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Description of key information

Short description of key information on bioaccumulation potential result:  

In accordance with Regulation (EC) 1907/2006, the toxicokinetic behaviour of the substance has been assessed to the extent that can be derived from the relevant available information. Short description of key information on absorption rate:  Dermal absorption of the substance has been assessed to the extent that can be derived from the relevant available information.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

Information about the toxicokinetic behaviour of the UVCB substance Reaction Products of C4 alcohols and C4 alkenes obtained as by-products from the manufacturing of butan-2-ol by sulfuric acid esterification and hydrolysis of butene can be derived from the toxicokinetic behaviour of the main constituents. The main constituent is 2,2’-oxybisbutane, also known as sec-butyl ether or SBE, which is present at a level of approximately 60%. The other main constituents are C4 hydrocarbons (mainly butenes, excluding 1,3-butadiene) at a level of approximately 20%, C8 hydrocarbons (mainly alkenes) at a level of approximately 15%, and butan-2-one (also known as methyl ethyl ketone or MEK) at a level of approximately 5%.

 

Sec-butyl ether (SBE) is expected to be efficiently absorbed orally and via inhalation, based on its water solubility and molecular weight. Some dermal absorption is expected, although to a limited extent.SBE is a structural analogue of isopropylether (IPE, also known as diisopropylether or DIPE), in that both are small molecular weight molecules containing two short-chain alkyl groups linked by an oxygen on the secondary carbon. The metabolism of DIPE was investigated by Stagliola and Schatz (2007) to determine if the two major metabolites were as predicted, isopropyl alcohol (IPA) and acetone (dimethyl ketone or DMK). Using rat nasal mucosa microsomes in vitro, they found that the metabolites, IPA and DMK, were produced in a concentration-dependent manner. P450 isoforms, CYP2A3 and 2E1, were identified as the key enzymes involved in DIPE metabolism. In vivo studies showed a rapid systemic clearance of DIPE, SBA and DMK from the blood of rats within 24 hours following a 6-hour inhalation exposure. It can be postulated, given the close structural similarity between DIPE and SBE, that following exposure to SBE, P450 enzymes in the nasal mucosa, lung tissue, and liver would be involved with metabolizing SBE to butan-2-ol (also known as sec-butyl alcohol or SBA) and butan-2-one (MEK). Animal data show that SBA is absorbed, distributed and excreted rapidly in urine, mainly as MEK, following oral administration (Dietz et al., 1981). A small percentage of SBA is also excreted via urine and exhalation. Based on the predicted rapid clearance, SBE nor its biotransformation products are expected to bioaccumulate.

 

The absorption, distribution and excretion of C4 and C8 alkenes have been investigated by Dahl et al. (1988) and Eide et al. (1995) and Zahlsen (1993). 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, straight-chain and branched alkanes, alicyclics, and aromatics were examined. 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 100 ppm (240 mg/m3) is low (uptake 1.5 -1.8 nmol/kg/min/ppm) or 0.09 -0.1 micrograms/kg/min/ppm). Unsaturated compounds are absorbed better than saturated ones (Dahl et al., 1988), this is supported by the butenes database. Male Sprague-Dawley rats were exposed via whole body inhalation to 100 or 300 ppm vapour of the individual test substances for 12 hours/day for 3 consecutive days. Concentrations of the hydrocarbons were measured in blood, brain, liver, kidney and perirenal fat immediately following each 12 -hour exposure and 12 hours following the last exposure. The results show that 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 tissue. Higher concentrations of linear alpha olefins were measured in each of the respective organs compared with measured concentrations of the corresponding isoalkanes. Concentrations of 1-alkenes in blood and the different tissues increased with increasing number of carbon atoms (Eide et al., 1995 and Zahlsen, 1993).

 

Considering the physicochemical properties of MEK, absorption of MEK from various routes of exposure, such as oral, dermal or inhalation is expected. However, absorption of MEK is expected to mainly occur via oral and inhalation routes, with limited potential for dermal absorption.

The main portion of the inhaled MEK is converted to acetate or acetoactate via 3-hydroxy-2-butanone intermediate metabolite (Liira et al., 1988). Following absorption, MEK is anticipated to be distributed evenly throughout the body. Metabolic fate of MEK has been reported to include both oxidative and reductive pathways, with the latter leading to the production of sec-butyl alcohol (SBA, or butane-2-ol). The oxidative pathway involves MEK oxidation catalyzed by liver microsomal mixed-function oxidases to form 3-hydroxy-2-butanone, which is subsequently reduced to 2,3-butanediol. The hydroxylation product of MEK, 3-hydroxy-2-butanone is expected either to undergo conjugation with sulfate or glucuronic acid and elimination of the conjugated metabolites in the urine, or to enter intermediary metabolism to form carbon dioxide. Taking into consideration the low molecular weight and log P, and its considerable water solubility, MEK is not expected to bioaccumulate.

 

Overall, the data on the main constituents of Reaction Products of C4 alcohols and C4 alkenes obtained as by-products from the manufacturing of butan-2-ol by sulfuric acid esterification and hydrolysis of butene show that this UVCB substance is expected to be readily absorbed via the oral and inhalation routes of exposure and to a limited extent via the dermal route. The substance is expected to be efficiently metabolized resulting in a rapid systemic clearance, with the C8 alkenes being eliminated at a lower rate than the other constituents. The substance is not expected to bioaccumulate.

It should be noted that the vapour pressure of SBE (30 hPa) compared to the vapour pressure of the UVCB substance (410 hPa) is relatively low. Due to the high vapour pressure of the C4 constituents, main inhalation exposure is expected to be to these C4 constituents. Due to their rapid evaporation, dermal absorption will be minimal.

 

The following information is taken into account for any hazard / risk assessment:

In accordance with Regulation (EC) 1907/2006, the toxicokinetic behaviour of the substance has been assessed to the extent that can be derived from the relevant available information.

Value used for CSA: low bioaccumulation potential

 

References

Dahl A, Damon E, Mauderly J, Rothenberg S, Seiler F and McClellan R (1988). Uptake of 19 hydrocarbon vapors inhaled by F344 rats. Fundam. Appl. Toxicol. 10, 262-269.

 

Dietz FK et al. (1981) Pharmacokinetics of 2-butanol and its metabolites in the rat. J Pharmacokinet Biopharm, 9, 553-576.

 

Eide I., Hagemann R., Zahlsen K., Tareke E., Tornqvist M., Kumar R., Vodicka P., and Hemminki K. (1995) Uptake, distribution, and formation of hemoglobin and DNA adducts after inhalation of C2-C8 1-alkenes (olefins) in the rat. Carcinogenesis 16(7):1603-1609.

 

Liira, J., Riihimäki, V., and Pfäffli, P. (1988). Kinetics of methyl ethyl ketone in man: Absorption, distribution and elimination in inhalation exposure. International Archives of Occupational Environ. Health, 60:195-200.

 

Stagliola E. and Schatz R. (2007) In vivo and in vitro metabolism of diisopropyl ether (DIPE). The Toxicologist, Abstract 971.

 

Zahlsen K., Eide I., Nilsen A.M., and Nilsen O.G. (1993). Inhalation kinetics of C8 to C10 1-alkenes and iso-alkanes in the rat after repeated doses. Pharmacology and Toxicology 73:163-168. Testing laboratory: Department of Pharmacology and Toxicology Faculty of Medicine, University Medical Center, N-7005 Trondheim, & Statoil Research Center, N-7004 Trondheim, Norway.

Discussion on absorption rate:

No relevant data available.