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Toxicokinetic assessment

 

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), Lanolin fatty acids (CAS 68424-43-1) and their esters have been investigated. These substances have been shown to hydrolyse at pH 4, 7 and 9.

Lanolin alcohols is a UVCB substance derived from naturally occurring wool grease of ovine origin. It consists primarily of sterols but is also a complex mixture of aliphatic 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 fatty acids is a UVCB substance, composed of fatty acids derived from the saponification of lanolin derived from naturally occurring wool grease of ovine origin.

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

Lanolin alcohols has been tested for acute oral and repeated dose toxicity in rats. No signs of systemic toxicity were observed at 2000 mg/kg bw (Leuschner, 2001) and in a 90-day study (Dunster 2014) no treatment related effects were reported at 1000 mg/kg bw. 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.

Lanolin fatty acids

The results of the acute oral and the 90-day toxicity study in rats with lanolin fatty acids showed no evidence of toxicity (Lewis, 1977, Braun 2013). 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. Based on the low water solubility, the molecular weight range and the log Pow absorption of the substance or rather individual components is possible. For the components with a log Pow of <4 absorption may occur through passive diffusion, whereas components with a log Pow of >4 may be taken up by micellular solubilisation. In conclusion uptake is expected, but is expected to be limited.

Esters of lanolin alcohols and lanolin fatty acids

The esters are large molecules with a very low water solubility and a high log Pow. These substances are expected to dissolve into the gastrointestinal fluids to a very limited extent. Uptake by passive diffusion is unlikely given the molecular weight but micellular solubilisation by bile salts in the gastro-intestinal tract may allow some crossing of lipid biomembranes. It is expected that in the GI tract abiotic hydrolysis or hydrolysis via esterases occurs, leading to formation of the slightly less hydrophobic alcohols and fatty acids. These products or part of these may be taken up as described above.

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).

Lanolin alcohols

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 no dermal irritation and sensitization has been observed, thus no effects that could moderate the skin absorption. 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.

Lanolin fatty acids

The physicochemical properties (waxy solid, log Pow and water solubility) of Lanolin fatty acids and the molecular weight 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 fatty acids, no effects regarding to skin irritation were observed (Davies 1968), which could enhance dermal penetration of the substance. Data on skin sensitisation show that the substance is not sensitising in a LLNA (Bradshaw, 2010).

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

Esters of lanolin alcohols and lanolin fatty acids

The physicochemical properties (waxy paste, log Pow and water solubility) of the ester and the molecular weight are in a range suggestive of low absorption through the skin. The substance is not irritant to the skin in an in vitro test (XcellR8 2017).

Taking these characteristics into account, it can be concluded that dermal absorption is expected to be low

Absorption, inhalation

Lanolin alcohols and lanolin fatty acids

Lanolin alcohols and lanolin fatty acids are waxy solids with a vapour pressure of 360 Pa and 700 Pa at 20 °C . These values are deemed to be quite high for solids, and it was suspected that the samples contained water hence the magnitude of the results. In addition the boiling temperature of both substances has been determined to be 220 °C - 420 °C and 320 °C - 420 °C at normal pressure indicating that Lanolin alcohols and Lanolin fatty acids are 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 and Lanolin fatty acids 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.

Esters of Lanolin alcohols and Lanolin fatty acids

The ester has a very low vapour pressure and high melting point. In addition exposure to aerosols with inhalable or respirable droplets is considered not possible during use of the substance. It is therefore concluded in parallel to what is concluded above, that the inhalation uptake is expected to be low and does not need to be considered further.

 

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).

Lanolin alcohols

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).

Lanolin fatty acids

After being absorbed, fatty acids are (re-)esterified along with other fatty acids into triglycerides and released in chylomicrons into the lymphatic system. Fatty acids of carbon chain length ≤ 12 may be transported as the free acid bound to albumin directly to the liver via the portal vein, instead of being re-esterified. Chylomicrons are transported in the lymph to the thoracic duct and eventually to the venous system. Upon contact with the capillaries, enzymatic hydrolysis of chylomicron triacylglycerol fatty acids by lipoprotein lipase takes place. Most of the resulting fatty acids are taken up by adipose tissue and re-esterified into triglycerides for storage. Triacylglycerol fatty acids are likewise taken up by muscle and oxidized for energy or they are released into the systemic circulation and returned to the live. Stored fatty acids underlie a continuous turnover as they are permanently metabolised for energy and excreted as CO2.

Esters of lanolin alcohols and Lanolin fatty acids

After enzymatic or abiotic split of the ester bond, the acid and alcohol parts of the original molecules are expected to be taken up and distributed as described under the sections on Lanolin alcohols and Lanolin fatty acids.

Metabolism

Lanolin alcohols

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).

Lanolin fatty acids

Lanolin fatty acids is assumed to be metabolised via the standard metabolism pathways for fatty acids.

Fatty acids are degraded by mitochondrial β-oxidation which takes place in the most animal tissues and uses an enzyme complex for a series of oxidation and hydration reactions resulting in the cleavage of acetate groups in form of acetyl CoA. The alkyl chain length is thus reduced by 2 carbon atoms in each β-oxidation cycle. The complete oxidation of unsaturated fatty acids such as oleic acid requires an additional isomerisation step. Alternative pathways for oxidation can be found in the liver (ω-oxidation) and the brain (α-oxidation). Thus iso-fatty acids such as isooctadecanoic acid have been found to be activated by acyl coenzyme A synthetase of rat liver homogenates and to be metabolised to a large extent by ω-oxidation. Each two-carbon unit resulting from β-oxidation enters the citric acid cycle as acetyl CoA, through which they are completely oxidized to CO(Lehninger, 1998; Stryer, 1996).

The results of the in vitro genotoxicity studies did not show any evidence that the addition of the metabolic system either enhances or diminishes the activity of the substance (Bowles & Thompson, 2010; Bowles, 2010; Brown, 2010).

Esters of Lanolin alcohols and Lanolin fatty acids

After enzymatic or abiotic split of the ester bond, the acid and alcohol parts of the original molecules are expected to be taken up and metabolised as described under the sections on Lanolin alcohols and Lanolin fatty acids.

 

Excretion

Lanolin alcohols

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.

Lanolin fatty acids

In general, fatty acids are catabolised entirely by oxidative physiologic pathways ultimately leading to the production of carbon dioxide and water. Small amounts of ketone bodies resulting from the oxidation of fatty acids are excreted via the urine (Lehninger, 1998; Stryer, 1996). Unmetabolised Lanolin fatty acids that may be absorbed are assumed to be excreted in the bile and thus excreted via the faeces, as poorly water-soluble products are not favourable for urinary excretion. Any material that is not absorbed will be excreted in the faeces.

Esters of Lanolin alcohols and Lanolin fatty acids

After enzymatic or abiotic split of the ester bond, the acid and alcohol parts of the original molecules are expected to be taken up, metabolised and excreted as described under the sections on Lanolin alcohols and Lanolin fatty acids.

Conclusion

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

The available information showed some evidence that Lanolin fatty acids, is expected to be absorbed via the gastro-intestinal tract. Once absorbed, the substance may be distributed systemically and reversibly stored in the adipose tissue. The substance is assumed to be metabolised within the standard metabolic pathways for fatty acids resulting in complete oxidation to CO2. Biliary excretion is likely to be the most significant route of excretion for the unmetabolised part of the substance.

For the ester of the Lanolin alcohols and Lanolin fatty esters absorption via the oral route is expected only after hydrolysis of the ester bond. Dermal absorption is expected to be minimal. If absorbed the hydrolysis products are expected to be distributed, metabolised and excreted via the mechanism as described for Lanolin alcohols and Lanolin fatty acids.

 

In conclusion the human dermal, oral and inhalation absorption, and subsequent human metabolism, distribution and elimination profile of lanolin alcohols, lanolin fatty acids and esters of lanolin alcohols and lanolin fatty acids is predicted to mirror those of mammalian derived dietary lipids and to utilise the same biochemical pathways and cycles.

 


 

References (not cited in 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.

 

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information