Alcohols, lanolin, distn. residues

Endpoint summary

Additional information

Justification for grouping of substances and read-across

There are no toxicokinetic studies available for Alcohols, lanolin, distn. residues (CAS No. 90622-40-5). In order to fulfil the standard information requirements set out in Annex VIII, 8.8.1, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from an analogue substance is conducted in support of the substance specific assessment.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, the substance Alcohols, lanolin (CAS No. 8027-33-6) is selected as reference substance in support of the substance specific assessment of toxicokinetic behaviour of Alcohols, lanolin, distn. residues.

The read-across is mainly based on the common origin of the source and target substances, as the target substance is generated from the source substance by distillation, the target substance being the high-boiling fraction (residue) of the distillation process. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Alcohols, lanolin, distn. residues (CAS No. 90622-40-5) has been investigated. In accordance with Annex VIII, Column 1, Item 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 physicochemical and toxicological properties according to the relevant Guidance (ECHA, 2012) and taking into account further available information from the read-across source substance Alcohols, lanolin (CAS 8027-33-6).

The substance Alcohols, lanolin, distn. residues is a UVCB comprising a mixture of high molecular weight alcohols of low volatility, obtained as the last (high-boiling) fraction or residue from the fractional distillation of Alcohols, lanolin. Cholesterol (CAS 57-88-5) is a major constituent, the remaining identified constituent being structurally similar or related to cholesterol (details on composition are given in Section 1.2 of the technical dossier and Chapter 1.2 of the Chemical Safety Report). Available information on the toxicokinetic behaviour of cholesterol is taken into account as supporting evidence.

The molecular weight of the identified constituents of Alcohols, lanolin, distn. residues is in the range of 384.64 to 498.75 g/mol. The substance is a solid at 20 °C with a melting point range of 46.7-92.7 °C (Henke, 2012), calculated water solubility of < 0.1 mg/L (Cuesta, 2013), log Pow range of 5.002 to 5.951 (Brinkmann, 2012) and vapour pressure of 3.07E-06 Pa at 20°C (Henke, 2013).

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 octanol/water partition coefficient (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).

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).

The physicochemical characteristics (log Pow > 5 and water solubility < 0.1 mg/L) of the substance and the molecular weight (> 380 and < 500) are in a range suggestive of low absorption from the gastrointestinal tract subsequent to oral ingestion. The absorption rate may also be limited by the fact that the substance is still a solid at a body temperature of 37 °C. Nevertheless, absorption via micellar solubilisation cannot be ruled out.

The analogue substance Alcohols, lanolin has been tested for acute oral toxicity in two studies. While in one study no mortality and no signs of systemic toxicity were observed in rats given the test substance at 2000 mg/kg bw (Leuschner, 2001), in the other study 2/10 rats died after administration of 5000 mg/kg bw (Cade, 1980). The available toxicological data does not provide sufficient information for the extent of oral absorption.

Cholesterol is anticipated to be well-absorbed via the gastrointestinal 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 further identified constituents of Alcohols, lanolin, distn. residues, it appears likely that the substance may also follow this absorption pathway.

Overall, based on molecular weight and physicochemical properties, the oral absorption rate of Alcohols, lanolin, distn. residues is anticipated to be low. However, the absorption rate may be higher if the substance undergo micellar solubilisation as described for cholesterol.

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 physicochemical characteristics (log Pow > 5 and water solubility < 0.1 mg/L) of the substance and the molecular weight (> 380 and < 500) are in a range suggestive of low absorption through the skin.

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2004):

log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW

Kp is high for high log Pow in conjunction with low MW values. Thus, the highest dermal permeability coefficient for Alcohols, lanolin, distn. residues is calculated using the upper and lower limits of the log Pow (5.951) and MW (384.64 g/mol) ranges, respectively.

The Kp is thus 0.0941 cm/h. Considering the water solubility (0.0001 mg/cm³), the dermal flux is estimated to be ca. 9.41E-06 mg/cm²/h.

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).

Based on read-across from the analogue substance Alcohols, lanolin, the available animal and human data indicate that the substance Alcohols, lanolin, distn. residues is considered to be not irritating and not sensitising. In the available acute dermal toxicity study with Alcohols, lanolin, no mortality occurred and no signs of systemic toxicity were noted. The data thus suggest a low level of dermal uptake.

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

In conclusion, based on molecular weight and physicochemical properties as well as toxicological data from the analogue substance, the dermal absorption rate of Alcohols, lanolin, distn. residues is anticipated to be low to very low.

Inhalation

The substance Alcohols, lanolin, distn. residues is a solid with a very low vapour pressure (3.07E-06 Pa). The substance is marketed in a non-granular form and is not used in processes involving the generation of aerosols or droplets. Therefore, exposure by inhalation is unlikely.

As for oral absorption, the molecular weight and physicochemical properties of the substance 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.

Distribution and Accumulation

Distribution of a compound within the body depends on the physicochemical 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, the substance Alcohols, lanolin, distn. residues (or rather its constituents) are likely to distribute in fatty tissue. The available information on cholesterol summarised below is taken as representative.

As described above, 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 Alcohols, lanolin, distn. residues is limited to that available for cholesterol, which is summarised below and considered representative.

Cholesterol is primarily metabolised to bile acids in the liver. Most of the cholesterol is converted to bile acids and this is the mechanism by which excess cholesterol is removed from the organism. Another important metabolic pathway is the synthesis of steroid hormones in the adrenals, ovaries, testes and placenta. Furthermore, cholesterol is metabolised to cholesterol esters and sulphates, cholestanol and vitamin D3. In the gut, the cholesterol is metabolised predominantly into coprostanol and coprostanone by the intestinal flora (CIR, 1986).

The results of the in vitro genotoxicity studies with the analogue substance Alcohols, lanolin did not show any evidence that the addition of the metabolic system either enhances or diminishes the activity of the substance (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 Alcohols, lanolin, distn. residues.

Cholesterol is excreted as bile salts via the faeces, or eliminated via the urine, breast milk or skin (CIR, 1986). Biliary excretion would thus be the relevant route of excretion for Alcohols, lanolin, distn. residues.

References

Aungst B. and Shen D.D. (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). FinalReport 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.

US EPA (2004). Risk Assessment Guidance for Superfund (RAGS), Volume I: Human Health Evaluation Manual (Part E, Supplemental Guidance for Dermal Risk Assessment) Interim. http://www.epa.gov/oswer/riskassessment/ragse/index.htm