Isooctadecan-1-ol

Endpoint summary

Additional information

INTRODUCTION

1-Octadecanol (stearyl alcohol) is a lipophilic, white waxy solid that is practically insoluble in water.

  

ABSORPTION

As an aliphatic alcohol, some absorption of 1-octadecanol may occur following exposure by all common physiological routes (dermal, oral and inhalation) (OECD, 2006). The extent to which aliphatic alcohols are absorbed depends upon chain length. Dermal absorption studies in 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. When the close analogue, 1-hexadecanol (radiolabelled with¹⁴C on the 1-carbon atom) was applied to the skin of hairless mice, only about 1% of the dose was absorbed over 24 hours (Iwata et al. 1987). Under the same exposure conditions, dermal absorption of 1-octadecanol would be predicted to be similar or lower.

 

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. According to one expert review, numerous studies suggest that long-chain aliphatic alcohols are poorly absorbed from the gastrointestinal tract (CIR, 1985). Based simply on the difference between total ingested alcohol and total excreted unchanged in faeces, one group reported that rats absorbed 89% and 55% of ingested dose when stearyl alcohol was included at 1.8 and 7.5%, respectively, in the diet for 13 days (Calbert et al. 1951). In a rat feeding study that also took account of endogenous saponifiable alcohols in faeces, the extent of absorption of stearyl alcohol (5% in the diet for 10 days) was estimated to be 19% (Miyazaki, 1955). When rats with a cannulated thoracic duct were given a low (0.2 mg in corn oil) oral dose of a close analogue (1-hexadecanol;¹⁴C-labelled), about 34% was absorbed (Baxter et al. 1967). Together, these studies suggest that significant absorption of 1-octadecanol may occur following ingestion.

 

DISTRIBUTION

Any absorbed 1-octadecanol potentially could be widely distributed within the body (OECD, 2006), and its presence in the lymph of rats given the alcohol intraduodenally suggests the potential to distribute in total body water (Sieber et al. 1974). However, its likely rapid and efficient metabolism and elimination or utilisation suggests that retention and accumulation of 1 -octadecanol is unlikely (Bevan, 2001; OECD, 2006). Short-chain aliphatic alcohols readily penetrate the blood-brain barrier, whereas longer chain alcohols (C16-C18) cross the barrier in only trace amounts (Gelman and Gilbertson, 1975).

 

When rats with a cannulated thoracic duct were given a low (0.2 mg in corn oil) oral dose of a close analogue (1-hexadecanol;¹⁴C-labelled), about 34% was absorbed, with 25.8% in the lymph, 6.8% in the carcass, 0.6% in the liver and 1.1% in the expired air after 24 hours (Baxter et al. 1967).

 

 

METABOLISM

As a primary alcohol, absorbed 1-octadecanol will initially be metabolised (oxidised), primarily by alcohol dehydrogenase, to the corresponding aldehyde (octadecanal). The aldehyde is a transient intermediate that is rapidly converted by further oxidation to the acid (octadecanoic acid; stearic acid) by aldehyde dehydrogenase. Octadecanoic 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 of b-oxidation tends to increase with increasing chain length (JECFA, 1999). Mice excretedmore than 90% of the absorbed dose of a shorter-chain alcohol (radiolabelled n-[1-¹⁴C]dodecanol; C12) in expired air (evidently as carbon dioxide) following skin application, suggesting that metabolism of absorbed 1-octadecanol would also be extensive (Iwata et al. 1987). When a close analogue (1-hexadecanol) was given orally to thoracic duct-cannulated rats, about 85% of the absorbed dose was oxidised to saponifiable material (presumed to be hexadecanoic acid) during absorption into the thoracic lymph (Baxter et al. 1967).

 

An alternative metabolic pathway exists through microsomal or peroxisomal degradation of the carboxylic acid metabolite (octadecanoic 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.]

 

The acids formed from the 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). Following intraduodenal administration of radiolabelled 1-octadecanol to rats, radioactivity was found in phospholipids, cholesterol esters and triglycerides (Sieber et al. 1974).

 

The hydroxyl function of the parent 1-octadecanol and the carboxy function of the octadecanoic acid metabolite may also undergo conjugation reactions to form sulphates and/or glucuronides (Kamil et al. 1953; McIsaac and Williams, 1958). For linear aliphatic alcohols, this pathway generally accounts for less than 10% of the metabolism (Kamil et al. 1953; McIsaac and Williams, 1958).

 

 

EXCRETION

When a shorter (C12) analogue (1-dodecanol, radiolabelled with¹⁴C on the 1-carbon atom) was applied to skin of hairless mice, the small amount absorbed (2.84% of applied dose) was rapidly and extensively eliminated (more than 90% in expired air and a total of 3.5% in the faeces and urine), and only 4.6% of the absorbed dose [representing 0.13% of the applied dose] remained in the body after 24 hours (Iwata et al. 1987). A similar general pattern of rapid and extensive excretion would be expected for any absorbed 1¿octadecanol that was not utilized within the body.

 

Following oral administration of 1-octadecanol to rats, 50% was recovered unchanged in the faeces (Miyazaki, 1955). Unchanged 1-octadecanol was also detected in faeces after oral dosing of rabbits (Kamil et al. 1953).

 

In thoracic duct-cannulated rats given 1-octadecanol intraduodenally at 5 µmol/kg bw, 56.6% of the absorbed dose was eliminated in the lymph in 24 hours (Sieber et al. 1974).

 

The glucuronic acid conjugates formed during the metabolism of most aliphatic alcohols are excreted in the urine (Wasti, 1978; Williams, 1959).For 1-octadecanol, 7.6% of an oral dose was excreted by rabbits in urine as glucuronide (Kamil et al. 1953).

 

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

 

 

REFERENCES

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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.

 

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Calbert CE, Greenberg SM, Kryder G and Deuel HJ (1951). The digestibility of stearyl alcohol, isopropyl citrates and stearyl citrates and the effect of these materials on the rate and degree of absorption of margarine fat. Food Research 16, 294-305 (cited in FDA, 1978).

 

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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.

 

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Marzulli FN, Callahan JF and Brown DW (1965). Chemical structure and skin penetrating capacity of a short series of organic phosphates and phosphoric acid. Journal of Investigative Dermatology 44, 339-344 (cited in Casarett and Doull, 1991).

 

McIsaac WM and Williams RT (1958). The metabolism of spermaceti. WA Journal of Biological Chemistry 2, 42-44.

 

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Mukherjee KD, Weber N, Mangold HK et al. (1980). Competing pathways in the formation of alkyl, alk-1-enyl and acyl moieties in the lipids of mammalian tissues. European Journal of Biochemistry 107, 289-294.

 

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