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EC number: 270-689-2
CAS number: 68476-49-3
are no specific studies on the streams of the Other Petroleum Gases
category but the toxicokinetic behaviour of components 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).
of both rats and humans to propene concentrations of approximately 25
ppm (43 mg/m3) results in similar concentrations of propene in blood
however concentrations of propene oxide in human blood were
approximately 60-fold lower than in rat blood. PBPK modelling indicates
that following exposure as described above, 35% of inhaled propene
enters the blood and 20% of this is metabolised; this indicates that 7%
of inhaled propene is metabolised, the remainder is exhaled unchanged.
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
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).
are too many references concerning the toxicokinetics of 1,3-butadiene
in laboratory animals and humans to be all listed here. The EU Risk
Assessment Report (EU RAR, 2002) contains a comprehensive review of the
toxicokinetic information on 1,3-butadiene that is still current. As
this document has been peer-reviewed and is accepted by the European
Chemicals Bureau, parts of the summary section are reproduced here
(indicated within quotation marks). Some additional references that
post-date the EU RAR (2002) have been added and are listed below.
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
(2007).Toxicological profile for benzene.U.S. Department of Health and
Human Services Public Health Service Agency for Toxic Substances and
RAR (2002). European Union Risk Assessment Report for 1,3-butadiene.
Vol. 20. European Chemicals Bureau (http: //ecb. jrc. ec. europa.
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. 33-40.
P, Sram RJ and Neumann HG. (2001). Hemoglobin adducts of epoxybutene in
workers occupationally exposed to 1,3-butadiene. Arch Toxicol 74: 680-87.
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,
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: 356-357.
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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