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Administrative data

Link to relevant study record(s)

Description of key information

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

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
Absorption rate - dermal (%):
Absorption rate - inhalation (%):

Additional information

There 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.

Dahl 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.

These 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 urine.

Haq 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.

Tsukamoto 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.

Uptake 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)

In 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 variable.

More 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.

Similar 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 (NTP, 1988).

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.


The 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).


The 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:

“Studies 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”.

“There 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). 

“In 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.”

 “In 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.  

Haemoglobin 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 quantities.


Additional references:

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. eu/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/REPORT/butadienereport019. pdf)  

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. 33-40.

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: 356-357.

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