Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - dermal (%):
7

Additional information

Alcohols, C14 -15-branched is a colourless liquid with a vapour pressure of <5 Pa at 20°C.

Absorption

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. In a well conducted in vivo percutaneous absorption study using mice, the percutaneous absorption rate of the unbranched C-10 alcohol, decan-1-ol, was ca 7%. (Iwata et al., 1987). This was confirmed in a reliable in vitro study, where the percutaneous absorption rate of decan-1-ol (10% (w/w) FRM in 9:1 (v/v) ethanol: water mixture) using unoccluded porcine skin was ca 8% (Berthauld et al., 2011).

Read across from a well conducted in vitro study using human skin and an unbranched structural analogue myristyl alcohol (C14 – alcohol), gave a percutaneous absorption rate of 1.2% at 6 hours and 6.3% at 24 hours (P&G, 2008). This confirms the findings of the Iwata paper that aliphatic alcohols show an inverse relationship between absorption potential and chain length.

Similar to the dermal absorption potential, it is expected that orally administered aliphatic alcohols also 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 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 (Gelman, 1975). 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.

 

Distribution

Absorbed alcohols, C12 -13 -branched has potential to be widely distributed within the body (OECD, 2006). However, as a result of the rapid and efficient metabolism, it is not anticipated that alcohols, C12 -13 -branched will remain in the body for any significant length of time.

 

Metabolism

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 β -oxidation process. This mechanism removes C2 units in a stepwise process and linear acids are more efficiently broken down 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 β-oxidation cycle are trans, an auxiliary enzyme, enoyl-CoA isomerase catalyses the shift from cis to trans. Thereafter, β-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 way for branched aliphatic acids (Verhoeven,et al., 1998). The acids formed from the longer chained aliphatic alcohols can also enter the lipid biosynthesis and may be incorporated in phospholipids and neutral lipids (Bandiet al, 1971 a and b and Mukherjeeet al. 1980). A small fraction of the aliphatic alcohols may be eliminated unchanged or as the glucuronide conjugate (Kamilet al., 1953).

 

A comparison of the linear and branched aliphatic alcohols shows a high degree of similarity in biotransformation. For both sub-categories the first step of the biotransformation consists of an oxidation of the alcohol to the corresponding carboxylic acids, followed by a stepwise elimination of C2 units in the mitochondrial β-oxidation process. The metabolic breakdown for both the linear and mono-branched alcohols is highly efficient and involves processes for both sub-groups of alcohols. The presence of a side chain does not terminate the β-oxidation process, however in some cases a single Carbon unit is removed before the C2 elimination can proceed.

 

Elimination

When rats were given an oral dose of 1-octanol, an unbranched analogue of alcohols, C12 -13 -branched, 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).

 

Following the 24-hour application of the unbranched analogue 1-dodecanol (radiolabelled with14C ) 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 also be expected for alcohols, C12 -13 -branched.

 

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 alcohols, C12 -13 -branched 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).

 

 

REFERENCES

 

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.

 

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

 

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

 

MiyazakiM (1955). Nutritive value of aliphatic alcohols II. The nutritive value and toxicity of saturated alcohols of six to eighteen carbon atoms. Journal of the Agricultural and Chemical Society of Japan 29, 501-505 (cited in FDA, 1978).

 

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.

 

OECD (2006). Long Chain Alcohols. SIDS Initial Assessment Report for SIAM 22.

SCF (2002).

 

Verhoeven NM, Wanders RJ, Poll-The BT, Saudubray JM and Jacobs C (1998). The metabolism of phytanic acid and pristanic acid in man. A review.Journal of Inherited and Metabolic Diseases 21, 697-728 (cited in OECD, 2006).

 

Wasti K (1978). A literature review - problem definition studies on selected toxic chemicals. Environmental Protection Research Division, US Army Medical Research and Development Command, Maryland USA (cited in CIR, 1988).

 

Williams RT (1959). Detoxification Mechanisms. 2ndEdition, Chapman and Hall,London.

 

WHO (1999). Evaluation of Certain Food Additives and Contaminants, WHO technical Report Series 884.