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Key value for chemical safety assessment

Additional information

The information on toxicokinetics has been read-across from a structural analogue, the linear isomer octan-1-ol.

INTRODUCTION

1-Octanol is a colourless, viscous liquid that has a low water solubility and a strong odour.

 

ABSORPTION

As an aliphatic alcohol, 1-octanol is likely to be absorbed following exposure by all common physiological routes (dermal, oral and inhalation) (OECD, 2006). The extent of absorption of aliphatic alcohols varies with chain length. For example, in rats, the extent of dermal penetration increases up to C7 (1-heptanol) and thereafter declines with longer carbon chain lengths (Valette and Cavier, 1954). Dermal absorption studies using hairless mice, and comparative in vitro skin permeation data, show that for aliphatic alcohols with chain lengths varying from 8 to 16 carbon atoms, there is an inverse relationship between absorption and chain length with the short to intermediate chain alcohols (up to C12) having a significant absorption potential. Thus approximately 50% of a dose of radiolabelled n-[1-14C]octanol was absorbed upon skin application to mice for 24 hours, a figure that decreased with increasing chain length to about 7% for similarly labelled 1-decanol (C10) and 2.84% for 1-dodecanol (C12) (Iwata et al. 1987).

 

Lipophilic substances that come into contact with the skin can readily penetrate the lipid-rich stratum corneum by passive diffusion at a rate proportional to their lipid solubility and inversely to their molecular weight (Marzulli et al. 1965).

 

The extent of absorption of aliphatic alcohols from the gastrointestinal tract also depends upon chain length. Although no actual data ware found for 1-octanol, short-chain aliphatic alcohols are known to be rapidly and extensively absorbed from the gastrointestinal tract (Aaes-Jorgensen et al. 1959; Bandi et al. 1971a, 1971b), whereas long-chain saturated alcohols (e.g. C18) are said to be poorly absorbed (CIR, 1985). The presence of only <0.5% of an oral dose of1-octanol in the faeces of rats (Miyazaki, 1955) supports the view that absorption is likely to be extensive following ingestion.

 

 

DISTRIBUTION

Absorbed 1-octanol potentially could be widely distributed within the body (OECD, 2006). However, its rapid and efficient metabolism and elimination from the body suggests that 1¿octanol is not expected to be retained or to accumulate (Bevan, 2001; OECD, 2006). Short¿chain aliphatic alcohols readily penetrate the blood-brain barrier, whereas longer chain alcohols (C16-C18) cross this barrier in only trace amounts (Gelman and Gilbertson, 1975).

 

 

METABOLISM

As a primary alcohol, absorbed 1-octanol will initially be metabolised (oxidised), primarily by alcohol dehydrogenase, to the corresponding aldehyde (octanal). The aldehyde is a transient intermediate that is rapidly converted by further oxidation to the acid (octanoic acid) by aldehyde dehydrogenase. Octanoic acid is then susceptible to degradation via acyl-CoA intermediates by the mitochondrialb-oxidation process. This mechanism removes C2 units in a stepwise process. The rate ofb¿oxidation tends to increase with increasing chain length (JECFA, 1999). Mice excretedmore than 90% of the absorbed dose of a similar alcohol (radiolabelled n¿[1¿14C]dodecanol) in expired air (evidently as carbon dioxide) following skin application, suggesting that metabolism of absorbed 1¿octanol would also be extensive (Iwata et al. 1987).

 

An alternative metabolic pathway exists through microsomal or peroxisomal degradation of the carboxylic acid metabolite (octanoic acid) viaw- orw-1 oxidation followed by ß-oxidation (Verhoeven et al. 1998). [This pathway provides an efficient route for the degradation of branched-chain alcohols.]

 

Although probably not applicable to 1-octanol, it is noted that the acids formed from longer¿chained aliphatic alcohols can also enter lipid biosynthesis and may be incorporated in phospholipids and neutral lipids (Bandi et al. 1971a, 1971b; Mukherjee et al. 1980).

 

The hydroxyl function of the parent octanol and the carboxy function of the octanoic acid metabolite may also undergo conjugation reactions to form sulphates and/or glucuronides. For linear aliphatic alcohols, this pathway generally accounts for less than 10% of the metabolism (Kamil et al. 1953; McIsaac and Williams, 1958).

 

 

EXCRETION

Following the 24-hour application of the close analogue 1-dodecanol (radiolabelled with14C on the 1¿carbon atom) to skin of hairless mice, more than 90% of the absorbed dose was excreted in expired air and 3.5% was eliminated in the faeces and urine after 24 hours; only 4.6% of the absorbed dose [representing 0.13% of the applied dose] remained in the body (Iwata et al. 1987). A similar general pattern of extensive and rapid excretion would be expected for 1-octanol.

 

When rats were given an oral dose of 1-octanol, only trace amounts (<0.5%) of unchanged alcohol were detected in the faeces (Miyazaki, 1955). Faecal recoveries of unchanged alcohol were 20 and 50%, respectively, when rats were given an oral dose of the higher alcohols 1¿hexadecanol and 1-octadecanol (McIsaac and Williams, 1958; Miyazaki, 1955).

 

The glucuronic acid conjugates formed during the metabolism of most aliphatic alcohols are excreted in the urine (Wasti, 1978; Williams, 1959).For 1-octanol, 9.5% of an oral dose was excreted by rabbits in urine as glucuronide (Kamil et al. 1953).

 

Although lipophilic alcohols such as 1-octanol have the physiochemical potential to accumulate in breast milk, rapid metabolism to the corresponding carboxylic acid followed by further degradation suggests that breast milk can only be, at most, a minor route of elimination from the body (OECD, 2006).

These conclusions have been read-across to 2-methyl-1-heptanol.

 

 

REFERENCES

Aaes-Jorgensen E, Privett OS and Holman RT (1959). Essential fatty acid activities of hydrocarbons and alcohols analogous to linoleate and linolenate. Journal of Nutrition 67, 413-421 (cited in Gelman and Gilbertson, 1975).

 

Bandi ZL, Mangold HK, Holmer G and Aaes-Jorgensen E (1971a). The alkyl and alk-1-enyl glycerols in the liver of rats fed long chain alcohols or alkyl glycerols. FEBS Letters 12, 217-220.

 

Bandi ZL, Aaes-Jorgensen E and Mangold HK (1971b). Metabolism of unusual lipids in the rat. 1. Formation of unsaturated alkyl and alk-1-enyl chains from orally administered alcohols. Biochimica et Biophysica Acta 239, 357-367.

 

Bevan C (2001). Monohydric Alcohols - C7 to C18, aromatic and other alcohols. Patty¿s Toxicology. Eds E Bingham, B Cohrssen and CH Powell. 5th Edition, Vol. 6, J. Wiley and Sons, New York (cited in OECD, 2006).

 

Casarett and Doull (1991). Toxicology. The basic science of poisons. Eds MO Amdur, J Doull and CD Klassen. 4thEdition, Pergamon Press, New York.

 

CIR (1985). Final report on the safety assessment of stearyl alcohol, oleyl alcohol and octyl dodecanol. Journal of the American College of Toxicology 4, 1-29.

 

CIR (1988). Final report on the safety assessment of ceteayl alcohol, cetyl alcohol, isostearyl alcohol, myristyl alcohol and behenyl alcohol. Journal of the American College of Toxicology 7, 359-413.

 

FDA (1978). Monograph on stearyl alcohol. US Department of Commerce. NTIS PB-289 664. Food and Drug Administration, Washington DC.

 

Gelman RA and Gilbertson JA (1975). Permeability of the blood-brain barrier to long-chain alcohols from plasma. Nutrition and Metabolism 18, 169-175.

 

Iwata Y, Moriya Y and Kobayashi T (1987). Percutaneous absorption of aliphatic compounds. Cosmetics and Toiletries 102, 53-68.

 

JECFA (1999). Evaluation of certain food additives and contaminants. 49thReport of the Joint FAO/WHO Expert Committee on Food Additives. WHO Tech Rep Series No 884. WHO, Geneva.

 

Kamil IA, Smith JN and Williams RT (1953). Studies in detoxication 46. The metabolism of aliphatic alcohols. The glucuronic acid conjugation of acyclic aliphatic alcohols. Biochemical Journal 53, 129-136 (cited in McIsaac and Williams, 1958).