FINAL REPORT

MONOGRAPH ON HUMAN EXPOSURE TOCHEMICALS IN THE WORKPLACE:

ETHYLENE OXIDE

Prepared by:

Center for Chemical Hazard AssessmentSyracuse Research Corporation

Syracuse, NY 13210

Prepared for:

Division of Cancer EtiologyNational Cancer Institute

Bethesda, MD 20205

Contract N01-CP-26002-03

July, 1985

REPRODUCED BY

NATlONAL TECHNICALINFORMATION SERVICE

u.s. DEPARTMENT OF COMMERCESPRINGFIELD. VA. 22161

PB861435591111111111111111111111111111111111111111111111111111111

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 pressu~,

odor threshold, nature of industrial process, etc.

The Syracuse Research Corporation was responsible for preparation of tm~

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......................................................... v~

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,

~1'

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 CareFacilities .•••.•••.•.••.•.••••••.•••.••••••••••.••••••••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. ABSORPTION••••••••o ••••••••••••••••••••••••••••••••••••••••••••

4.2. DISTRIBUTION•.••••••••..••••••••••.••••.•.•.••.••••.•.•••.••••4- ., 3. l-tETABOLISM••••••••••••••••••••••••••••••••••••••••••••••••••••4:. -_11:. -_ ~:K.-Gti_~~1.0N •••••••••••••••••••••••••••••••• - ••••••••••• - ••••••••

BIOLOGICAL DATA RELEVANT TO CARCINOGENESIS•••••••••••••••••••••••••

5.1. ANIMAL CARCINOGENICITy••••••••••••••••••••••••••••••••••••••••5 .2. MOTAGENICITY••••••••••••••••••••••••••••••••••••••••••••••••••

EPIDEMIOLOGICAL STUDIES••••••••••••••••••••••••••••••••••••••••••••

SUMi1ARY AND CONCLUSIONS •• _••••••.• •••••••••••••••• '•••••••••••••••••

REFERENCES. _ _••••••••••••••••••••••••••••••

iv

T-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 TaskCategory/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

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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 miscib Ie 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 aleohc4~

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 1~

thermodynamically unstable, decomposing exothermically at >500 c C in the abse~e

of a catalyst to methane, carbon monoxide, ethane, hydrogen and carbcc. ~s

vapors of ethylene oxide are flammable and explosive.

Commercially, ethylene oxide is sold only as a high-purity chemical. ~e

purity is so high (>99.95S) that no specific impurities are listed in t.~e

s~~if'Jccat1Qna ssc shown belcrw" (Cawsa e.t- aL-~; 1~O }:

a,cidity

aldehydes

water

re.l?~due

suspended matter

color

acetylene

0.002 wt~ max as acetic acid

0.003wt~ 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 Table~

2-1, which states that sales total only ~10~ of production, indicating that most~

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 2.7~ per year (CHR, 1981); demand is expected t~

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 ethylen~

chlorohydrin and the direct oxidation processes (Cawse et al., 1980). The firs~

process is older and involves the reaction of ethylene with hypochlorous aci~

followed by dehydrochlorination of the resulting chlorohydrin with lime ~

produce ethylene oxide and calcium chloride. Figure 2-1 depicts the chlorohydrm

p~ocess. In 1955, the chlorohydrin process accounted for 50-60~ of the Unit~

States ethylene oxide production, but advantages of the direct oxidaticm.

technology reduced this percentage to s3~ in 1978. Dow Chemical's Freeport, TX~

facility is the only United States plant using this chlorohydrin technology.

The direct oxidation process completely dominates the ethylene oxide fiel~

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 cC, mm Hg)(at 30cC, mm Hg)

Density (kg/t at 20 CC)Viscosity (cP atOCC)Refractive index (n7/D)

Flash point (tag open cup, CC)

Explosive limits in air, vol%upperlower

Critical temperature (CC)Dielectric constant (at OCC)

Con~~rsion factors

·Source: Cawse et al., 1980; Verschueren, 1983

;l-I

Value

------------75-21-8

/Q\CH

2-CH

2

C2H~O

10.14-112.5

49~

10941558

0.86970.3251.3597

<18

lOa3

195.813.71

1 mg/m3 = O~~5 pp~1 ppm = 1.83 mg/m.J

TABLE 2-1

United States Production and Sales of Ethylene Oxide.

-----------------------,----Year

Millions of PoundsProduction Sales

--------------------------------------------------------------1983198219811980

19791978197719761975

19741973197219711970

19691968196719661965

19641963196219611960

1955195019401930

5200 NR4987 3794937 3445220 531

5665 5605012 5254364 5494184 4394467 409

4200 4574200 5014250 4543740 3913990 411

3525 4382805 3942410 3022410 3042190 256

2163 1981889 1701595 1571329 128"13'7'9- 123

876 128454 NR110 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 lIItdeondantIr Hydrolv"'

flit"......Idadiltillatlon

IV"-

I.1'.~

FCV

I.1'3

, •• R.,....•'hyleneOIlHb '0

.'or.

Ii LeVB ~tn.t

i\:I

Mllfe 01 lime

R8llVejIe••hy....,,11

Chlorlfll ,.,~

Eth'Iane~'·'~mmt

N•W

Wa'. -,.,-e-t-I Wa....c.,cimnth'OIhlaand tome""y'a",Ili"II01;d.

Chlorln....hydroc8fbonby - prodllC:tIt,. t8GOllllry

"nit

Flg'ln, 2 I. G.b.lOI'ohydrln pI'oce ss foI' manufaetu:ring \ethylene oxj.de (Schultze, 1965) \

of ethylene with oxygen over a silver-based catalyst to yield ethylene o~

Direct oxidation processes are divided into two categories depending on tlT~

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"

se~aration unit is employed as the source of the oxidizing agent. F~~

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¥' b~

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 presente~

below.-

Ethylene Glycol: By far, the largest single use of ethylene oxide is- in:, tllt~

synthesis of ethylene glycol. Ethylene glycol is used to make polyester f~

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!

JDanuraot~re• Diethylene glyool is used to make polyurethane and polyest,&.l'

resins, morpholine, textile agents, 1n gas dehydration, in solvent extractL~

and 1n antifreeze blending (CMR, 1979), while triethylene glyoolis used in ~

2-4

I\)

~

Main,reactor

~. Compressor

Ma~

absor,MrPur...

fIIl1Ctor

RecVc'e wator

Ethvlene oKide lolution

PufllworMr OMorber Stripper

Steom

neflner

EthVleneoKidll

Fli',de :~ 2. ui"ecl' ())(LL,tiol\ l'rl"'l'~:;' 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 KodakICI AmericasInter North (Northern Petrochem)Olin Corp.

PD GlycolCPPG IndustriesShell ChemicalSun Olin Chem.TexacoUnion Carbide

Geismar, LAClear Lake, TXFreeport, TXPlaquemine, LA

Longview, TXBayport, TXMorris, ILBrandenburg, II

Beaumont, TXBeaumont, TXGeismar, LAClaymont, DEPort Neches, TXPenuelas, PRSeadrift, TXTaft, LA

Total

480450280b450

190500230110

455155700100700630

10001325

7755

------------------------------------------------------------------------aSource: SRI, 1983

bTo be increased to 850 million poundst! ~ ~ .-Joint venture of PPG Ind. and Du~ont

2-6

TABLE 2-3

Ethylene Oxide Consumption Patterns in the United States

Derivative Year

Ethylene 81ycol

Surfactants

Glycol ethers

Ethanolamines

Miscellaneous (includeshigher glycols, urethanepolyols, exports)

Percent

198~a 1981b 1978c 1975d

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

aSource::CHR, 197~b .Source: CMR, 1981

~Source: CHE, 1978

dSource~ CME, 1975eSource: Lawler, 1977

Year

63

11

6

5

5

2

2

TABLE 2-11

Ethylene Oxide Consumption for Derivatives 1n 1982

---------------.............-~..."....----

Derivative

Millions of PoundsEthyleneOxide

1982 Productiona consumptionb Percentage

---------------------------------------------------------~---~.-

Glycols:Ethylene glycolDiethylene glycol~riethylene glycol?olyethylene glycol~etraethylene glycol

Ethanolamines:MonoethanolamineDiethanolamineTriethanolamine

Glycol Ethers:Ethylene gly~ol - monoethyl ether

- monomethyl ether- monobutyl ether

Diethylene glycol - monoethyl ether- monomethyl ether- monobuty1 ether

Triethylene glycol - monoethyl ether- monomethy1 ether- monobutyl ether

11309394957317

150145120

17889

21728281182022

6

3232331868016

3745113128112

353

96528919212816184

34-3--

64.86.61.11.60.3

75.0

2.32.62.3

7.2

---------------------------_.-, -------&uSITC, 1983bCalculated 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

"

LooationEthylene GlycolGlycol Ethers

DiethyleneGlycol

Ethanol TriethyleneAmines Glycol

Polyethylene PolyetherGlycol Polyols

AncoBASF Wyandotte

carpenter Chem.Celanese Chem.Dow Chemical

Eastman Kodak"oadag ChemicalICI Americas .3MMobay Chem.

I\)I

~ Northern Petroohem.011n Corp.

Pelron Corp.PPG Industriea

Shell Chem.Texaco Chem.Union Carbide

\tIitco Chem.

-----_....----------------------------------------------------------------------------------,'.

Channelview, TX XWyandotte. HI XGe1l'Jmar, LA 1 1 XWashington, NJ X XSpartanburg, SC XBayport, TX XClear Lake, TI X X XFreeport, TX X X X X XPlaquemine, LA X X X 1 XMidland. HI XLongview, TI 1 X X XSkokie, IL XBayport, TI 1 1 X 1 1Decatur, AL XCedar Bayou. TI XNew Martinsville, WV XMorris, IL X 1Lake Charles, LA XBrandenburg, KY X X X X XLyons, IL X

. Beaumont, TI X X X XCircleville, OU XGeismar, LA X X 1 XPort Neohes, 11 1 1 1 X 1 X XSeadri rt, TX X 1 X XTaft, LA X X X XPenuelas, PO X X X XTexas City, TX XInstitute and S.·Charleston, WV XChicago, IL X

_____________~ ,u__~_~ ~__~__~ ~ ~~__~ ~__~~_~_~ ~ ~ ~_-- _

"So-'f'at}.~ 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 th~

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 an~

Company, Rohm and Haas, Texaoo, Union Carbide, Emery and BASF Wyandotte (SRI~

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 197~ (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 annually~

Ethylene carbonate, made from the reaction of ethylene oxide and carbon

dioxide, i~ used as a ~olvent (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 10-30~ ethylene oxide in carbon dioxide or 12~ 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 M~

Probable Average Exposure.. Since occupational exposure estimates obt~

from personal air sampling are best described by a log normal distributiew:

(Esmen, 1979), values for geometric standard deviation are necessary to allQ~

for transformation of the data to a normal distribution in order to reprea~~

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 Max~~~

Probable Average Exposures. Table 3-1 presents a summary of measured area and

breathing zone ethylene oxide concentrations, and predicted and estimat~j

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 representa~

tive of Task Categories for which no exposure data have been reported.

3-1

TABLE 3-1

'.ported and Prediol~ed Exposure to Ethylene Oxide by Unitortl Task Category/Industrial Seotor

WI

N

Produotion - lnYolYlna direct orindireot oontaot with ethylene oxldedurins lts ..nutaoture.

Produotion - lnyolYina dlreat orindirect oontaot with ethylene oxidedurins ..nuraoture or other ohe.loala.

Produotion - lnyolYina direat orlndirect oontaot with ethylene oaidedurins aterill.atlon or "'ioalproduota by the ..nuraoturer.

Produotion - lnyolYlns direat orIndirect oontaot with ethylen. oxidedurins aterillaatlon of rinlahedapioea and other .laoellaneousoo.-oditlea.

Uae - lnyolYinc direat or indirectcontaot with ethylene oxlde durinsinstru..nt aterillaatlon in healthoare raoUitiea.

Mean 01' AreaMeasurellejnh , pp.

(rane;e)

10.25a (5-33)b1.2~a (5-33)b

11.6 (NI:I_56)b

HR

HR

Hfta b0.911a (0,,29-1.6~

<3.0 (2,,0-11.5)

Hft

<1I.5b ,d «1_12}b,d<1.0b,e '<1.0)fl,eHft <1_2)1

a b<11.2 (:<2-51.1)

Mean 8-hour TVA orPeraonal Sa.plea,

pp. (range)

Hft

bHft (0.6-6)b<111 (6-28)

0.3b (NR)

1.8h (NO-23)r

<lOb (HR)HR (0.1-2.0)

HR<50b (NR)HO

0.611a (0.06-3.12)a

>o.9~a (NR) a0.55 (0.23-0.92)

1I.1a (0.116-9.30)a

b a<1 b(0.21-0.112)2.~ (NR)<5 (HR)bNR 0-6)HR (O_19)b

Long Ter. AveraseExposure, pp.

(OH, GSO)

NA

<100

h1.1 (0.8,2.11)

<100

<100

0.68a (0.1111, 2.56)a

0.56a (0.52, 1.1I1)a

8.911 (1.93, 5.16)a

Maxi... ProbableAverase Exposure,

pp.

HA

<12.50

1.8h

<12.5

<12.50

1.1)a

0.16­

11.118

Rererenoe

Joyner, 19611

Rosatedt et aI.,1919aFlorea, 1983

Oaer, 1919

OSHA, 1983OsaA, 1983

Ooldsraben andZank, 1981Gor_n andHoran, 1981

Ooldsraben andZank, 1981Korpela et al.,1983Glu8r, 1911Hines and Spear,19811Ooldsraben andZank, 1981He_inki, 1983OSHA, 1983

Mean, or AreaMeasurements, pp.

(range).0

TABLE 3-1 (cant.)

Mean O-hour TWA orPersonal SoNples,

ppm (range)

Long Term AverageExposure, ppm

(OH, 050)

MaxiMUm Probable.Average Exposure,

PPIII Rererenoe

0.3b (un) <100 <12.50 'lares, 1903NO (NO-NO) NA UA Oaer, 1978ND (UO-NO) Nl NA Oaer, 1979

1.11: (0.111-2 .ll)a 2.13a (0.99, 3.115)a 3.1l1a Joyner, 196"2.8 (Nn) h 52.9h Florea, 198321.1h (UD-82) 113.9 <3.1, 17.1) Oaer, 1918

1.0b (Nn) <1.00 <1.250 OSfIA, 1983

u.sI

u.s

Cleanue - involving direot andindireot oontaot uith ethylene oxideduring oleaning or produotion andnon-produotion areas.

Maintenanoe - involving dlraot andindlreot oontaot uith ethylene oxideduring repair and upkeep or ethyleneoxide produotion and handling eQuipaent.

Oualitl Control - direot and indirectoontaot uith ethylene oxide duringsoaplins or produotion strea.a andanalysis.

Quality Control - direot and indirectoontaot uith ethylene oxide duringinspeotion or goods steriliZed uithethylene oxide.

Shi2~inR - involvin« direct andindirect oontaot uith ethylene oxideduring tranafer and shipping ofpaokaged aaterial. .

lin

un «1~9600)bunUO

linun «1~1900)bUO

NO

Nn (2-150)bun

UD

".ob(Mn)".3h (IID-8)g

UA

NA h11.8 (2.19, 6.2")

UA

NA13.68h

IIA

Florea, 1983Oaer, 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 a8~U~ing that NO • 0.6 ppm (~6teotlon limit)

NA II Not IWItHn"l", ,m PI "o~ d~t~!)MflJ ~n ! "9t, f!IlJlortM'

Estimates of the Maximum Probable Average Exposure in Table 3-1 are based o~

the assumption (Rock, 1982) that exposure variability for most America~

workers is characterized by a aSD ranging between 1.2 and 2.5.

3.2. DETERMINATION OF SPECIFIC JOBS OR OPERATIONS WITHIN INDUSTRIAL SECTOR~

WITH POTENTIAL FOR ETHYLENE OXIDE EXPOSURE

3.2.1. Ethylene Oxide Production. Specific job titles in ethylene OXi:~E>

3-4

production facilities identified as having at least some ethylene ~!=_

exposure are:

Maintenance workers (Hogstedt et al., 1979a; Oser, 1978, 197~~

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 man~~...

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 ethy~

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. Ster±l±za.ttCH'! of Other- Commodities by the- Manufacturer.- G-o-rman- an~·

Horan (1981) investigated the potential for ethylene oxide exposure to wcrke~~

,in a Ralston Purina animal food production plant. Ethylene oxide is used tc

disinfect food extruders. The authors stated that extruder operators a~a

potentially exposed during mixing, filling and cleaning operations.

3.2.5. Other Operations Using Ethylene Oxide as a Sterilant. Goldgraben an~

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 identifiet~

3.3. EXTENT OF OCCUPATIONAL EXPOSURE

Potential for occupational exposure to ethylene oxide exists in fLV£~

major industrial sectors: ethylene oxide production, chemical synthes~

(ethoxylation), health care facilities (sterilization), medical produ~

manufacturers (sterilization) and miscellaneous manufacturers (e.g. spi~

sterilization). The latter three sectors use =2% of all ethylene oxide pro;­

duced in the United States, but they represent the population with th€9

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 chamb~~

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 ExposedDirectly Indirectly

Ethylene oxide production and synthesisof 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/ProcessSize ofCohort

Estimated Exposureto Ethylene Oxide Additional Exposure Refer,,::'.c".'

BASF ethylene oxideproduction facility,West Germany;Ethylene chloro­hydrin process

Texaco Chemical Co.Plant, Port Neches,TX. Ethylene oxideproduction processnot characterized.

11

6

21

5

767

Long-term exposure(>20 years). Areaconcentrations takenafter the fact were<1-1900 ppm.

Moderate exposure(9-18 years). Areaconcentrations takenafter the fact were<1-1900 ppm.

Moderate to long-termexposure (7-42 years)at <1-1900 ppm, plusat least one highexposure during anaccident.

One brief exposureduring an accident.

5-18 years to <10 ppm(measured after thefact) •

other alkylene oxides, Th1ass ~t a!.chlorine, hydrogen 1981sulfide

other alkylene OXides,chlorine, hydrogensulfide, benzene

other alkylene oxides,chlorine, hydrogensulfide, benzene

other alkylene oxides,chlorine, hydrogensulfide, benzene

Mor~:: et al.1981

Swedish Ethylene 2535Oxide ProductionPlant. Ethylenechlorohydrin process.

Production andmaintenance workersexposed to <700 ppmin 1940's, 6-28 ppm(avg. <14 ppm) in1950's-1960's, 0.6­6 ppm in 1970's

ethylene, ethylenedichloride, ethylenechlorohydrin, bis­(2-chloro) ether,chloroform, chloral,DDT, chlorine,ethylene glycol

Hog~tted+

et al.,j iSC'9a

---------------------------------------_..__..-

3-8

Size ofPlant/Process Cohort

Dow Chemical Co. 84facility for produc-tion of ethyleneoxide, ethyleneglycol, glycol ethersand ethanolamines

TABLE 3-3 (cont.)

Estimated Exposureto Ethylene Oxide

Yearly average TWAexposures for theperiod 1977-1980were typically below1.0 ppm•• Indivi­dual TWA measure­ments ranged from<0.1-5.7 ppm.

3-9

Additional Exposure

ethylene dichloride,biphenyl and biphenyloxide, ethyleneglycol

~ie:

at; al~, f9&l.J

Hines and Spear (1984) estimated the statistical distribution of ethylen~

oxide exposures experienced by hospital sterilizer operators during th~

transfer of materials from sterilizer to aerator. The sterilizer gas mixtur~

was 12~ 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 ~20 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) ~t

a typical exposure during sterilizer door opening was ~20 minutes at 5-10 ~,

This would result in 8-hour TWA concentrations <1.0 ppm.

Hogstedt et ale (1979a) conducted an epidemio~ogical investigation of

ethylene oxide production and maintenance workers. They estimated that d~~ng

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 eth~l.ne

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 sur'~~~

121 ethylene oxide use sites in 100 hospitals in Southern California an~

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 sterili~a­

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 expQ5Ur$~

medical service personnel operating sterilizer chambers are probably the best

characterized. Limited data are available on workers who were exposed dur~S

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 ta~en 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 sample_~

were taken with charcoal tubes and analysis was performed by gas chromato­

graphy (detection limit =0.6 ppm). Monitoring of workers involved in ethyl~

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

~ho h~d}ed 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; , or2 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 oxid~ 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 studied~

Excretion studies with mice (Ehrenberg et al., 197~) 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 [1,2-3HJ~ethylene 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, epididym~s, 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 2~ 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 + 2~.5 minutes and 120 +- -~2.~ 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 (9~ of the dose) and !-acetyl-.§-(2-hydroxyetbW'1U)

cysteine (33~ of the dose) in the urine, which suggests that the metabolism Qt'

ethylene oxide involves conjugation with glutathione (Jones and Wells, 198n.,

Small percentages of the dose were exhaled as 14C02 (1.5~) and unchanged ethylene:

oxide (1~).

4.4. EXCRETION

Ethylene oxide and its metabolites appear to be eliminated primarily in eh~

urine. Ehrenberg et al. (1974) found that 78% of the radioactivity absorbed~

a 15-minute exposure to 1.15 ppm r1,2-3H]-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 1~ 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 th~

urine of dogs as ethylene glycol within 24 hours (Martis et al., 1982).. . 14

Approximately 1.5~ of a single 2 mglkg intraperitoneal dose of C-ethylene

oxide was exhaled by mice as t4co2 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 a~d

29/50 in the control, low-dose and high-dose groups, respectively. Tu~!"

incidences were reportedly not increased at sites other than the stomach;

however, histological examinations were only performed on tissues that wer'~

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 ws~e

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 fibroma~~

pancreatic adenomas and peritoneal mesotheliomas were found in the high-do~..e

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 per~e

suggested that the normal appearance of this tumor was accelerated by expO$~~

to ethylene oxide. SUbsequent histologic examination of the brain tis~~

revealed statistically increased (p<O. 05) incidences of brain gli~

(primarily mixed astrocyte and oligodendroglia cell) in both the males (33 ~Q

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 Swis~

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 week~

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. Recess±:'v~

lethal mutations were induced in Drosophila melanogaster (Bird, 1952; WatSQn,

1966). Dominant lethal mutations were induced in cats and mice (Appelgren ~t

a1., 1977; Embree et a1., 1977; Generoso et a1., 1980, 1983), and heritatJ;l.~

translocations were induced in Drosophila melanogaster (Watson, 1966) and mi~~

(Generoso et al., 1980). Ethylene oxide produced sister chromatid exhanges ~~

cultured human lymphocytes in vitro (Garry et a1., 1981, 1982), in cultu~~

lymphocytes from rats and rabbits that were treated in vivo (Yager and Ben~~

1982), and in cultured lymphocytes taken from occupationally exposed work~f'~

(Garry et al., 1979; Lambert and Lindblad, 1980; Laurent et al., 1982; Y~r­

et al., 1983). Micronuclei were found in the erythrocytes of rats and m:1.Q~

that were exposed to ethylene oxide in vivo (Applegren et al., 1978; Jenss~~

and Ramel, 1980). Incidences of chromosome aberrations (Ehrenberg a~~

Hallstrom, 1967; Theiss et al., 1981; Pero et al., 1981) and unscheduled O~~

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/m3 (with

occasional exposures up to the odor threshold of 1300 mg/m3) during 1941-19~7,

but concurrent exposure to ethylene chlorohydrin (25 mg/m3), ethytene

dichloride (:100 mg/m3), bis(2-chloroethyl) ether (:0.05 mg/m3) and ethybn~

(:600 mg/m3), with possible momentary excursions up to 1000 times these c~..

centrations, also occurred. Exposure time during this period was estimated &5

slightly more than 1 hour/shift. From 1950-1963, exposure to chemicals o~r

than ethylene oxide decreased because of production changes, but exposure ,~

ethylene oxide increased (:10-50 mg/m3 with peaks above the odor threshold).

Subsequent years (1970s) were characterized by lower ethylene oxide exposW",~

(:1-10 mg/m3 with higher peaks), and also by exposure to propylene oxide (:1e­

2S mglm3i occassionall~ :l~Q-l~Q mg/m3). The follow-up period included tbf!

years 1961-1971.

The expected number of deaths due to malignancies were calcula ted ~

the cause-, sex- and age-specific Swedish national death rates from respect1~

5-year age categories, and were determined in unexposed, intermittentl~

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 full-t~

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.

O.O~ 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 equipment--s~e-r~liziIig 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. Se7~n

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 showe~

that the a-hour TWA concentrations of ethylene oxide were "well below" th~

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 hav~

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 t~

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 la tenet"

period).

A retrospective cohort mortality study of 602 workers who had be~

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 worker~

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 worker~

(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 Manufactu~ing

Associates are currently discussing plans for a cohort mortality study- ~t

medical equipment-manufacturing personnel who use ethylene oxide a~ a

sterilant (CAG, 1984). The results will not be available until at least t:~~5

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 u~rl

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 worker~

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 t~

evaluate any abnormalities of the hematopoietic, hepatic, or renal systemlJ ..

The only difference found between the two groups was an increased prevale~

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%);

et~anolamines (=7S) and polyether polyols for flexible polyurethane foams

(='.5~). 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

T-b~ 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 ma~ufaoture 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 mammals~

ethylene oxide is rapidly metabolized and excreted, with the major route of

elimination being urinary excretion. Ethylene oxide is a suitable substrate fo~

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, a~

indication of increased cancer risk, especially for leUkemia, was indicated fo~

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 coho~

mortality stUdy of ethylene oxide production workers. An additional cohQri

mortality study is in the planning stage for workers involved in ethylene OX~.sterilization of medical supplies.

Pen~ing the results of on-going and planned epidemiological studies, t~

appears to be little immediate need for investigating additional occupati~'

groups baving exposure to ethylene oxide. In the event that the associa~

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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8-3

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8-4

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8-5

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8-6

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8-8

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8-9

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8-10

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*S02n-lC1RE'DRT DOCUMENTATiO;.J 11• Fl£FOlrr NO.

PAGE I~

4. Tnle lind Subtitle

MONOGRAPH ON HUMAN EXPOSURE TO CHEMICALS IN THEWORKPLACE: Ethylene oxide

5. Repcrt OateJuly{1985

7. Authllr{S) Joseph Santodonato, Ph.D., Project Director, etal 8. Farfllrmin.. Or.;anization Flellt No.

9. Performing Or.;anization Name lind Addra~s

Center for Chemical Hazard AssessmentSyracuse Research CorporationSyracuse, NY 13210

12. S/Xlnsllring 01'll'anization Nama and Add~

Division of Cancer EtiologyNational Cancer InstituteBethesda, Md. 20892

15. Supplemllntary Note~

Prepared under contract with the National Cancer Institute

15. Abstract (limit: 200 wor~)

10. Proj~lTa~l</WorJ(Unit No.

U. CoMtract(C) or Grant(G) No.

(C),- NOl-CP-26002-03NCI CONTRACT

(G)

13. Ty~ of Repcrt & Fllricd CoY'!!l'3d

final14.

This report presents a summary and evaluation of information relevant to anoccupational hazard assessment of the chemical. Pertinent toxicologic data werelocated through on-line and manual literature searches for the period extendingback approximately ten years from 1984. No attempt was made to exhaustivelyreview the tox.icologic literature; where appropriate the reader is referred tocomprehensive reviews on this topic. Special attention in this report was focusedon summarizing the available information regarding the carcinogenic potential ofthe chemical. .

17. Document Ana!~i~ 8. Deseripttlr:l

b. Identifiers/Open·Ended Terms

c. COSAn Field/GTllUll

18. AYailability Statemen:

(See ANSI-239.1S)

release unlimited19. Security Clall~ (Tills FllllXlrt>

IINf'1 1""11-'11-'11::20. Security Cla~s (Ti'll~ Fagll)

UNCLASSIFIED

21. No. of Fage~

22. Price

OPTIONAL FDR'-I 272 (4-77)(Formerly NTl$-35)Department of CommeTee

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