Isovaleric acid

Endpoint summary

Description of key information

Isovaleric acid is rapidly absorbed and removed from the blood due to rapid metabolic degradation to 3-HMG-CoA, acetoacetate and acetyl-CoA. The pathway is the same as for the amino acid leucine, i.e. isovaleric acid does physiologically occur in the intermediary metabolisms . Bioaccumulation does not occur.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

Isovaleric acid is rapidly absorbed from the GI tract, and it is rapidly removed (50% within 11 minutes; Al-Bassam and Sherrat, 1981)) from the blood after iv injection into mice. Metabolism occurs primarily in the liver on the same pathway as the ketogenic amino acid leucine and via the ß-pathways for fatty acids, i.e. it does also naturally occur as a metabolite of the amino acid leucine. First, 3-Hydroxymethyl-glutaryl-CoA (HMG-CoA) is formed which is then further degraded to acetoacetate and acetyl-CoA. Alternatively, HMG-CoA and acetyl-CoA may be used as precursors of fatty acids and cholesterol (HSDB, 2003; Semino, 1998). Thus, isovaleric acid is utilised in the intermediary metabolism and there is no bioaccumulation potential.

Read Across 

The view above is supported by observations with a closely related substance, isobutyric acid. The metabolic fate of isobutyric acid (IBA) was investigated by oral (gavage) administration of radiolabelled [1-14C]isobutyric acid to groups of 4 male CD rats at doses of 4, 40, and 400 mg/kg bw and to 4 female CD rats at 400 mg/kg bw. IBA was eliminated rapidly in the breath of the dosed animals as expired ¹⁴CO₂. At 4 hr 67 to 83% and at 48 hr 85 to 90% of the dose was eliminated in the breath. There were no differences between sexes. Urinary radioactivity averaged 3.5% of the dose with about 2/3 of the radioactivity present as urea. Faecal radioactivity was less than 1% of the dose. Isobutyric acid disappeared rapidly from the plasma of rats dosed by gavage with 400 mg/kg bw. Plasma levels peaked between 0.5 and 1 hr (11.4 ± 2.4 µg/ml), decreased to3.3 µg/mL at 1 hr, and were below the limit of detection at 4 hr (DiVicenzo, 1979).

Justification of Read Across to isobutric acid

The metabolism of isovaleric acid is considered to be similar to that of isobutyric acid. Differences are, however, expected regarding the velocity and the extent of elimination as CO₂in the breath because the isovaleric acid is metabolised by a pathway other than ß-oxidation due to the 3-methyl group, and because 3-hydroxymethylglutaryl-CoA may be used as precursor of cholesterol.

Conclusions from Read Across

However, quantitative conclusions can be drawn as follows: Isovaleric acid is expected to be rapidly absorbed from the gastro-intestinal tract with peak plasma levels after 0.5 to 1 hour after dosing, followed by rapid and complete elimination due to rapid metabolism, and return to normal plasma levels within few hours after dosing. Bioaccumulation does not occur.

Absorption rates 

In the absence of pharmacokinetic studies on isovaleric acid, the absorption rate for the free acid is considered to be 100% for the oral, inhalation and dermal routes of exposure, based on the provisions in the respective chapters contained in the Guidance document R7 (2008; Fig 7.12 -5 etc.).