1,6-Hexanolide

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result:
E-caprolactone will be rapidly hydrolysed in the stomach or bloodstream to form 6-hydroxyhexanoic acid.

The highly water-soluble hydrolysis product is predicted to be rapidly excreted in the urine. No bioaccumulation is likely, however the hydrolysis product may be incorporated into normal fatty acid metabolism.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

A theoretical assessment of the toxicokinetics of e-caprolactone indicates that the substance will be rapidly chemically or enzymically hydrolysed under physiological conditions (i.e. in the stomach or following absorption into the bloodstream) with the subsequent production of 6 -hydroxyhexanoic acid. The half-life of capa monomer in the stomach is approximately 0.4 hours (pH 1.2, temperature 37 C). Human serum paraoxonase (PON1) isozymes Q and R are able to hydrolyse lactone substances including e-caprolactone; half-lives of less than one minute are reported for struturally similar substances. The hydrolysis product is water soluble and expected to be distributed throughout the body and excreted rapidly in the urine. Bioaccumulation of the substance is not predicted. However it is theoretically possible that the hydrolysis product may be further metabolised and incorporated to some extent in metabolic pathways due to its structural similarity to endogenous fatty acids; this is not considered to represent bio-accumulation per se.

Discussion on bioaccumulation potential result:

No specific studies are required. According to Column 1 of Annex VIII of the REACH regulation, Assessment of the toxicokinetic behaviour of the substance (to the extent that can be derived from the relevant available information) is required and this is provided. An adequate assessment of the basic toxicokinetics of e-caprolactone can be made from the exisiting toxicity data and theoretical considerations, wtithout the need for specific testing.

Absorption

The substance will be rapidly hydrolysed in the stomach following oral administration (with a half-life of approximately 0.4 hours). The intact molecule satisifies Lipinski's rule of 5 (OECD QSAR Toolbox) and therefore is likely to be bioavailable, however absorption of the hydrolysis product is most likely. Absorption following inhalation is also likley to be extensive. Dermal absorption is likely to be less extensive, but is likely to occur to some extent as shown by the systemic toxicity in the acute dermal toxicity study.

Distribution

The intact substance is unlikely to be significantly distributed. Rapid hydrolysis in the stomach will limit absorption and any substance which is absorbed systemically is likely to be rapidly hydolysed by serum esterases; half-lives of <1 minute are reported for structurally similar compounds. The hydrolysis product 6 -hydroxyhexanoic acid is highly water soluble and therefore is likley to be rapidly and extensively distributed in the blood.

Metabolism

As discussed above, the substance will be hydrolysed rapidly either chemically (in the stomach) or enzymically (by serum esterases) to the hydrolysis product 6 -hydroxyhexanoic acid. The hydrolysis product is structurally similar to endogenous fatty acids and therefore may be incorporated into lipid metabolism pathways.

Excretion

Rapid urinary excretion of the highly-water soluble hydrolysis product is likely; no bioaccumulation is therefore predicted.