Alcohols, lanolin

Endpoint summary

Description of key information

All available substance specific data on physico-chemical and toxicological properties of Lanolin alcohols and available information for cholesterol, one of the main constituents, suggest that Lanolin alcohols is expected to be absorbed orally or subcutaneously. Overload of the substance would result in accumulation in the adipose tissues and changes in metabolism. Biliary excretion may well be significant route for the substance.

Additional information

In accordance with Annex VIII, Column 1, Section 8.8.1, of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behaviour of the substance is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties. There are no studies available in which the toxicokinetic behaviour of Lanolin alcohols (CAS 8027-33-6) has been investigated.

Lanolin alcohols is an UVCB substance. It consists primarily of sterols but is also a complex mixture of aliphathic alcohols and lipid species. The complex combination of alcohols is obtained by hydrolysis of lanolin. One of the main constituents of Lanolin alcohol is cholesterol (ca. 30%). Lanolin alcohols is a yellow waxy solid with a molecular weight range of 300 – 500 g/mol. It has a melting temperature estimated to be in the range 45 °C - 80 °C at normal pressure (Atkinson, 2010) and a low water solubility of 0.21 mg/L at 20 °C (Cook, 2010). The vapour pressure of the test material has been determined to be 360 Pa at 20°C (Younis, 2012). The octanol/water partition coefficient (log Pow) was calculated for three main components of Lanolin alcohols. Estimated log Pow values were as follows: cholesterol 8.73; Lanosta-8,24 -dien-3 -ol (lanosterol) 10.79 and 1-Hexadecanol 6.73 (calculated with EPI suite TM) indicating that the substances are highly lipophilic. Thus, Lanolin alcohols is not considered to be hydrophilic but highly lipophilic.

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the log Pow value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2012).

Absorption, oral

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds may be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) which would otherwise be poorly absorbed (Aungst and Chen, 1986; ECHA, 2012).

Lanolin alcohols has been tested for acute oral toxicity in rats. While in one study no mortality and no signs of systemic toxicity were observed at 2000 mg/kg bw (Leuschner, 2001), in the other study 2/10 rats died after administration of 5000 mg/kg bw (Cade, 1980). With regard to the dose administered and the effects observed, no final conclusion can be drawn if the substance possesses either a low toxic potency or a low absorption in combination with a low systemic toxicity. Based on the molecular weight range (300-500 g/mol) and on the physico-chemical properties (log Pow > 6 and water solubility of 0.21 mg/L), absorption of the substance or of rather individual components from the GI tract after oral ingestion cannot be ruled out.

Cholesterol, which is one of the major constituents of Lanolin alcohols, is anticipated to be well-absorbed via the GI tract (CIR, 1986). Cholesterol is absorbed primarily in the proximal small intestine following micellar solubilisation by bile salts and incorporation into chylomicrons. Chylomicrons are absorbed from the intestine into the lymph and distributed systemically. Given the structural similarity between cholesterol and the other identified constituents (lanosterol, dihydrolanosterol, etc.) of Lanolin alcohols, it appears likely that the substance may also follow this absorption pathway.

Overall, based on molecular weight and physico-chemical characteristics, the oral absorption rate of Lanolin alcohols is anticipated to be low. However, the absorption rate may be higher if the substance undergoes micellar solubilisation as described for cholesterol.

Absorption, dermal

The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Dermal uptake is anticipated to be low, if the water solubility is < 1 mg/L; low to moderate if it is between 1-100 mg/L; and moderate to high if it is between 100-10000 mg/L. Dermal uptake of substances with a water solubility > 10000 mg/L (and log Pow < 0) will be low, as the substance may be too hydrophilic to cross the stratum corneum. Log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if water solubility is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2012).

The physico-chemical properties (waxy solid, low water solubility and log Pow > 6) and the molecular weight (300-500 g/mol) of Lanolin alcohols are in a range suggestive of low absorption through the skin. The results of the acute dermal toxicity study in rats showed no evidence of toxicity (Bradshaw, 2010). As the lack of effects may be based on the absence of absorption or the absence of toxicity of the substance, no final conclusion can be drawn.

If a substance shows skin irritating or corrosive properties, damage to the skin surface may enhance penetration. If the substance has been identified as a skin sensitizer then some uptake must have occurred although it may only have been a small fraction of the applied dose (ECHA, 2012).

For Lanolin alcohols, moderate effects regarding skin irritation were observed in a non-standard animal study. However, the skin irritation study was considered inappropriate as the exposure conditions presenting a worst case scenario compared to the current OECD test guideline 404. According to OECD 404, the patch with the test substance should be loosely held in contact with the skin by means of a suitable semi-occlusive dressing for the duration of the exposure period, which is normally 4 hours. This is in contrast to the exposure conditions of the available in-vivo skin irritation study of Cade (1980): the exposure period lasted 24 h under occlusive conditions indicating a worst case scenario. Furthermore, the available dermal acute toxicity study in rats indicates no signs of dermal irritation at a dermal dose level of 2000 mg/kg bw. Based on the exposure conditions of the skin irritation study and the outcome of the acute dermal toxicity study, the skin irritation study was disregarded and the result was not considered further for skin irritation effects. Evaluation of several data on human patch-tests indicated that exposure to Lanolin alcohols will not lead to skin sensitization in a substantial number of persons.

Cholesterol occurs naturally in skin surface lipids and sebum and is absorbed via the skin (CIR, 1986). There is, however, not sufficient information on the dermal absorption potential of cholesterol.

Overall, taking all available information into account, dermal uptake might be assumed but the dermal absorption potential is considered to be rather low.

Absorption, inhalation

Lanolin alcohols is a waxy solid with a vapour pressure of 360 Pa at 20 °C (Younis, 2012). The vapour pressure was deemed to be quite high for a solid, and it was suspected that the sample contained water hence the magnitude of the results. EPI suite TM (version 4.11) calculated vapour pressure results in <0.001 Pa (at 25 °C). In addition the boiling temperature of the test material has been determined to be 220 °C - 420 °C at normal pressure indicating that Lanolin alcohols is not highly volatile. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not significant.

However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed (e.g. as a formulated product). In humans, particles with aerodynamic diameters below 100 µm have the potential to be inhaled. Particles with aerodynamic diameters below 50 µm may reach the thoracic region and those below 15 µm the alveolar region of the respiratory tract (ECHA, 2012).

As for oral absorption, the molecular weight and physico-chemical properties of Lanolin alcohols are in a range suggestive of low absorption across the respiratory tract epithelium. Absorption by micellar solubilisation may occur, but this mechanism is more relevant for oral absorption due to the requirement of the emulsifying bile salts.

In conclusion, absorption via inhalation cannot be excluded, but is expected to be rather low. The Lanolin alcohol is marketed in a non-granular form and is not used in spray applications. Therefore, exposure by inhalation is unlikely.

Distribution and accumulation

Distribution of a compound within the body depends on the physico-chemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration, particularly in fatty tissues (ECHA, 2012).

Due to its lipophilicity (log Pow > 6), Lanolin alcohols or rather its constituents are likely to distribute in fatty tissues. The available information on cholesterol summarised below is taken as representative. Cholesterol is incorporated into chylomicrons and absorbed from the intestine into the lymph (CIR, 1986). The cholesterol-containing micelles are then absorbed into blood capillaries and degraded. The resulting chylomicron remnants containing cholesterol are absorbed into the liver. In the following, cholesterol (either absorbed or endogenously synthetized) is incorporated into very low-density lipids (VLDL), intermediate-density lipids (IDL), and low-density lipids (LDL). The latter enters blood circulation and the contained cholesterol is available for different metabolic pathways.

Cholesterol undergoes a continuous turnover as it is permanently metabolised, e.g. for the production of bile acids, steroid hormones, cholesterol esters, cholesterol sulphates and vitamin D3 (CIR, 1986). Bioaccumulation of cholesterol, e.g. in adipose tissue, takes places, if its intake exceeds the metabolic capacity of the organism to produce bile acids, which is the major excretory pathway for cholesterol (CIR, 1986).

Metabolism

Information on the potential metabolism of Lanolin alcohols is limited to that available for cholesterol, which is summarised below and considered representative.

Cholesterol is metabolised via two major pathways in mammals: metabolism to bile acids in the liver and metabolism to steroid hormones in the endocrine organs. It is also metabolised into cholesterol esters, cholesterol sulphate, cholestanol and vitamin D3. In the gut, the cholesterol is metabolised predominantly into coprostanol and coprostanone by the intestinal flora (CIR, 1986). Massive accumulation of cholesterol, following repeated oral exposure, was observed in the mice liver (Lee, 1981). Fatty liver, caused by lipid overloading, was reversible.

The results of the in-vitro genotoxicity studies with bacterial or mammalian cells did not show any evidence that the addition of a metabolic system either enhances or diminishes the activity of Lanolin alcohols (Bowles and Thompson, 2010; Bowles, 2010; Brown, 2010).

Excretion

As for metabolism, the available information on cholesterol is considered representative for assessment of the excretion of Lanolin alcohols.

Cholesterol is excreted as bile salts via the faeces, or eliminated via the urine, breast milk or skin (CIR, 1986). The substance has similar physico-chemical properties as cholesterol therefore it is expected to be eliminated via the same routes. Biliary excretion would be the significant route of excretion for this substance. Any test material that is not absorbed will be excreted in the faeces.

Conclusion

The available information for cholesterol, one of its main constituents, suggest that Lanolin alcohols is expected to be absorbed orally or subcutaneously. Overload of the substance would result in accumulation in the adipose tissues and changes in metabolism. Biliary excretion may well be significant route for the substance.

 

References (not cited in the IUCLID)

Aungst and Shen (1986). Gastrointestinal absorption of toxic agents. In Rozman K.K. and Hanninen O. Gastrointestinal Toxicology. Elsevier, New York, US.

Cosmetic Ingredient Rview Panel (CIR) (1986). Final Report on the safety Assessment of Cholesterol. Journal of the American College of Toxicology, 1986, 5 (5), 491-516.

ECHA (2012). Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance.

Lee SP (1981). Short Communication: Increased Heatic Fibrogenesis in the Cholesterol-Fed Mouse. Clinical Science, 1981, 61, 253-256. Testing laboratory: Gastroenterology Section, Department of Medicine, University of Auckland, Auckland, New Zealand. Owner company: Gastroenterology Section, Department of Medicine, University of Auckland, Auckland, New Zealand.