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Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Fatty acids, tall-oil, triesters with trimethylolpropane (CAS No. 94581-09-6) 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 Fatty acids, tall-oil, triesters with trimethylolpropane was conducted based on 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, 2012) and taking into account further available information on the structurally related substances from which data was used for read-across to cover data gaps.

The UVCB substance Fatty acids, tall-oil, triesters with trimethylolpropane is an organic liquid. It is poorly water soluble (< 1 mg/L in the ester fraction, Scott, 2014) with a molecular weight of 398.62 - 927.51 g/mol, a log Pow 7.84- log Pow> 10 (Müller, 2014) and a vapour pressure < 0.0001 Pa at 20 °C (Szymoszek, 2014).

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 Fatty acids, tall-oil, triesters with trimethylolpropane is to great extent > 500 g/mol and therefore, absorption of the molecule in the gastrointestinal tract is not likely.

Absorption after oral administration can be assessed applying the “Lipinski Rule of Five” (Lipinski et al. (2001), refined by Ghose et al. (1999)). The Fatty acids, tall-oil, triesters with trimethylolpropane fails two rules for good bioavailability (the molecular weight is partially >500 and the log Pow is >5), and therefore oral absorption is not expected to be higher either.

The log Pow 7.84 -> 10 of the substance suggests that Fatty acids, tall-oil, triesters with trimethylolpropane is favourable for absorption by micellar solubilisation, as this mechanism is of importance for highly lipophilic substances (log Pow >4), who are poorly soluble in water (1 mg/L or less in the ester fraction).

In the gastrointestinal tract (GIT), metabolism prior to absorption via enzymes of the microflora 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 Volpenhein, 1972a). However, lower rate of enzymatic hydrolysis in the GIT were showed for compounds with more than three 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, probably the results of different rates of hydrolysis in the intestinal lumen (Mattson and Volpenhein, 1972c).

The available data on oral toxicity of structurally related substances are also considered for assessment of oral absorption. Three acute oral toxicity studies were available with the structurally related substances Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6), Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane (Formerly CAS 85005-23-8), and Fatty acids, C8-10(even), C14-18(even) and C16-18(even)-unsatd., triesters with trimethylolpropane (Formerly CAS 85186-89-6). At a concentration of 2000 mg/kg bw in rats no signs of systemic toxicity were seen (Sanders, 2002; Busschers, 1997; Kuszewski, 1996).

Four oral repeated dose toxicity studies conducted with the structurally related substances Fatty acids, C7-8, triesters with trimethylpropane (CAS 189120-64-7), Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7), Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS 146289-36-3), and Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6) were also considered for the assessment of oral absorption.

In the 28-day repeated dose toxicity study performed with the structurally related substances 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 of 1000 mg/kg bw/day in male and female rats. An increased amount of hyaline droplets (the main constituent of which is alpha-2µ-globulin) in the proximal cortical tubular epithelium was confirmed microscopically in the cytoplasm of the renal cortical tubular epithelial cells in male rats treated with 300 and 1000 mg/kg bw/day, respectively. However this phenomenon is widely accepted to be specific to the male rat and as such is considered to have no relevance to man (Trimmer, 2000). In a further study, repeated dietary administration (28-day) of Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7) to rats, did not induce any evidence of overt toxicity up to and including the high dose level of 1450 mg/kg bw/day for male rats and 1613 mg/kg bw/day for female rats (Brammer, 1993). Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS 146289-36-3) showed no systemic effects up to 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). A further 90-day oral toxicity study with Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6) displayed no toxicologically relevant effects and therefore the NOAEL was set as ≥ 1000 mg/kg bw/day (McRae, 2004).

The above described studies show that source substances which are structurally related to Fatty acids, tall-oil, triesters with trimethylolpropane revealed a low potential for toxicity after acute and repeated exposure, although no assumptions can be made regarding the absorption potential based on the experimental data.

In general, after oral ingestion, aliphatic esters of polyhydroxy alcohol (Polyol) and 1 – 6 fatty acids will undergo chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis. Trimethylolpropane (TMP, parental polyol) as well as the fatty acids will be formed, even if according to the available literature hydrolysis is not assumed to be rapid for pentaerythriol- and dipentaerythritol-ester and in general for polyol esters with more than three ester groups (multiple linked polyol esters) due probably to steric hindrance. In-vitro the hydrolysis rate of Pentaerythritol tetraoleate when compared with the hydrolysis rate of the triglyceride Glycerol trioleate was very slow (Mattson and Volpenhein, 1972). Since it is assumed that esters of polyols (pentaerythritol, dipentaerythritol and trimethylolpropane) have the same metabolic fate, TMP polyol esters are expected to be hydrolysed slowly as well.

The physico-chemical characteristics of the 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). However, also for both cleavage products, it is anticipated that they will be absorbed in the gastro-intestinal tract.

The highly lipophilic fatty acids will be absorbed by micellar solubilisation (Ramirez et al., 2001). A study by Mattson and Nolen (1972) determined the absorbability of the fatty acid moiety of the complete oleate esters of alcohols containing from one to six hydroxyl groups. The fatty acids of the compounds containing less than four ester groups were almost completely absorbed. As the number of ester groups was increased (erythritol and pentaerythritol tetraoleate and xylitol pentaoleate) the absorbability of the fatty acids decreased but was still present.

The TMP, on the basis of its physical-chemical properties (molecular weight 134.2 g/mol, log Pow -0.47, water solubility >100 mg/L, OECD SIDS, 2013), will readily dissolve into the gastrointestinal fluids.

In summary the above discussed physico-chemical properties of Fatty acids, tall-oil, triesters with trimethylolpropane and relevant data from available literature on fatty acid esters with more than three ester bonds do not indicate rapid hydrolysis before absorption of Fatty acids, tall-oil, triesters with trimethylolpropane. On the basis of the above mentioned data, a low absorption of the parent substance 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 Fatty acids, tall-oil, triesters with trimethylolpropane is 398.63-927.54 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). Read-across performed with the Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6) shows that the test substance is not considered as skin irritating in humans (Sanders, 2002). Therefore, an enhanced penetration of the substance due to local skin damage can be excluded.

Based on QSAR a dermal absorption value for Fatty acids, tall-oil, triesters with trimethylolpropane of between 2.72 E-06 and 8.28E-05 mg/cm2/event (low) was calculated (Episuite 4.1, DERMWIN 2.01, 2014). Based on this value, the substance has a 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 Fatty acids, tall-oil, triesters with trimethylolpropane is less than 1 mg/L (in the ester fraction) and log Pow is 7.84 -> 10, dermal uptake is likely to be very low.

The available data on dermal toxicity on structural related substances Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6) and Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) are also considered for assessment of dermal absorption.

An acute dermal toxicity studies was available for Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6) At a concentration of up to 2000 mg/kg bw in rats no signs of systemic toxicity were seen (Sanders, 2004). In the 90-day repeated dose toxicity study performed with the Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2), no toxicologically relevant effects were noted up to and including the highest dose level of 2000 mg/kg bw/day in male and female rats.

Overall, the calculated low dermal absorption potential, the low water solubility, the high molecular weight (>100), the high log Pow values and the fact that the substance is not irritating to skin implies that dermal uptake Fatty acids, tall-oil, triesters with trimethylolpropane in humans is considered as low.

Inhalation

Fatty acids, tall-oil, triesters with trimethylolpropane has 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 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 Pow > 4, that are poorly soluble in water (1 mg/L or less) like Fatty acids, tall-oil, triesters with trimethylolpropane can be taken up by micellar solubilisation.

Esterases present in the lung lining fluid may also hydrolyse the substance, hence making the resulting alcohol and acid available for respiratory absorption. Due to the high molecular weight of the substance, absorption is driven by enzymatic hydrolysis of the ester to the respective metabolites and subsequent absorption. However, as discussed above, hydrolysis of fatty acid esters with more than three ester bounds is considered to be slow (Mattson und Volpenhein, 1968, 1972a) and the possibility the test substance to be hydrolysed enzymatically to the respective metabolites and its relative absorption is considered to be low as well.

The available data on inhalation toxicity on the structurally related substances Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS 68424-31-7), Heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol (CAS 68855-18-5) and Fatty acids C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) are considered for the assessment of the respiratory absorption. An acute inhalation toxicity study was performed with Heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol, in which rats were exposed nose-only 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. In an acute inhalation toxicity study conducted with Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (Parr-Dobrzans, 1994) in rat bodyweight, bodyweight gain and lung weights for all treated animals were within normal limits and there were no gross pathological findings. In general, animals showed rapid recovery from effects seen (reversible and consistent clinical signs as hunched position, chromodacryorrhea, piloerection, stains around the nose and wet fur).The medium lethal concentration in the rat is considered to be in excess of 5.1 mg/L. In the 90-day repeated dose inhalation toxicity study performed with the Fatty acids, C5-9, tetraesters with pentaerythritol (Dulbey, 1992), no toxicologically relevant effects were noted up to and including the highest dose level of 0.5 mg/L in male and female rats.

Therefore, respiratory absorption of Fatty acids, tall-oil, triesters with trimethylolpropane is considered not to be higher than absorption through the intestinal epithelium.

Overall, a systemic bioavailability of Fatty acids, tall-oil, triesters with trimethylolpropane in humans is considered likely after inhalation but 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 of 7.84->10 implies that Fatty acids, tall-oil, triesters with trimethylolpropane may have the potential to accumulate in adipose tissue (ECHA, 2012).

Absorption is a prerequisite for accumulation within the body. As absorption of Fatty acids, tall-oil, triesters with trimethylolpropane is considered to be low, the potential of bioaccumulation is low as well.

Nevertheless, as further described in the section metabolism below, esters of trimethylolpropane and fatty acids will undergo esterase-catalyzed hydrolysis, leading to the cleavage products respective alcohol and the fatty acids.

The log Pow of the first cleavage product trimethylolpropane is -0.47 and it is highly soluble in water (>100 g/L) (OECD SIDS, 2013). Consequently, there is no potential for trimethylolpropane to accumulate in adipose tissue. The other cleavage products, the fatty acids, 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. 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 Fatty acids, tall-oil, triesters with trimethylolpropane is considered low based on its physico-chemical characterisation as poor water solubility and high molecular weight.

Esters of trimethylolpropane and fatty acids will undergo chemical changes as a result of slow enzymatic hydrolysis, leading to the cleavage products trimethylolpropane and the different fatty acids.

Only the potential cleavage products of Fatty acids, tall-oil, triesters with trimethylolpropane after chemical changes as a result of enzymatic hydrolysis, namely trimethylolpropane and the fatty acids, might be distributed within the body.

Trimethylolpropane, a small, water-soluble substance 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, 2013).

The 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).

Overall, the available information indicates that the cleavage products, trimethylolpropane and fatty acids can be distributed in the organism.

Metabolism

On the basis of the properties of the test substance characteristics a low absorption of Fatty acids, tall-oil, triesters with trimethylolpropane is predicted.

The hydrolysis of esterified alcohol with more than three ester groups is assumed to be slow as discussed above. This is supported by in vivo studies in rats, in which a decrease in absorption was observed with increasing esterification. For example, for the polyol ester Pentaerythritol tetraoleate ester an absorption rate of 64% and 90% (25% and 10% of dietary fat) was observed while an 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 another polyol ester (Pentaerythritol tetraoleate) was lower when compared with the hydrolysis rate of the triglyceride glycerol trioleate (Mattson and Volpenhein, 1972a).

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 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.

Fatty acids, tall-oil, triesters with trimethylolpropane are slowly hydrolysed to the corresponding alcohol (trimethylolpropane) and fatty acids by esterases. 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 first cleavage products, fatty acids are stepwise degraded by beta-oxidation based on enzymatic removal of C2 units 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. For the complete catabolism of unsaturated fatty acids such as oleic acid, an additional isomerization reaction step is required. The omega- and alpha-oxidation, alternative pathways for oxidation, can be found in the liver and the brain, respectively (CIR, 1987).

The other cleavage product trimethylolpropane due to its physico-chemical properties (low molecular weight, low log Pow, and solubility in water) is easily absorbed and can either remain unchanged or may further be metabolized or conjugated (e.g. glucuronides, sulfates, etc.) to polar products that are excreted in the urine (OECD SIDS, 2013).

Excretion

On the basis of the low absorption data the main route of excretion for Fatty acids, tall-oil, triesters with trimethylolpropane (parental substance) is expected to be excreted via faeces.

Assuming that hydrolysis for Fatty acids, tall-oil, triesters with trimethylolpropane (parental) takes place fatty acids and trimethylolpropane as breakdown products will occur in the body. 

Potential cleavage products, the fatty acid components (C18 unsatd.) will be metabolized for energy generation or stored as lipids in adipose tissue or used for further physiological properties e.g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1996). Therefore, the fatty acid components are 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.

The other cleavage product trimethylolpropane may either further be metabolized or conjugated to polar products (e.g. glucuronides, sulfates, etc.) or excreted unchanged via urine (OECD SIDS, 2013).