Isononanoic acid, mixed esters with dipentaerythritol, heptanoic acid and pentaerythritol

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol (CAS 84418-63-3, UVCB) has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behavior of the substance 3,5,5 trimethylhexanoic acid, mixed esters with dipentaerythritol, was conducted to the extent that can be derived from the relevant available information on physico-chemical and toxicological characteristics.

 

The substance 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol is an organic liquid composed of esters of dipentaerythritol and C9 branched fatty acids which meets the definition of an UVCB substance based on the analytical characterization. It is poorly water soluble (< 10 µg/L at 20 °C, pH=6.3, Seiler, 2015) with a molecular weight of 815.17-1095.61 g/mol, a log Pow >10 based on QSAR predictions (Szymoszek, 2015) and a vapour pressure of < 0.0001 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 g/mol are favorable for oral absorption (ECHA, 2012). As the molecular weight of Isononanoic acid, mixed esters with dipentaerythritol ranges from 815.17-1095.61 g/mol, absorption of the parent substance is considered to be very limited in the gastrointestinal tract (GIT).

 

Furthermore, absorption after oral administration is also unexpected when the “Lipinski Rule of Five” (Lipinski et al. (2001), refined by Ghose et al. (1999)) is applied to 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol, as the substance fails three rules for good bioavailability (more than 10 H-bond acceptors, a molecular weight > 500 and a log Pow is > 5).

 

Moreover, the log Pow of >10 suggests that the absorption of 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol may be limited by the inability to dissolve into gastrointestinal (GI) fluids. However, absorption might be enhanced 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).

 

In the GIT, metabolism prior to absorption may occur. In general, after oral ingestion, fatty acid esters with glycerol (glycerides) have been shown to be rapidly hydrolysed by ubiquitously expressed esterases followed by almost complete absorption (Mattsson and Volpenhein, 1972a). However, a lower rate of enzymatic hydrolysis in the GIT was shown for compounds with more than 3 ester groups (Mattson and Volpenhein, 1972 a,b). In vitro hydrolysis rate of pentaerythritol ester was about 2000 times slower in comparison to glycerol esters (Mattson and Volpenhein, 1972 a,b). Moreover, in vivo studies in rats demonstrated incomplete absorption of the compounds containing more than three ester groups. This decrease became more pronounced as the number of ester groups increased (Mattson and Volpenhein, 1972c). In vivo studies in rats showed that the hexaester of sorbitol is not absorbed (Mattson and Nolen, 1972). Based on this, it can be assumed that 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol is not considered 1) to be rapidly hydrolysed in the GIT by esterases based on the higher degree of esterification (more than 3 ester groups) and 2) that absorption of the parent substance is considered to be very low.

Even though hydrolysis is assumed to be slow, it needs to be addressed that the physico-chemical characteristics of the theoretical cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) will 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).

Therefore it has to be considered that absorption of the products of the slow and stepwise hydrolysis, namely dipentaerythritol (diPE, parental Polyol, MW 254 g/mol, log Pow -2.0, water solubility 3000 g/L) and the fatty acid moity (3,5,5-trimethylhexanoic acid) might occur in the GIT.

 

In addition to the physico-chemical properties, the available data on oral toxicity of structurally related analogue substances are also considered for assessment of oral absorption.

An acute oral toxicity study was available for the structurally related substance 3,5,5-trimethylhexanoic acid hexaester with dipentaerythritol (CAS 84418-63-3, Mono), in which rats showed no signs of systemic toxicity after gavage of 2000 mg/kg bw (MaCall, 1991). Repeated dietary administration over 28 days of the structurally related substance Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7) to rats, up to and including a dose level of 1450 mg/kg bw/day for male rats and 1613 mg/kg bw/day for female rats, did not produce any evidence of overt toxicity (Brammer, 1993). The structurally related substances Dipentaerythritol ester with fatty acids C5- and C9iso (CAS 647028-25-9) showed no systemic effects in two 28-day studies and the NOAEL was set at 1000 mg/kg bw/day (Jones, 2000). Therefore, if absorption of either the parental compound or the respective metabolites occurred, it resulted in a low order of systemic toxicity. Most of the analogue substances are tetraesters, having a lower molecular weight in comparison to the target substance 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol. Therefore, higher rates of hydrolysis to the respective fatty acids and the polyol pentaerythritol has to be assumed for the analogue substances. Absorption of the analogue substance is therefore assumed to be higher than the absorption of the target substance 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol. These results suggest that the target substance is of low systemic toxicity, either due to low toxic potency or to low absorption in combination with low systemic toxicity.

 

In summary, the above discussed physico-chemical properties of 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol do not indicate rapid hydrolysis of the parent substance to the respective fatty acid and polyol dipentaerythritol moieties prior to absorption. Thus, on the basis of the above discussed data, low oral absorption potential of 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol is assumed.

 

Dermal

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 g/mol favors dermal absorption, above 500 g/mol the molecule may be too large (ECHA, 2012). As the molecular weight of 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol is in the range of 815.17-1095.61 g/mol, dermal absorption is considered to be limited.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012). No studies assessing skin irritation are available for 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol (UVCB). Taken into account the available read-across data from the monoconstituent 3,5,5-trimethylhexanoic acid hexaester with dipentaerythritol (CAS 84418-63-3, Mono), the target substance is not considered as skin irritating (McCall, 1991). Therefore, enhanced penetration of the substance due to local skin damage is not expected.

Applying QSAR algorithms, a dermal absorption value of 1.46E-10 to 8.45E-15 mg/cm2/event was calculated for 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol (Episuite 4.1, DERMWIN 2.01, 2015) indicating a very low dermal absorption potential. 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 limit absorption across the skin, and the uptake into the stratum corneum itself is slow. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis (ECHA, 2012). As the water solubility of 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol is < 10 µg/L and the log Pow is estimated to be >10, dermal uptake is likely to be very low.

 

Overall, the calculated dermal absorption potential, the low water solubility, the high molecular weight (>100 g/mol), the high log Pow values and the fact that the substance is not irritating to skin implies that dermal uptake of 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol can be considered as very low.

 

Inhalation

The substance 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol has a low vapour pressure <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 not expected.

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 Pow > 4, that are poorly soluble in water (1 mg/L or less) like 3,5,5 -trimethylhexanoic acid, mixed esters with dipentaerythritol can be taken up by micellar solubilisation.

Additionally, as described above, 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol might theoretically be hydrolysed enzymatically to the respective metabolites, for which absorption would be higher. However, as discussed above, hydrolysis of fatty acid esters with more than 3 ester bounds is considered to be slow (Mattson and Volpenhein, 1972a) and hence, respiratory absorption of either the parent or metabolites is regarded to be low.

 

The available data on inhalation toxicity of the structurally related substances, Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7, Parr-Dobrzansk, 1994) and Fatty acids, C5-9, mixed esters with dipentaerythritol and pentaerythritol (CAS 85536-35-2, Parr-Dobrzansk, 1994) showed no effects of systemic toxicity in rats. Thus, acute toxicity and/or absorption of the test substance following inhalation is low.

 

Overall, systemic bioavailability of 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol following inhalation is considered to be low but cannot be excluded after inhalation of aerosols with aerodynamic diameters below 15 μm. 

 

Accumulation

Highly lipophilic substances in general tend 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 >10 implies that 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol may have the potential to accumulate in adipose tissue (ECHA, 2012).

Absorption is a prerequisite for accumulation within the body. As absorption of 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol is considered to be very low following the oral, dermal and inhalation route, it is not expected to bioaccumulate within the human body.

 

Nevertheless, as described below in the section metabolism, esters of dipentaerythritol and fatty acids may undergo slow esterase-catalyzed hydrolysis, leading to the cleavage products dipentaerythritol and the respective fatty acid moieties.

The log Pow of the first cleavage product dipentaerythritol is -2.0 and it is highly soluble in water (3000 g/L) (OECD SIDS, 2009). Consequently, there is no potential for dipentaerythritol to accumulate in adipose tissue. In general, fatty acids can be stored as triglycerides in adipose tissue depots or be incorporated into cell membranes. However, as 3,5,5-trimethylhexanoic 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 parent 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).

Furthermore, the concentration of a substance in blood or plasma and subsequently its distribution is dependent on the rate of absorption.

 

As discussed above, absorption of 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol is considered very low based on its physico-chemical properties such as poor water solubility and high molecular weight.

As data from acute and repeated dose toxicity available for the target and source substances show no signs of systemic toxicity, the lack of toxicity might be due to either low toxicity and/or to low distribution of 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol within the body. 

Regarding the possibility that 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol might be slowly hydrolysed, distribution of the potential resulting cleavage products, namely dipentaerythritol and the respective fatty acid moieties might be distributed within the body.

 

Dipentaerythritol, on the basis of its physico-chemical properties, is expected to be distributed in aqueous fluids by diffusion through aqueous channels and pores whereas protein binding is not expected. Moreover, dipentaerythritol is distributed poorly in fatty tissues (OECD SIDS, 2009).

In general, fatty acid moieties are considered to be distributed in the organism and can be taken up by different tissues. Furthermore, they can be stored as triglycerides in adipose tissue depots (Masoro 1977). However, 3,5,5-trimethylhexanoic acid is expected to be rather urinary eliminated in form of more polar metabolites in the urine.

 

Overall, the available information indicates negligible distribution of the parent substance but possible distribution of the breakdown products if hydrolysis occurs.

 

Metabolism

Esters of fatty acids are generally known to be hydrolysed to the corresponding alcohol and fatty acid moieties 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. However, as discussed previously, it is not anticipated that enzymatic hydrolysis of the parent substance is taking place in the GIT due to the high molecular weight and the higher degree of esterification.

 

Thus, 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol is expected to be slowly hydrolysed to the corresponding alcohol (dipentaerythritol) and the respective fatty acid moieties (3,5,5-trimethylhexanoic acid)  by esterases. It was shown in-vitro that the hydrolysis rate for another polyol ester (pentaerythritol tetraoleate) was lower when compared with the hydrolysis rate of the triglyceride glycerol trioleate (Mattson and Volpenhein, 1972). Thus, it is assumed that the hydrolysis rate for 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol is even lower in comparison with pentaerythritol esters.

Therefore, ester bond hydrolysis is expected to occur to a minor extent in the GIT.

 

Nevertheless possible cleavage products should be discussed here as hydrolysis cannot be excluded totally. The fatty acid moiety, 3,5,5-trimethylhexanoic 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). The remaining breakdown product, the alcohol moiety dipentaerythritol is considered to be further metabolized/ conjugated to a more polar structure which is capable for urinary excretion.

 

Overall, due to its high molecular weight and complex structure, absorption of 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol is not likely to occur and thus, no extensive metabolism but rather excretion is expected. Possible products of hydrolysis are expected to be metabolized leading to formation of polar metabolites which can be eliminated.

 

Excretion

Low absorption is expected for 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol via the GIT, thus much of the ingested substance is assumed to be excreted in the faeces.

 

However, if hydrolysis of the parent takes place, 3,5,5-trimethylhexanoic 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).

The remaining metabolite, dipentaerythritol may either be further metabolized or conjugated to a more polar structure which is capable for urinary excretion.

 

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