Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2) 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 Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2) 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 Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2) meets the definition of an UVCB substance based on the analytical characterisation. Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2) is liquid at room temperature and has a molecular weight between 368.59 and 1386.27g/mol and a water solubility < 5 µg/L at 20 °C. The log Pow is > 10 and the vapour pressure is < 0.0001 Pa at 20 °C.

 

Absorption

No measured data are available regarding absorption, hydrolysis (before and after absorption), and the resulting systemic availability (concentration in blood) of Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2). The toxicokinetic statement was thus based on available information from the predicted hydrolysis products of the target substance: C18-unsatd. dimerized fatty acid and 2-ethylhexanol. In addition, an assessment based on the physico-chemical information given for the target substance and supporting information on the hydrolysis product neopentyl glycol was considered.

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 are favourable for oral absorption (ECHA, 2017). As Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2) is an UVCB, the molecular weight ranges from 368.59 to 1386.27g/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) likeFatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycolwith a calculated log Pow of 22.01 and a water solubility <1 µg/L.

In an acute oral toxicity study with Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters (CAS 68440-06-2) performed according to OECD TG 423 (acute toxic class method) and GLP, a LD50 value > 2000 mg/kg bw was derived. Another acute oral toxicity study according to OECD TG 423 and GLP with Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane (CAS 147256-33-5) revealed no adverse effects resulting in a LD50 value > 2000 mg/kg bw.

After oral ingestion, an ester undergoes 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 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 target substance before absorption into the blood takes place, and hence the predictions based upon the physico-chemical characteristics of the target substance do no longer apply (ECHA, 2017). For the predicted hydrolysis product 2-ethylhexanol, it is known that it will be absorbed in the gastro-intestinal tract by dissolution into the gastrointestinal fluids quite rapidly (Deisinger, 1994). The second hydrolysis product, Fatty acids, C18 unsatd., dimers, seems to be absorbed at a lower rate than monomeric fatty acids, as indicated by studies carried out to investigate the absorption, distribution and excretion of dimeric fatty acids(Hsieh and Perkins, 1976). Upon oral administration only ca. 0.4% of the 14C-labeled dimeric fatty acid methyl esters given by gastric intubation were absorbed within 12 h. Ca. 1% of the labeled material was excreted via urine and ca. 2% as CO2. Ca. 80% of the radioactivity was recovered in the gastrointestinal tract and the faeces. About 0.115% of the administered test material was incorporated in the liver and metabolized to different lipid classes.

Overall, systemic bioavailability of Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2) and/or the respective hydrolysis products 2-ethylhexanol, neopentyl glycol and Fatty acids, C18-unsatd., dimers in humans are considered possible but limited after oral uptake due to the high molecular weight of the target substance.

 

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 Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2) ranges from 368.59 to 1386.27g/mol, the dermal absorption of the molecule is likely to be very limited.

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 substance Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters (CAS 68334-05-4) and Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane (CAS 147256-33-5) indicate that Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2) is not skin irritating in humans and enhanced penetration of the substance due to local skin damage can be excluded.

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 >20 and a water solubility <1 µg/L, dermal uptake of Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2) is likely to be low.

Overall, based on physico-chemical properties and available data with the source substances, dermal absorption of the target substance Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2) is likely to be very limited.

 

Inhalation:

Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2) have a low vapour pressure below 0.0001 Pa and therefore of low volatility. Thus, under normal use and handling conditions, inhalation exposure and the availability for respiratory absorption of the substance in the form of vapours, gases, or mists is considered to be negligible.

In an acute aerosol inhalation study with the source substance Fatty acids, C18 -unsaturated dimers, 2-ethylhexyl esters (CAS 68334-05-4) performed according to OECD guideline 436 (acute toxic class method, limit test), an LC50 value of greater than 5.3 mg/L was found for rats. No systemic effects indicating absorption after inhalation were observed.

Overall, a systemic bioavailability of Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2) in humans via the inhalation route is considered to be 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 Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2) 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 Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2), and therefore accumulation is not favoured either. An esterase-catalysed hydrolysis of Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2) will generate the relevant hydrolysis products. 2-ethylhexanol is known to be metabolized and excreted rapidly, therefore no accumulation is expected (Deisinger, 1994). The second hydrolysis product, the fatty acid, can be re-esterified and stored as triglycerides in adipose tissue depots or be incorporated into cell membranes. Fatty acids are also required as a source of energy and 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. The available information indicates that dimeric fatty acids are poorly absorbed and that the absorbed fraction follows the same pattern of metabolism and excretion as the monomeric acids. Therefore, no significant bioaccumulation in adipose tissue is expected.

Overall, the available information indicates that no significant bioaccumulation of the target substance in adipose tissue is anticipated.

 

Distribution

The level of distribution within the body via 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 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 target substance is not expected as only very limited absorption will occur. Only the potential hydrolysis products of Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2) might be distributed within the body.

 

Metabolism

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 gastro-intestinal fluids. In contrast, substances that are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will generally take place. Dimeric acids have more complex structures than the simple fatty acid esters. Therefore, ester bond hydrolysis is expected to occur only to a minor extent. The first possible hydrolysis product, 2-ethylhexanol, is metabolized by oxidation and/or glucuronidation. The second hydrolysis product, neopentyl glycol, is metabolized by glucoronidation leading to 3-hydroxy-2,2-dimethylpropionic acid (Gessner et al., 1959). The third hydrolysis product, the fatty acid, is degraded stepwise by beta-oxidation based on enzymatic removal of C2 units. This occurs in the matrix of the mitochondria in most vertebrate tissues. The C2 units are cleaved as acyl-CoA, the entry molecule for the citric acid cycle. The cyclic portion of dimers cannot be degraded by β- or ω-oxidation and is probably hydroxylated or conjugated, which are common detoxification mechanisms of cyclic compounds, leading to polar metabolites readily excreted via urine (Iwaoka and Perkins, 1978).

Overall, the part of Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2) that is systemically available, may be hydrolysed and the hydrolysis products will be physiologically metabolized via beta-oxidation and/or glucuronidation. However, due to its high molecular weight, the absorption of the target substance is limited. Thus, no extensive metabolism is expected and direct elimination will be the most likely fate of the substance.

Excretion

The main route of excretion of Fatty acids, C18-unsatd., dimers, polymers with 2-ethylhexanol and neopentyl glycol (CAS 68552-19-2) is expected to be excretion of unabsorbed substance with the faeces. The second route of excretion is expected to be by expired air as CO2after metabolic degradation (betaoxidation). The potential hydrolysis products may likewise be excreted unchanged via the urine, or metabolised and exhaled (Deisinger, 1994; Hsieh and Perkins, 1976). The metabolism of 2-ethylhexanol (CAS 104-76-7) was studied in rats (Deisinger, 1994). Following oral administration, 2-ethylhexanol was absorbed effectively by the gastrointestinal tract. The major portion of the dose was excreted within 24 h, primarily in the urine. Metabolisation of 2-ethylhexanol into the corresponding acid, which is primarily glucuronidated, will also be excreted via the urine. Smaller amounts of the dose were excreted in the faeces primarily within 24 h. A mean of 11% of the dose was recovered as14CO2, but only a fraction of a percent of the dose was recovered from the breath as [14C] volatile organics.

Following dermal application, only a small portion of the dose was absorbed, which was eliminated primarily in the urine, with smaller amounts eliminated in the faeces, and as 14CO2, in the breath.

References:

Deisinger, P.J. (1994). Metabolism of 2-ethylhexanol administered orally and dermally to the female Fischer 344 rat. XENOBIOTICA, 1994, VOL. 24, NO. 5 , 429-440.

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

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

Gessner, P.K., Parke D.V. and Williams R.T. (1959): Studies in Detoxication. Biochem J. 74(1): 1-5.

Hsieh, A. and Perkins, E. G. (1976). Nutrition and Metabolic Studies of Methyl Ester of Dimer Fatty Acids in the Rat. Lipids, 11(10):763-768.

Lehninger, A.L., Nelson, D.L. and Cox, M.M. (1993): Principles of Biochemistry.Second Edition. Worth Publishers, Inc., New York, USA. ISBN 0-87901-500-4.

Mattson, F.H. and Volpenhein, R.A. (1969): Relative rates of hydrolysis by rat pancreatic lipase of esters of C2 - C18 fatty acids with C1 - C18 primary n-alcohols.J Lipid Res Vol(10): 271 - 276.