Butanone

Endpoint summary

Description of key information

In accordance with Regulation (EC) No 1907/2006 Annex VIII section 8.8.1, a toxicokinetics study is not required as assessment of the toxicokinetic behaviour of the substance has been derived from the relevant available information. This assessment is located within the endpoint summary for toxicokinetics, metabolism and distribution.

Key value for chemical safety assessment

Absorption rate - dermal (%):

4

Absorption rate - inhalation (%):

54

Additional information

Considering the physicochemical properties of MEK, [i.e. low molecular weight (72.11 g/mol), low log Kow value (0.3), and vapor pressure of 12.6 kPa at 25°C], 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 metabolic fate of MEK has been reported to include both oxidative and reductive pathways, with the latter leading to the production of secondary butyl alcohol, sBA). 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.

Additional information on the toxicokinetics of read-across substances, secondary butanol (sBA) and methyl isobutyl ketone (MIBK) is also included to support the read-across justification.

Animal data show that secondary butanol (sBA) is absorbed, distributed and excreted rapidly in urine, mainly as MEK, following oral administration. A small percentage of sBA is also excreted via urine and exhalation. Orally administered sBA is metabolized via alcohol hydrogenase to MEK. The maximum concentration of MEK in blood was seen six hours after dosing. Further oxidation of MEK appeared to proceed by hydroxylation of the omega-1 carbon to form 3-hydroxy-2-butanone, which is further reduced to 2,3-butanediol. 2,3-Butanediol was also detected in human urine following inhalation exposure to MEK (Liira, 1988 and 1990). The main portion of the inhaled MEK is converted to acetate or acetoactate via 3-hydroxy-2-butanone intermediate metabolite. Following absorption, MEK is anticipated to be distributed evenly throughout the body. The pharmacokinetic data available for sBA demonstrate that it may be used as a surrogate for MEK considering that sBA is rapidly metabolized to MEK, and that the two share common metabolites (3-hydroxy-2-butanone and 2,3-butanediol). 

Summary of absorption

Inhalation: 54% retention has been reported from inhalation exposures (Ibriani et al., 1989), which is in agreement with the results from human exposure (Liira, 1988 and 1990).

Oral: MEK has a molecular weight of <500 g/mol and a log Kow between 0 and 4; therefore, it is assumed to be well absorbed equivalently by the oral and inhalation route; therefore, oral assumed to be 54%.

Dermal: dermal absorption of MEK, in vivo, was reported to be 4% (NIOSH, 2002).

Summary of distribution

The solubilities of MEK in water, blood and oil are similar, with distribution coefficients reported to be 254 for water/air, 202 for blood/air and 263 for oil/air (Saida, 1976). These values suggest that MEK is distributed evenly in the soft tissues (Liira, 1988). Studies in humans show that, following inhalation exposure, MEK is retained in the blood, as shown by the low excretion of MEK in exhaled air (Liira, 1988).

Summary of metabolism

The main metabolites of MEK found in serum and urine after intraperitoneal administration to guinea pigs or inhalation exposure of humans were 3-hydroxy-2-butanone and 2, 3-butanediol (DiVincenzo et al, 1976).

The main metabolites of MIBK found in serum after intraperitoneal administration to guinea pigs were 4-methyl-2-pentanol and 4-hydroxy-4-methyl-2-pentanone. 4-hydroxy-4-methyl-2-pentanone was the principal metabolite (DiVincenzo et al, 1976).

Minimal qualitative and quantitative differences have been found between the metabolism of sBA and that of MEK (Dietz, 1981),

The metabolic pathways of MEK, sBA and MIBK have been established.

Summary of elimination

After inhalation exposure of humans, 2-3% of the absorbed dose is eliminated by exhalation, and the majority of the absorbed dose is eliminated in the urine as the metabolite sBA (Liira, 1988). Urinary excretion of parent MEK after inhalation exposure of humans has been shown to be very low, about 0.2% of the absorbed dose (Liira, 1990). After oral exposure in the form of gelatin (sic) capsules, pulmonary excretion is reported to be about 30% of the administered dose (Munies, 1965).

Please refer to the document attached to Section 13 for further discussion of toxicokinetics.

References

Imbriani, M., Ghittori, S., Pezzagno, G., & Capodaglio, E. (1989). Methyl ethyl ketone (MEK) in urine as biological index of exposure. Giornale italiano di medicina del lavoro, 11(6), 255-261.

NIOSH (2002) https://www.cdc.gov/niosh/docs/2003-154/pdfs/8319.pdf

Munies R, Wurster DE (1965) Investigation of some factors influencing percutaneous absorption III Absorption of methyl ethyl ketone J Pharmacol Sci 54:1281-1284, as cited in Liira, 1988.Saida K, Mendell JR, Weiss HS (1976) Peripheral nerve changes induced by methyl n-butyl ketone and potentiation by methyl ethyl ketone J Neuropathol Exp Neurol 35:207-225, as cited in Liira, 1988.

Discussion of human information

Human data show that uptake via the inhalation route is between 46% and 56%, and the ultimate metabolite of MEK excreted in the urine is secondary butanol (sBA) (Liira, 1988 and 1990).