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Basic toxicokinetics

There are no experimental studies available in which the toxicokinetic behaviour of 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates (CAS No. 85711-80-4) 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, 2012), an assessment of the toxicokinetic behaviour of the substance 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates 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 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates is a diester of C7 and C9 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 (≥ 0.8 ≤ 8.7 µg/L at 20 °C, pH = 6.3 (Seiler, 2015)) with a molecular weight range of 328.49 -384.59 g/mol, log Pow = 6.68 to 8.5 (Szymoszek, 2015) and a vapour pressure < 0.001 Pa at 20 °C (Szymoszek, 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, 2012).

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 328.49 - 384.59 g/mol, absorption of 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates is in general anticipated in the gastrointestinal tract. The log Pow > 4 suggests that 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates is favourable for absorption 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 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates after oral administration is not expected when the “Lipinski Rule of Five” (Lipinski et al. (2001), refined by Ghose et al. (1999)) is applied to 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates, 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.

Furthermore, metabolism prior to absorption 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). With regard to the polyol ester, 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 literature available, 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates, being 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. Furthermore, the result of the pancreatic digestion of the structural related substance Heptanoic acid, ester with 2,2-dimethyl-1,3–propanediol, 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, 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, 2012). However, the cleavage products are anticipated to be absorbed in the GI tract. The highly lipophilic fatty acids (covering C7 and isoC9 acid) will be absorbed by micellar solubilisation (Ramirez et al., 2001), whereas 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)).

Moreover, the available acute oral toxicity study performed with 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates and the structurally related substance Heptanoic acid, ester with 2,2-dimethyl-1,3 –propanediol consistently showed LD50 values > 2000 mg/kg bw. Furthermore, no systemic toxic effects were observed (Bouffechoux , 1995 and Doyle, 1996).

In the 28-day repeated dose toxicity study performed with the analogue substance Fatty acids, C7-8, triesters with trimethylpropane (CAS 189120-64-7), no toxicologically relevant effects were noted up to and including the highest dose level tested of 1000 mg/kg bw/day in male and female rats. In a further study, repeated dietary administration (28-day) of Fatty acids, C5-10 , esters with pentaerythritol (CAS 68424-31-7) did not induce any evidence of overt toxicity up to and including the highest dose level tested of 1450 or 1613 mg/kg bw/day in male and female rats, respectively (Brammer, 1993). 

Overall, systemic bioavailability of 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates 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, 2012). As the molecular weight of 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates is 328.49 - 384.59 g/mol, dermal absorption of the molecule cannot be excluded.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012). As 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates is not skin irritating in humans, enhanced penetration of the substance due to local skin damage can be excluded.

Based on a QSAR calculated dermal absorption value range of 8.40*10E-7 -5.84*E-5 mg/cm²/event (low) a low potential for dermal absorption is predicted for 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates (Dermwin v.2.01, 2011).

This assumption is supported by the physico-chemical properties of 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates: 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, 2012). As the water solubility is less than 1 mg/L and the log Pow > 6, dermal uptake of 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates 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 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates in humans is considered as very low.

Inhalation:

1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates has a low vapour pressure of <0.001 Pa at 20 °C (QSAR) thus being of low volatility (Szymoszek, 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, 2012). Lipophilic compounds with a log Kow > 4, that are poorly soluble in water (1 mg/L or less) like 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates 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 observation period. Likewise, another structural analogue substance (CAS 68424-31-7) did not induce mortality after inhalation of 5 mg/L.

Overall, systemic bioavailability of 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates 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 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates may have the potential to accumulate in adipose tissue (ECHA, 2012).

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 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates. Due to its physico-chemical properties (good 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 (C7 and isoC9 acid), especially C7, 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. However, as isoC9 acid is expected to be rather eliminated in form of more polar metabolites than being stored within the body, accumulation of this breakdown product is considered as unlikely.

Overall, the available information indicates that no significant bioaccumulation in adipose tissue of the parents substance and cleavage products 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, 2012).

1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates undergoes chemical changes as a result of enzymatic hydrolysis, leading to 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 different tissues. Similarly, 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, isoC9 acid is expected to be rather urinary eliminated in form of more polar metabolites in the urine.

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). Thus, 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates is expected to undergo hydrolysis within the human body. Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different sites 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 basically take place.

The first cleavage product, 2,2-dimethyl-1,3-propanediol, is likely to be conjugated by UDP-glucuronosyltransferases. The glucuronidated product is then going to be excreted in the urine (Gessner, 1960).

The second cleavage product, C7 fatty acid, is metabolised by stepwise beta-oxidation, following the same pattern as other odd- carbon number, straight-chain, aliphatic acids (Bingham et al 2001; HSDB, 2013). The remaining fatty acid moiety, isoC9 acid does not undergo beta oxidation due to an uneven methyl substitution. The metabolism is suspected to occur via omega- and omega-1-oxidation, which lead to formation of various polar metabolites capable of excretion in the urine (WHO, 1998).

Excretion

No data on excretion of 1,3-Propanediol, 2,2-dimethyl-, C5-9 carboxylates is available. Based on the enzymatic hydrolysis described above, fatty acids and 2,2-dimethyl-1,3-propanediol as breakdown products will occur in the body to a high extent. The fatty acid component 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 C7 fatty acid component is 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. In contrast, isoC9 acid is expected to be excreted via bile or urine following omega- or omega-1-chain hydroxylation and subsequent formation of various polar metabolites (WHO, 1998). With regard to the remaining cleavage products, the main route for elimination of the alcohol is renal excretion via the urine (Gessner, 1960).

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within the CSR.