2-methylbutan-2-ol

Endpoint summary

Description of key information

2-Methylbutan-2-ol is absorbed following oral, dermal and inhalation exposure. Following uptake the compound is distributed through the body. As major metabolites the glucuronic acid conjugate and the oxidation product 2,3 -dihydroxy-2 -methyl-butane were identified. Excretion occurs mainly via the urine and the expired air.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

In line with chapter R.7 c (ECHA, 2012) the main toxicokinetic properties of 2-Methylbutan-2-ol are assessed on the basis of the available toxicokinetic and standard toxicity studies. In addition, relevant physico-chemical properties were taken into account.

 

1. Relevant physico-chemical properties of 2-Methylbutan-2-ol 

Molecular weight: 88.15 g/mol

Physical state: liquid

Log Pow: 0.77 (25°C)

Water solubility: 121 g/L (20°C)

Vapour pressur: 15.5 hPa at 20°C

 

2. Absorption 

Oral absorption

 

In a study conducted by Kamil et al., (1953) rabbits were orally exposed to 2-Methylbutan-2-ol by gavage. 2-Methylbutan-2-ol was excreted as conjugate with glucuronic acid in the urine. Also, Amberg et al. (1999) and Thierfelder et al. (1885) found the glucuronic acid conjugate in the urine of rabbits and rats after oral administration of 2-Methylbutan-2-ol. Moreover, in the key acute oral toxicity study (BASF AG, 1968) signs of systemic toxicity were seen in rats after oral administration of 2-Methylbutan-2-ol.

In summary, the available data demonstrate that 2-Methylbutan-2-ol is orally bioavailable.

 

Absorption after inhalation

 

Since the test substance has a vapour pressure of 1.15 KPa (15.5 hPa) 2-Methylbutan-2-ol is available for inhalation as a vapour.

Following repeated inhalation exposure of mice, rats and dogs to 2-Methylbutan-2-ol for 6 h per day for 59 to 61 days (NTIS, 1992) the substance was identified in plasma. In addition, Nolan et al. (1979) reported the occurrence of the substance in plasma after inhalation exposure of rats for 6 h.

In the acute inhalation toxicity studies (Rowe and McCollister, 1982; BASF AG, 1968) and the key repeated dose toxicity study (BASF SE, 2013) clinical signs indicative of systemic toxicity were observed.

In summary, the study results clearly indicated absorption after inhalation exposure in different species.

 

Dermal absorption

 

Dermal absorption of 2-Methylbutan-2-ol has been assessed on the basis of its physico-chemical properties and the results of the standard toxicity studies performed with this substance since dermal absorption studies are not available.

For dermal absorption a substance must be sufficiently lipophilic to cross the stratum corneum. Furthermore, the substance must be adequately soluble in water to partition from the stratum corneum into the viable epidermis. Since 2-Methylbutan-2-ol shows a log Pow of approximately 1 and a good water solubility a dermal absorption is expected. This assumption is supported by the results obtained in the acute and repeated dose dermal toxicity studies (Rowe and McCollister, 1982). In both studies the substance caused serious systemic effects.

In summary, the available data demonstrate that 2-Methylbutan-2-ol is dermally absorption in toxicologically relevant amounts.

 

3. Distribution/Metabolism 

The physico-chemical data and effects seen in standard toxicity studies (e.g. CNS-effects typical for alcohol intoxication) indicate that the substance is distributed throughout the body.

The half-life in and the clearance from plasma have been reported by NTIS (1992) and Nolan et al. (1979): After inhalation, the apparent half-life in the plasma of mice (exposed to 1000 ppm), rats (exposed to 50 ppm) and dogs (exposed to 50 ppm) were t1/2 = 29 min, t1/2 = 47 min and t1/2 = 69 min, respectively.The clearance from plasma lasted 100 min and was in an apparent first order manner when rats were exposed by inhalation.

 

Conjugation and oxidation reactions were found as main metabolic pathways. Kamil et al. (1953) and Thierfelder et al. (1885) revealed conjugates with glucuronic acid as metabolites of 2-Methylbutan-2-ol when rabbits were orally exposed to the test item. Tert-amyl alcohol glucuronide, 2-methyl-2,3-butanediol and its glucuronide were identified the as major metabolites after oral administration or inhalation of 2 -Methylbutan-2 -ol in rats (Amberg et al., 1999; Collins et al., 1998). Cytochrome P450 oxidation and glucuronide conjugation were the two mechanisms relevant for metabolism. Lington et al. (1990) reported that 2 -Methylbutan-2 -ol is not a substrate of alcohol dehydrogenase.

4. Excretion

Pohl et al. (1908) showed an unchanged excretion of 2-Methylbutan-2-ol in the expired air of dogs, rabbits and cats after i.v. or s.c. administration. Haggard et al., (1945) reported that after i.p. administration 26.4 % of the substance was eliminated via the expired air and 8.9% was excreted in the urine within 50 h after administration. Urinary elimination of 2-Methylbutan-2-ol metabolites is described by Kamil et al. (1953), Thierfelder et al. (1885) and Amberg et al. (1999) when rabbits and rats were orally exposed to 2-Methylbutan-2-ol.

In summary, the results of the available studies show that urinary elimination of metabolites and excretion of the parent substance via the expired air are the major routes of excretion for 2-Methylbutan-2-ol.

 

 

5. Generic absorption rates 

The available data indicate a high absorption via the oral, dermal and inhalation route. For DNEL derivation an inhalation absorption of 100% is assumed. As all systemic DNELs were based on inhalation toxicity data, also 100% oral and dermal absorption has been assumed, representing the worst case regarding DNEL setting.