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EC number: 272-205-5
CAS number: 68783-65-3
A complex combination of hydrocarbons obtained by subjecting a petroleum distillate to a sweetening process to convert mercaptans or to remove acidic impurities. It consists predominantly of saturated and unsaturated hydrocarbons having carbon numbers predominantly in the range of C2 through C4 and boiling in the range of approximately -51°C to -34°C (-60°F to -30°F).
No experimental information is available on
the toxicokinetic behaviour of the streams comprising this category,
however equivalent information is available for the marker substances
that are present. For streams containing benzene and buta-1,3 -diene,
the substances that drive risk characterisation, uptake of inhaled
butadiene is assumed to be 100% (European Commission, 2002) while dermal
uptake of benzene is approx. 0.1 % (Modjtahedi and Maibach, 2008) with
oral uptake assumed to be 100%. No measured information is available on
bioconcentration potential of these streams, however calculated log BCF
values for the marker substances are in a range 0.78 – 2.31 i.e.
indicative of a low bioconcentration potential.
European Commission (2002) European Union Risk Assessment Report:
1,3-butadiene, Volume 20. European Commission, Luxembourg, 194 pp
Modjtahedi BS, and Maibach HI (2008) In vivo percutaneous absorption of
benzene in man: forearm and palm. Food Chem Toxicol. 46, 1171 - 1174
are no specific studies on the streams of the Other Petroleum Gases
category but the toxicokinetic behaviour of constituents of the category
has been studied and reported.
et al (1988) investigated the comparative rates of uptake of 19
hydrocarbon vapours by rats. Representative compounds from the chemical
classes of alkenes, alkynes, alicyclics, straight-chain and branched
alkanes and aromatics were investigated and included butane, isobutane
and propene. It was concluded that absorption tends to increase with
molecular weight so that straight chain molecules are more highly
absorbed than branched isomers, and aromatic molecules are more highly
absorbed than paraffins. Thus short chain C1-C4 alkanes which exist as a
vapour at room temperature, are very poorly absorbed, and if absorbed,
are normally rapidly exhaled. Isobutane absorption following inhalation
exposure is low (uptake 0.6 -1.0 nmol/kg/min/ppm, lower than butane).
Butane absorption following inhalation exposure at 100ppm (240 mg/m3) is
low (uptake 1.5 -1.8 nmol/kg/min/ppm) or 0.09 -0.1
micrograms/kg/min/ppm). From this the Health Council of the Netherlands
(2004) calculated approx 10% is absorbed.
data are supported by Daugherty (1988) who reported that ethane absorbed
during exposure for 8 h by inhalation is metabolised to carbon dioxide
and eliminated in exhaled air. A small proportion (1%) is eliminated in
and Hameli (1980) report a death involving asphyxiation by propane
inhalation. The rate of propane absorption was reported to be slow, the
relative concentration of propane was found in the autopsy to be brain >
liver > lung > blood > and kidney specimens, however accurate
interpretation of the data are difficult given the likely variability
with time of death and time from exposure to testing.
et al (1985) investigated the metabolism of volatile hydrocarbons. He
reported propane is metabolised to acetone and isopropanol in mice
inhaling propane for 1 hour, and to isopropanol by mice liver microsomes
in vitro; isobutane is metabolised to tert-butanol in mice inhaling
isobutane for 1 hour, and by mice liver microsomes in vitro; and
n-butane is metabolised to sec-butanol and methyl ethyl ketone in mice
inhaling n-butane for 1 hour, and to sec-butanol by mice liver
microsomes in vitro.
of propene in the lung is controlled by the blood: air partition
coefficient, the perfusion rate of the lungs and at high concentrations
by saturable metabolism (Svensson
and Osterman-Golkar, 1984).
At concentrations of propene that do not result in saturation of
metabolism, about 90% of inhaled propene was exhaled unchanged; this is
due to the low uptake from the alveoli into blood (Filser
et al., 2000).
Metabolism of propene to propene oxide is saturable(Filser
et al., 2008).
Blood concentrations of propene oxide at steady state are low and not
expected to increase substantially above the value reached at 3000 ppm
(5,200 mg/m3). Volunteer studies indicate that a similar situation, at
least in part, exists in humans (Filser
et al., 2000, 2008).
Exposure of rats and mice to
2-methylpropene, at concentrations up to 500 ppm (1147 mg/m3), resulted
in first order elimination. The maximal metabolic elimination rates were
340 µmol/kg/h for rats and 560 µmol/kg/h for mice. The Km was 1200 ppm
(2754 mg/m3) and 1800 ppm (4131 mg/m3) for rats and mice respectively.
The metabolism was saturable in both species and was blocked by
inhibitors of the cytochromes P450 (Csanady et al., 1991)
many circumstances the body burden of the substance and/or metabolites
is dependent upon several factors such as the rate and extent of uptake,
distribution, metabolism and excretion. In mixtures such as Other
Petroleum Gases, however, the toxicokinetics of even well-studied pure
substances may vary depending upon interaction with other chemical
species available within the mixture. For example, the substances
present may compete for the uptake, metabolism, and/or elimination of
the complex mixture. This situation, already complicated, is further
exacerbated when the composition of the mixture is uncertain and
extensive metabolism and distribution studies have been carried out on
the butene isomer, 2-methylpropene (isobutene). A higher rate of
metabolism in the mouse and saturation of metabolism in rats and mice
have been demonstrated in vivo by Csanady et al (1991) and Henderson et
al (1993). In the study of Csanady et al (1991), rats and mice were
exposed to 2-methylpropene, at concentrations up to 500 ppm (1147 mg/m3),
metabolic elimination was first order. The maximal metabolic elimination
rates were 340 µmol/kg/h for rats and 560 µmol/kg/h for mice. The
atmospheric concentration at which Vmax/2 was reached was 1200 ppm (2754
mg/m3) for rats and 1800 ppm (4131 mg/m3) for
mice. The metabolism was saturable in both species and was blocked by
inhibitors of P450 enzymes. In the study of Henderson et al (1993), rats
were exposed to 2-methylpropene at concentrations from 40 to 4000 ppm
(91.8-9180 mg/m3). Rapid metabolism to oxidised metabolites
excreted in the urine occurred and isobutenediol and 2-hydroxyisobutyric
acid were identified as metabolites. Blood levels of 2-methylpropene
were linearly related to exposure up to 400ppm (918 mg/m3)
but were supralinear at 4000 ppm (9180 mg/m3) indicating
saturation of metabolism at this higher dose level.
findings were reported during a carcinogenicity study on 2-methylpropene
(NTP, 1988). The major urinary metabolite of 2-methylpropene
(2-hydroxyisobutyric acid: HIBA) was measured in the urine of rats and
mice as an indicator of exposure. F344/N rats and B6C3F1 mice were
exposed to 2-methylpropene at concentrations of 0, 500, 2,000 or 8,000
ppm, (1147, 4589, 18,359 mg/m3) for 105 weeks. In both
species, the amount excreted increased with increasing exposure
concentration but when HIBA concentration was normalized to isobutene
exposure concentration, the relative amount of HIBA excreted decreased
with increasing exposure concentration, implying nonlinear kinetics
The absorption, distribution, elimination,
haemoglobin adduct formation and DNA adduct formation of individual
C2-C8 1-alkenes was studied in the rat after exposure to 300 ppm
(688mg/m3), 12 h a day for 3 consecutive days. The concentrations of the
alkenes were measured in blood, lung, brain, liver, kidney and
peri-renal fat immediately after each exposure and 12 h after the third
exposure. Concentrations of 1-alkenes in blood and organs reached a
steady-state level after the first 12 h exposure, and the concentrations
12 h after the last exposure were generally low, except in fat.
Concentrations of 1-alkenes in blood and the different tissues increased
with increasing number of carbon atoms. However, DNA adducts and
haemoglobin adducts decreased with increasing number of carbon atoms
with the most pronounced decrease being from C2 to C3. The decrease in
haemoglobin adducts was more pronounced than DNA adducts. All 1-alkenes
caused formation of detectable levels of haemoglobin and DNA adducts,
although the levels of haemoglobin adducts after C4-C8 exposure were
low. These results also indicate that extrapolation within the
homologous series is possible.
toxicokinetics of benzene has been extensively studied and was recently
reviewed by ATSDR (Toxicological profile for benzene, ATSDR, 2007).
ATSDR concluded "Inhalation exposure is probably the major route of
human exposure to benzene, although oral and dermal exposures are also
important. Benzene is readily absorbed following inhalation or oral
exposure. Although benzene is also readily absorbed from the skin, a
significant amount of a dermal application evaporates from the skin
surface. Absorbed benzene is rapidly distributed throughout the body and
tends to accumulate in fatty tissues. The liver serves an important
function in benzene metabolism, which results in the production of
several reactive metabolites. Although it is widely accepted that
benzene toxicity is dependent upon metabolism, no single benzene
metabolite has been found to be the major source of benzene
hematopoietic and leukaemogenic effects. At low exposure levels, benzene
is rapidly metabolized and excreted predominantly as conjugated urinary
metabolites. At higher exposure levels, metabolic pathways appear to
become saturated and a large portion of an absorbed dose of benzene is
excreted as parent compound in exhaled air. Benzene metabolism appears
to be qualitatively similar among humans and various laboratory animal
species. However, there are quantitative differences in the relative
amounts of benzene metabolites”. The present analysis confirms the ATSDR
statement. More specifically, human inhalation exposure is estimated to
be approximately 50%, oral exposure assumed to be 100% (this value used
for DN(M)EL calculations). Percutaneous absorption is estimated at 0.1%
(Modjtahedi and Maibach, 2008) whereas a QSAR model determined a maximum
value of 1.5% (Ten Berge, 2009).
EU Risk Assessment Report (EU RAR, 2002)is a peer reviewed report that
contains a comprehensive review of the toxicokinetic information on
1,3-butadiene. To summarise:
in rodents and non-human primates have shown that 1,3-butadiene is
absorbed via the lungs. In rodents, uptake and metabolism of
1,3-butadiene obeys simple first order kinetics at concentrations up to
about 1,500 ppm, above which saturation of the process appears to occur.
1,3-Butadiene is widely distributed throughout the body. The first step
in the metabolic pathway is the formation of epoxybutene, catalysed by
mixed function oxygenases. The further metabolism of epoxybutene can
proceed by a number of different pathways. There is some conjugation
with glutathione. A second possible pathway is hydrolysis to butenediol,
catalysed by epoxide hydrolase. Another possibility is further
epoxidation to diepoxybutane. Further epoxidation and/or hydrolysis
reactions can then occur, which ultimately lead to erythritol formation”.
are quantitative species differences in the toxicokinetics of
1,3-butadiene. In comparison with the rat, the mouse absorbs and retains
approximately 4-7 fold higher concentrations of 1,3-butadiene per kg
bodyweight. The mouse also produces approximately 2-20 fold higher
concentrations of the metabolite, epoxybutene, than does the rat, for
equivalent exposures. Very low concentrations of the diepoxide
metabolite have been detected in the blood and various tissues of rats
and mice at relatively high 1,3-butadiene exposures.” “Where
measurements are available, tissue levels of diepoxybutane are generally
higher in mice compared with rats, by up to 163-fold. ” More recent
studies using 1,3-butadiene exposures at 1 ppm 1,3-butadiene for 4
weeks, which are more occupationally relevant, showed that the
concentration of the haemoglobin adduct of the diepoxide metabolite
(pyr-Val) was greater than 30-fold in the blood of mice compared to that
in rats (Swenberg et al. 2007).
vitro studies indicate that in the mouse, lung and liver tissue have
similar capacity for 1,3-butadiene metabolism while in rats and humans,
liver tissue has a greater capacity for metabolism than does lung
tissue, although some metabolism does take place in lung tissue.
Detoxification pathways are kinetically favoured over activation
pathways in rodent and human tissue, although the ratio of activation:
detoxification is highest in mouse tissue compared with rat or human
tissue.” A recent study (Filser et al, 2009) showed a qualitative
species difference in the metabolism of 1,3-butadiene in isolated
perfused livers from rats and mice. In 1,3-butadiene perfusions,
predominantly epoxybutene and butenediol were found in both species but
diepoxybutane was only detected in mouse livers. “From the limited
comparative information available from in vitro and in vivo studies, it
appears that in relation to the formation of epoxide metabolites, the
metabolism of 1,3-butadiene in humans is quantitatively more similar to
that in the rat, rather than the mouse.”
workers exposed by inhalation to 3-4 ppm 1,3-butadiene, metabolism to
epoxybutene with subsequent hydrolysis to butenediol occurs. In one
study, the mercapturic acid (glutathione) conjugate of butenediol has
been identified as a urinary metabolite although no detectable levels of
the epoxybutene mercapturate were found in the same study. This suggests
that detoxification of epoxybutene proceeds by hydrolysis to butenediol,
with subsequent conjugation.
adducts from various metabolites of 1,3-butadiene have been identified
and measured in humans (Albertini et al., 2004). Elevated levels of the
haemoglobin adducts of epoxybutene have been reported in the blood of
occupationally exposed workers (EU RAR, 2002; Bergemann et al.,
2001). Analytical techniques have recently been developed to measure the
haemoglobin adduct of the diepoxide metabolite of 1,3-butadiene
N,N-(2,3-dihydroxy-1,4-butadiyl) valine (pyr-Val). In one study, the
pyr-Val adduct was not quantifiable in human blood samples from workers
with cumulative occupational exposures of up to 6.3 ppm-weeks (Swenberg
et al., 2007). In a subsequent study in which improvements were made to
the technique to improve the sensitivity, quantifiable amounts of
pyr-Val (0.079 to 0.859 pmol/g globin) were found in the blood of
occupationally exposed workers (Georgieva et al., 2008). This indicates
that the diepoxide metabolite is produced in humans, albeit in very low
ATSDR (2007).Toxicological profile for
benzene.U.S. Department of Health and Human Services Public Health
Service Agency for Toxic Substances and Disease Registry.
EU RAR (2002). European Union Risk
Assessment Report for 1,3-butadiene. Vol. 20. European Chemicals Bureau
(http: //ecb. jrc. ec. europa.
Albertini R (2004). Mechanistic insights
from biomarker studies: somatic mutations and rodent/human comparisons
following exposures to potential carcinogens, in: R. J. Buffler P, Bann
R, Bird M, Bofetta P (Ed.), Mechanisms Epidemiology, IARC Sci Publ, pp.
Bergemann, P, Sram RJ and Neumann HG.
(2001). Hemoglobin adducts of epoxybutene in workers occupationally
exposed to 1,3-butadiene. Arch Toxicol 74: 680-87.
Filser JG, Bhowmik S, Faller TH, Hutzler C,
Kessler W, Midpanon S, Pütz C, Schuster A, Semder B, V, Csanády GA
(2009). Quantitative investigation on the metabolism of 1,3-butadiene
and of its oxidized metabolites in once-through perfused livers of mice
and rats. Tox Sci, Dec 2009, advance publication.
Georgieva, NL, G Boysen, P Upton, et al.
(2008). Analysis of 1,2;3, 4-diepoxybutane specific protein adduct in
occupationally exposed workers, Part 2. The Toxicologist Abstract #1736:
Swenberg JA, Boysen G, Georgieva N, Bird MG,
Lewis RJ. (2007). Future directions in butadiene risk assessment and the
role of cross-species internal dosimetry. Chem Biol Interact. 166: 78-83
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