Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers

Endpoint summary

Additional information

Basic toxicokinetics

There are no experimental studies available in which the toxicokinetic behaviour of Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers 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, 2014), an assessment of the toxicokinetic behaviour of the substance Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers was conducted to the extent that can be derived from relevant available information on physico-chemical and toxicological properties and taking into account available information on polyol esters.

The substance Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers is a diester of C18 unsaturated fatty acids with 2,2-dimethyl-1,3-propanediol (neopentylglycol) which meets the definition of an UVCB substance based on the analytical characterization. The substance is an organic liquid which is poorly water soluble <0.05 mg/L at 20 °C, pH = 6.3 (Frischmann, 2011 and 2012)) with a molecular weight range of 580.97 - 1189.90 g/mol, log Pow >10 (Erler, 2015) and a vapour pressure < 0.0001 Pa at 20 °C (Erler, 2015).

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, 2014).

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, 2012). With a molecular weight of 580.97 - 1189.90, absorption of Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers is in general expected to be low in the gastrointestinal (GI) tract. The log Pow > 4 suggests that Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers may be absorbed by micellar solubilisation, as this mechanism is of importance for highly lipophilic substances that are poorly soluble in water (1 mg/L or less).

Applying the “Lipinski Rule of Five” (Lipinski et al. (2001), refined by Ghose et al. (1999)) to Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers, shows that three rules are not fulfilled: the substance has a the molecular weight above 500, a high log Pow, which is above the given range of ‑0.4 to 5.6 and has more than 10 hydrogen bond. This indicates a low potential for oral absorption.

Metabolism of the test substance via enzymes and the microflora in the gastrointestinal (GI) tract may occur. In fact, after oral ingestion, fatty acid esters with glycerol (glycerides) are rapidly hydrolysed by ubiquitously expressed esterases (Mattsson and Volpenhein, 1972a). In general, it is assumed that the hydrolysis rate varies depending on the fatty acids/alcohol combinations, and grade of esterification (Mattson and Volpenhein, 1969; Mattson and Volpenhein, 1972a,b). For polyol esters, a lower rate of enzymatic hydrolysis in the GI tract was shown for compounds with more than 3 ester groups (Mattson and Volpenhein, 1972a, b). The in vitro hydrolysis rate of pentaerythritol ester was about 2000 times slower in comparison to glycerol esters (Mattson and Volpenhein, 1972a,b). Based on the available literature Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers, a diester of long chain fatty acids and 2,2-dimethyl-1,3-propanediol, is considered to undergo stepwise chemical changes in the GI-fluids as a result of enzymatic hydrolysis after oral ingestion. Furthermore, the result of the pancreatic digestion of the structurally related substance Heptanoic acid, ester with 2,2-dimethyl-1,3 –propandiol, shows a degradation of the ester of almost 90% within 4 hours (Oßberger, 2012).

The physico-chemical characteristics of the cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure) are likely to be different from those of the parent substance, and hence the predictions regarding absorption based on the physico-chemical characteristics of the parent substance no longer apply (ECHA, 2014). The cleavage products are anticipated to be absorbed in the GI tract. The highly lipophilic fatty acids (covering C16 to C18 unsaturated fatty acids) are expected be absorbed by micellar solubilisation (Ramirez et al., 2001), and the alcohol moiety is readily dissolved into the GI-fluids and will be absorbed because of its physico-chemical parameters (MW = 104.15 g/mol, log Pow= 0.12 at 25 °C and moderate water solubility (OECD SIDS, 2013)).

The indications that the target substance has relatively low oral absorption and/or low acute toxicity due to its physico-chemical characteristics are supported by the available data on acute oral toxicity for the structurally related substances neopentyl glycol dioleate (CAS 42222-50-4), Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane (CAS 147256-33-5), 9-Octadecenoic acid (Z)-, ester with 2,2-dimethyl-1,3-propanediol (CAS 67989-24-6) consistently showed LD50 values > 2000 mg/kg bw. Furthermore, no systemic toxic effects were observed (Weiß, 1997; Sanders, 2012; Potokar, 1988). In the 90-day oral repeated dose toxicity study performed with the analogue substance Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6), no toxicologically relevant effects were noted up to and including the highest dose level of 1000 mg/kg bw/day in male and female rats.

Overall, systemic bioavailability of Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers and/or the respective cleavage products in humans is considered likely after oral uptake of the substance.

Dermal

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 favours dermal absorption, above 500 the molecule may be too large (ECHA, 2014). As the molecular weight of Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers is 580.97 - 1189.9 g/mol, the dermal absorption is expected to be low.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2014). As the results with source substances do not indicate skin irritating potential, Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers is not expected to be skin irritating in humans, and enhanced penetration of the substance due to local skin damage can be excluded.

Based on a QSAR calculated dermal absorption value range of 8.15*10E-9 - 6.92*10E-14 mg/cm²/event (low) a low potential for dermal absorption is predicted for Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers (EPA, 2012).

This assumption is supported by the physico-chemical properties of Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers: 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 hence limit absorption across the skin. Therefore, the uptake of such substances into the stratum corneum itself is limited (ECHA, 2014). As the water solubility is less than 1 mg/L and the log Pow > 6, dermal uptake of Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers is likely to be low.

Overall, the calculated low dermal absorption potential, the low water solubility, the molecular weight (>100), the high log Pow value and the fact that the substance is not irritating to skin implies that dermal uptake of Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers in humans will be very low.

Inhalation

Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers has a low vapour pressure of <0.0001 Pa at 20 °C (QSAR) and therefore low volatility (Erler, 2015). 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 expected to be significant.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 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, 2014). Lipophilic compounds with a log Kow > 4 that are poorly soluble in water (1 mg/L or less) like Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers can be taken up by micellar solubilisation.

An acute inhalation toxicity study was performed with the structurally related substance Heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol (CAS 68855-18-5), in which rats were exposed nose-only to up to 5.22 mg/L of an aerosol for 4 hours (Griffith, 2012). No mortality occurred and no toxicologically relevant effects were observed at the end of the study period.

Overall, systemic bioavailability of Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers in humans is considered likely after inhalation of aerosols but is not expected to be higher than following oral exposure.

Accumulation

Highly lipophilic substances tend in general to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate within the body. 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 > 5 implies that Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers may have the potential to accumulate in adipose tissue (ECHA, 2014).

However, as further described in the section ‘Metabolism’ below, esters of alcohols and fatty acids undergo esterase-catalysed hydrolysis, depending of the fatty acid chain length and degree of esterification, leading to the respective cleavage products, namely fatty acids and alcohol moieties.

2,2-dimethyl-1,3-propanediol is the first cleavage product of Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers. Due to its physico-chemical properties (high water solubility and low molecular weight), accumulation of 2,2-dimethyl-1,3-propanediol in adipose tissue is considered to be unlikely. The second cleavage products, the fatty acid moieties (C16 and C18 unsaturated), can be stored as triglycerides in adipose tissue or be incorporated into cell membranes. At the same time, fatty acids are also required as a source of energy. Therefore, 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 in adipose tissue of the parent substance and cleavage products will occur.

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, 2014).

The enzymatic hydrolysis of Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers results in the cleavage products 2,2-dimethyl-1,3-propanediol (neopentyl glycol) and the respective fatty acids. 2,2-dimethyl-1,3-propanediol will be distributed in aqueous compartments of the organism and may also be taken up by various tissues. Similarly, fatty acids are also distributed in the organism and can be taken up by various tissues. They can be stored as triglycerides in adipose tissue depots or be incorporated into cell membranes (Masoro, 1977).

Overall, the available information indicates that the cleavage products, 2,2-dimethyl-1,3-propanediol and fatty acids will be distributed in the organism.

Metabolism

Esters of fatty acids are hydrolysed to the corresponding alcohol and fatty acids by esterases (Fukami and Yokoi, 2012). Therefore, Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers is expected to undergo hydrolysis within the human body. 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 GI fluids. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will take place. The first cleavage product, 2,2-dimethyl-1,3-propanediol, is likely to be conjugated by UGTs. The glucuronidated product is then excreted in the urine (Gessner, 1960). The other cleavage products, C16-C18 unsaturated fatty acids, are metabolised by stepwise beta-oxidation before entering the citric acid cycle as acetyl CoA (Stryer 1996).

Excretion

No data on excretion of Reaction products from the esterification of neopentylglycol with fatty acids, C16-18 (even numbered) and C18-unsatd. and fatty acids, C18-unsaturated, dimers is available. Based on the anticipated enzymatic hydrolysis, fatty acids and 2,2-dimethyl-1,3-propanediol as breakdown products will be present in the body. The fatty acid components will be metabolized for energy generation and afterwards mainly excreted by expired air as CO2, or stored as lipids in adipose tissue or used for further physiological properties e.g., incorporation into cell membranes (Stryer, 1996). Therefore, the C16 – C18 unsaturated fatty acid components are not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as CO2 or stored as described above. The main route for elimination of the alcohol is renal excretion via the urine (Gessner, 1960).

References

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