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There are no experimental data on toxicokinetics available for diethyl ketone (DEK). Thus, the toxicokinetic profile of DEK is evaluate below based on its physicochemical properties and taking into account toxicokinetic data on the structural analogue methyl ethyl ketone (MEK) as well as general information on metabolism and excretion of aliphatic ketones (see section 13 of the IUCLID for justification of the read-across from MEK).

 

Absorption

Based on the molecular weight of 86.1 and the physical-chemical properties of diethyl ketone (log Pow of 0.85, vapour pressure of 38 hPa at 20°C, water solubility of ~50 g/L), it can be assumed that substance is well absorbed following oral and inhalation exposure and also following dermal exposure when the skin is occluded. In contrast, dermal penetration through the non-occluded skin will be significantly less, as a large amount of the substance will evaporate due to the relatively high vapour pressure of DEK and thus, will not be available for dermal penetration.

These assumptions are supported by the data for MEK. MEK is rapidly absorbed after inhalation and after dermal, oral and intraperitoneal administration (WHO, 1993). In workers exposed to MEK concentrations up to 300 mL/m³ , the alveolar retention was 70 % and was independet of the exposure concentration. In volunteers exposed to a MEK concentration of 200 mL/m³ for 4 hours, 53 % of the inhaled substance was absorbed by the lungs. Rapid dermal absorption was demonstrated on intact human skin, when 2.5 - 3 minutes after application MEK appeared unchanged in the exhaled air. The concentration in the exhaled air reached a plateau after 2 -3 hours.

 

Distribution

Due to its low molecular weight, the log Pow of 0.85 and the water solubility of ~50 g/L a wide distribution of Diethyl ketone is likely. As the log Pow is above 0 the intracellular concentration may be higher than the extracellular concentration. There is no indication of an accumulation potential. 

MEK is rapidly distributed in the body via the bloodstream (WHO 1993). The distribution was examined in two workers who died at the workplace where they were exposed to solvents. It could be shown that the distribution and solubility of MEK is similar in all tissues (Perbellini, 1984). This information is in line with the above assumptions on DEK.

 

Metabolism and Excretion

Generally, when aliphatic ketones are absorbed into the bloodstream, they are reduced to secondary alcohols or oxidized to hydroxyketones, diketones, and carbon dioxide by a variety of metabolic pathways. The major elimination routes for parent compound and metabolites are urinary excretion and expiration. 

These metabolic pathways and elimination routes can also be expected for diethyl ketone.

The data on metabolism and excretion of methyl ethyl ketone were summarized recently in the technical support document on the derivation of AEGLs (Anonymous, 2009): 

MEK is metabolised in male guinea pigs to 3-hydroxy-2-butanone, 2,3-butanediol, and 2-butanol, the latter a minor metabolite (DiVincenzo et al. 1976). Based on these metabolites, the study authors concluded that the metabolism of MEK follows both oxidative and reductive pathways. Reversible reduction of the ketone group yields 2 -butanol; microsomal ω-oxidation yields 3-hydroxy-2-butanone which is reduced to the diol. In this study, the serum half-life of MEK was 270 minutes and the clearance time was 12 hours. Dietz et al. (1981) detected the same three metabolites in the blood of male Sprague-Dawley rats treated orally with 1.69 g/kg bw.

2-Butanol and 2,3-butanediol were measured in the serum or whole blood (Liira et al. 1990b) and 3-hydroxy-2-butanone and 2,3-butanediol (but not 2-butanol) were identified in the urine (Liira et al. 1988a; 1988b; Perbellini et al. 1984) of human subjects exposed to MEK which indicates the metabolism in man is similar to that in animals. As excretion of 2,3-butanediol accounted for less than 3% of the inhaled dose and only 5% was exhaled by the lungs as unmetabolised MEK, most of the absorbed MEK apparently enters intermediary metabolism pathways (Liira et al. 1990a; Liira et al. 1991). Urinary excretion of 2,3-butanediol showed great individual variation. Although metabolism is fairly rapid, with an estimated half-life in the blood of 20 to 49 minutes (Brown et al. 1987; Fiserova-Bergerova 1985), Di Vincenzo et al. (1976) states that, compared to other ketones, the metabolism of MEK is relatively slow.

References

Anonymous (2009). Methyl ethyl ketone (CAS Reg. No. 78-93-3): Interim acute exposure guideline levels (AEGLs) for NAS/COT Subcommittee.November 2008. Interim 3: 02/2009.

Brown WD, Setzer JV, et al. (1987). Body burden profiles of single and mixed solvent exposures. J. Occup. Med. 29:877-883.

Dietz FK, Rodriguez-Giaxola M, et al. (1981). Pharmacokinetics of 2-butanol and its metabolites in the rat. J. Pharmacokin. Biopharm. 9:553-576. DiVincenzo GD, Kaplan CJ and Dedinas J (1976). Characterization of the metabolites of methyl n-butyl ketone, methyl iso-butyl ketone, and methyl ethyl ketone in guinea pig serum and their clearance. Toxicol. Appl. Pharamcol. 36:511 -522.

Fiserova-Bergerova V (1985). Toxicokinetics of organic solvents. Scand. J. Work Environ. Health 11 (suppl. 1):7-21.

Liira J, Riihimaki V and Pfaffli A (1988a). Kinetics of methyl ethyl ketone in man: absorption, distribution and elimination in inhalation exposure. Int. Arch. Occup. Environ. Health 60:195-200.

Liira J, Riihimaki V and Engstrom K (1988b). Coexposure of man to m-xylene and methyl ethyl ketone: kinetics and metabolism. Scand. J. Work Environ. Health 14:322-327.

Liira J, Johanson G and Riihimaki V (1990a). Dose-dependent kinetics of inhaled methylethylketone in man. Toxicol. Lett. 50:195-201.

Liira J, Riihimaki V and Engstrom K (1990b). Effects of ethanol on the kinetics of methyl ethyl ketone in man.Br. J. Ind. Med. 47:325-330.

Liira J, Elovaara E, et al.(1991). Metabolic interaction and disposition of methyl ethyl ketone and m-xylene in rats at single and repeated inhalation exposure. Xenobiotica 21:53-63.

Perbellini L, Brugnone F, et al.(1984). Methyl ethyl ketone exposure in industrial workers: uptake and kinetics. Int. Arch. Occup. Environ. Health 54:73-81.

WHO (World Health Organization). 1993. Environmental Health Criteria 143: Methyl Ethyl Ketone., 6: World Health Organization.

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