ETHYENE

This substance was considered by a previous Working Group, in February 1978 (IARC,
1979). Since that time, new data have become available, and these have been incorporated
into the monograph and taken into consideration in the present evaluation.

1. Exposure Data
1.1 Chemical and physical data

1.1.1 Nomenclature

Chem. Abstr. Sem Reg. No.: 74-85-1

Replaced CAS Reg. No.: 33060-30-9; 87701-64-2; 87701-65-3
Chem. Abstr. Name: Ethene
IUPAC Systematic Name: Ethylene
Synonyms: Acetene; bicarburetted hydrogen; elayl; olefiant gas

1.1.2 Structural and molecular formulae and relative molecular mass

H2C = CH2
C2H4 Relative molecular mass: 28.05
1.1.3 Chemical and physical properties of the pure substance
(a) Description: Colourless gas (Lide, 1991)
(b) Boiling-point: -103.7 °c (Lide, 1991)
(c) Melting-point: -169°C (Lide, 1991)
(d) Spectroscopy data: Infrared (prism, 1131), ultraviolet and mass spectral data have
been reported (Weast & Astle, 1985; Sadtler Research Laboratories, 1991).
(e) Solubilty: Very slightly soluble in water (0.26% vol/vol); slightly soluble in acetone,
benzene and ethanol; soluble in diethyl ether (American Conference of Govern-
mental Industrial Hygienists, 1991; Lide, 1991)
if Vólatility: Vapour pressure, 4270 kPa at 0 °C; relative vapour density (air = 1),
0.9686 (Grantom & Royer, 1987)
(g) Stabilty: Lower explosive limit (in air), 2.75 vol% or 34.6 g/m3 at 100 kPa and 20°C
(Grantom & Royer, 1987)
(h) Octanol-water partition coeffcient (P): log ~ 1.13 (Hansch & Leo, 1979)

-45-
 46 IARC MONOGRAPHS VOLUME 60

(i) Conversion factor: mg/m3 = 1.15 xppma

1.1.4 Technical products and impurities

The purity of ethylene is normally greater than 99.9 wt%; quality is adjusted to meet
specific requirements. Sulfur, oxygen and acetylene are the most troublesome but carefully
controlled impurities, especially when ethylene from multiple sources is mixed for
transportation. Specification ranges (mg/kg) for maximal levels of key contaminants in
ethylene are: methane + ethane, 50-2000; propylene and heavier, 7-200; acetylene, 1.4-10;
hydrogen, 0.1-10; carbon monoxide, 0.15-10; carbon dioxide, 2.2-50; oxygen, 0.6-10; sulfur,
tom & Royer, 1987 (results of a survey of 10 US producersl;
1-10; and water, 0.6-20 (Gran

Dow Chemical Co., 1989; Amoco ChemIcal Co., 1993). Specifications for the quality of
ethylene in Europe, lapan and the USA are similar (Grantom & Royer, 1987).
1.1.5 Analysis

Atmospheric hydrocarbons, including ethylene, can be determined by capilary column

gas chromatography with flame ionization detection (Locke et al., 1989; Khalil &
Rasmussen, 1992). The lower limit of detection with this method is 10 ppb (10 l.IlL) by
volume (Locke et al., 1989). A variation on this method consists of preconcentration with a
two-stage cryotrap system and an aluminium oxide-coated column; the limit of detection is
2.5 ppt (Schmidbauer & Oehme, 1985) or 2 pg (Matuška et al., 1986). A similar method is
based on sample enrichment with a solid sorbent, a zeolite, at room temperature, followed by
heat desorption for gas chromatographic separation and flame ionization detection (Persson
& Berg, 1989). Use of solid sorbent tubes in series (Tenax TA+ Carbosphere S) has been
suggested, with analysis by gas chromatography and an electron capture detection system
parallel to a tandem photoionization and flame ionization system; the limit of detection for
ethylene was 24 ppt (Reineke & Bächmann, 1985).
Methods have been developed for the biological monitoring of occupational exposure
to ethylene, which are based on determination of a haemoglobin adduct (N-(2-hydroxy-
ethyl)valine l of the metabolite, ethylene oxide, using gas chromatography/mass spectro-
metry (Törnqvist et al., 1986a) and gas chromatography/electron capture detection
(Kautiainen & Törnqvist, 1991).

1.2 Production and use

1.2.1 Production

Ethylene is the petrochemical produced in largest quantities worldwide. Recovered

from coke-oven gas and other sources in Europe since 1930, ethylene emerged as a large-
volume intermediate in the 1940s when US oil and chemical companies began separating it
from refinery waste gas and producing it from ethane obtained from refinery by-product
streams and from natural gas. Mter that time, the industry rapidly switched its raw material
base from coal to hydrocarbons (Grantom & Royer, 1987).

aCalculated from: mg/m 3 = (relative molecular mass/24.45) X ppm, assuming normal temperature (25°C) and
pressure (101.3 kPa)
 ETHYLENE 47

Over 95% of the worldwide annual commercial production of ethylene is currently

based on steam cracking of petroleum hydrocarbons. Various feedstocks, including ethane,
propane, butanes, naphthas and gas oils, are used to produce ethylene. Naphthas are the
principal raw material used in western Europe and lapan, accounting for over 80% of the
ethylene produced. Ethane is the primary feedstock in the USA, followed by propane,
naphthas, gas oils and butane. Small amounts of ethylene are recovered from other
feedstocks, such as retrograde-field condensates and refinery waste gases. Dehydration of
ethanol is the third commercial route to ethylene (Grantom & Royer, 1987). Production of
ethylene in 19 countries and regions is presented in Table 1. Total European Union
production in 1990 was 12 820 thousand tonnes (European Commission, 1993).

Table 1. Worldwide production of ethylene (thousand tonnes)

Country or region 1982 1984 1986 1988 1990 1992

Argentina NR 255 258 NR NR NR

Belarusa 145 NA
Canada 1013 1464 1909 2346 2434 2521
China 565 648 642 1231 1572 1 982b
Former Czechoslovakia NR NR NR 683 619 NA
France 1865 2078 2259 2432 2244 2650
GermanyC 2634 3217 2662 3125 3072 3393
Hungary NR 265 269 264 234 281
Italy 872 1136 NR NR NR NR
J apan 3590 4384 4291 5057 5810 6104
Mexico 396 643 767 916 NR NR
Poland 175 256 279 328 308 NA
Republic of Korea 374 526 534 60 1054 2769
Romania NR 317 312 335 243 132d
Russiaa 200 2543 2799 3175 2318 NA
Thiwan 452 66 868 852 776 734
Ukrainea 446 NA
United Kingdom 1113 1153 1 736 2025 1495 1934
USA 11 113 14 235 14 905 16875 16541 18 327b

From Scientific & Technical Information Research Institute of the Ministry of Chemi-
cal Industry of China (1984); Anon. (1985, 1987, 1988, 1989, 1990); Giménez et al.
(1990); Anon. (1991a, 1992, 1993); NA, not available; NR, not reported
ileported as part of USSR from 1981 through 1988
bpreliminary
CWestern
~stimate
Information available in 1991 indicated that ethylene was produced by 17 companies in
the USA, 13 in Japan, nine in Germany, five in France, four each in Brazil and the United
Kingdom, three each in Canada and the Netherlands, two each in Argentina, Australia,
Belgium, China, the Republic of Korea, Saudi Arabia and the former Yugoslavia, and one
each in Austria, the former Czechoslovakia, Finland, India, Italy, Mexico, Norway,
 48 IARC MONOGRAPHS VOLUME 60

Singapore, South Africa, Spain, Thailand, Turkey and Venezuela (Chemical Information
Servces Ltd, 1991).

1.2.2 Use

About 80% of the ethylene used in western Europe, J apan and the USA is for producing
polyethylene (high density, low density and linear low density), ethylene oxide/ethylene
glycols and ethylene dichloride/vinyl chloride. Significant amounts are also used to make
ethylbenzene/styene, oligomer products (e.g. alcohols and a-olefins), acetaldehyde/acetic
acid and vinyl acetate (Grantom & Royer, 1987). Typical patterns for use of ethylene in
western Europe, lapan and the USA are presented in Table 2.
Table 2. Use patterns (%) for ethylene in western Europe,
Japan and the USA
Use Western Japan USA
Euro)ea
(1983 1983 1991 1983 1991

LD-LLD polyethyleneb 35 30 29 28.5 27

HD polyethyleneC 15 20 19 20 24
Ethylene oxide 12 11 11 17 14
Ethylene dichloride 19 18 14 14 13
Ethylbenzene 8 9 10 7 7
Ethanol + acetaldehyde 6 5 4 4 2
Vinyl acetate monomer -d 3 2.5 3
Miscellaneous 5 4 13 7 10

From Grantom and Royer (1987), Anon. (1991b) and Japan Petro-
chemical Industry Association (1993)
llelgium, Germany, France, Italy, Luxembourg, the Netherlands
and the United Kingdorn
bLD, low density; LLD, linear low density
CJD, high density
d¡ncluded in 'miscellaneous'
While most commercially produced ethylene is used as a feedstock in the production of
polymers and industrial chemicals, a relatively small amount is used for the controlled
ripening of citrus fruits, tomatoes, bananas and many other fruits, vegetables and fIowers.
Endogenous production of ethylene in plant tissue generally increases rapidly during
ripening. Application of ethylene to plants before the time of this natural increase not only
tes the ripening process but also increases endogenous ethylene production. Ethylene
initia

has commonly been used in this way since the early part of this century (Nickell, 1982; Kader
& Kasmire, 1984; Bridgen, 1985; Reid, 1985; Kader, 1986; Watada, 1986).

1.3 Occurrence

Ethylene is ubiquitous in the environment, arising from both natural and man-made
sources. Major sources are as a natural product from vegetation of aIl tyes (Sawada &
 ETHYLENE 49

Totsuka, 1986; Rudolph et al., 1989); as a product of burning vegetation, agricultural wastes
and refuse, and the incomplete combustion of fossil fuels; and releases during the production
and use of ethylene (Sawada & Totsuka, 1986).
Total annual emission of ethylene from the global surface has been estimated to be
18-45 million tonnes per year, of which approximately 74% is released from natural sources
and 26% from anthropogenic sources. Releases from terrestrial ecosystems comprise about
89% of the natural sources and aquatic ecosystems, about Il %. Burning of biomass to clear
land for agriculture or other uses is believed to be the largest anthropogenic source
of
ethylene emissions (77%); the combustion of various fossil fuels also accounts for a
significant fraction (21 %) of anthropogenic emissions (Sawada & Totsuka, 1986).

1.3.1 Naturaloccurrence

Ethylene is a natural product emitted by fruits, flowers, leaves, roots and tubers
(AItshuller, 1983). The rate of release varies during the life cycle of the plant. Plants that
normally produce 0.6-6 J.g/kg fresh weight per hour may produce up to 120 J.g/kg per hour
during ripening of fruits and during senescence and loss of leaves (Dörffing, 1982; Tille et al.,
1985). Ethylene is also produced endogenously by humans and other mammals (see section
4.1).
Other natural sources of ethylene include volcanic emissions and natural gas. Volcanos
emit only trace concentrations of ethylene, and leaked natural gas contains mainly saturated
hydrocarbons (Sawada & Totsuka, 1986).

1.3.2 Occupational exposure

The National Occupational Exposure Survey conducted by the US National Institute for
Occupational Safety and Heal th between 1981 and 1983 indicated that 12280 US employees
were potentially exposed occupationally to ethylene (US National Institute for Occupational
Safety and Health, 1993). The estimate is based on a survey of US companies and did not
involve measurements of actual exposures.
There is thought to be little opportunity for occupational exposure to ethylene during its
manufacture in a closed system. Exposure may occur as a result of leaks, spils and other
accidents and from work in tanks that contained ethylene (Dooley, 1983). No data on
measured levels of exposure to ethylene during its manufacture or processing were available
to the Working Group. Hogstedt et al. (1979) estimated that during the period 1941-47,
ethylene levels in an ethylene oxide production plant in Sweden would have been
approximately 600 mg/m3.
Personal and stationary monitoring of ethylene in a company where this gas was used for
controlling the ripening of bananas showed air concentrations to be in the range of 0.02-3.35
ppm (0.02-3.85 mg/m3), with an estimated average concentration of 0.3 ppm (0.35 mg/m3)
(Törnqvist et al., 1989a). ln a study on exposure of firefighters, samples taken during the
'knockdown' phase of a fire showed a concentration of 46 ppm (53 mg/m3) ethylene; none
was detected during the 'overhaul phase (Jankovic et al., 1991).
 50 IARC MONOGRAPHS VOLUME 60

1.3.3 Air
Ethylene concentrations in ambient air at rural and remote sites worldwide are generally
in the range of .. 1-5 J.g/m3 (Altshuller, 1983; Anlauf et al., 1985; Colbeck & Harrison, 1985;
Davidson et al., 1986; Van Valin & Luria, 1988; Kanakidouetal., 1989; Lightmanetal., 1990;

Hov et al., 1991; Mowrer & Lindskog, 1991; Satsumabayashi et al., 1992).
ln urban and indoor air contaminated with combustion products, ethylene
concentrations tyically range from a few to over 1000 J.g/m3. For example, a me
di an
concentration of21.4 ppb as carbon (PpbC) (12.3 J.g/m3) ethylene, with a maximum of 1001
ppbC (573 J.g/m3), was measured in over 800 ambient air samples obtained from 39 US cities
during 1984-86 (Seinfeld, 1989). ln 1985, geometric mean atmospheric concentrations of
ethylene ranging from 3.2 to 45.8 ppb (3.7-52.7 J.g/m3) were determined in an industrial
suburb of Bombay, India (Rao & Pandit, 1988). ln northwest England, geometric mean
ambient air concentrations of ethylene during the summer of 1983 were 41.2 ppbC (23.6
J.g/m3) in urban air samples and 1.5 ppbC (0.86 J.g/m3) in rural air samples (Colbeck &
Harrison, 1985). Ethylene concentrations averaged 4.0 ppb (4.6 J.g/m3) in 1980 and 2.2 ppb
(2.5 J.g/m3) in 1981 in 258 air samples taken over Tokyo, lapan (Uno et al., 1985).
One of the major sources of atmospheric ethylene globally-the burning of biomass
(Sawada & Totsuka, 1986)-can also be a source of locally high concentrations. A mean
ethylene concentration of 490 ppbC (281 J.g/m3) was measured in the indoor air of rural
Nepali houses. where biomass combustion is the main source of energy; the mean
concentration in outdoor air at Katmandu was 2.1 ppbC (1.2 J.g/m3) (Davidson et al., 1986).
Vehicle exhaust emissions make an important contribution to urban air concentrations
of ethylene. Estimates in the mid-1980s for countries of the European Union (Table 3) show
that emissions from gasoline- and diesel-fuelled vehicles make a significant contribution in
that region (Bouscaren et al., 1987).
AIthough ethylene is not a fuel component, it is present in motor vehicle exhaust as a
result of fuel-rich combustion of hydrocarbon fuels (Stump et al., 1989). Mean ethylene
emissions from 25 vehicIes in the United KIngdom were 211.94 mg/km in urban road tests,
123.20 mg/km In suburban road tests and 93.9 mg/km in rural road tests (Bailey et al.,
1990a,b). The following levels ofethylene were determined in air samples representative of
various traffc emissions in Sweden: 68 and 64 J.g/m3 (two sites, urban intersection); 13 and
9.8 J.g/m3 (two sites, fast suburban traffic); and 56 J.g/m3 (cold starts at a garage exit)
(Löfgren & Petersson, 1992). Ethylene concentrations of 51-405 J.g/m3 were measured in
the Tingstad Tunnel in Göteborg, Sweden (Barrefors & Petersson, 1992).
Industrial emissions of ethylene to the air in the USA in 1991 were reported to amount to
17400 tonnes (US National Library of Medicine, 1993); industrial emissions in the countries
of the European Union are shown in Table 3.
Cigarette smoke is also a significant source of exposure to ethylene, as 1-2 mg ethylene
are released per cigarette. The exposure of the average cigarette smoker to ethylene is
roughly 10 times that from urban air pollution (Persson et al., 1988; Shaikh et al" 1988). ln
two studies of smokey tavern air, the ethylene levels were 56 and 110 J.g/m3; the corres-
ponding outdoor air concentrations at the time were 16 and 12 J.g/m3 ethylene (Löfroth et al.,
1989).
 ETHYLENE 51

Table 3. Estimated ethylene emissions in member

states orthe European Union (thousand tonnes/year)
Country Source

Road traffic Chemical Other

industrya sources
Gasoline Diesel

Belgium 4.7 1.3 1 0.9

Denmark 2 0.7 NR NR
Germany 27 9.5 2.2 11
France 28 8.8 2.5 1
Greece 2.8 1.4 NR 0.01
Ireland 1.3 0.2 NR NR
Italy 28 8.1 2 1
Luxemburg 0.23 0.05 NR NR
Netherlands 5.1 1.6 2.6 3.1
Portugal 1. 1.3 0.3 0.1
Spain 8.9 4.4 1 0.8
United Kingdom 33 5.5 1 1.5
Total 145 45 13 20
(approximate)
From Bouscaren et al. (1987); NR, not reported
aproduction of ethylene and ethylene polymers and copolymers

ln laboratory studies, ethylene has been detected as a thermal degradation product of

polyethylene and polypropylene (Hoff et al., 1982; Frostling et al., 1984).
Ethylene is degraded in the troposphere mainly by reactions with OH radical and ozone.
Its average atmospheric lifetime is estimated at two to four days (Sawada & Totsuka, 1986;
Rudolph et al., 1989).

1.3.4 Uáter

Although ethylene is only slightly soluble in water, low concentrations have been
measured in various surface waters. Pacific and Atlantic Ocean surface waters (7r N to
75° S) contained 0.7-12.1 nI/L, fresh water lakes and rivers in the USAfrom 4.8 to 13.0 nI/L,
and more polluted waters in the Mississippi River delta and near the shore in Miami, FL,
from 26 to 35 nI/L (Sawada & Totsuka, 1986).

1.4 Regulations and guidelines

Ethylene has been classified in several countries as an asphyxant because its presence at
high concentrations in air lowers the available oxygen concentration. Countries in which it is
classified as an asphyxant include Australia, Belgium, Canada, Finland, Hungary, the
Netherlands, the United Kingdom and the USA. Nevertheless, the major hazard is due to its
inflammable and explosive character. No exposure limits have been recommended in most
52 lARe MONOGRAPHS VOLUME 60

countries, but Switzerland established a time-weighted average occupational exposure limit

of 11 500 mg/m3 (about one-half the lower exposure limit) in 1987 (ILO, 1991; American
Conference of Governmental Industrial Hygienists, 1993; UNEP, 1993). ln Germany, no
exposure limit is given for ethylene because it is 'justifiably suspected of having carcinogenic
potential' (Deutsche Forschungsgemeinschaft, 1993).
ln the USA, ethylene is exempted from the requirement of a tolerance for residues when
it is used as a plant regulator on fruit and vegetable crops and when it is injected into the soil
to cause premature germination of witchweed for a variety of crops (US Environmental
Protection Agency, 1992). The US Food and Drug Administration (1993) permits use of
ethylene-containing polymers in products in contact with food.

2. Studies of Cancer in Humans

Sorne cohorts involved in the manufacture of ethylene oxide are likely to have been
exposed to ethylene; however, in the only study in which exposure to ethylene was assessed
(Hogstedt et al., 1979), described in detail on pp. 89-90, the risk for cancer in relation to
ethylene was not assessed separately.

3. Studies of Cancer in Experimental AnimaIs

3.1 Inhalation exposure

Rat: Groups of 120 male and 120 female Fischer 344 rats, six to seven weeks of age, were
exposed by inhalation to 0,300, 1000 or 3000 ppm (0, 345, 1150 or 3450 mg/m3) ethylene
(? 99.9% pure) for 6 h per day on five days per week for up to 24 months, at which time the
experiment was terminated. The high dose was chosen to avoid the hazard of explosion.
Necropsies were performed at six (5 rats/dose and per sex), 12 (5 rats/dose and per sex), 18
(19-20 rats/dose and per sex) and 24 (aIl survvors) months. AIl rats that died spontaneously
were also necropsied. There was no significant difference in survival between control and
treated groups. The high-dose and control animaIs were examined histologically. The
authors reported that there was no evidence of treatment-related toxicity and no increase in
tumour incidence (Hamm et al., 1984).

3.2 Induction of enzyme-altered fod in a two-stage liver system

Rat: Groups of male and female Sprague-Dawley rats, three to five days of age, were
exposed by inhalation to 0 (5 male and 9 female rats) or 10000 ppm (11500 mg/m3, 2 males
and 10 females) ethylene (purity unspecified) for 8 h per day on five days per week for three
weeks. One week later, the rats received oral administrations of 10 mg/kg bw Clophen A 50
(a mixture of polychlorinated biphenyls (not otherwse specified)) by gavage twce a week for
up to eight additional weeks (promotion), at which time the experiment was terminated and
the IIvers were examined for ATPase-deficient foci. The number of ATPase-deficient foci ¡n
 ETHYLENE 53

the rats exposed to ethylene did not exceed the control values. ln the same experiment,
ethylene oxide, administered as a positive control, produced a significant increase in the
incidence of ATPase-deficient foci in females (Denk et al., 1988).

3.3 Carcinogenicity of metabolites

See the monograph on ethylene oxide.

4. Other Data Relevant for an Evaluation of

Carcinogenicity and Its Mechanisms

The toxicology of ethylene has been reviewed (National Research Council Canada,
1985; Gibson et al., 1987; Angerer et al., 1988; Greim, 1993).

4.1 Absorption, distribution, metabolism and excretion

4.1.1 Humans
The inhalation pharmacokinetics of ethylene have been investigated in human
volunteers at atmospheric concentrations of up to 50 ppm (57.5 mg/m3) by gas uptake in a
closed spirometer system (Shen et al., 1989; Filser et al., 1992). The uptake, exhalation and
metabolism of ethylene can be described by first-order kinetics.
Uptake of ethylene into the body is low. Clearance due to uptake, which reflects the
transfer rate of ethylene from the atmosphere into the body, was 25 L/h for a man of 70 kg.
This value represents only 5.6% of the experimentally obtained alveolar ventilation rate of
450 L/h. The majority (94.4%) of ethylene inhaled into the lungs is exhaled again without
becoming systemically available via the blood stream. Maximal accumulation of ethylene in
the same man, determined as the thermodynamic partition coefficient whole body:air (Kea
= COnCanimal/COnCair), was 0.53. The concentration ratio at steady state was even smaller
(0.33), owing to metabolic elimination. Clearance due to metabolism, in relation to the
concentration in the atmosphere, was calculated to be 9.3 L/h for a man of 70 kg. This
indicates that at steady state about 36% of systemically available ethylene is eliminated
metabolicallyand 64% is eliminated by exhalation as the unchanged substance, as can be
calculated from the values of clearance of uptake and of clearance of metabolism. The
on of ethylene at steady state
biological half-life of ethylene was 0.65 h. The alveolar retenti

was calculated to be 2% (Filser et al., 1992). From theoretical considerations of the lung
uptake of gases and vapours (J ohanson & Filser, 1992), it can be deduced that the low uptake
rate of ethylene is due to its low solubility in blood: Ostwald's solubility coefficient for human
blood at 37°C, 0.15 (Steward et aL., 1973).

(a) Endogenous formation

Endogenous production of ethylene can be deduced from its exhalation by unexposed
subjects (Ram Chandra & Spencer, 1963; Shen et al., 1989; Filser et aL., 1992). For a man of
54 IARC MONOGRAPHS VOLUME 60

70 kg, a mean production rate of 32 nmoI/h (0.9 i.g/h) and a corresponding mean body
burden of 0.011 nI/ml tissue (equivalent to 0.44 nmoI/kg bw or 0.012 i.g/kg bw) was
calculated for ethylene gas (Filser et al., 1992). The amount of ethylene in the breath of
women Is increased significantly at the time of ovulation; no difference was observed in the
basal ethylene outputs of non-pregnant and pregnant women and of men (Harrison, 1981).
The biochemical sources of ethylene are unknown; however, several mechanisms bywhich it
might be produced in mammals are discussed below.

(b) Haemoglobin adducts

The ethylene metabolite, ethylene oxide, reacts with nucleophilic centres in cellular
macromolecules (see monograph on ethylene oxide). ln several studies, the haemoglobin
(Hb) adducts N-(2-hydroxyethyl)histidine (HOEtHis) and N-(2-hydroxyethyl)valine
(HOEtVal) have been used as internaI dose monitors of the formation of ethylene oxide from
ethylene. ln nonsmokers, the background levels of HOEtVal range between Il and 188
pmoI/g Hb (Törnqvist et al., 1986b; Bailey et al., 1988; Törnqvist et al., 1989a; Sarto et al.,
1991; Filser et aL., 1992; Törnqvist et al., 1992; van Sittert et al., 1993; van Sittert & van Vliet,
1994). Farmer et al. (1986) reported background levels of 30-930 pmoI/g Hb in three
subjects, without considering smoking habits. ln Hb of subjects presumed not to be exposed
to ethylene, the levels of2-hydroxyethyl adducts were 1500-4300 pmol/g Hb N-(2-hydroxy-
ethyl)cysteine (HOEtCys) in three subjects, 30-530 pmoI/g Hb HOEtVal in five subjects; 60
and 300 pmoI/g Hb N1T-HOEtHis in two subjects and 110-290 pmoI/g Hb NT-HOEtHis in
five. Tobacco smoke, urban air and endogenous production were included as possible
man, 1986). HOEtHis levels in 31 control subjects ranged from
sources of ethylene (Calle

~ 20 to 4700 pmoI/g Hb. Smoking did not contribute to these background alkylations (van
Sittert et al., 1985).
Exposure to environ mental ethylene concentrations of 10-20 ppb (11.5-23 i.g/m3) was
associated with an HOEtVal increment of 4-8 pmoI/g globin at steady state (Törnqvist &
Ehrenberg, 1990). Background levels of HOEtVal were predicted on the basis of
pharmacokinetic parameters of ethylene and ethylene oxide, together with the rate constant
of the reaction of ethylene oxide with the N-terminal valine in Hb and confirmed by
measured data. HOEtVal levels resulting from endogenous ethylene onlywere calculated to
be about 12 pmol/g Hb. Those resulting from both endogenous and environmental ethylene
(15 ppb (17.25 l1g/m3)) in the area of Munich (Germany) were computed to be about
18 pmoI/g Hb; the measured level was about 20 pmoI/g Hb and, hence, in close agreement
with that predicted (Filser et al., 1992). No difference in HOEtVal adduct levels was seen in
nonsmoking workers in an ethylene plant and in nonsmoking controls not occupationally
exposed (van Sittert & van Vliet, 1994).
Significantly higher levels of HOEtVal (129-690 pmol/g Hb) were found in cigarette
smokers (10-30 cigarettes/day) than in nonsmokers (Törnqvist et al., 1986b; Passingham
et al., 1988; Persson et al., 1988; Törnqvist et al., 1989a; Sarto et al., 1991). Ethylene (0.25
mg/cigarette; Elmenhorst & Schultz, 1968) and ethylene oxide (0.005 mg/cigarette; Binder &
Lindner, 1972) present in tobacco smoke were considered to be major causes of the elevated
adduct levels (Törnqvist et al., 1986b; Persson et al., 1988; Törnqvist et aL., 1989a). Smoking
 ETHYLENE 55
10 cigarettes per day was associated with an additional 60-114 pmol/g Hb HOEtVal
(Törnqvist et al., 1986b; Bailey et al., 1988; Passingham et al., 1988; van Sittert et al., 1993).
Nonsmoking fruit store workers exposed occupationally to atmospheric ethylene (0.02-
3.35 ppm (0.023-3.85 mg/m3)) used for the ripening of bananas had levels of 22-65 pmol/g
Hb HOEtVal, whereas nonsmoking con
an
troIs had 12-27 pmol/g Hb. On the basis of a me

exposure concentration of 0.3 ppm (0.345 mg/m3), it was estimated that about 3% (range,
1-10%) ofinhaled ethylene was metabolized to ethylene oxide (Törnqvist et al., 1989a). This
percentage is equal to the alveolar retention at steady state calculated from inhalation
pharmacokinetics (see above). The two values are in agreement. An increment of 100-120
pmol/g Hb HOEtVal was estimated for a time-weighted average exposure (40 h/week) to
1 ppm ethylene (1.15 mg/m3) (Kautiainen & Törnqvist, 1991; Ehrenberg & Törnqvist, 1992).
On the basis of the relationship between HOEtVal levels and exposure levels of ethylene
or ethylene oxide, an 'uptake' (i.e. amount metabolized) of 1 mg ethylene/kg bw was calcu-
lated to be equivalent to a tissue dose of ethylene oxide ofO.7x 10-6 molxh/L (0.03 mgxh/kg
bw) (Törnqvist et al., 1988). This value is in agreement with the value of 0.5 x 10-6 molxh/L
that can be calculated from the pharmacokinetic data for ethylene and ethylene oxide
published by Filser et al. (1992).

4.1.2 Experimental systems

Four male CBA mice (average body weight, 31 g) were exposed together for 1 h in
a closed glass chamber (5.6 L) to 14C-ethylene (22 mCi/mmol) in air at 17 ppmxh (22.3
(mg/m3)xh, equivalent to about 1 mg/kg bw). Blood and organs from two mice were pooled
4 h after the end of exposure. Radioactivity was about the sarne in kidney (0.16 i.Ci/g wet
weight) and liver (0.14 i.Ci/g) but lower in testis (0.035 i.Ci/g), brain (0.02 llCi/g) and Hb
. (0.0094 llCi/g Hb). Urine was collected from the two other mice during 48 h, and blood was
collected after 21 days. S-(2- Hydroxyethyl)cysteine was identified as a metabolite of ethylene
in urine (3% of 14C in urine) by thin-Iayer chromatography. The radioactivity in Hb was
0.011 llCi/g Hb. These data, together with those on specific hydroxyethyl derivatives at
amino acid residues of Hb (see below), indicated that ethylene was metabolized to ethylene
oxide (Ehrenberg et al., 1977).
ln several experiments, disposition of 14C-ethylene (free of 14C-acetylene or ? 97%
pure) in male Fischer 344 rats (170-220 g) was determined over 36 h following 5-h exposures
in a closed chamber (35 L) to 10000 ppm (11 500 mg/m3). ln each experiment, up to four rats
were exposed together in a single chamber. Within about 1 min after the end of exposure,
animaIs were transferred to individual all-glass metabolism cages. Most of the eliminated 14C
was exhaled as ethylene (18 llmol (504 llg) per rat exposed to acetylene-containing ethylene);
smaller amounts were excreted in urine (2.7 llmol ethylene equivalents/rat) and faeces (0.4
i.mol) and exhaled as COz (0.16 i.mol). Radioactivity was also found in blood (0.022 llmol
ethylene equivalents/ml), liver (0.047 llmol ethylene equivalents/liver), gut (0.034 llmol
ethylene equivalents/gut) and kidney (0.006 llmol ethylene equivalents/kidney). Pre-
treatment of animaIs with a mixture ofpolychlorinated biphenyls (Arocior 1254; 500 mg/kg
bw; single intraperitoneal injection five days before exposure) had no measurable influence
on ethylene exhalation but resulted in a significant (p .. 0.05) increase in exhaled 14C01
(2.04 llmol ethylene equivalents/rat) and of 14C in urine (11.1 llmol ethylene equivalents/rat)
56 IARC MONOGRAPHS VOLUME 60

and in blood (0.044 ¡.mol ethylene equivalents/ml). The organ burden of 14C was one to two
orders of magnitude greater in Aroclor 1254-treated than in untreated animaIs. Radio-
activity also became detectable in lungs, brain, fat, spleen, heart and skeletal muscle. The
data were interpreted as indicating that the metabolism of ethylene can be stimulated byan
inducer of the mixed-function oxidase system (Guest et al., 1981).
The pharmacokinetics of inhaled ethylene have been investigated in male Sprague-
Dawley rats using closed exposure chambers in which the atmospheric concentration-time
course was measured after injection of a single dose into the chamber atmosphere (BoIt et al.,
1984; Bolt & Filser, 1987; Shen et al., 1989; Filser, 1992). Uptake of ethylene into the body
was low. Clearance due to uptake (as described above) was 20 ml/min for one rat of 250 g,
which represents only 17% of the alveolar ventilation (117 ml/min; Arms & Travis, 1988).
Most (83 %) inhaled ethylene that reaches the lungs is exhaled again without becoming
systemically available via the blood stream. Maximal accumulation of ethylene in the
organism, determined as the thermodynamic partition coefficient, whole body:air (Kea =
ConCanimal/Concair), was 0.7. The concentration ratio at steady-state whole body:air was
somewhat lower owing to metabolic elimination, and it decreased from 0.7 to 0.54 at
exposure concentrations below 80 ppm (92 mg/m3); however, at very low atmospheric
concentrations, the concentration ratio at steady-state whole body:air increased again, owÍng
to endogenous production of ethylene: For instance, it was almost twice the value of the
thermodynamic partition coefficient whole body:air at an exposure concentration of 0.05
ppm (0.06 mg/m3) (calculated using the pharmacokinetic parameters and equation 18 of
Filser, 1992). At concentrations between 80 and 0.1 ppm (92 and 0.12 mg/m3), clearance was
seen, due to metabolism related to the concentration in the atmosphere of about 4.7 ml/min
for a 250-g rat. ln that concentration range at steady state, therefore, about 24% of
systemically available ethylene is eliminated by metabolism and 76% by exhalation of the
unchanged substance (taking into account values of clearance of uptake and clearance of
metabolism). The alveolar retention of ethylene at steady state was 3.5%, and the biological
half-life was 4.7 min (Filser et al., 1992). At atmospheric concentrations greater than 80 ppm
(92 mg/m3), metabolism of ethylene became increasingly saturated, reaching a maximal rate
of metabolism (VmaJJ of 0.035 ¡.mol/(minx250 g bw) (0.24 mg/(hxkg bw)) at about
1000 ppm (1150 mg/m3). The apparent Michaelis constant (Km) related to the average
concentration of ethylene gas within the organism was 130 nI/ml tissue, which corresponds to
an atmospheric concentration of 208 ppm (239 mg/m3) at V max2, calculated by means of the
kinetic parameters given by Filser (1992).
Gas uptake studies with male Fischer 344 rats gave values for V max of 0.24 mg/(hxkg
bw) and an 'inhalational Km' (related to the atmospheric concentration) of 218 ppm
(251 mg/m3) (Andersen et al., 1980).
Involvement of cytochrome P450-dependent monooxygenases in the metabolism of
ethylene in male Sprague- Dawley rats was suggested by the complete inhibition of metabolic
elimination after intraperitoneal treatment with 200 mg/kg diethyldithiocarbamate 15 min
before exposure and by an increase in the rate of its metabolism with a V max of about
14 ¡.moI/(hxkg bw) (0.33 mg/(hxkg bw)), after treatment with a single dose of Aroclor 1254
(500 mg/kg bw) six days before the experiment (BoIt et al., 1984).
 ETHYLENE 57
The metabolism of 14C-ethylene in 15 male CBA mice kept for 7 h in a cIosed exposure
chamber (11 L), in which the atmospheric concentration-time course was measured after
generation of an initial atmospheric concentration of 10 ppb (11.5 J1g/m3), was reduced by
co-exposure to propylene at 1260 ppm (1267 mg/m3), suggesting inhibition of ethylene
metabolism by propylene (Svensson & Osterman-Golkar, 1984).
ln liver microsomes prepared from male Sprague- Dawley rats, ethylene at concen-
trations of up to 10% (115 g/m3) in the gas phase was metabolized to ethylene oxide in the
presence of an NADPH regenerating system (1 h, pH 7.5,37 CC). The rate of formation of
ethylene oxide was saturable (V max, 0.67 nmollh per mg protein) and could be reduced by the
addition of diethyldithiocarbamate or ß-naphthofIavone to the microsomal suspension.
Treatment of the rats with phenobarbital (single intraperitoneal injection of 80 mg/kg bw
0.1 % in drinking-water) before preparation ofliver microsomes did
followed by three days of

not change the V max (Schmiedel et al., 1983).

Male Sprague-Dawley rats exposed to ethylene exhaled ethylene oxide. ln these
experiments, two animaIs were kept together up to 21 h in a closed exposure chamber (6.4 L).
The concentration of ethylene in the atmosphere of the chamber was maintained at greater
than 1000 ppm (1150 mg/mg3) by repeated additions, in order to maintain V max conditions
for ethylene. One hour after the beginning of exposure, the atmospheric concentration of
exhaled ethylene oxide reached a peak value of 0.6 ppm (0.69 mg/m3). After about 2.5 h, the
concentration had decreased to about 0.3 ppm (0.345 mg/m3) and then remained constant.
On the basis of the concentration-time courses of atmospheric ethylene, it was speculated
that this decrease was due to rapid induction of ethylene oxide metabolizing enzyes,
whereas the rate of ethylene metabolism remained unaffected (Filser & Bolt, 1984). ln male
Sprague-Dawley rats exposed to concentrations greater than 1000 ppm, the amount of
ethylene taken up per unit time from the atmosphere of a closed cham
ber remained constant
over exposure times of up to 30 h (Boit et al., 1984). Pharmacokinetic data for ethylene and
ethylene oxide indicated that under steady-state conditions only 29% of metabolized
ethylene is available systemically as ethylene oxide. Therefore, assuming that the liver is the
principal organ in which ethylene is metabolized, an intrahepatic first-pass effect for the
intermediate ethylene oxide was suggested (Filser & Bolt, 1984).
ln view of the saturability of ethylene metabolism, the maximal possible average body
concentration of its metabolite, ethylene oxide, was calculated to be 0.34 nmollml tissue
(15 l1g/kg bw) in an open exposure system (infinitely large atmospheric volume). The same
value was computed to result from exposure to ethylene oxide at an atmospheric concen-
tration of 5.6 ppm (10.2 mg/m3) at steady state (Bolt & Filser, 1987).
Ethylene oxide was found in the blood of male Fischer 344/N rats during exposure to an
atmospheric ethylene concentration of 600 ppm (690 mg/m3). A maximal value of about
3 J1g/g blood of ethylene oxide was seen 8 min after the start of exposure to ethylene; this
value was followed 4 min later by an immediate decrease to about 0.6 llg/g, and the level
remained constant for the following 46 min. During exposure, the cytochrome P450 content
in the liver was reduced to 94% after 20 min and to 68% after 360 min. It was speculated that
an ethylene-specific cytochrome P450 isozyme was rapidly deactivated during exposure to
ethylene, resulting in reduced formation of ethylene oxide (Maples & Dahl, 1993). This
speculation is based on results obtained by an unspecific method for the determination of
58 IARC MONOGRAPHS VOLUME 60

cyochrome P450 which is not suItable for the determination of cyochrome P450 isozyes;
however, under certain conditions, suicide metabolism of ethylene in rat liver does seem to
occur, as indicated from experiments of induction of cyochrome P450-dependent mono-
oxygenases. ln male Sprague-Dawley rats treated with phenobarbital (80 mg/kg bw, intra-
peritoneal injection daily for four days, exposure to ethylene on day 5) and then exposed for
3 h to a mixture of commercial ethylene (contaminated with about 10 ppm acetylene) and air
(1:1 v/v), a green pigment was found in the liver 4 h after exposure. The same pigment was
formed in vitro during incubation of acetylene-free ethylene with the 9000 x g supernatant of
a rat liver homogenate (from phenobarbital-pretreated animaIs) in the presence ofNADPH.
No controls were used (Ortiz de Montellano & Mico, 1980). The pigment was identified as a
N-(2-hydroxyethyl)protoporphyrin ix, an alkylation product of the prosthetic haem of
cyochrome P450-dependent monooxygenases. It was concluded that the phenobarbital-
inducible form of cyochrome P450 was destroyed during oxidative metabolism of ethylene
(Ortiz de Montellano et aL., 1980, 1981).
The further metabolic fate of ethylene oxide is described in the monograph on that
chemicaL.

(a) Endogenous formation

Four possible sources of endogenous ethylene have been suggested: lipid peroxidation
(Lieberman & Mapson, 1964; Lieberman & Hochstein, 1966; Frank et aL., 1980; Sagai &
Ichinose, 1980; Törnqvist et al., 1989b; Kautiainen et aL., 1991); enzye- (Fu et aL., 1979),
copper- (Lieberman et al., 1965) or iron- (Kessler & Remmer, 1990) catalysed oxidative
destruction öf methionine; oxidation of haemoglobin (Clemens et al., 1983); and the meta-
bolism of intestinal bacteria (Törnqvist et al., 1989b).
gai & Ichinose, 1980;
Ethylene is also exhaled by untreated rats (Frank et al., 1980; Sa

Shen et al., 1989). The endogenous production rate in a Sprague-Dawley rat (250 g bw) was
determined to be 2.8 nmol/h (0.31 iig/(h x kg bw)), resulting in a body burden of ethylene gas
of 0.032 nI/ml tissue (0.036 iig/kg bw) (Filser, 1992). The corresponding exhalation rate may
be calculated from the pharmacokinetic parameters of Filser (1992) as 0.24 iig/(hxkg bw).

(b) Haemoglobin adducts

Hydroxyethyl adducts at cysteine, histidine and the N-terminal valine of Hb were iden-
tified in several animal species exposed to ethylene and have been ascribed to the formation
of ethylene oxide (Ehrenberg et al., 1977; Osterman-Golkar et al., 1983; Segerbäck, 1983;
Törnqvist et al., 1986a, 1988, 1989b; Kautiainen et al., 1991). Background levels of Hb
adducts, partially due to exposure to endogenous and environmental ethylene, are listed in
Table 4.
ln male CBA mice exposed for 70 h to an atmospheric concentration of 9100 ppm
ethylene (10 465 mg/m3), the level of the Hb adduct HOEtCys was 7200 pmol/g Hb
(Ehrenberg et al., 1977).
Further support for the proposaI that ethylene oxide is the reactive metaboliteof
ethylene arose from the finding of similar relative patterns of the Hb adducts HOEtCys,
HOEtHis and HOEtVal in male CBA mice either exposed in a closed chamber to atmos-
pheric 14C-ethylene at initial concentrations of 0.25, 1.1 or Il ppm (0.29, 1.27, 12.7 mg/m3)
 ETHYLENE 59

(exposure dose 1,6.5 or 50 ppmxh (1.15,7.48,57.5 mgxh/m3D or treated intraperitoneally

with 14C-ethylene oxide (44 ¡.mol/kg bw (1.9 mg/kg bwD (Segerbäck, 1983).
Table 4. Hydroxyethyl (HOEt) haemoglobin adducts measured in animaIs after
endogenous and environmental exposure to ethylene and related metabolites
Species and Sex Haemoglobin adducts measured Reference
strain (pmollg Hb)
HOEtCys HOEtHis HOEtVal

CBA mouse Male 1400 Ehrenberg et al. (1977)

Mouse NR 20- 1 20 Törnqvist et al. (1986a)
B6C3F 1 mou se Male 58 Walker et al. (1992a)
F344 rat Male 1300, Osterman-Golkar et al.
2800 (1983)
Rat NR ~100 Törnqvist et al. (1986a)
F344 ra t Male, female 75,60 Törnqvist et al. (1988)
F344 rat Male 42 Walker et al. (1992a)
Syrian hamster NR ~loo Törnqvist et al. (1986a)
Syrian hamster Male, female 120, 105 Törnqvist et al. (1988)
NR, not reported

It was calculated from the value of 2-2.4 pmol HOEtCys/g Hb per (ppm h) of ethylene
and the value of 30 pmol HOEtCys/g Hb per (ppm x h) of ethylene oxide that 7-8% of
inhaled ethylene is metabolized in male CBA mice to ethylene oxide (Ehrenberg et al., 1977;
Segerbäck, 1983). These mice had been exposed to ethylene at concentrations below20 ppm
(23 mg/m3), at which first-order kinetics of metabolism can be assumed. The value is equal to
the alveolar retention of ethylene at steady state and is similar to the values calculated for rats
and humans (see above).
HOEtVal was determined in Hb of male and female Fischer 344 rats and male and
female Syrian hamsters exposed for six months to gasoline and diesel exhausts (mean atmos-
pheric concentrations of ethylene, -( 0.1-2.28 ppm ( -( 0.115-2.62 mg/m3D. ln hamsters, the
levels of HOEtVal increased almost linearly with dose. The increments at the highest dose
were similar in female rats (505 pmol/g Hb) and hamsters (615 pmol/g Hb) and in male rats
(450 pmol/g Hb) and hamsters (420 pmol/g Hb). These values were about 50-90% of those
predicted from the data on mice, indicating that ethylene behaves similarly in these species. It
was estimated from the results of studies on animaIs that an uptake (i.e. amount metabolized)
of 1 mg ethylene/kg bw is associated with a tissue dose of ethylene oxide of 0.7 x 10-6
molxh/L (0.03 mgxh/kg bw), similar to the value obtained for humans (Törnqvist et al.,
1988).

4.1.3 Comparison between humans and experimental animais

Formation of ethylene oxide was determined directly in rats exposed to ethylene, but no
su ch data are available for humans. Assuming that the metabolism of ethylene in humans
proceeds quantitatively via ethylene oxide, however, the average body burden of ethylene
60 lARC MONOGRAPHS VOLUME 60

oxide resulting from exposure to ethylene can be calculated from pharmacokinetic para-
meters obtained for the two compounds. A value for ethylene oxide of 0.17 pmol/ml tissue
(7.5 ng/kg bw) would result from ethylene produced endogenously; taking into account
additional exposure to 15 ppb (17.3 ¡.g/m3) atmospheric ethylene, as measured in Munich,
Germany, the body burden of ethylene oxide can be computed as 0.25 pmol/ml tissue
(11 ng/kg bw) (Filser et al., 1992).
For exposure concentrations below 50 ppm (57.5 mg/m3), the pharmacokinetic para-
meters of inhaled ethylene obtained in rats were extrapolated to humans by means of an
allometric method based on a surface factor equal to two-thirds of body weight (Filser,
1992). The deviation between the values predicted from rats and the measured values did not
exceed a factor of 2.3.

4.2 Toxic effects

4.2..1 Humans
No data were available to the Working Group.

4.2.2 Experimental systems

Exposure to atmospheric ethylene alone did not lead to toxic effects, whether after
single exposures of male Holtzman rats (4 h up to 57 000 ppm (65 550 mg/m3)) or male
Fischer 344 rats (5 h to 10000 ppm (11500 mg/m3)) (Conolly & laeger, 1977; Conollyet aL.,
1978; Conolly & laeger, 1979; Guest et al., 1981), after 90-day exposures ofmale and female
Sprague- Dawley rats (6 h/day, 5 days/week, up to 10 000 ppm (11 500 mg/m3D (Rhudy et aL.,
1978) or after two-year exposures of male and female Fischer 344 rats (6 h/day, 5 days/week,
up to 3000 ppm (3450 mg/m3)) (Hamm et al., 1984). This lack of toxicity, which might be
predicted from results obtained for ethylene oxide, is due to saturation of the metabolic
activation of ethylene (see section 4.1.2).
Single exposures of male Holtzman rats to atmospheric ethylene (4 h; 10000,23000-
30000,50000-57000 ppm (11 500,26450-34500,57 500-65 550 mg/m3)) one day after
treatment with Aroclor 1254 (100 mg/kg bw, equivalent to 300 ¡.mol/kg bw, once daily by
gavage for three days induced dose-dependent acute hepatotoxicity. Hepatic effects were
indicated 24 h after beginning of exposure by elevated serum concentrations of sorbitol
dehydrogenase and of alanine-cx-ketoglutarate transaminase and by histological findings
such as cell ballooning and haemorrhagic necrosis in centrilobular zones (Conolly & Jaeger,
1977; Conolly et al., 1978; Conolly & Jaeger, 1979). Treatment 0.5 h before start of the
exposure with diethylmaleate (0.5 ml/kg bw), in order to deplete reduced glutathione, or with
trichloropropene oxide (0.1 ml/kg bw), in order to inhibit epoxide hydrolase, had no effect on
the hepatotoxicity of ethylene in Aroclor 1254-pretreated rats (Conolly & laeger, 1979).
ln two male Fischer 344 rats treatedwith Aroclor 1254 (500 mg/kg; single
intraperitoneal injection five days before exposure), a 5-h exposure to 10 000 ppm
(11 500 mg/m3)14C-ethylene (free of 14C-acetylene) in a closed recirculating system (35 L) .
caused uniform hepatic centrilobular necrosis, which was seen 36 h after exposure.
Treatment with Aroclor 1254 without subsequent exposure to ethylene resulted in slight
 ETHYLENE 61

hypertrophy of centrilobular liver cells without hepatocellular necrosis. The authors

suggested that Aroclor 1254 affects the metabolism of ethylene in such a way that a toxic
metabolite is produced in suffcient quantities to elicit hepatotoxicity (Guest et al., 1981).

43 Reproductive and prenatal efTects

No data were available to the Working Group.

4.4 Genetic and related efTects (see also Table 5 and Appendices 1 and 2)
4.4.1 Humans
ln the DNA of peripheral lymphocyes of eight people not occupationally exposed to
ethylene or ethylene oxide, 7-(2-hydroxyethyl)guanine (7-HOEtGua) was detected at a back-
ground level of 8.5 :1 5.7 nmol/g DNA. Possible sources for this DNA adduct were not
discussed (Föst et al., 1989).
No other data were available to the Working Group.

4.4.2 Experimental systems

(a) DNA adducts

The ratio between 7-HOEtGua in DNA in various organs and HOEtVal in Hb of rats
exposed to ethylene oxide was over 100 times higher in unexposed than in animaIs exposed
for four weeks (Walker et al., 1992a,b). (This suggests that factors other than ethylene oxide
are involved in the formation of 7-HOEtGua.)
7 - HOEtGua was found by gas chromatography-mass spectrometry at background levels
of 2-6 nmol/g DNA in DNA of lymphocyes from blood of untreated male Sprague-
Dawley rats (Föst et al., 1989) and in DNA ofvarious tissues from male Fischer 344 rats and
B6C3F1 mice (Walker et al., 1992b). Alkylation of 7-guanine was measured in DNA from
liver, spleen and testis of mice 14 h after exposure by inhalation to 14C-ethylene at an initial
concentration of II ppm (12.9 mg/m3) (exposure dose, 50 ppmxh (58.5 mgxh/m3D for 8 h.
The values of degree of alkylation were 0.17 for liver, 0.098 for spleen and 0.068 nmollg
DNA for testis, representing .c 10% of the background levels. The ratios of 7-guanine in
DNA to NT-His in Hb were approximately the sa
me as those obtained after intraperitoneal
injection of ethylene oxide (Segerbäck, 1983).

(h) Mutation and alled effects

Gene mutations were not induced in Salmonella typhimurium TAlOO exposed for 7 h to
20% ethylene in air, either with or without an exogenous metabolic system. Ethylene did not
induce micronuclei in bone-marrow cells of rats or of mice exposed to up to 3000 ppm
(3500 mg/m3) for 6 h/day, five days/week for four weeks.
 0\
N

Table 5. Genetic and related efTects of ethylene

Test system Resulta Doseb Reference

(LED/HID)
Without With ..
exogenous exogenous ;i
metabolic metabolic ~
system system a=
o
SAO, Salmonella typhimurium TA100, reverse mutation 225.00C Victorin & Ståhlberg (1988) z
o
MVM, Micronucleus test, mouse bone-marrow cells in vivo 1200, inhaL. 6 h Vergnes & Pritts (1994) o
5 d/wk 4 wks
MV, Micronucleus test, rat bone-marrow cells in vivo 725, inhaL. 6 h Vergnes & Pritts (1994)
~
""
5 d/wk 4 wks ::
C/
BVD, Binding (covalent) to mou se DNA in vivo + 5.90, inhaL. 8 h Segerback (1983) ..
ot"
Protein binding c:
BHp, Binding (covalent) to human haemoglobin in vivo + 0.075, inhaL. 8 h Tömqvist et al. (1989a) a=
t'
BHp, Binding (covalent) to human haemoglobin in vivo + 0.~~ Filser et al. (1992) 0\
o
a + , positive; -, negative
bln-vitro tests, ¡.g/ml; in-vivo tests, mg/kg bw
CAtmospheric concentration in exposure chamber
 ETHYLENE 63

5. Summary of Data Reported and Evaluation

5.1 Exposure data

Ethylene, the petrochemical manufactured in largest volume worldwide, is produced

primarily by the steam-cracking ofhydrocarbons. It is used mainly as a chemical intermediate
in the production of polymers and other industrial chemicals; small amounts are used to
promote the ripening of fruits and vegetables. Ethylene is introduced into the environment
from both natural and man-made sources, including emissions from vegetation, as a product
of burning of organic material (such as cigarettes) and of incomplete combustion of fossil
fuels, and in its production and use. Few data are available on levels of occupational
exposure.

5.2 Human carcinogenicity data

The available data did not allow the Working Group to evaluate the carcinogenicity of
ethylene to humans.

5.3 Animal carcinogenicity data

Ethylene was tested for carcinogenicity in one experiment in rats exposed by inhalation.
No increase in tumour incidence was reported.

5.4 Other relevant data

Endogenous but unidentified sources of ethylene exist in man and experimental animaIs.
on of ethylene is less than 10% in both man and rat. The bio-
Steady-state alveolar retenti

logical half-time of ethylene in humans is about 0.65 h. ln rats and man, the processes of
uptake, exhalation and metabolism are described by first-order kinetics, at least up to
50 ppm; in rats, ethylene metabolism follows first-order kinetics up to about 80 ppm. The
maximal rate of metabolism in rats is reached at about 1000 ppm, the initial metabolite being
ethylene oxide; hydroxyethyl cysteine is a urinary metabolite in mice. Because ethylene
metabolism can be saturated, the maximal possible concentration of ethylene oxide in rat
tissues is about 0.34 nmoI/ml (15 ng/g bw).
Exposure to ethylene results in the formation of adducts with proteins. ln nonsmokers,
the background concentrations of the hydroxyethyl valine adduct of haemoglobin were
12-188 pmoI/g haemoglobin. Environmental ethylene contributes to these concentrations;
the endogenous contribution was calculated to be about 12 pmoIlg haemoglobin in
nonsmoking control subjects. The increment of N-terminal hydroxyethyl valine formed
during a 40-h work week has been estimated as 100-120 pmoI/g haemoglobin per part per
million of ethylene. Tobacco smoke contributes to formation of this adduct: smoking 10-
30 cigarettes/day was reported to result in 600-690 pmoI/g haemoglobin.
Background concentrations of 7-hydroxyethyl guanine were 8.5 nmoI/g DNA in one
study of human peripheral lymphocytes and ranged from 2 to 6 nmoI/g DNA in various
64 IARC MONOGRAPHS VOLUME 60

tissues of rats and mice. A single exposure of mice to 50 ppm ethylene for 1 h resulted in
0.1-0.2 nmollg DNA
No data were available on the genetic and related effects of ethylene in exposed humans.
ln a single study, no micronuclei were induced in bone-marrow cells of mice and rats exposed
in vivo. Gene mutation was not induced in Salmonella typhimurium. AIthough the genetic
effects of ethylene have not been weIl studied, Its metabolite, ethylene oxide, is genotoxic in a
broad range of assays.

5.5 Evaluation1

There is inadequate evidence in humans for the carcinogenicity of ethylene.

There is inadequate evidence iD experimental animaIs for the carcinogenicity of ethylene.

Overall evaluation

Ethylene is not classifiable as to ils carcinogenicity ta humans (Group 3).

6. References

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United States. Atmos. Environ., 17,2131-2165
American Conference of Governmental Industrial Hygienists (1991) Documentation of the Threshold
Limit Válues and Biological Exposure Indices, 6th Ed., Cincinnati, OH, pp. 598-599
American Conference of Governmental Industrial Hygienists (1993) 1993-1994 Threshold Limit
Válues for Chemical Substances and Physical Agents and Biological Exposure Indices, Cincinnati,
OH, p. 21
Amoco Chemical Co. (1993) Ethylene Specification, Chicago, IL
Andersen, M.E., Gargas, M.L., Jones, RA. & lenkins, L.J., Jr (1980) Determination of the kinetic
constants for metabolism of inhaled toxicants in vivo using gas uptake measurements. Toxicol.
appl. Pharmacol., 54, 100-116
Angerer, l., Herrmann, H., Jungen, H., Täuber, U. & Wenzel-Hartung, R.P. (1988) Wirkung von
Ethylen auf Mensch und Tier (Effects of Ethylene on Man and AnimaIs) (Project 174-4),
Hamburg, DGMK Deutsche Wissenschaftiche Gesellschaft für Erdöl, Ergas und Kohle eV
Anlauf, K.G., Bottenheim, J.W, Brice, K.A., Fellin, P., Wiebe, HA., Schiff, H.I., Mackay, G.I.,
Braman, RS. & Gilbert, R (1985) Measurement of atmospheric aerosols and photochemical
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Anon. (1985) Facts & figures for the chemical industry. Chem. Eng. News, 63, 22-86
Anon. (1987) Facts & figures for the che mie al industry. Chem. Eng. News, 65, 24-76
Anon. (1988) Facts & figures for the chemical industry. Chem. Eng. News, 66, 34-82
Anon. (1989) Facts & figures for the chemical industry. Chem. Eng. News, 67, 36-90

lFor definition of the italicized terms, see Preamble, pp. 27-30.

 ETHYLENE
65
Anon. (1990) Facts & figures for the chemical industry. Chem. Eng. News, 68, 34-83
Anon. (1991a) Facts & figures for the chemical industry. Chem. Eng. News, 69, 28-9
Anon. (1991b) Chemical profie: ethylene. Chem. Mark Rep., 239, 19, 46
mi cal industry. Chem. Eng. News, 70, 32-75
Anon. (1992) Facts & figures for the che

Anon. (1993) Facts & figures for the chemical industry. Chem. Eng. News, 71, 38-83
Amis, A.D. & Travis, c.c. (1988) Reference Physiological Parameters in Pharmacokinetic Modeling
(Technical Report No. EPN600/6-88/004), Washington DC, US Environmental Protection
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Bailey, E., Brooks, A.G.F., Dollery, C.T., Farmer, P.B., Passingham, B.J., Sleightholm, M.A. & Yates,
D.W (1988) Hydroxyethylvaline adduct formation in haemoglobin as a biological monitor of
cigarette smoke intake. Arch. Toxicol., 62, 247-253
Bailey, J .c., Gunary, K., SchmidL, B. & Wiliams, M.L. (1990a) Speciated hydrocarbon emissions from
pIe of UK vehicles on the road over a range of speeds. Sei total Environ., 93, 199-20
a sam

Bailey, J.c., Schmidl, B. & Wiliams, M.L. (1990b) Speciated hydrocarbon emissions from vehicles
operated over the normal speed range on the road. Atmos. Environ., 24A, 43-52
Barrefors, G. & Petersson, G. (1992) Volatie hazardous hydrocarbons in a Scandinavian urban road
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