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Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate (CAS No. 93803-89-5) 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 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics.

The substance 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate is a monocostituent substance based on the analytical characterization. The organic liquid is an ester of pentaerythritol and 3,5,5-trimethylhexanoic acid.It is poorly water soluble (< 0.15 mg/L, Frischmann, 2012) with a molecular weight of 697 g/mol, a log Pow of > 10 based on QSAR predictions (Hopp, 2011) and a vapour pressure of < 0.0001 Pa at 20 °C (Nagel, 2012).

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 substance 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate is 697 g/mol absorption of the molecule in the gastrointestinal tract is considered to be very limited.

Absorption after oral administration is also unexpected when the “Lipinski Rule of Five” (Lipinski et al. (2001), Ghose et al. (1999)) is applied to the substance 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate, as the substance fails two rules for good biovailability (molecular weight is > 500 and the logPow is > 5). Thus, oral absorption is not expected to be high either.

The log Pow of > 10 of the substance 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate suggests that the absorption of such a highly lipophilic substance may be limited by the inability to dissolve into gastrointestinal (GI) fluids. It 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). However, for large molecules the gastrointestinal absorption is not likely to occur.

In the gastrointestinal tract (GIT), metabolism prior to absorption may occur. In fact, after oral ingestion, fatty acid esters with glycerol (glycerides) are rapidly hydrolised by ubiquitously expressed esterases and almost completely absorbed (Mattsson and Volpnhein 1972a). However, lower rates of enzymatic hydrolysis in the GIT were shown for compounds with more than 3 ester groups (Mattson and Volpenhein, 1972a,b) . In vitro hydrolysis rate of a pentaerythritol ester was about 2000 times slower in comparison to glycerol esters (Mattson and Volpenhein, 1972a,b).

Moreover in vivo studies in rats demonstrated the 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). Based on this, it can be assumed that, on the one hand, the tetraester of pentaerythritol is not considered to be rapidly hydrolysed in the GIT by esterases and, on the other hand, absorption of the whole substance can be 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).

Pentaerythritol, being a highly water-soluble substance (25 g/L, OECD SIDS, 1998), will readily dissolve into the gastrointestinal fluids. DiCarlo et al., 1964 showed that 10 mg/kg C14-labled PE orally administered to mice was absorbed rapidly. Almost half of the administered dose left the gastrointestinal tract within 15 minutes. The available data on oral toxicity of structurally related analogue substances are also considered for assessment of oral absorption.

Acute oral toxicity studies were available for Isononanoic acid, mixed esters with dipentaerythritol, heptanoic acid and pentaerythritol (CAS # 84418-63-3) and Pentanoic acid, mixed esters with pentaerythritol, isopentanoic and isononanoic acid (CAS# 146289-36-3). The acute oral toxicity studies at concentrations of 2000 mg/kg bw in rats showed no signs of systemic toxicity (McCall, 1991 and Sterzel, 1991).

Repeated dietary administration (28-day) of the structurally related substances 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 of nC5/iC9 acids (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) .The analogue substance Pentanoic acid, mixed esters with pentaerythritol, isopentanoic and isononanoic acid (CAS # 146289-36-3) showed no systemic effects in the high-dose group (1000 mg/kg bw/day) in a 90-day repeated dose toxicity study (NOAEL = 1000 mg/kg bw/day; Müller, 1998). Therefore, if absorption of the intact parental compound or the respective metabolites occurred, it resulted in a low order of systemic toxicity. These results suggest that test substance is of low systemic toxicity, either due to low toxicity potency or by a low absorption in combination with a low systemic toxicity.

In summary, the above discussed physico-chemical properties of 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate and relevant data from available literature on fatty acid esters with more than 4 ester bonds do not indicate rapid hydrolysis before absorption of 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate the respective fatty acids and the polyols pentaerythritol. On the basis of the above mentioned data, a low absorption of the test material is predicted.

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 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate is 697 g/mol, a dermal absorption of the molecule is not likely.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012). A skin irritation study with Isononanoic acid, mixed esters with dipentaerythritol, heptanoic acid and pentaerythritol (CAS# 84418-63-3) showed that the substance was not considered as skin irritating in humans (McCall, 1991). Therefore, an enhanced penetration of the substance due to local skin damage is not expected.

Based on QSAR a dermal absorption value for 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate of 1.04E-09 mg/cm2/event (very low) was calculated (Episuite 4.1, DERMWIN 2.01, 2012). Based on this value, the substance has a very low potential for dermal absorption.

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, 2012). As the water solubility of 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate is less than 1 mg/L and log Pow is estimated to be > 10, dermal uptake is likely to be very low.

Overall, the calculated low 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 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate in humans is considered as very low.

Inhalation

2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate have a low vapour pressure of less than 0.0001 Pa at 20 °C 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 vapors, 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 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate can be taken up by micellar solubilisation.

Additionally, as described above, 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate can be hydrolysed enzymatically to the respective metabolites, for which absorption would be higher. However hydrolysis of fatty acid esters with more than 3 ester bounds is considered to be slow (Mattson and Volpenheim, 1972a). Therefore 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate will be slowly hydrolysed enzymatically to the respective metabolites and thus, their respiratory absorption is considered 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) in rats showed no effects of systemic toxicity. Thus, the acute toxicity of the substance is low and/or absorption after inhalation exposure is low. Overall, a systemic bioavailability of 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate in humans cannot be excluded, e.g. after inhalation of aerosols with aerodynamic diameters below 15 μm, but is not expected to be higher than following oral exposure.

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 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate may have the potential to accumulate in adipose tissue (ECHA, 2012).

Absorption is a prerequisite for accumulation within the body. As absorption of 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate is considered to be very low the potential of bioaccumulation is very low as well.

Nevertheless, as further described in the section metabolism below, esters of pentaerythritol and fatty acids may undergo slow esterase-catalyzed hydrolysis, leading to the cleavage products pentaerythritol and the fatty acids (3,5,5-trimethylhexanoic acid).

The log Pow of the first cleavage product pentaerythritol is < 0.3 and it is highly soluble in water (25 g/L) (OECD SIDS, 1998).Consequently, there is no potential for pentaerythritol to accumulate in adipose tissue. The other cleavage product, the 3,5,5-trimethylhexanoic acid, it is not highly likely to accumulate in adipose tissue.

Overall, the available information indicates that no significant bioaccumulation in adipose tissue of the parent substance and cleavage products can be 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 rates of absorption.

As discussed above, absorption of 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate is considered very low based on its physicochemical characterisation as poor water solubility and high molecular weight.

Esters of pentaerythritol and fatty acids can undergo chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products pentaerythritol and the fatty acids.

Only the potential cleavage products of 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate after chemical changes as a result of enzymatic hydrolysis, namely pentaerythritol and the fatty acids (3,5,5-trimethylhexanoic acid) , might be distributed within the body.

Pentaerythritol on the basis of its physicochemical properties will be distributed in aqueous fluids by diffusion through aqueous channels and pores. There is no protein binding and it is distributed poorly in fatty tissues (OECD SIDS, 1998).

3,5,5-trimethylhexanoic acid are also distributed in the organism and can be taken up by different tissues.

Overall, the available information indicates that the cleavage products, pentaerythritol and 3,5,5-trimethylhexanoic acid can 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). 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 gastrointestinal tract due to the high molecular weight and the complex structure of the molecule. Additionally, the hydrolysis of esterified alcohol with more than 3 ester groups is assumed to be slow as discussed above. In in vivo studies in rats, a decrease in absorption was observed with increasing esterification. For example, pentaerythritol tetraoleate ester had an absorption rate of 64% and 90%, when ingested at 25% and 10% of dietary fat, respectively while the absorption rate of 100% was observed for glycerol trioleate when ingested at 100% of dietary fat (Mattson and Nolen, 1972). In addition, it has been shown in-vitro that the hydrolysis rate of pentaerythritol tetraoleate was about 2000 times lower when compared with the hydrolysis rate of the triglyceride Glycerol trioleate (Mattson and Volpenhein, 1972a). Therefore for 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate the absorption rate is expected to be low.

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.

2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate is slowly hydrolysed to the corresponding alcohol (pentaerythritol) and fatty acids (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 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate is low as well.

Therefore, ester bond hydrolysis is expected to occur to a minor extent in the gastrointestinal tract and after systemic uptake. Nevertheless possible cleavage products should be discussed here.

The other cleavage product, 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 second cleavage product pentaerythritol is absorbed rapidly but excreted unchanged. DiCarlo et al. 1965 reported that 10 mg/kg C14-labled PE orally administered to mice was absorbed and excreted rapidly from the gastrointestinal tract. Almost half of the administered dose left the gastrointestinal tract within 15 minutes and 68% of the dose appeared as unchanged PE in the urine and faeces after 4 hours already.

Overall, the part of 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate that have become systemically available, might be hydrolysed and the cleavage products can be further metabolized.

Excretion

Low absorption is expected for 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate via the gastrointestinal tract, thus much of the ingested substance is assumed to be excreted in the faeces.

The other cleavage product, 3,5,5-trimethylhexanoic acid does not undergo beta oxidation due to an uneven methyl substitution. 3,5,5-trimethylhexanoic acid is expected to be excreted via bile or urine following omega- or omega1-chain hydroxylation and subsequent formation of various polar metabolites (WHO, 1998). The pentaerythritol is not metabolized but excreted unchanged via urine. 10 mg/kg C14-labled PE orally administered to mice was absorbed from the gastrointestinal tract rapidly and excreted via urine. Almost half of the administered dose left the gastrointestinal tract within 15 minutes and 68% of the dose appeared as unchanged pentaerythritol in the urine and faeces after 4 hours (DiCarlo et al., 1964). The amount found in faeces was assumed to be contamination from urine due to the setup of the metabolic cages. Additionally, Kutscher (1948) found 85-87% of unaltered PE in the urine of humans ingesting pentaerythritol.

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