3-methylbutan-1-ol

Endpoint summary

Description of key information

Members of the read-across category "pentanols" are metabolised rapidly and to a high extent. The main metabolic pathway for the degradation of these primary pentanols is the formation of aldehydes via oxidation by alcohol dehydrogenases, and subsequently the formation of the corresponding acids. Additionally, oxidation of pentanols via hepatic CYP P450 enzymes and glucuronidation were observed. The metabolisation products are renally excreted.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no state of the art pharmacokinetic studies available with 3 -methylbutan-1 -ol or its structural analogues in animals or humans, but these substances have been subject of investigation in numerous in vivo and in vitro studies concerning their metabolism, distribution and elimination.

Due to their structural similarities, effects observed after administration of the single isomeric pentanols are expected to be caused by all members of this group of chemicals to the same or comparable extent (pentan-1-ol, 2-methylbutan-1-ol, 3-methylbutan-1-ol and pentanol, branched and linear).

 

Absorption

Absorption of 3-methylbutan-1-ol occured after oral (Kamil et al.1953) and also inhalative exposure (Kumagaiet al.1999). Furthermore, three studies regarding dermal absorption properties of the read-across substance pentan-1 -ol are available:

As the solubility of the alcohols in nonpolar liquids increases from methanol to octanol, the rate of penetration from an aqueous solution also increases. The alcohols penetrate more rapidly from vehicles in which they are less soluble. When the dermal penetration of pentan-1-ol in saline and olive oil was analyzed on autopsied human abdominal skin, the rate of penetration from saline was about 20 times that of ethanol and about one-ninth that of octanol (Blank 1964).

In another study by the same author, the skin permeability of pentan-1-ol in water ranged from about 0.2*10 -2 cm/hr at 5°C to 9*10-2 cm/hr at 50°C (Blank et al. 1967).

The third study determined permeability data of pentan-1-ol for human epidermis (Scheuplein & Blank 1971):

1. as aqueous solution:

- partition coefficient (Km) = 5.0;

- permeability constant at zero volume flow (kp) = 6.0*10 -3 cm/hr

- membrane diffusivity (Dm) = 0.88 *10-9 cm2/sec;

2. as pure liquid:

- partition coefficient (Km) = 0.11;

- permeability constant at zero volume flow (kp) = 0.051*10 -3 cm/hr

- membrane diffusivity (Dm) = 0.17 *10-9 cm2/sec.

The studies conducted with human skin during 1964 to 1971 are consistent with a more recent percutaneous absorption study with 3 -methylbutan-1-ol using skin from new-born piglets and static diffusion cells (Schenk 2018). 3 -methylbutan-1-ol showed skin permeabilities (Kp) ranging from "moderate" (10-4 cm/h) to "very high" (10-2 cm/h) depending on the concentration applied (1 to 100%). 

Taken together, pentanols are considered to be absorbed via oral, inhalation and dermal route. This assumption is confirmed by the results of the toxicity studies described in the following sections, as clinical symptoms and mortality evidence systemic availability of the substances.

 

Distribution

After inhalative exposure (2 hours) to vapour concentrations of 2000 ppm (corresponding to approx. 7.32 mg/L) pentan-1-ol and a mixture of pentan-1-ol and 2-methylbutan-1-ol, respectively, in the blood of male Sprague-Dawley rats the corresponding acid metabolites valeric acid and methyl butyric acid were detected. Valeric acid was found at all times at only trace amounts between 3–7 µM, whereas methyl butyric acid was detected at blood concentrations between 5.2 and 25.1 µM (Oxo Process Panel – ACC 2004).

 

In conclusion, after absorption the molecules will be readily metabolised and their metabolisation products will be distributed through the bloodstream. The category members and their acid metabolites are generally highly water soluble but nevertheless seem to be able to pass the blood-brain barrier and have access to the CNS. This assumption was further confirmed by results of a repeated dose toxicity study with 3-methylbutan-1-ol, where sedation in behaviour was observed in some animals. Transient narcotic effects of pentan-1-ol and 3-methylbutan-1-ol were reported in publications (Maickel & Nash 1985, Frantiket al. 1994). No selective or cumulative neurotoxicity was observed.

 

Metabolism

Generally, pentanols were found to be metabolised rapidly and to a high extent (Haggard et al. 1945, Greenberg 1970).The amounts of unchanged pentanols exhaled into air or excreted into urine were found to be low (Haggard et al. 1945).

Pentanols are mainly metabolized in the liver. Several in vitro studies are available assessing the metabolisation of pentanols:

In vitro experiments conducted with Class I, II and III alcohol dehydrogenases (ADH) isolated from human liver demonstrated that oxidation of 2-methylbutan-1-ol and 3-methylbutan-1-ol (at 10-100 µM) to the corresponding aldehydes was mainly mediated by the isoenzymes of Class I ADH. At pharmacologically relevant concentrations of ethanol, the oxidation of the isoamyl alcohols was inhibited in vitro since these congeners and ethanol compete for the same metabolising enzymes (Ehriget al.1988).

This notion is supported by in vivo experiments in rats (Greenberg 1970) and in the isolated perfused rat liver (Auty & Branch 1976). Isovaleraldehyde has been identified as intermediary metabolite of 3-methylbutan-1-ol (Greenberg 1970). The formed aldehydes are again rapidly metabolised, presumably to the corresponding acids (Haggardet al.1945).

Hepatic and pulmonary alcohol dehydrogenase activities were investigated in cytosolic fractions prepared from Sprague-Dawley male rats after addition of pentan-1-ol. Pulmonary ADH activity was considerably lower than hepatic ADH activity. Optimum conditions for pulmonary ADH activity were found to require an alkaline pH and high substrate concentrations suggesting a minimal role for the lung in the metabolism of alcohols in the intact animal (Carlson & Olson 1995). 

In vitro experiments have demonstrated additional oxidation of pentan-1-ol, 3-methylbutan-1-ol, and 2-methylbutan-1-ol by rat liver microsomes via CYP P450 enzymes, and glucuronidation (Iwersen & Schmoldt 1995).

The maximum transformation rates for glucoronidation and oxidation were 8.7 and 1.7nmol/min mg protein for pentan-1-ol, 12.5 and 2.1nmol/min mg protein for 3-methylbutan-1-ol, and 18 and 3.6nmol/min mg protein for 2-methylbutan-1-ol.

After gavage administration of a dose of 25 mmol amyl alcohol/rabbit (corresponding to approx. 735 mg/kg bw) 7 %, 9 %, and 10 % of the dose was excreted by the rabbits into urine as glucuronides, when they had received pentan-1-ol, 3-methylbutan-1-ol, and 2-methylbutan-1-ol, respectively (Kamil et al. 1953).

Taken together, in vivo and in vitro experiments demonstrated that the main metabolic pathway for the degradation of pentanols is via oxidation by alcohol dehydrogenase to the corresponding aldehydes and subsequently to the acids. Additionally, oxidation of pentanols via hepatic CYP P450 enzymes and glucuronidation was shown to be possible, but to play a minor role in the metabolism of these alcohols.

 

Excretion

The amounts of unchanged pentanols exhaled into air or excreted into urine were found to be low (Haggardet al.1945). After metabolisation to acids or glucuronidation the molecules are renally excreted. No major differences were found and are to be expected regarding excretion of the metabolised category members.