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Description of key information

The systemic bioavailability of Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid is expected to be limited via the oral and dermal route. Via inhalation a systemic bioavailability is also considered to be low, but may be possible after inhalation of aerosols with aerodynamic diameters below 15 µm. Due to steric hindrance, hydrolysis of its ester bonds in the gastrointestinal tract and mucus membranes to the respective fatty acids, alcohol and adipic acid, which facilitates the absorption is expected to occur to a minor extent only. Therefore, metabolism, distribution and accumulation of Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid within the body is also not expected. The main route of excretion of Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid is expected to be excretion of unabsorbed substance with the faeces.The second route of excretion is expected to be by expired air as CO2 after metabolic degradation (β-oxidation).

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

There were no studies available in which the toxicokinetic behaviour of Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid has been investigated. Therefore, in accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) No. 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), an assessment of the toxicokinetic behaviour of the substance Fatty acids, C18-unsatd., dimers, hydrogenated, diisopropyl esters (CAS 103213-20-3) 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 according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017) and taking into account further available information on structurally similar substances and hydrolysis products.

 

The substance Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid is an organic liquid with a molecular weight range of514.7 - 1223.7g/mol. The measured water solubility was < 165 µg/L at 20 °C, pH 6.3. The log Pow was calculated to be 8.3 - > 10 (QSAR models: VEGA / ALogP version 1.0.0, EPI Suite / KOWWIN version 1.68, refer to IUCLID section 4.7).

 

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, 2017).

 

Oral

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 g/mol are favourable for oral absorption (ECHA, 2017). As the molecular weight range of Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid is 514.7 - 1223.7 g/mol, absorption of the molecule in the gastrointestinal tract is considered to be low. If absorption occurs, the mechanism favoured will be absorption by micellar solubilisation, as this mechanism is of importance for highly lipophilic substances (log Pow > 4), which are poorly soluble in water (1 mg/L or less) like Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid with a log Pow of 8.3 - > 10 and a water solubility of < 165 µg/L. No studies by the oral route are available for Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid, thus no additional information from animal studies is available for the target substance.

However, in acute oral toxicity studies with the read across substances Fatty acids, C8-10, mixed esters with adipic acid and trimethylolpropane (CAS 95912-89-3), Fatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol (CAS 11138-60-6) and Isononanoic acid, mixed esters with 2-methylbutanoic acid, 3-methylbutanoic acid, pentaerythritol and valeric acid (CAS 146289-36-3) performed according to OECD TG 425 and 401, respectively, LD50 values of > 5000 mg/kg bw and > 2000 mg/kg bw were derived.

After oral ingestion, an ester undergoes hydrolysis of the ester bond by gastrointestinal enzymes (Lehninger, 1970; Mattson and Volpenhein, 1972). The respective alcohol as well as the corresponding acid is formed. In general, the physico-chemical characteristics of the hydrolysis products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) are likely to be different from those of the parent substance before absorption into the blood takes place, and hence the predictions based upon the physico-chemical characteristics of the parent substance do no longer apply (ECHA, 2017). However, in case of Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid it is not anticipated that enzymatic hydrolysis of the parent substance is taking place in significant quantities due to steric hindrance of the complex structure. Nevertheless, for the hydrolysis products, it is anticipated that they have a higher potential for being absorbed in the gastrointestinal tract. In case of long carbon chain substances and thus rather low water solubility absorption will take place via micellar solubilisation (Ramirez et al., 2001), and for small and water soluble hydrolysis products by dissolution into the gastrointestinal fluids (ECHA, 2017).

Overall, a systemic bioavailability of Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid in humans is considered possible but limited after oral uptake of the substance due to its high molecular weight.

 

Dermal

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 g/mol favours dermal absorption, above 500 g/mol the molecule may be too large (ECHA, 2017). As the molecular weight range of Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid is 514.7 - 1223.7 g/mol, dermal absorption of the substance is not likely. If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2017). As the read across substances Fatty acids, C8-10, mixed esters with adipic acid and trimethylolpropane (CAS 95912-89-3) and Fatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol (CAS 11138-60-6) are not skin irritating in vitro and in vivo, respectively, enhanced penetration of Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid due to local skin damage is not assumed.

For substances with a log Pow above 4, the rate of dermal penetration is limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. For substances with a log Pow above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin, and the uptake into the stratum corneum itself is also slow. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis (ECHA, 2017). With a log Pow of 8.3 - > 10 and a water solubility < 165 µg/L at 20 °C, dermal uptake of Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid is likely to be low. This is also supported by QSAR calculations of the source substances which result in a very low dermal absorption potential for the source substance.

In an acute dermal toxicity study with the read across substance Fatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol (CAS 11138-60-6) performed according to OECD guideline 402 no mortality or clinical signs of systemic toxicity were noted in any animal during the study period. 4 male animals lost 0.1 kg body weight whereas the remaining animals had a constant body weight over the study period. Necropsy at study termination revealed no abnormalities. Thus, the acute dermal LD50 in rabbits for Fatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol was found to exceed 2000 mg/kg bw.

Overall, the physico-chemical characteristics ofFatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid, as well as the calculated low dermal absorption potential indicate that dermal absorption of Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid is likely to be very limited.

 

Inhalation

Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid has a low vapour pressure below 0.0001 Pa at 20°C (QSAR, ARChem SPARC. version 4.6) thus being of low volatility. 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 considered negligible. However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed. In humans, particles with aerodynamic diameters below 100μm have the potential to be inhaled. Particles with aerodynamic diameters below 50μm may reach the thoracic region and those below 15μm the alveolar region of the respiratory tract (ECHA, 2017). Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid can be taken up by micellar solubilisation.

In an acute aerosol inhalation study with the read across substance Fatty acids, C8-10, mixed esters with adipic acid and trimethylolpropane (CAS 95912-89-3) performed according to OECD guideline 403 (limit test) no mortality was observed, but slight ataxia, slight tremor and slight dyspnoea occurred immediately after the end of exposure (up to 3 h), most probably due to impaired gas exchange. Based on these results, the LC50 value for Fatty acids, C8-10, mixed esters with adipic acid and trimethylolpropane was considered to be > 5.05 mg/L air.

Overall, a systemic bioavailability of Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid in humans is considered to be low but may be possible after inhalation of aerosols with aerodynamic diameters below 15 µm.

 

Accumulation

Highly lipophilic substances tend in general to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally the case that substances with high log Pow values have long biological half-lives. The high log Pow of 8.3 - > 10 implies that Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid may have the potential to accumulate in adipose tissue (ECHA, 2017).

Absorption is a prerequisite for accumulation within the body. Due to its molecular weight and high log Pow, absorption is expected to be minimal for Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid, therefore accumulation is not favoured as well.

In the exceptional case of esterase-catalysed hydrolysis of absorbed Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid, the ultimate hydrolysis products are pentaerythritol, C8-10 fatty acids and adipic acid. No potential for accumulation is expected for pentaerythritol and adipic acid. The C8-10 fatty acids, can be stored as triglycerides in adipose tissue depots or be incorporated into cell membranes. At the same time, fatty acids are also required as a source of energy. Thus, stored fatty acids underlie a continuous turnover as they are permanently metabolised and excreted. Bioaccumulation of fatty acids only takes place, if their intake exceeds the caloric requirements of the organism.

Overall, the available information indicates that no significant bioaccumulation of the parent substance and its expected hydrolysis products in adipose tissue is anticipated.

 

Distribution

Distribution within the body through the circulatory system depends on the molecular weight, the lipophilic character and water solubility of a substance. 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 its extracellular concentration particularly in fatty tissues (ECHA, 2017). Distribution of the parent substance is not expected as only very limited absorption will occur. Only the potential hydrolysis products of Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid, pentaerythritol, C8-10 fatty acids and adipic acid, might be distributed within the body.

 

Metabolism

In general, esters of fatty acids are hydrolysed to the corresponding alcohol and fatty acid by esterases (Fukami and Yokoi, 2012). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: After oral ingestion, esters of alcohols and fatty acids undergo enzymatic hydrolysis already in the gastrointestinal fluids. In contrast, substances absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will basically take place. Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid, however, is of more complex structure than simple fatty acid esters. Therefore, due to steric hindrance, hydrolysis of its ester bonds is expected to occur to a minor extent only. Taken together, it is highly unlikely that Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid is metabolised in the body. In the unlikely case of hydrolysis, a major metabolic pathway for linear and simple branched fatty acids isβ-oxidation for energy generation. Pentaerythritol is absorbed rapidly and mainly excreted unchanged without metabolic conversion. Adipic acid might also be excreted unchanged or metabolised and exhaled (OECD SIDS, 2004).

 

Excretion

The main route of excretion of Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid is expected to be excretion of unabsorbed substance with the faeces. The second route of excretion is expected to be by expired air as CO2 after metabolic degradation (β-oxidation). It is assumed, however, that the hydrolysis rate is low as a result of steric hindrance due to the number of ester bonds and the complexity of the parent substance. If hydrolysis occurs, a major metabolic pathway for linear and simple branched fatty acids isβ-oxidation for energy generation. Pentaerythritol is mainly excreted unchanged via the urine. Adipic acid might also be excreted via the urine, unchanged or metabolised and exhaled (OECD SIDS, 2004).

Overall, the part of Fatty acids, C8-10-(even numbered), esters with pentaerythritol and adipic acid that has become systemically available, may be hydrolysed and the hydrolysis products are metabolised by β-oxidation. However, due to its high molecular weight, absorption of the parent substance is not likely and thus, no extensive metabolism is expected but rather direct elimination via the faeces.

 

References:

ECHA (2017): Guidance on information requirements and chemical safety assessment - Chapter R.7c: Endpoint specific guidance. European Chemicals Agency, Helsinki.

Lehninger, A.L. (1970). Biochemistry. Worth Publishers, Inc.

Mattson F.H. and Volpenhein R.A. (1972). Hydrolysis of fully esterified alcohols containing from one to eight hydroxyl groups by the lipolytic enzymes of rat pancreatic juice. J Lip Res 13, 325-328.

Ramirez M. et al. (2001). Absorption and distribution of dietary fatty acids from different sources. Early Human Development 65 Suppl.: S95-S101.

Fukami, T. and Yokoi, T. (2012). The Emerging Role of Human Esterases. Drug Metabolism and Pharmacokinetics, Advance publication July 17th, 2012.

OECD SIDS (2004). Adipic acid. http://www.inchem.org/documents/sids/sids/124049.pdf