2,2-dimethyl-1,3-propanediyl didecanoate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Type:

other: ester hydrolysis in intestinal fluid simulant

Results:

85.7, 86.1 and 89.4% after 1, 2 and 4 h, respectively Source: CAS 68855-18-5, FABES, 2012

Conclusions:

Nearly 90% hydrolysis of an analogue source substance was observed after pancreatic digestion for 4 h. As explained in the analogue justification, this result is considered to be valid also for the target substance.

Description of key information

Absorption:

Systemic bioavailability of the parent substances and/or its hydrolysis products is considered likely after oral uptake. Uptake after inhalatory exposure to aerosols is not expected to be higher than following oral exposure. Dermal uptake is expected to be very low.

Distribution and accumulation:

The hydrolysis products will be distributed in the organism. No bioaccumulation in adipose tissue of the parent substance and the hydrolysis products is anticipated.

Metabolism and excretion:

Hydrolysis of the parent substance is expected. 2,2-dimethyl-1,3-propanediol (neopentyl glycol) is likely to be conjugated by UDP-glucuronosyltransferases and the glucuronidated product is going to be excreted in the urine. Decanoic acid is metabolised by stepwise β-oxidation and will mainly be excreted by expired air as CO₂, or stored as lipids in adipose tissue or used for further physiological processes.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no experimental studies available in which the toxicokinetic behaviour of neopentyl glycol dicaprate (CAS 27841-06-1) has been investigated. Therefore, in accordance with Annex VIII, Column 1, Item 8.8.1, of REACH (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 neopentyl glycol dicaprate was conducted to the extent that can be derived from relevant available information on physico-chemical and toxicological properties.

Neopentyl glycol dicaprate is a diester of decanoic acid with 2,2-dimethyl-1,3-propanediol (neopentyl glycol). It meets the definition of a mono-constituent substance based on the analytical characterisation. Its main constituent is the diester, whereas the monoester and free fatty acids are present as impurities only. The substance is a poorly water soluble (< 2.4 µg/L, pH = 6.3) liquid with a molecular weight of 412.65 g/mol. The partition coefficient log Pow has been estimated to be in the range 8.5 to 9.89 and the vapour pressure was calculated to be < 0.001 Pa at 20 °C.

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). With a molecular weight of 412.65 g/mol, absorption of neopentyl glycol dicaprate is in general anticipated in the gastrointestinal (GI) tract. The log Pow > 4 and the low water solubility suggest that the most favourable absorption mechanism is by micellar solubilisation, as this mechanism is of importance for highly lipophilic substances, which are poorly soluble in water (1 mg/L or less). However, absorption of neopentyl glycol dicaprate after oral administration is not predicted according to the “Lipinski Rule of Five” (Lipinski et al. (2001), refined by Ghose et al. (1999)), as two rules are not fulfilled: the substance has a high log Pow, which is above the given range of ‑0.4 to 5.6 and has more than 10 hydrogen bond.

Metabolism via enzymes and the microflora in the GI tract may occur prior to absorption. Following oral ingestion, fatty acid esters are hydrolysed by ubiquitously expressed esterases (Mattson and Volpenhein, 1972a). In general, it is assumed that the hydrolysis rate varies depending on the fatty acids/alcohol combinations, and the degree of esterification (Mattson and Volpenhein, 1969; Mattson and Volpenhein, 1972a, b). With regard to esters of polyols (i.e., alcohols with more than one hydroxyl (OH) function), a lower rate of enzymatic hydrolysis in the GI tract was shown for compounds with more than three ester groups (Mattson and Volpenhein, 1972a, b). The in vitro hydrolysis rates of pentaerythritol esters (i.e., compounds with four ester functions) was about 2000 times slower in comparison to glycerol esters (i.e., esters with three ester groups (Mattson and Volpenhein, 1972a, b)). Based on the literature available, neopentyl glycol dicaprate (a diester of medium 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. This is supported by a study measuring the pancreatic digestion of the structural related analogue substance heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol (CAS 68855-18-5, source substance 1), which shows a degradation of the ester of almost 90% within 4 h (FABES, 2012). Since the fatty acid moieties in the target substance neopentyl glycol dicaprate differ from those in heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol only in terms of their carbon-chain lengths (10 vs. 7 carbon-atoms), it is reasonable to assume a similar hydrolysis rate.

The physico-chemical characteristics of the hydrolysis products (e.g., physical form, water solubility, molecular weight, octanol/water partition coefficient and vapour pressure) are likely to be different from those of the parent substance before absorption into the blood takes place, and the predictions based upon the physico-chemical characteristics of the parent substance do not apply to the hydrolysis products (ECHA, 2017). The hydrolysis products are predicted to be absorbed in the GI tract. The highly lipophilic decanoic acid will primarily be absorbed by micellar solubilisation (Ramirez et al., 2001), whereas 2,2-dimethyl-1,3-propanediol is readily dissolved into the GI fluids and will be absorbed by passive diffusion because of its physico-chemical parameters (MW = 104.15 g/mol, log Pow= 0.12 at 25 °C and water solubility of 190 g/100 mL (OECD, 2013)).

Overall, systemic bioavailability of neopentyl glycol dicaprate and/or the respective hydrolysis products decanoic acid and 2,2-dimethyl-1,3-propanediol 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 g/mol favours dermal absorption, whereas a molecular weight > 500 g/mol may be too high for absorption (ECHA, 2017). As the molecular weight of neopentyl glycol dicaprate is 412.65 g/mol, dermal absorption of the substance cannot be excluded although it will not be favoured. This conclusion is supported by the physico-chemical properties. 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, 2017). As the water solubility of neopentyl glycol dicaprate is less than 1 mg/L and the log Pow > 6, dermal uptake of the substance is likely to be low.

If a substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2017). As neopentyl glycol dicaprate was tested to be not irritating to skin in an appropriate in vivo study, enhanced penetration of the substance due to local skin damage can be excluded. Moreover, based on a QSAR model (Dermwin v.2.02, September 2012), a calculated dermal absorption value of 2.87E-06 mg/cm²/event (very low) and, hence, a very low potential for dermal absorption has been predicted for neopentyl glycol dicaprate.

Overall, the calculated low dermal absorption potential, the low water solubility, the molecular weight, the high log Pow value and the fact that the substance is not irritating to skin indicate that dermal uptake of neopentyl glycol dicaprate in humans will likely be very low.

Inhalation

Neopentyl glycol dicaprate has a low vapour pressure of < 0.001 Pa at 20 °C and a low volatility. Under normal use and handling conditions, inhalation exposure and 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 or becomes otherwise airborne. 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, 2017). Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like neopentyl glycol dicaprate can be taken up by micellar solubilisation.

As discussed above, absorption after oral administration of neopentyl glycol dicaprate will mainly be driven by enzymatic hydrolysis of the ester groups and subsequent absorption of the hydrolysis products. As the presence of esterases and lipases in the mucus lining fluid of the respiratory tract is expected to be lower than in the GI tract, absorption of the hydrolysis products in the respiratory tract is considered to be less effective than in the GI tract.

In summary, systemic bioavailability of neopentyl glycol dicaprate or its hydrolysis products in humans is considered likely after inhalation of aerosols but is not expected to be higher than following oral exposure.

Distribution and accumulation

Distribution within the body through the circulatory system depends on the molecular weight, the lipophilic character and the 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).

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 accepted that substances with high log Pow values have long biological half-lives. The high log Pow value of > 5 indicates that neopentyl glycol dicaprate may have the potential to accumulate in adipose tissue (ECHA, 2017). However, as described in the section ‘Metabolism and excretion’ below, esters of polyols and fatty acids undergo esterase-catalysed hydrolysis, leading to the respective hydrolysis products fatty acids and polyol. The hydrolysis rate and degree will depend on the fatty acid chain length and degree of esterification. 2,2-dimethyl-1,3-propanediol is the first hydrolysis product of neopentyl glycol dicaprate. 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 hydrolysis product, decanoic acid, can be stored as triglyceride 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, there is a continuous turnover of fatty acids 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 data indicate that the hydrolysis products, 2,2-dimethyl-1,3-propanediol and decanoic acid, will be distributed in the organism. No bioaccumulation in adipose tissue of the parent substance neopentyl glycol dicaprate and its hydrolysis products is anticipated.

Metabolism and excretion

It has already been mentioned that esters of fatty acids are hydrolysed to the corresponding alcohol and fatty acids by esterases (Fukami and Yokoi, 2012). The first hydrolysis product, 2,2-dimethyl-1,3-propanediol, is likely to be conjugated by UDP-glucuronosyltransferases. The glucuronidated product will be excreted in the urine (Gessner, 1960). The second hydrolysis product, decanoic acid, is metabolised by stepwise β-oxidation, following the same pattern as other even-numbered, straight-chain, aliphatic acids (Bingham et al 2001; HSDB, 2013). It will, therefore, mainly be excreted by expired air as CO2, or stored as lipids in adipose tissue or used for further physiological processes, e.g., incorporation into cell membranes (Stryer, 1996).

References

Bingham, E.; Cohrssen, B.; Powell, C. H.; Patty's Toxicology. Volumes 1-9 5th ed. John Wiley &amp; Sons. New York, N. Y. (2001), p. 725

ECHA (2017). Chapter R.7c: Endpoint specific guidance, ECHA-17-G-11-EN, version 3.0, June 2017, European Chemicals Agency

FABES (2012). Investigation of the hydrolysis behaviour of Propane-1,2,3-triyl-3,5,5-trimethylhexanoate and 2,2-dimethyl-1,3-propandiolheptanoate, Testing facility: FABES Forschungs-GmbH, Munich,

Germany, Report no. 3635-12, Study sponsor: [Company name], Report date: 2012-12-20

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

Gessner PK, Parke DV, Williams RT (1960) Studies in detoxication. 80. The metabolism of glycols Biochem J 74: 1-5

Ghose et al. (1999). A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. J. Comb. Chem. 1 (1): 55-68.

HSDB (2013). Hazardous Substances Data Bank, Toxnet Home, National Library of Medicine, http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB (last accessed: 2019-04-29)

Lipinski et al. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Del. Rev. 46: 3-26.

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.

Mattson F.H. and Volpenhein R.A. (1972a). 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

Mattson F.H. and Volpenhein R.A. (1972b). Digestion in vitro of erythritol esters by rat pancreatic juice enzymes. J Lip Res 13, 777-782

OECD (2013): SIDS Neopentyl Glycol http://www.inchem.org/documents/sids/sids/126307.pdf (last accessed: 2019-04-29)

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

Stryer, L. (1994): Biochemie. 2nd revised reprint, Heidelberg; Berlin; Oxford: Spektrum Akad. Verlag.