hogstedt et al., 1979a; Oser, 1978,
Production workers (Hogstedt et al., 1979a)
Operators (Joyner, 1964)
Instrument repairmen (Joyner, 1964)
Weighmaster (Joyner, 1964)
Mechanic (Joyner, 1964; Oser, 1979)
Laborer (Joyner, 1964)
Pipefitter (Joyner, 1964; Oser, 1978)
Pumper (Oser, 1978, 1979)
Tank cal" unloaders (Oser, 1978)
Quality assurance technicians (Oser, 1978)
Electrician (Oser, 1979)
3.2.2. Sterilization of Medical Products by the Manufacturer. OSHA (1983)
identified several operations within Lederle Laboratories which have potential
for occupational exposure to ethylene oxide during sterilization of ...
tured medical products:
Chamber operation
Maintenance
Sterile room operation
Finishing operations
Sterile kitchen operations
Surgical supplies packaging
Quality control
3.2.3. Sterilization of Medical Products in Health Care Facilities.
( 1983) determined that while this population uses only 0.5% of the
oxide produced in the United States, it has the most potential
occupational exposure.
listed below:
Some of the specific operations and job titles a<r.'"
Sterilizer operators (OSHA, 1983)
Aerator operators (OSHA, 1983)
Maintenance workers (OSHA, 1983)
Sterile room operators (OSHA, 1983)
Finishing operation (OSHA, 1983)
Packaging surgical supplies (OSHA, 1983)
Operating room personnel (OSHA, 1983)
Catheterization laboratory personnel (Glaser, 1977)
Anesthesiology department personnel (Glaser, 1977)
Ear-Nose-Throat clinic personnel (Glaser, 1977)
Dental clinic personnel (Glaser, 1977)
Intensive care unit personnel (Glaser, 1977)
Urology department personnel (Glaser, 1977)
Inhalation therapy personnel (Glaser, 1977)
Tissue bank personnel (Glaser, 1977)
Laboratory animal handlers (Glaser, 1977)
3.2.4. Sterlza.ttCH'! of Other- Commodities by the- Manufacturer.- G-o-rman-
Horan (1981) investigated the potential for ethylene oxide exposure to
,
in a Ralston Purina animal food production plant. Ethylene oxide is used tc
disinfect food extruders. The authors stated that extruder operators
potentially exposed during mixing, filling and cleaning operations.
3.2.5. Other Operations Using Ethylene Oxide as a Sterilant. Goldgraben
Zank (1981") reported that ethylene oxide sterilization of items in libraries;
3-5
museums, animal breeding labs, microbiology labs, cancer research facili ties'!"
transportation vehicles, ports of entry and dairy packaging operations
have potential for worker exposure. Specific job titles were not
3.3. EXTENT OF OCCUPATIONAL EXPOSURE
Potential for occupational exposure to ethylene oxide exists in
major industrial sectors: ethylene oxide production, chemical
(ethoxylation), health care facilities (sterilization), medical
manufacturers (sterilization) and miscellaneous manufacturers (e.g.
sterilization). The latter three sectors use =2% of all ethylene oxide pro;-
duced in the United States, but they represent the population with th9
greatest potential for worker exposure (OSHA, 1983). OSHA estimated tha-
=80,000 and 144,000 workers in the five sectors are exposed to ethylene oxid
directly and indirectly, respectively (OSHA, 1983). Table 3-2 presentsJ
estimates of the exposed populations existing in various industrial sectors,
Several epidemiologic investigations have been undertaken to determine)
the adverse health effects of occupational exposure to ethylene oxide
production and use facilities. These studies afford an opportunity to:
identify exposed populations and to determine cohorts for additional studt,y
(Table 3-3).
Korpela et a1. (1983) investigated the effects of relative humidity am:di
rates of local exhaust ventilation on airborne concentrations of ethylED.1!:
oxide in a hospital sterilizer operation. Area measurements were obtair:nfldi
using a portable infrared spectrophotometer during the opening of the
door folloWing purging. Higher ethylene oxide concentrations were observed:
above the door and in the absence of exhaust ventilation (see Table 3-1) "
Relative humidity did not appear to affect measured ethylene oxide levels.
3-6
TABLE 3-2
Number of Workers Exposed to Ethylene Oxide by Industry Sectcr*
------------_._------
Industry Sector
-------
Number of Workers Exposed
Directly Indirectly
Ethylene oxide production and synthesis
of chemicals by ethoxylation
Sterilization - health care facilities
Sterilization - medical products manufacture
Sterilization - spice manufacturers
.Source: OSHA, 1983
HB =Not reported, but together =2100
3-7
3,676
62,370
14,000
160
Nit
25,000
116,900
NE
TABLE 3-3
Summary of Exposure Information From Epidemiology Studies
---------------------------------_.._----.-
Plant/Process
Size of
Cohort
Estimated Exposure
to Ethylene Oxide Additional Exposure Refer,,::'.c".'
BASF ethylene oxide
production facility,
West Germany;
Ethylene chloro-
hydrin process
Texaco Chemical Co.
Plant, Port Neches,
TX. Ethylene oxide
production process
not characterized.
11
6
21
5
767
Long-term exposure
(>20 years). Area
concentrations taken
after the fact were
<1-1900 ppm.
Moderate exposure
(9-18 years). Area
concentrations taken
after the fact were
<1-1900 ppm.
Moderate to long-term
exposure (7-42 years)
at <1-1900 ppm, plus
at least one high
exposure during an
accident.
One brief exposure
during an accident.
5-18 years to <10 ppm
(measured after the
fact)
other alkylene oxides, Th1ass a!.
chlorine, hydrogen 1981
sulfide
other alkylene OXides,
chlorine, hydrogen
sulfide, benzene
other alkylene oxides,
chlorine, hydrogen
sulfide, benzene
other alkylene oxides,
chlorine, hydrogen
sulfide, benzene
et al.
1981
Swedish Ethylene 2535
Oxide Production
Plant. Ethylene
chlorohydrin process.
Production and
maintenance workers
exposed to <700 ppm
in 1940's, 6-28 ppm
(avg. <14 ppm) in
1950's-1960's, 0.6-
6 ppm in 1970's
ethylene, ethylene
dichloride, ethylene
chlorohydrin, bis-
(2-chloro) ether,
chloroform, chloral,
DDT, chlorine,
ethylene glycol

et al.,j iSC'9a
---------------------------------------_.. __..-
3-8
Size of
Plant/Process Cohort
Dow Chemical Co. 84
facility for produc-
tion of ethylene
oxide, ethylene
glycol, glycol ethers
and ethanolamines
TABLE 3-3 (cont.)
Estimated Exposure
to Ethylene Oxide
Yearly average TWA
exposures for the
period 1977-1980
were typically below
1.0 ppm Indivi-
dual TWA measure-
ments ranged from
<0.1-5.7 ppm.
3-9
Additional Exposure
ethylene dichloride,
biphenyl and biphenyl
oxide, ethylene
glycol
~ i e :
at; a l ~ , f9&l.J
Hines and Spear (1984) estimated the statistical distribution of
oxide exposures experienced by hospital sterilizer operators during
transfer of materials from sterilizer to aerator. The sterilizer gas
was ethylene oxide and 88% Freon-12. Breathing zone ethylene oxide con-
centrations were obtained with a portable infrared spectrophotometer during 3e
transfer operations. The task typically took 3-5 minutes to perform.. The:
cumulative exposures experienced by five operators were reported, and were
observed to be not significantly different from each other. The arithm:etic::
mean and geometric mean doses of ethylene oxide experienced by the opel!'atol."S
were 9.60 and 8.96 mg, respectively. The GSD of exposure measurement's was
reported to be 1.47. Assuming that the resp1.ratory minute volume of workers
engaged in light activity is 1/minute and that the exposure period was 5
minutes, the arithmetic mean and geometric 1I1ean 8-hour TWA breathing
ethylene oxide/air concentrations were 0.55 and 0.52 ppm, respectively.
Hemminki (1983) reported in a personal communication to OSHA (1983)
a typical exposure during sterilizer door opening was minutes at 5-10
This would result in 8-hour TWA concentrations <1.0 ppm.
Hogstedt et ale (1979a) conducted an investigation of
ethylene oxide production and maintenance workers. They estimated that
the 1950s and 1960s, average exposure levels were <14 ppm (range 6-28 ppm end
were reduced to 0.6-6 ppm during the 1960s.
OSHA (1983) requested and subsequently received information from
oxide users regarding their exposure experience. Lederle Laboratories" e.
manufacturer of medical products that require sterilization, reported that its
employees were typically exposed to O. 1-2.0 ppm ethylene oxide on an 8-hour
TWA basis. Chamber operators at St. Anne's Hospital were exposed to 2.5 ,pm
3-10
TWA while unloading three loads per week. Council Shared Services
121 ethylene oxide use sites in 100 hospitals in Southern California
reported that TWA exposures to ethylene oxide users were <5 ppm in 114'/121;
sites. Sterilizer operation at Doylestown Hospital and Veteran's Administra-
tion Hospitals resulted in 3-6 and <5 ppm TWA exposures to their employees"
respectively. ECBI surveyed 27 hospitals and reported that TWA exposures to
sterilizer operators were <1, <4 and >10 ppm in 9/27, 16/27 and 5/27, respec-
tively. Operation of aerators was observed to result in breathing :.aone
ethylene oxide concentrations of 0-19 ppm. From the data submitted QSEA
(1983) concluded that, "the exposure profile for sterilizer operation is
greatly influenced by the. pattern and frequency of ethylene oxide
tion," (i.e., it is normal for high concentrations of the gas to oacm" f'er
brief periods while unloading sterilizer chambers).
Of all the populations with potential for ethylene oxide
medical service personnel operating sterilizer chambers are probably the best
characterized. Limited data are available on workers who were exposed
production of ethylene oxide or synthesis of chemicals from ethylene oxide.
Joyner (1964) measured area ethylene oxide concentrations in unit contrel
rooms and throughout the production unit in Union Carbide's Texas City
ethylene oxide production plant. Area samples taken in control rooms ranged
from 5-33 ppm, with average concentrations of 7.25 and 10.25 ppm. Area
samples throughout the plant ranged from not detectable to 5-6 ppm, with
a mean concentration of 11.6 ppm. Two grab samples taL:en from a worker's
breathing zone during quality control sample collection contained 22 and 121
ppm. The collection activity was performed 3 times/day and lasted about 3
3-11
minutes each. The 8-hour TWA exposure resulting from sample collection was
0.41 and 2.38 ppm, respectively.
The National Institute for Occupational Safety and Health conducted in-
depth industrial hygiene surveys at Union Carbide ethylene oxide facilities at
Kanawha Valley, West Virginia (Oser, 1978) and South Charleston, West Virginia
(Oser, 1979). Ethylene oxide was used in the manufacture of a variety of
derivatives (e.g., hydroxyethyl cellulose compounds such as CELLOSIZE, higher
molecular weight polyethylene glycols such as CARBOWAX, surfactants and
flexible and rigid polyols) at the Kanawha Valley plant, but was not prodQced
captively. At South Charleston, ethylene oxide was produced for captive use
in the manufacture of flexible polyols (NIAX products), specialty oxide
adducts (e.g., hydraulic flUids, heat transfer fluids), alkanolamines and
glycol ethers at four different on-site plants. Personal 6-hour air
were taken with charcoal tubes and analysis was performed by gas chromato-
graphy (detection limit =0.6 ppm). Monitoring of workers involved in
oxide at the South Charleston plant was not, however, conducted.
Ethylene oxide was determined to be below the detection limit in aLl but
several samples, and the detectable exposures occurred primarily in workers
the chemical (Oser, 1978, 1979). As detailed in Table 3-1, only Z,
of 48 samples were above the detection limit at the Kanawha Valley plant; , or
2 samples collected from tank car unloaders showed an ethylene oxide tV!
concentration of 8 ppm and 1 of 3 samples collected from laboratory (quality
control technicians) showed a TWA concentration of 82 ppm. Ethylene was
detected in 4 of 41 samples from the South 9harleston plants; 2 of 2 utility
mechanics showed TWA exposures of 1.5 and 3.5 ppm, and 2 of 10 operators
showed TWA exposures of 11 and 23 ppm.
3-12
4. PHARMACOKINETICS
4. 1. ABSORPTION ,
The absorption of ethylene oxide has not been specifically
Excretion studies with mice (Ehrenberg et al., indicate that ethylene oxide
is readily absorbed from the respiratory tract (see Section 4.4 below).
4.2. DISTRIBUTION
Inhalation exposure to 1.15 ppm of oxide for 75 minutes
produced highest initial levels of radioactivity in the lungs, kidneys and liver
of mice (Ehrenberg et al., 1974). Lower levels of radioactivity were found in
the testes, brain and spleen, but additional tissues were not analyzed. Whole
body autoradiography on mice that were intravenously injected with 14c_ethYlene
oxide showed high levels of radioactiVity in the liver, kidneys, lungs:
intestinal mucosa, testes and cerebellum 20 minutes-4 hours after
injection (Appelgren et al., 1977). Twenty-four hours. after injection,
radioactivity was still observed in the liver, intestinal mucosa, epididymis ana
cerebellum, as well as the bronchi and bone marrow.
Single intravenous doses of 25 or 75 mg/kg ethylene oxide disappeared frOQ
the plasma of dogs (four/dose), with mean half-lives for elimination of 29.3 :
5.7 and 36.5 + 18.5 minutes, respectively (Martis et a1., 1982). Plasma level$
- - - -- -- - - .-..:
declined to less than of the inital concentrations within 5 hours.
4.3 METABOLISM
The metabolic fate of ethylene oxide is incompletely .characterized.
Ethylene glycol was formed quite rapidly in dogs follOWing intravenous
administration of ethylene oxide. (Martis' et a1., 1982); mximum plasma
concentrations of ethylene glycol were reached by 90 + minutes and 120 +
- -
minutes after single injections of 25 and 75 ltg/kg ethylene oxide,
respectively.
4-1
Intraperitoneal injection of 2 mglkg 14C-ethYlene oxide in rats produced
(2-hydroxyethyl) cysteine of the dose) and !-acetyl-.-(2-hydroxyetbW'1U)
cysteine of the dose) in the urine, which suggests that the metabolism Qt'
ethylene oxide involves conjugation with glutathione (Jones and Wells, 198 n.,
Small percentages of the dose were exhaled as 14
C02
and unchanged ethylene:
oxide
4.4. EXCRETION
Ethylene oxide and its metabolites appear to be eliminated primarily in
urine. Ehrenberg et al. (1974) found that 78% of the radioactivity absorbed
a 15-minute exposure to 1.15 ppm r1,2-
3
H]-ethylene oxide vapor was excreted 1a
the urine of mice within 48 hours. Approximately 43% of the administered
radioactivity from a single intraperitoneal injection of 2 mg/kg 14C_ethYlene
oxide was excreted in the urine of mice over 50 hours, most of Which (==-0%)
appeared within hours of dosing (Jones and Wells, 19B 1) Approximately 14J at
single intravenous doses of 25 or 15 mg/kg ethylene OXide was excreted 1ft
urine of dogs as ethylene glycol within 24 hours (Martis et al., 1982).
. . 14
Approximately of a single 2 mglkg intraperitoneal dose of C-ethylene
oxide was exhaled by mice as t4
co2
and as unchanged compound in 6 hours (Jones
and Wells, t 981) These are not maximum values. however, because exhaled
radioactiVity was not sampled at later post-exposure tlmes.
5. BIOLOGICAL DATA RELEVANT TO CARCINOGENOUS
5.1. ANIMAL CARCINOGENICITY
Twice-weekly administration of ethylene oxide by gavage at doses of
.7.5 and 30 mg/kg for life elicited dose-related induction of local malignant
tumors (primarily squamous_cell carcinomas of the forestomach) in female
Sprague-Dawley rats (Dunkelberg, 1982). The incidences were 0/50, 8/50
29/50 in the control, low-dose and high-dose groups, respectively.
incidences were reportedly not increased at sites other than the stomach;
however, histological examinations were only performed on tissues that
grossly abnormal.
Two chronic inhalation bioassays have been conducted that also demon-
strate ethylene oxide-induced carcinogencity (Snellings et al., 1984; Lynch et
al., 1984). In the- Snellings et al. (1984) stUdy, F344 rats of each sex
exposed to 0, 10, 33 or 100 ppm ethylene oxide vapor for 6 hour/day, 5
days/week for 24.5-25 months. Increased-incidences of subcutaneous
pancreatic adenomas and peritoneal mesotheliomas were found in the
males, and there was a dose-related increase in the incidence of mononucle2.T'
cell leukemia in the females. The frequency of pituitary adenomas was Mit
increased in either sex, but an indication of decreased latency
suggested that the normal appearance of this tumor was accelerated by
to ethylene oxide. SUbsequent histologic examination of the brain
revealed statistically increased (p<O. 05) incidences of brain
(primarily mixed astrocyte and oligodendroglia cell) in both the males (33
100 ppm) and females (100 ppm).
5-1
The results of a NIOSH chronic inhalation study were reported by Lynch et
al. (1984). In this study, male F344 rats were exposed to 0, 50 or 100 ppm
ethylene oxide for 7 hour/day, 5 days/week for 24 months. Exposure to
ethylene oxide was associated with dose-related increases in the occurrence of
mononuclear cell leukemia and peritoneal mesothelioma (primarily on the tunica
vaginalis surrounding the testes and epididymis) and with mixed-cell brain
gliomas at the high dose.
The NTP (1985) is conducting a carcinogenesis bioassay of ethylene oxide
in mice exposed via inhalation. Quality assessment of the chronic phase ot
this study is in progress at the time of this writing.
Reyniers et ale (1964) found that tumors developed at various site$
(e.g., ovaries, lymphatic system, lungs) in 63 of 86 female germ-free S w i s ~
Webster mice that were accidentally exposed for life (900 days maximum) to
ground-corncob bedding treated with ethylene oxide. Tumors were not observed
in 83 female mice (100-600 days old) that were not exposed to treated bedding.
It should be noted that this study was not designed to test the carcino-
genicity of ethylene oxide and that the presumed causative agent in the
bedding was not identified by chemical analysis.
Weekly subcutaneous injections of 0.1-1.0 mg ethylene oxide for 95 w e e k ~
induced dose-related occurrences of local sarcomas, but not tumors at distant
sites, in female NMRI mice (Dunkelberg, 1979).
5.2. MUTAGENICITY
Ethylene oxide was shown conclua!vely to be both mutagenic and clasto-
genic, and in vitro studies indicate that it is a direct-acting mutagen. Gene
mutations were induced in bacteria (... typhimurium, Rannug et al., 1976, ~
Pfeiffer and Dunkelberg, 1980i E. coli, Kolman and Maeslund, 1983i 13..
- -
5-2
subtilis, Tanooka, 1979), fungi (.. pombe, Migliore et al., 1982) and
ma1ian cells (L5178Y mouse lymphoma, Brown et a1., 1979, and Krell et al....
1979; Chinese hamster ovary, Tan et a.l., 1981) treated in vitro.
lethal mutations were induced in Drosophila melanogaster (Bird, 1952; Wat SQn,
1966). Dominant lethal mutations were induced in cats and mice (Appelgren
a1., 1977; Embree et a1., 1977; Generoso et a1., 1980, 1983), and
translocations were induced in Drosophila melanogaster (Watson, 1966) and
(Generoso et al., 1980). Ethylene oxide produced sister chromatid exhanges
cultured human lymphocytes in vitro (Garry et a1., 1981, 1982), in
lymphocytes from rats and rabbits that were treated in vivo (Yager and
1982), and in cultured lymphocytes taken from occupationally exposed
(Garry et al., 1979; Lambert and Lindblad, 1980; Laurent et al., 1982;
et al., 1983). Micronuclei were found in the erythrocytes of rats and
that were exposed to ethylene oxide in vivo (Applegren et al., 1978;
and Ramel, 1980). Incidences of chromosome aberrations (Ehrenberg
Hallstrom, 1967; Theiss et al., 1981; Pero et al., 1981) and unscheduled
synthesis (Pero et al., 1981) in peripheral lymphocytes were also increased
ethylene oxide-exposed workers.
5-3
6. EPIDEMIOLOGICAL STUDIES
Occupational exposure to ethylene oxide has been associated with
increased risk of leukemia. In one study, mortality due to cancer was asc:er-
tained in groups of 66, 86 and 89 Swedish ethylene oxide production plant
workers who had no exposure, intermittent exposure (maintenance workers) and
full-time exposure, respectively, to ethylene oXide (Hogstedt et al., 1979aJ1.
The workers were exposed to estimated ethylene oxide levels of <25 mg/m
3
(with
occasional exposures up to the odor threshold of 1300 mg/m
3
) during
but concurrent exposure to ethylene chlorohydrin (25 mg/m
3
), ethytene
dichloride (:100 mg/m
3
), bis(2-chloroethyl) ether (:0.05 mg/m
3
) and
(:600 mg/m
3
), with possible momentary excursions up to 1000 times these ..
centrations, also occurred. Exposure time during this period was estimated &5
slightly more than 1 hour/shift. From 1950-1963, exposure to chemicals
than ethylene oxide decreased because of production changes, but exposure
ethylene oxide increased (:10-50 mg/m
3
with peaks above the odor threshold).
Subsequent years (1970s) were characterized by lower ethylene oxide
(:1-10 mg/m
3
with higher peaks), and also by exposure to propylene oxide (:1e-
2S mglm
3
i mg/m
3
). The follow-up period included tbf!
years 1961-1971.
The expected number of deaths due to malignancies were calculated
the cause-, sex- and age-specific Swedish national death rates from
5-year age categories, and were determined in unexposed,
exposed and full-time-exposed workers with at least 1 year of exposure and 10
years of latency (955, 1211 and 1324 person-years, respectively) (Hogstedt
al. , 1979a) A total of 9 cancel' deaths were observed in the
6-1
exposure group while only 3.4 were expected (p<0.01), but there were no sta-
tistically significant differences between the observed and expected number of
cancer deaths in the no exposure and intermittent exposure groups. Among the
9 cancer deaths, 5 were from stomach cancer (3 deaths) or leukemia (2 deaths);
the other cancers were not characterized, but the deaths due to these cancers
were significantly (p<0.01) greater than the rate expected (3 observed vs. 0.4
expected for stomach cancer and 2 observed vs. 0.14 expected for leukemia).
When the mortality in a subcohort of unexposed, intermittently-exposed and
full-tims-exposed workers with at least 10 years of employment and 20 years of
latency (603, 736 and 372 person-years, respectively) were tabulated, it was
found that deaths due to overall cancer and leukemia were significantly
greater than expected (5 observed vs. 1.1 expected [p<0.011 and 1 observed va.
expected [p<O.05], respectively). Two cases of cancer (testis and
prostate cancer) were identified in the surviving full-time workers. This
raised the total number of cancer cases (both living and dead) to 11 as
opposed to an expected number of 5.9 (p<O. 05), but the expected number of
cases by tumor site was not indicated.
Hogstedt et aL (197gb) identified three cases of leukemia that occurred
in a group of 230 Swedish workers who were exposed for 9 years (1968-1977) to
fugitive emissions in a hospital f'a<:lility that us-e-a- 5-nf
ethylene oXide/50% methyl formate as a sterilant. The expected number of
leukemia cases in this group for the above-mentioned period based on the 5SZ-
and age-specific U.S. national leukemia incidences for 1972, was 0.2.
of the workers (4 males, 3 females) were sterilizer operator; 70 workers ;(tiE
females, 2 males) were exposed via outgassing from treated boxes in astor-age
hall for 8 hr/day; and 153 other workers (101 females, 52 males) were employed
6-2
in neighboring rooms. . The a-hour TWA concentration of ethylene oxide in the
storage hall in 1977 was 20 + 10 ppm (range 2-70 ppm), a level reportedly
higher than in the sterilizing room itself because of leakage from treated
boxes. The three workers who developed cancer were exposed for 4-8 years and
were employed in the storage halls (two women) and elsewhere (one male plant
manager, who was estimated to have been exposed 3 hr/wk and had a history of
occasional contact with benzene).
Morgan et ale (1981) found no significant excess of deaths from leukemia
or other malignant neoplasms in a group of 767 male workers who were poten..
tially exposed to ethylene oxide for 5-18 years (between 1955-1977) at a U.S.
production facility. A 1971 industrial hygiene survey of the plant
that the a-hour TWA concentrations of ethylene oxide were "well below"
OSHA 50 ppm limit, and that detectable concentrations were routinely <10 ppm.
A total of 11 deaths from malignant neoplasms occurred where 15.24 would
been expected, but there were more deaths than expected from pancreatic cancel"
(3 vs. 0.8) , bladder cancer ( 1 vs. 0.31), brain and central nervous systftl
cancer (2 vs. 0.7) and Hodgkin's disease (2 vs. 0.35). Although the 95% lower
confidence limits for the standardized mortality ratios (observed + expected
100) for these cancers were all less than 100, CAG (1984) noted that the
number of deaths from pancreatic cancer and Hodgkins' disease are
significantly (p<O. 05) more than expected by hypothesis testing using
Poisson test. It should be noted that mortality analysis by length of follow-
up was not conducted ( 1. e., there was no indication of a sufficient latenet"
period).
A retrospective cohort mortality study of 602 workers who had
employed for at least 6 months in the alkylene oxide (ethylene oxide/propylen;
6-3
oxide) production or processing areas of nine BASF plants in West Germany
during 1928-1980 was conducted by Theiss et ale (1982) and summarized by CAG
(1984). Vital status was ascertained for 553 of the workers, and the w o r k e r ~
were reported to have been exposed to a variety of other compounds (not
specified) in addition to the alkylene oxides. The observed number of deaths
from cancer at any site was not significantly (p<0.05) higher than that
expected, based on comparisons with corresponding local or national mortality
data. Deaths from cancer of the brain among workers followed for at least 10
years did, however, approach statistical significance (p<O.07) when compared
with the local mortality data. When the observed number of cancer deaths (14)
was compared with that expected in an internal cohort of 1662 styrene w o r k e r ~
(9.44), the difference was not statistically significant (p>0.05). A signifi-
cant (p<0.05) excess number of cancer deaths was, however, found among workerz
aged 65-74 years in the alkylene oxide cohort when compared to that expected
in the same-age styrene workers (10 observed vs. 3.6 expected). One case of
myeloid leukemia occurred where only about 0.15 would have been expected,
based on local mortality data, but this difference was not statistically sig-
nificant (p>0.05).
CAG (1984) also summarized a proportionate mortality study by SchnON'
(1982) of decedents who had been members or District 1199 of ffie National
Hospital and Health Care Workers Union. It was found that the proportionate
mortality ratio (PMR) for neoplasms of lymphatic and hematopoietic tissue, a2
well as for other types of tumors (not indicated in CAG, 1984), was signifi-
cantly elevated for certain job categories (e.g., "service" and "nursing";
that included job titles of ethylene oxide-exposed personnel (e.g., hospital
central service employees, registered nurses, licensed practical nurses afld
6-4
nurse's aides). The U.S. EPA is currently funding a case-control study of'
cases of lymphatic and hematopoietic tissue cancer in members of the same
union (CAG, 1984). The results are expected to be available in late 1984.
Other studies in progress include a retrospective cohort mortality stUdy
of approximately 1000 ethylene oxide production workers in the Kanawha Vatley
of West Virginia, currently being conducted by NIOSH and the Union Carb-;i;de
Corporation (CAG, 1984). The results of this study will not be availa.ble
until at least mid-1984. NIOSH and the Health Industry
Associates are currently discussing plans for a cohort mortality study-
medical equipment-manufacturing personnel who use ethylene oxide a
sterilant (CAG, 1984). The results will not be available until at least
if the study is initiated.
A cross-sectional health survey was recently conducted on 84 worQt"'L'
classified either as producers of ethylene oxide and ethylene glycol or
of ethylene oxide for the manufacture of glycol ethers and ethanolamUt1'
(Currier et al., 1984). Individual time-weighted average exposures to
ethylene oxide were in the range of <0. 1-5.7 ppm. Most jobs typically bid
yearly mean time-weighted average exposures below 10 ppm. The exposed
were matched with an unexposed control population to account for the variablez
of age, hire date, race, smoking, alcohol consumption history, and date of
medical examination. Hematological and biochemical studies were conducted
evaluate any abnormalities of the hematopoietic, hepatic, or renal systemlJ..
The only difference found between the two groups was an increased
of proteinuria 1n the workers exposed to ethylene oxide. This finding VIU
considered clinically insignificant.
6-5
7. SUMMARY AND CONCLUSIONS
Ethylene oxide 1s a highly reactive explosive gas, which has been produced
commercially in the United States for =60 years. Although >5 billion pounds of
ethylene oxide are produced annually, at least 90% of production is captively
consumed on-site in the manufacture of various derivatives. Commercial grade
ethylene oxide is extremely pure (>99.95%), and is produced almost exclusively by
the direct oxidation of ethylene using a silver-based catalyst. Ethylene oxide
is manufactured in large quantities at 16 locations in the United States,
primarily in the Southwest.
More than 98% of the total produotion of ethylene oxide is converted to
derivatives such as: glycols (=75%); 5urfactants (=12%); glycol ethers (=7%);
(=7S) and polyether polyols for flexible polyurethane foams
The only commercially significant end-use for ethylene oxide per!! is
in fumigation and gas sterilization applications, where it accounts for =10
million pounds of ethylene oxide annually.
Occupational exposure to ethylene oxide has been a matter of concern for the
past several years. Monitoring data are available for worker exposures, which
oocur during the production of ethylene oxide and during sterilization of medical
available data indicate equipment
maintenance, Quality oontrol and transfer and handling operations present a
eignificant potential for Short-term, high-level exposures; in some oases, area
ooncentrations of ethylene oxide have exoeeded 1000 ppm. Partioular ooncern has
-
arisen for exposures associated with gas sterilization aotivities, where it is
estimated that 80,000 workers are directly exposed to ethylene oxide, and where
in many oases engineering oontrols are minimal or inadequate. Little is known
regarding the extent or magnitUde of worker exposure to ethylene oxide that
oocurs during the of ethylene oxide derivatives.
7-1
Ethylene oxide appears to be well-absorbed and widely distributed to the
body tissues following inhalation exposure of experimental animals. In
ethylene oxide is rapidly metabolized and excreted, with the major route of
elimination being urinary excretion. Ethylene oxide is a suitable substrate
glutathione conjugation, as demonstrated by the appearance of significant
amounts of radiolabeled mercapturic acids in the urine of rats following exposure
to 14C_ethylene oxide.
Several chronic bioassays have provided clear evidence of the carcinogenic
potential of ethylene oxide in rats. Oral administration of ethylene oxide was
associated with tumors of the forestomach, while inhalation exposure wal
associated with increased incidences of leukemia and brain tumors. Positivo
results from short-term mutagenicity tests in bacteria and cultured mammalian
cells support the genotoxicity of ethylene oxide.
Retrospective cohort mortality studies have been conducted for ethylene
oxide production workers, and for gas sterilizer workers. Limitations in design
and the small number of cancer cases provided by these cohorts mak,
interpretation of results difficult for these investigations. Nevertheless,
indication of increased cancer risk, especially for leUkemia, was indicated
several of the cohorts exposed to ethylene oxide. Several epidemiological
studies are currently in progress: a case-control and pro-po-rtlonate= mortality
stUdy of unionized hospital and health care workers, and a retrospective
mortality stUdy of ethylene oxide production workers. An additional cohQri
mortality study is in the planning stage for workers involved in ethylene
.
sterilization of medical supplies.
the results of on-going and planned epidemiological studies,
appears to be little immediate need for investigating additional
groups baving exposure to ethylene oxide. In the event that the
7-2
between ethylene oxide exposure and increased cancer risk becomes more firmly
established as a result of current investigations, several additional groups
could be targeted for study. These would be particularly those workers who use
ethylene oxide in the synthesis of glycols, glycol ethers, surfactants,
ethanolamines and related derivatives.
7-3
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8-10
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*S02n-lC1
RE'DRT DOCUMENTATiO;.J 1
1
FlFOlrr NO.
PAGE

4. Tnle lind Subtitle
MONOGRAPH ON HUMAN EXPOSURE TO CHEMICALS IN THE
WORKPLACE: Ethylene oxide
5. Repcrt Oate
July{1985
7. Authllr{S)
Joseph Santodonato, Ph.D., Project Director, etal
8. Farfllrmin.. Or.;anization Flellt No.
9. Performing Or.;anization Name lind
Center for Chemical Hazard Assessment
Syracuse Research Corporation
Syracuse, NY 13210
12. S/Xlnsllring 01'll'anization Nama and
Division of Cancer Etiology
National Cancer Institute
Bethesda, Md. 20892
15. Supplemllntary
Prepared under contract with the National Cancer Institute
15. Abstract (limit: 200
10. Unit No.
U. CoMtract(C) or Grant(G) No.
(C),- NOl-CP-26002-03
NCI CONTRACT
(G)
13. of Repcrt & Fllricd CoY'!!l'3d
final
14.
This report presents a summary and evaluation of information relevant to an
occupational hazard assessment of the chemical. Pertinent toxicologic data were
located through on-line and manual literature searches for the period extending
back approximately ten years from 1984. No attempt was made to exhaustively
review the tox.icologic literature; where appropriate the reader is referred to
comprehensive reviews on this topic. Special attention in this report was focused
on summarizing the available information regarding the carcinogenic potential of
the chemical. .
17. Document 8. Deseripttlr:l
b. Identifiers/OpenEnded Terms
c. COSAn Field/GTllUll
18. AYailability Statemen:
(See ANSI-239.1S)
release unlimited
19. Security (Tills FllllXlrt>
IINf'1 1""11-'11-'11
::20. Security Fagll)
UNCLASSIFIED
21. No. of
22. Price
OPTIONAL FDR'-I 272 (4-77)
(Formerly NTl$-35)
Department of CommeTee
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