Olefines polymer, oxidized, hydrolyzed, distn. residues, from C20 alcohols manuf.

Endpoint summary

Additional information

INTRODUCTION

Olefines polymer, oxidized, hydrolyzed, distillation residues, are by-products of the C20 alcohols manufacturing process. The substance, ‘Olefines polymer, oxidized, hydrolyzed, distillation. residues, are by-products from C20 alcohols manufacturing’, is a UVCB substance that comprises several linear long chain alcohols, predominantly docosan-1-ol (C22), tetracosan-1-ol (C24), hexacosan-1-ol (C26) and eicosan-1-ol (C20). Together, these constituents make up over 80% of the composition ofOlefines polymer, oxidized, hydrolyzed, distillation. residues, are by-products from C20 alcohols manufacturing. Other constituents include, to a much lesser extent, secondary long chain alcohols and complex mixtures of long chain carboxylate esters. On this basis, study data, where available, for each of the long chain alcohol constituents has been evaluated and considered together; this is consistent with the Category approach applied for Long Chain Alcohols (LCA) under REACH.  In a conservative approach the most sensitive study result from the constituents of the LCA category have been identified and used to address the endpoint in question.

  

ABSORPTION

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.

 

 

DISTRIBUTION

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).

 

 

METABOLISM

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).

 

 

EXCRETION

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).

 

 

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.

 

Baxter JH, Steinberg D, Mize CE and Avigan J (1967). Absorption and metabolism of uniformly 14C-labelled phytol and phytanic acid by the intestine of the rat studied with thoracic duct cannulation. Biochemica and Biophysica Acta 137, 277-290 (cited in Opdyke, 1978).

 

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

 

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).

 

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

 

CIR (1985). Final report on the safety assessment of stearyl alcohol, oleyl alcohol and octyl dodecanol. Journal 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 theof 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. 49^thReport of the Joint FAO/WHO Expert Committee on Food Additives. WHO Tech Rep Series No 884. WHO,.

 

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).

 

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.

 

Miyazaki M (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.

 

Natarajan V and Schmid HH (1977). Chain-length specificity in the utilization of long chain alcohols for ether lipid biosynthesis in rat brain. Lipids 12, 872-875.

 

OECD (2006). Long Chain Alcohols. SIDS Initial Assessment Report for22.

 

Opdyke DLJ (1978). Fragrance raw materials monograph. Cetyl alcohol. Food and Cosmetics Toxicology 16, 683-684.

 

Sieber SM, Cohn V and Wynn T (1974). The entry of foreign compounds into the thoracic duct lymph of the rat. Xenobiotica 4, 265-284.

 

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,(cited in CIR, 1988).

 

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