Nonanoic acid, esters with adipic acid and trimethylolpropane

Endpoint summary

Description of key information

Due to the physico-chemical properties, Nonanoic acid, esters with adipic acid and trimethylolpropaneis expected to have a low absorption potential via the oral, dermal and the inhalation route. To the minor extent that absorption occurs,systemic bioavailability of Nonanoic acid, esters with adipic acid and trimethylolpropaneby micellar solubilisation in humans might be possible via the oral and the inhalation route. Since absorption is a prerequisite, accumulation within the body and distribution of the parent molecule is not very likely. Moreover, Nonanoic acid, esters with adipic acid and trimethylolpropaneis not expected to be enzymatically hydrolysed to a high extent due to the steric hindrance. In the unlikely case of esterase-catalysed hydrolysis, the ultimate cleavage products nonanoic acid, adipic acid and trimethylolpropane (TMP) are produced and may be absorbed. However, no extensive metabolism is expected and direct elimination of unabsorbed test substance with the faeces will be the most likely fate of the substance.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic behaviour of Nonanoic acid, esters with adipic acid and trimethylolpropane 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), assessment of the toxicokinetic behaviour of the substance Nonanoic acid, esters with adipic acid and trimethylolpropane 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).

The substance Nonanoic acid, esters with adipic acid and trimethylolpropane meets the definition of an UVCB substance. Nonanoic acid, esters with adipic acid and trimethylolpropane is liquid at room temperature with a molecular weight between 799.13 and 2337.15 g/mol and a water solubility of 13.5 - 43 µg/L. The log Pow is estimated to be > 10 and the vapour pressure is estimated to be < 0.0001 Pa at 20 °C.

Both source substances Fatty acids, C8-10, mixed esters with adipic acid and trimethylolpropane (CAS 95912-89-3, source 1) and 2-ethyl-2-[[(1-oxononyl)oxy]methyl]propane-1,3-diyl dinonan-1-oate (CAS 126-57-8, source 2) are also liquids with a log Pow > 5.7, a vapour pressure ≤ 0.0013 Pa at 20 °C and a water solubility < 0.08 mg/L.

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).

Esterification is, in principle, a reversible reaction (hydrolysis). Therefore, the alcohol, dicarboxylic acid and fatty acid moieties are simultaneously precursors and breakdown products of the target and source substances. Taking into account the high MW, the very complex structures, the high log Pow and the very limited water solubility, absorption of the target and source substance 1 Fatty acids, C8-10, mixed esters with adipic acid and trimethylolpropane (CAS 95912-89-3) is highly unlikely. Enzymatic hydrolysis in the gastrointestinal tract and/or liver - usually identified as the biological process by which the breakdown of esters takes place - is highly unlikely for the target and the source substance 1. Target and source substance 1 have a complex structure consisting of mixed polyols linked by adipic acid and esterified by mixed fatty acids that is not anticipated to arrange itself at the lipid/water interface of lipid droplets in the gastrointestinal tract. This is considered a crucial step for ester hydrolysis by e.g. pancreatic lipase/colipase complex, which hydrolyses emulsified triacylglycerols in the diet. Source substance 2 2-ethyl-2-[[(1-oxononyl)oxy]methyl]propane-1,3-diyl dinonan-1-oate (CAS 126-57-8) is characterized by a more simple structure due to the absence of adipic acid. The metabolic fate of this substance involves a very slow stepwise hydrolysis of the ester bond to the corresponding free fatty acid and the respective alcohol by enzymatic hydrolysis (Mattson and Volpenhein, 1972a-c). Considering the physico-chemical properties of these substances and available toxicity data, a very low absorption of the intact parent compound via oral, inhalation and dermal route is assumed. Thus bioavailability of all substances is assumed to be very low.

Oral:

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 are favourable for oral absorption (ECHA, 2017). As Nonanoic acid, esters with adipic acid and trimethylolpropane is an UVCB the molecular weight ranges from 799.13 and 2337.15 g/mol, absorption of the molecule in the gastrointestinal tract is likely to be low. To the extent that absorption occurs, the most favourable mechanism 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 Nonanoic acid, esters with adipic acid and trimethylolpropane with log Pow > 10 and a water solubility of 13.5 – 43 µg/L.

In an acute oral toxicity study with the source substance Fatty acids, C8-10, mixed esters with adipic acid and trimethylolpropane (CAS 95912-89-3) performed according to OECD TG 425 and under GLP conditions, a LD50 value > 5000 mg/kg bw was derived. Another acute oral toxicity study performed according to OECD TG 423 and under GLP conditions with the source substance trimethylolpropane tripelargonate (CAS 126-57-8) revealed no adverse effects resulting in a LD50 value > 2000 mg/kg bw. In these studies no mortality and no clinical signs occurred.

After oral ingestion, an ester may undergo stepwise 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 this case, enzymatic hydrolysis of the target substance is not expected to take place due to the high molecular weight and the complex structure of the molecule. Hence, potential hydrolysis products probably do not play a prominent role in the toxicokinetic behaviour of Nonanoic acid, esters with adipic acid and trimethylolpropane, nevertheless they will be discussed briefly here.

In general, the physico-chemical characteristics of the cleavage 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 not longer apply (ECHA, 2017). However, for the cleavage products, it is anticipated that they have a higher potential for being absorbed in the gastro-intestinal tract. In case of long carbon chain substances and thus rather low water solubility by micellar solubilisation (Ramirez et al., 2001), and for small and water soluble cleavage products by dissolution into the gastrointestinal fluids (ECHA, 2017).

Overall, the absorption potential via the oral route of Nonanoic acid, esters with adipic acid and trimethylolpropane is considered to be very low. However to the extent that absorption occurs, systemic bioavailability of Nonanoic acid, esters with adipic acid and trimethylolpropane by micellar solubilisation in humans cannot be excluded.

Dermal:

The smaller the molecule, the more easily it may be absorbed via the dermal route. In general, a molecular weight below 100 favours dermal absorption, while above 500 the molecule may be too large (ECHA, 2017). As the molecular weight of Nonanoic acid, esters with adipic acid and trimethylolpropane ranges from 799.13 and 2337.15 g/mol, the dermal absorption of the molecule may be very limited.

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. The uptake into the stratum corneum itself is assumed to be slow. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis (ECHA, 2017). With a log Pow > 10 and a water solubility of 13.5 - 43 µg/L, dermal uptake of Nonanoic acid, esters with adipic acid and trimethylolpropane is likely to be low. If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2017). The available data from the structurally similar source substances Fatty acids, C8-10, mixed esters with adipic acid and trimethylolpropane (CAS 95912-89-3, source 1) and trimethylolpropane tripelargonate (CAS 126-57-8, source 2) indicate that Nonanoic acid, esters with adipic acid and trimethylolpropane is not skin irritating in humans and enhanced penetration of the substance due to local skin damage can be excluded. Moreover, an acute dermal toxicity of the source substance trimethylolpropane tripelargonate (CAS 126-57-8) was investigated following dermal administration of a single dose of 2000 mg/kg bw to the rat (RTC, 2014). No mortality occurred and no signs of toxicity were observed in male or female animals during the observation period. Therefore, the LD50 value was considered to be greater than 2000 mg/kg bw.

Taking into account the high MW, the very complex structure, the high log Pow and the very limited water solubility, absorption of the target substance is highly unlikely.

Overall, based on physico-chemical properties and available data with the source substances, dermal absorption of the target substance Nonanoic acid, esters with adipic acid and trimethylolpropane is likely to be very low.

Inhalation:

Nonanoic acid, esters with adipic acid and trimethylolpropane has a low vapour pressure below 0.0001 Pa 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. Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like Nonanoic acid, esters with adipic acid and trimethylolpropane can be taken up by micellar solubilisation.

In an acute aerosol inhalation study with the source substance Fatty acids, C8-10, mixed esters with adipic acid and trimethylolpropane (CAS 95912-89-3) performed according to OECD TG 403, a LC50 value ≥ 5.05 mg/L was found for rats. 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.

Overall, a systemic bioavailability of Nonanoic acid, esters with adipic acid and trimethylolpropane by micellar solubilisation in humans is considered possible after inhalation of aerosols with aerodynamic diameters below 15 μm. However, the absorption potential via the inhalation route of Nonanoic acid, esters with adipic acid and trimethylolpropane is considered to be very low.

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 > 10 indicates that Nonanoic acid, esters with adipic acid and trimethylolpropane may have the potential to accumulate in adipose tissue (ECHA, 2017).

Absorption is a prerequisite for accumulation within the body. Due to its MW and high log Pow, absorption is expected to be minimal for Nonanoic acid, esters with adipic acid and trimethylolpropane. Moreover, the substance is not expected to be enzymatically hydrolysed to a high extent due to the steric hindrance. In the unlikely case of esterase-catalysed hydrolysis, the ultimate cleavage products nonanoic acid, adipic acid and trimethylolpropane (TMP) are produced and may be absorbed. The log Pow of the ultimate cleavage product TMP is < 0 indicating a high water solubility (OECD SIDS, 1991). Consequently, there is no potential for TMP to accumulate in adipose tissue. The cleavage product (di)carboxylic/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 metabolized 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 or its 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 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 Nonanoic acid, esters with adipic acid and trimethylolpropane might be distributed within the body. TMP, a rather small (MW = 134.20 g/mol) substance of moderate water solubility is expected to be mainly distributed in aqueous compartments of the organism and may also be taken up by different tissues (OECD SIDS, 1991). Fatty acids are also distributed in the organism and can be taken up by different tissues. They can be stored as triglycerides in adipose tissue depots or they can be incorporated into cell membranes (Masoro, 1977). However, as already described above enzymatic hydrolysis in the gastrointestinal tract and/or liver is highly unlikely for the target and the source substance 1. The metabolic fate of the source substance 2 involves a very slow stepwise hydrolysis of the ester bond to the corresponding free fatty acid and the respective alcohol by enzymatic hydrolysis (Mattson and Volpenhein, 1972a-c). Thus, absorption and consequently distribution of the parent molecule and of the possible hydrolysis products is unlikely due to the physico-chemical properties and the slow hydrolysis rate, respectively.

Metabolism

As already described above, the alcohol, dicarboxylic acid and fatty acid moieties are simultaneously precursors and breakdown products of the target and both source substances. However, target and source 1 are characterized by high MW, very complex structure, high log Pow and limited water solubility. The absorption of these substances is therefore highly unlikely, as well as the enzymatic hydrolysis in the gastrointestinal tract and/or liver (usually the biological process, by which the breakdown of esters takes place). Source 2 is characterized by a simpler structure due to the absence of adipic acid. The metabolic fate of this substance involves a very slow stepwise hydrolysis of the ester bond to the corresponding free fatty acid and the respective alcohol by enzymatic hydrolysis (Mattson and Volpenhein, 1972a-c). Considering the physico-chemical properties of these substances and available toxicity data, a very low absorption of the intact parent compound via oral, inhalation and dermal route is assumed. However, if a previous stepwise hydrolysis by esterases and lipases to the free fatty acids and the polyol trimethylolpropane is assumed, absorption of the hydrolysis products may occur. The possible breakdown products are fatty acids and a respective polyol. The metabolism of the hydrolysis products would lead to the ultimate excretion products carbon dioxide and water from the fatty acids and to a rapid excretion of the highly polar polyol component with the urine and faeces.

Overall, the small part of Nonanoic acid, esters with adipic acid and trimethylolpropane that is systemically available, may be hydrolysed and the hydrolysis products nonanoic acid, adipic acid and trimethylolpropane will be produced. The fatty acids nonanoic acid and adipic acid will probably be physiologically metabolized via beta-oxidation and/or glucuronidation. For the water soluble alcohol trimethylolpropane glucuronidation and sulfatation of the hydroxyl groups might be possible. However, due to its high molecular weight, the absorption of the target substance is limited. Only the small fraction that is hydrolysed and absorbed is expected to be extensively metabolised. In conclusion, no extensive metabolism is expected and direct elimination will be the most likely fate of the substance.

Excretion

The main route of excretion of Nonanoic acid, esters with adipic acid and trimethylolpropane is as unabsorbed substance with the faeces. The second route of excretion is expected to be by expired air as CO2 after extensive metabolic degradation (betaoxidation). The hydrolysis products may likewise be excreted unchanged via the urine, or metabolised and excreted as CO2 (Deisinger, 1994; Hsieh and Perkins, 1976).

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