Castor oil, hydrogenated, ethoxylated

Endpoint summary

Description of key information

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 Castor oil, hydrogenated, ethoxylated has been investigated.

The substance, Castor oil, hydrogenated, ethoxylated is a UVCB substance, composed of hydrogenated, ethoxylated fatty acids derived from castor oil, a vegetable oil obtained from the seeds of the castor oil plant (Ricinus communis).

Castor oil (structure see attached document in 7.1.1)

Major fatty acid component Ricinoleic acid C₁₈H₃₄O₃ (structure see attached document in 7.1.1)

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).

Castor oil, hydrogenated, ethoxylated has a molecular weight of ca 1026. The substance is waxy solid with an extremely high logKow and a water solubility of <0.5 mg/L. The substance’s physico-chemical properties are indicative for a low absorption, but some micellular solubilisation by bile salts in the gastro-intestinal tract an concomitant crossing of lipid biomembranes cannot be excluded.

Castor oil is a triglyceride of mainly ricinoleic acid ((9Z,12R)-12-Hydroxyoctadec-9-enoic acid). This substance, as is its ethoxylated form, are expected to be subject to lipolysis by pancreatic lipases in the gastro-intestinal tract. The resulting ethoxylated ricinoleic acid (and other ethoxylated, hydrogenated fatty acids in the substance) are expected to be taken up to a certain extent (depending on their carbon chain length, logKow and water solubility).

The absence of adverse effects in oral acute toxicity tests and the repeated dose reproduction study (Envigo 2018) is either indicative for low absorption and/or low toxicity. No local effects on the membranes of the gastro-intestinal tract lining or irritant effects are reported in any of these studies. Therefore local irritation as potential for enhanced absorption can be excluded.

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 (>1000 g/mol) of Castor oil, hydrogenated, ethoxylated are in a range suggestive of low absorption through the skin. The substance shows no skin irritating or corrosive properties and therefore no damage to the skin surface, which could lead to increased absorption is expected. Taking this information into account the dermal absorption potential is considered to be rather low and is set at the default value of 10%.

Absorption, inhalation

Castor oil, hydrogenated, ethoxylated is a waxy solid with a vapour pressure of < 1E-6 Pa at 20 °C (calculated 1.17 E-30 Pa). Based on these properties under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours 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 Castor oil, hydrogenated, ethoxylated 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 (set at default value of 10%).

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).

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 liver. Stored fatty acids underlie a continuous turnover as they are permanently metabolised for energy and excreted as CO2.

No data are available for hydrogenated ethoxylated fatty acids, but a similar process can be expected for ethoxylated ricinoleic acid after lipolysis of Castor oil, hydrogenated, ethoxylated, although especially the ethoxylation may be of influence on the accessibility of the acid groups for re-esterfication.

Metabolism

Castor oil, hydrogenated, ethoxylated is assumed to be metabolised via the standard metabolism pathways for fatty acids. In case of exposure to large aggregates of triglyceride, the hydrophobic parts of bile acids intercalate into the lipid, with the hydrophilic domains remaining at the surface. This coating with bile acids supports the breakdown of large aggregates into smaller and smaller droplets, which makes them easier assessable for pancreatic lipases. These lipases are responsible for the split into monoglycerides and fatty acids, that form micelles with bile acids and other fatty acids.

Fatty acids are then 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).

No data are available for hydrogenated ethoxylated fatty acids, but a similar process can be expected for ethoxylated ricinoleic acid after lipolysis of Castor oil, hydrogenated, ethoxylated. 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 (Envigo 2018) and therefore metabolic conversion to the products as described and concomitant degradation to carbon dioxide and water can be expected.

Excretion

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 ricinoleic acid (or other ethoxylated hydrogenated fatty acids) that may be absorbed is 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.

Conclusion

For Castor oil, hydrogenated, ethoxylated absorption via the oral route is expected only after lipolysis. Dermal absorption is expected to be minimal. If absorbed, hydrogenated, ethoxylated fatty acids are expected to be distributed, metabolised and excreted via a mechanism similar to that for fatty acids.

In conclusion the human dermal, oral and inhalation absorption, and subsequent human metabolism, distribution and elimination profile of Castor oil, hydrogenated, ethoxylated 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.

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

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

10