Isononyl alcohol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Biochemical toxicology of environmental agents.

Author:

DeBruin, A.

Year:

1976

Bibliographic source:

Elsevier/North-Holland Biomedical Press.

Reference 2

Reference Type:

publication

Title:

Patty's Industrial Hygiene and Toxicology, Fourth Edition

Author:

Lington AW, Bevan C.

Year:

1994

Bibliographic source:

John Wiley & Sons, Inc, Chapter Thirty, “Alcohols,” pp. 2585-2710.

Reference 3

Reference Type:

publication

Title:

Aldehydes: occurrence, carcinogenic potential, mechanism of action and risk assessment.

Author:

Feron, V.J., Til, H.P., de Vrijer, F., Woutersen, R.A., Cassee, F.R., van Bladeren, P.J.,

Year:

1991

Bibliographic source:

Mutation Research. 259, 363-385.

Reference 4

Reference Type:

publication

Title:

Biotransformation of Xenobiotics. In: Klaassen, C.D. (Ed.). Casarret and Doull's Toxicology: The Basic Science of Poisons. 5th Ed.

Author:

Parkinson A.

Year:

1996

Bibliographic source:

5th Ed. McGraw-Hill, New York, pp.113-186.

Reference 5

Reference Type:

publication

Title:

Physiological mech. involved in hangover. I. Oxid. of some lower aliph. fusel alcohols and aldehydes in rat liver and their effect on the mitochondrial oxid. of var. substrates.

Author:

Hedlund, S.G., Kiessling, K.H

Year:

1969

Bibliographic source:

Acta Pharmacol. Toxicol. 27, 381-396.

Reference 6

Reference Type:

publication

Title:

The metabolism of 2-ethylhexanol in rats

Author:

Albro PW.

Year:

1975

Bibliographic source:

Xenobiotica 5, 625-636

Reference 7

Reference Type:

publication

Title:

Human liver aldehyde dehydrogenase: partial purification and properties

Author:

Blair, A.H., Bodley, F.H.

Year:

1969

Bibliographic source:

Can. J. Biochem. Cell Biol. 47, 265-272.

Reference 8

Reference Type:

publication

Title:

Purification and properties of a membrane-sound aldehyde dehydrogenase from rat liver microsomes.

Author:

Nakayasu H., Mihara, K and Sato, R.

Year:

1978

Bibliographic source:

Biochemical and Biophysical Research Communications, 83(2), 697-703.

Reference 9

Reference Type:

publication

Title:

Metabolism of citral, an α,β-unsaturated aldehyde, in male F344 rats.

Author:

Diliberto J.J., Srinivas P., Overstreet D., Usha G., Burka L.T. and Birnbaum L.S.

Year:

1990

Bibliographic source:

Drug Metabolism and Disposition, 18, No. 6 866-875.

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

linear and branched alcohols

IUPAC Name:

linear and branched alcohols

Details on test material:

The materials being descibed are linear and branched alcohols.

Applicant's summary and conclusion

Executive summary:

Orally administered aliphatic alcohols show a chain-length dependant potential for gastro-intestinal absorption, with shorter chain aliphatic alcohols having a higher absorption potential than longer chain alcohols.

With regards to the blood-brain barrier, a chain-length dependant absorption potential exists with the lower aliphatic alcohols and acids more readily being taken up than aliphatic alcohols/acids of longer chain-length. Taking into account the efficient biotransformation of the alcohols and the physico-chemical properties of the corresponding carboxylic acids, the potential for elimination into breast milk is considered to be low.

Based on comparative in vitro skin permeation data and dermal absorption studies in hairless mice, aliphatic alcohols show an inverse relationship between absorption potential and chain length with the shorter chain alcohols having a significant absorption potential.

A comparison of the linear and branched aliphatic alcohols shows a high degree of similarity in biotransformation.  The initial step in the mammalian metabolism of primary alcohols is the oxidation to the corresponding carboxylic acid, with the corresponding aldehyde being a transient intermediate. These carboxylic acids are susceptible to further degradation via acyl-CoA intermediates by the mitochondrial b-oxidation process. This mechanism removes C2 units in a stepwise process and linear acids are more efficient in this process than the corresponding branched acids. In the case of unsaturated carboxylic acids, cleavage of C2-units continues until a double bond is reached. Since double bonds in unsaturated fatty acids are in the cis-configuration, whereas the unsaturated acyl-CoA intermediates in the b-oxidation cycle are trans, an auxiliary enzyme, enoyl-CoA isomerase catalyses the shift from cis to trans. Thereafter, b-oxidation continues as with saturated carboxylic acids.  An alternative metabolic pathway for aliphatic acids exists through microsomal degradation via w-or w–1 oxidation followed by β-oxidation. This mechanism provides an efficient stepwise chain-shortening pathway for branched aliphatic acids.

The acids formed from the longer chained aliphatic alcohols can also enter the lipid biosynthesis and may be incorporated in phospholipids and neutral lipids. A small fraction of the aliphatic alcohols may be eliminated unchanged or as the glucuronide conjugate.

The long chain aliphatic carboxylic acids are efficiently eliminated and aliphatic alcohols are therefore not expected to have a tissue retention or bioaccumulation potential. Longer chained aliphatic alcohols within this category may enter common lipid biosynthesis pathways and will be indistinguishable from the lipids derived from other sources (including dietary glycerides).