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Ziegler Bottoms are characterized as comprising of two primary constituents; icosan-1-ol and docosan-1-ol. Together these constituents represent a structural class of components (alcohols) that constitute approximately 82% of the composition of Ziegler Bottoms. Study data, where available, for each of these primary constituents has been evaluated and considered together. Both docosan-1-ol (behenyl alcohol) and icosan-1-ol are highly lipophilic, waxy solids which are practically insoluble in water.



As aliphatic alcohols, some absorption of docosan-1-ol and icosan-1-ol may occur following exposure by all common physiological routes (dermal, oral and inhalation) (OECD, 2006). The extent of dermal absorption is likely to be very limited for docosan-1-ol and icosan-1-ol due to their long chain length. When a shorter-chain 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 both docosan-1-ol and icosan-1-ol would be predicted to be even lower.


Upon skin contact, lipophilic substances can penetrate the lipid-rich stratum corneum by passive diffusion at a rate proportional to their lipid solubility and inversely related 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). One study where rats were fed a close structural analogue (1-octadecanol; C18) at 5% in the diet for 10 days indicated that about 19% was absorbed (Miyazaki, 1955). Another, probably less-reliable study had suggested that rats absorbed 89% and 55% of ingested dose when 1-octadecanol was included at 1.8 and 7.5%, respectively, in the diet for 13 days (Calbert et al. 1951). When rats with a cannulated thoracic duct were given a low (0.2 mg in corn oil) oral dose of a shorter-chain analogue (1-hexadecanol;14C-labelled), about 34% was absorbed (Baxter et al. 1967). Together, these studies suggest that some absorption of docosan-1-ol and icosan-1-ol may occur following ingestion.




Although any absorbed docosan-1-ol or icosan-1-ol potentially could be widely distributed within the body (OECD, 2006), the likely rapid and efficient metabolism and elimination or utilization means that they are not expected to be retained or to accumulate unchanged (Bevan, 2001; OECD, 2006). Short chain aliphatic alcohols readily penetrate the blood-brain barrier, whereas longer chain alcohols (C16-C18 and above) cross this 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 shorter-chain 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).




As primary alcohols, any absorbed docosan-1-ol or icosan-1-ol will initially be metabolised (oxidised), primarily by alcohol dehydrogenase, to the corresponding aldehyde (e.g. docosanol to docosanal). The aldehyde is a transient intermediate that is rapidly converted to the acid (e.g. docosanoic acid) by aldehyde dehydrogenase. The 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 excreted more than 90% of the absorbed dose of a shorter-chain alcohol (radiolabelled n[114C]dodecanol; C12) in expired air (evidently as carbon dioxide) following skin application, suggesting that metabolism of any absorbed docosan-1-ol or icosan-1-ol could also be extensive (Iwata et al. 1987). When another shorter-chain 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 (docosanoic acid) via w- or w-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-chain 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 (C18) to rats, radioactivity was found in phospholipids, cholesterol esters and triglycerides (Sieber et al. 1974). After direct injection of a mixture of14C-labelled docosanol and cis-9-octadecenol into the brain of young rats, both alcohols were oxidised to the corresponding fatty acids. Radioactivity was incorporated into polar lipids, although docosanol was not utilised to any significant extent for alkyl and alk-1-enylglycerol formation (Natarajan and Schmid, 1977).


The hydroxyl function of the parent alcohol (e.g. docosan-1-ol) and the carboxy function of the acid metabolite (e.g. docosanoic acid) 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).




No data were identified for either docosan-1-ol or icosan-1-ol specifically. Following the application of a shorter chain length alcohol (dodecan-1-ol; C12; radiolabelled with14C on the 1-carbon atom) to the 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 just 4.6% of absorbed dose [representing 0.13% of applied dose] remained in the body after 24 hours (Iwata et al. 1987). A similar general pattern of extensive and rapid excretion would be expected for any absorbed, unutilized docosan-1-ol or icosan-1-ol.


The recovery of unchanged chemical in the faeces of rats following oral administration of aliphatic alcohols has been reported. For the C16 analogue (1-hexadecanol), approximately 20% of a dose of 2 g/kg bw was recovered in the faeces (McIsaac and Williams, 1958), while about 50% of an oral dose of 1-octadecanol (C18) was similarly recovered unchanged (Miyazaki, 1955).


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) e.g. rats excreted 6% of an oral dose of 1-hexadecanol in the urine as glucuronide (McIsaac and Williams, 1958) while rabbits excreted 7.6% of an oral 1-octadecanol dose as urinary glucuronides (Kamil et al. 1953).


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




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