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EC number: 947-718-9 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
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Endpoint summary
Administrative data
Link to relevant study record(s)
Description of key information
Oral absorption
Absorption after oral ingestion is predicted to be limited as hydrolysis in the gastrointestinal tract is expected to occur. Resulting hydrolysis products are expected to be readily absorbed.
Dermal absorption
The high water solubility, the high molecular weight and the high log Pow value indicate that dermal uptake in humans is likely to be low.
Inhalative absorption
A systemic bioavailability in humans after inhalation exposure cannot be excluded, e.g. after inhalation of aerosols with aerodynamic diameters below 15 μm. The absorption rate is not expected to be higher than that following oral exposure.
Distribution and accumulation
The intact parent compound is not assumed to distribute throughout the body due to hydrolysis in the gastrointestinal tract. In contrast, wide distribution within the body is expected for the hydrolysis products diglycerol and isostearic acid. However, no significant bioaccumulation of both the parent substance and its anticipated hydrolysis products in adipose tissue is expected.
Metabolism
Esters of fatty acids are hydrolysed to the corresponding alcohol and fatty acids by ubiquitously expressed esterases. If hydrolysis occurs, a major metabolic pathway for fatty acids is the β-oxidation for energy generation. In contrast, diglycerol is absorbed rapidly and mainly excreted unchanged without metabolic transformation.
Excretion
Hydrolysis is expected in the gastrointestinal tract. Thus, the substance is considered to be excreted only to a minor extent. Following the potential hydrolysis of the parent molecule, the isostearic acid is not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as CO2. Diglycerol is not metabolised but excreted mainly unchanged via urine.
Key value for chemical safety assessment
- Bioaccumulation potential:
- no bioaccumulation potential
Additional information
Basic toxicokinetics
There are no studies available in which the toxicokinetic behaviour of the target substance Isooctadecanoic acid, mixed esters with oxybis[propanediol] has been investigated. Therefore, in accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) No. 1907/2006 (REACH) and with the ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2017), an assessment of the toxicokinetic behavior was conducted based on relevant available information. This comprises a qualitative assessment of the available substance-specific data on physico-chemical and toxicological properties and taking into account further available information on source substances from which data was used for read-across to cover data gaps.
Isooctadecanoic acid, mixed esters with oxybis[propanediol] is an UVCB substance composed of a variety of different esterification products of isooctadecanoic acid (i.e. isostearic acid, C18iso) and diglycerol although triglycerol is also present in small quantities. Its composition is characterised by variable concentrations of the different constituents. Mono- and diesters are only present in small amounts of < 5% and < 15%, respectively, while the major part of the substance is made up of tri- and tetraesters (> 40% and > 20%, respectively). Free polyglycerol, mainly diglycerol oxybis[propanediol], is contained in the substance to < 5%. The target substance is a liquid with a water solubility of < 0.15 mg/L at 20 °C, pH 6.5-6.6 (read-across from similar substance). The molecular weight of its various constituents ranges between 432.63 – 1232.02 g/mol, the log Pow was estimated to be > 10 (QSAR models: VEGA / ALogP version 1.0.0 and EPI Suite / KOWWIN version 1.68) and the calculated vapour pressure is < 0.0001 Pa at 20 °C (QSAR, ARChem SPARC. version 4.6).
General considerations on 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 absorption
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, 2017). As the molecular weight of the target substance ranges between 432.63 and 1232.02 g/mol, absorption in the gastrointestinal tract is expected only for the low molecular weight constituents, i.e. the monoester of isooctadecanoic acid and diglycerol. Only limited absorption after oral administration is also expected when the “Lipinski Rule of Five” (Lipinski et al. (2001), refined by Ghose et al. (1999)) is applied. The log Pow value of > 10 is well above the given range of ¬0.4 to 5.6 and the molecular weight of most of the constituents of Isooctadecanoic acid, mixed esters with oxybis[propanediol] is well above 500 g/mol. The log Pow of > 1 suggests that the high molecular weight constituents might also be absorbed 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). Although the water solubility of the complete target substance has been measured to be < 0.15 mg/L, it is expected that the high molecular weight constituents are much less water soluble and hence exhibit an even higher log Pow.
The potential of a substance to be absorbed from the gastrointestinal tract (GIT) may be influenced by chemical changes taking place in gastrointestinal fluids, for instance due to metabolism by gastrointestinal flora or by enzymes released into the gastrointestinal tract or by acid-catalysed chemical hydrolysis under the low-pH conditions of the stomach. This is especially relevant for substances with a high solubility in water. However, the rate of hydrolysis can be expected to be limited for lipophilic substances. The changes will alter the physico-chemical characteristics of the substance and hence predictions based upon the physico-chemical characteristics of the parent substance may in some cases no longer apply (ECHA, 2017). After oral ingestion, fatty acid esters with glycerol are rapidly hydrolised by ubiquitously expressed esterases and almost completely absorbed (Mattsson and Volpenhein, 1972a; Michael and Coots, 1971). On the contrary, a lower rate of enzymatic hydrolysis in the GIT was demonstrated for compounds with more than 3 ester groups (Mattson and Volpenhein, 1972a,b) as is the case for the target substance containing mostly tri- and tetraesters.
As a consequence of the hydrolysis of fatty acid esters, the respective alcohol as well as the fatty acids are formed. In the case of the target substance the predicted metabolites are therefore isooctadecanoic acid (i.e. isostearic acid, C18iso) and diglycerol as well as triglycerol in small amounts. This assumption was confirmed by an in vitro hydrolysis test performed with the source substance Oleic acid, monoester with oxybis(propanediol) (CAS No. 49553-76-6) in intestinal fluid simulant, which was conducted according to EFSA Note for Guidance for Food Contact Materials Annex 1 to Chapter III “Measurement of hydrolysis of plastics monomers and additives in digestive fluid simulants (30/07/2008)” (Jensen, 2013). After incubation with the intestinal fluid, the remaining content of Oleic acid, monoester with oxybis(propanediol) was extracted and measured by gas chromatography. The in vitro experiment demonstrated that approximately 94% of the total oleic acid, monoester with oxybis(propanediol) was hydrolysed by intestinal fluid simulant within 4 hours at 37 °C (Jensen, 2013). Both hydrolysis products (oleic acid and diglycerol) are anticipated to be rapidly absorbed in the gastro-intestinal tract. The highly lipophilic fatty acids are absorbed by micellar solubilisation (Ramirez et al., 2001), whereas diglycerol is readily dissolved into the gastrointestinal fluids and absorbed from the gastrointestinal tract. Moreover, data from metabolism studies with fatty acid-labelled polyglycerol esters have shown that more than 90% of triglycerol moieties from respective esters were absorbed. Furthermore, it was shown that hydrolysis of the polyglycerol esters occurred to a large extent prior to absorption (Michael and Coots, 1971).
Therefore, hydrolysis of the target substance, i.e. the parent compound, is expected resulting in low systemic exposure to the parent compound itself, but absorption of metabolites, isooctadecanoic acid and diglycerol, from the gastrointestinal tract is expected to be high.
The available data on acute and repeated dose oral toxicity are also considered for assessment of the oral absorption. Acute oral toxicity investigations have been performed with the source substances Hexanedioic acid, mixed esters with decanoic acid, 12-hydroxyoctadecanoic acid, isostearic acid, octanoic acid, 3,3'-oxybis[1,2-propanediol] and stearic acid (CAS No. 130905-60-1), Isooctadecanoic acid, ester with oxybis[propanediol] (CAS No. 73296-86-3), 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS No. 63705-03-3) and di(isooctadecanoic) acid, diester with oxydi(propanediol) (CAS No. 67938-21-0). A single administration of 2000 mg/kg bw (Sasol, 1990a) and 5000 mg/kg bw (BASF, 1988a; Clariant, 1980) test material to male and female rats did not induce any mortality or any signs of systemic toxicity. The same result has been obtained using male and female mice (Lasem, 1990a) which tolerated a single dose of > 5000 mg/kg bw without signs of overt toxicity. Moreover, in a subacute repeated dose toxicity study performed with the source substance Hexanedioic acid, mixed esters with decanoic acid, 12-hydroxyoctadecanoic acid, isostearic acid, octanoic acid, 3,3'-oxybis[1,2-propanediol] and stearic acid (CAS No. 130905-60-1) and a combined repeated dose and reproduction / developmental screening with source substance 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS No. 63705-03-3) oral exposure of male and female rats over a period of 4 weeks did not yield any toxicologically relevant adverse effects and hence resulted in NOAEL values of ≥ 1000 mg/kg bw/day, corresponding to the highest doses tested (Sasol, 1990f; BASF, 2013a). However, it must be noted that the lack of systemic toxicity observed in the studies can also be attributed to a low degree of absorption. The lack of systemic toxicity is therefore only an indicator rather than a proof of no or a low toxicity after oral exposure. Based on these results, no final conclusions on the oral absorption potential of the target substance Isooctadecanoic acid, mixed esters with oxybis[propanediol] is possible.
In summary, the physico-chemical properties of the target substance discussed above and experimental data on in vitro hydrolysis and oral toxicity obtained with adequate source substances and further supported by literature data do indicate hydrolysis to isooctadecanoic acid and diglycerol before absorption in the GIT can take place. On the basis of the above mentioned data, absorption of the test material in the gastrointestinal tract after oral exposure is not expected to occur in a significant amount either due to a lack of absorption or due to hydrolysis. The hydrolysis products, however, are predicted be readily absorbed.
Dermal absorption
Similar to oral absorption, dermal absorption is favoured for small molecules. In general, a molecular weight below 100 g/mol favours dermal absorption, while a molecular weight above 500 g/mol may be considered too large (ECHA, 2017). As the molecular weight of the target substance ranges between 432.63 and 1232.02 g/mol, a dermal absorption at least for the low molecular weight mono-ester constituent cannot be excluded.
If a substance is irritating or corrosive to skin, damage to the skin surface may enhance penetration (ECHA, 2017). To this regard primary skin irritation studies conducted with the structurally related source substances Isooctadecanoic acid, ester with oxybis[propanediol] (CAS No. 73296-86-3), Hexanedioic acid, mixed esters with decanoic acid, 12-hydroxyoctadecanoic acid, isostearic acid, octanoic acid, 3,3'-oxybis[1,2-propanediol] and stearic acid (CAS No. 130905-60-1) and 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS No. 63705-03-3) showed no sign of skin irritation (Sasol, 1990c) or only minor erythema (Lasem, 2001; BASF, 1988b). Therefore, also the target substance is not considered to be irritating or corrosive to skin in humans and an enhanced penetration of the substance due to local skin damage can be excluded.
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, 2017). As the water solubility of the target substance is < 0.15 mg/L and the log Pow is estimated to be > 10, dermal uptake is considered to be low. However, it cannot be excluded and finally assessed based on these physico-chemical parameters alone. The low potential for dermal absorption is also supported by QSAR calculations of the dermal absorption rate. Calculations with the Episuite 4.1, DERMWIN 2.02 tool yielded dermal permeability constants Kp between 8.45E-04 cm/h (very low) and 25.9 cm/h (very low) for the high molecular weight and low molecular weight constituents, respectively. These results a dermal absorption rate of less than 1%. Based on these values, Isooctadecanoic acid, mixed esters with oxybis[propanediol] has a low potential for dermal absorption.
Overall, the calculated low dermal absorption potential, the high molecular weight (> 100 g/mol) and the high log Pow value of > 10 lead to the conclusion that dermal uptake of Isooctadecanoic acid, mixed esters with oxybis[propanediol] in humans is limited.
Inhalation absorption
Isooctadecanoic acid, mixed esters with oxybis[propanediol] 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. Particles deposited in the nasopharyngeal/thoracic region will mainly be cleared from the airways by the mucocilliary mechanism and will be swallowed subsequently (ECHA, 2017).
Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) can be taken up by micellar solubilisation. Moreover, esterases present in the lung lining fluid may also hydrolyse the substance, hence making the resulting isooctadecanoic acid and diglycerol available for respiratory absorption. As discussed above, due to the high molecular weight of the parent substance, absorption is mainly driven by enzymatic hydrolysis of the parent compound. The respective metabolites are then subsequently readily absorbed.
Overall, a systemic bioavailability of the target substance in humans is considered likely after inhalation of aerosols with aerodynamic diameters below 15 μm.
Accumulation and distribution
Distribution of a compound within the body through the circulatory system depends on the physico-chemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. 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. Furthermore, the concentration of a substance in blood or plasma and subsequently its distribution depends on the rates of absorption. 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 > 10 of Isooctadecanoic acid, mixed esters with oxybis[propanediol] is therefore indicative of the potential to accumulate in adipose tissue (ECHA, 2017). However as the absorption of the parent substance is considered to be very low as a consequence of hydrolysis in the gastric juice, the potential of its bioaccumulation is very low.
As discussed in length under oral absorption, esters of polyglycerols, e.g. diglycerol, and fatty acids will undergo esterase-catalysed hydrolysis, leading to the hydrolysis products polyglycerol, e.g. diglycerol, and fatty acids. Therefore, an assessment of distribution and accumulation of the hydrolysis products is considered more relevant. Diglycerol is a rather small substance (MW = 166.18 g/mol) of high water solubility and log Pow < 0 (Danish QSAR database, 2013). It will be distributed in aqueous compartments of the organism by diffusion through aqueous channels and pores and may also be taken up by different tissues (Michael and Coots, 1971). There is no protein binding assumed and it is distributed poorly in fatty tissues. Consequently, there is no potential to accumulate in adipose tissue. After being absorbed, fatty acids are (re-)esterified along with other fatty acids into triglycerides and released in chylomicrons into the lymphatic system. Fatty acids of carbon chain lengths ≤ 12 may be transported directly to the liver via the portal vein as the free acid bound to albumin, instead of being re-esterified. Chylomicrons are transported in the lymph to the thoracic duct and subsequently to the venous system. On contact with the capillaries, enzymatic hydrolysis of chylomicron triacylglycerol fatty acids by lipoprotein lipase takes place. Most of the resulting fatty acids are taken up by adipose tissue and re-esterified into triglycerides for storage. Triacylglycerol fatty acids are likewise taken up by muscle and oxidized to derive energy or they are released into the systemic circulation and returned to the liver, where they are metabolised, stored or re-enter the circulation (IOM, 2005; Johnson, 1990; Johnson, 2001; Lehninger et al., 1998; NTP, 1994; Stryer, 1996; WHO, 2001). There is a continuous turnover of stored fatty acids, as they are constantly metabolised to generate energy and then excreted as CO₂. Accumulation of fatty acids takes place only if their intake exceeds the caloric requirements of the organism.
Therefore, the available information indicates that no significant bioaccumulation in adipose tissue of the parent substance and its hydrolysis products is anticipated.
Metabolism
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 are hydrolysed already in the gastro-intestinal fluids – either as consequence to enzymatic activity or by an acid-catalysed purely chemical process. In contrast, esters which are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before they are transported to the liver where hydrolysis will basically take place. Thus, Isooctadecanoic acid, mixed esters with oxybis[propanediol] is expected to be hydrolysed to diglycerol and isooctadecanoic acid. The hydrolysis of fatty acid esters containing more than 3 ester groups is assumed to be slow as already discussed above. In vivo studies in rats demonstrated a decrease in absorption with increasing esterification degree. For example, for Pentaerythritol tetraoleate an absorption rate of 64% and 90% (25% and 10% of dietary fat) was observed, respectively, 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 pentaerythritol tetraoleate was lower when compared with the hydrolysis rate of the triglyceride Glycerol trioleate (Mattson and Volpenhein, 1972a).
In an in vitro enzymatic digestion method using fresh pancreatic juice plus bile described by King et al. (1971), fatty acid labelled polyglycerol esters were studied. Thin layer chromatography (TLC) and radio-assay procedures were used to determine the distribution of 14C among the products of digestion. After enzymatic digestion of an oleate-labelled polyglycerol ester, 89 - 92% of the recovered 14C was present as free oleic acid, whereas the remaining 8 and 11% was unhydrolysed or partially hydrolysed starting material. Hydrolysis of the eicosanoate-labelled polyglycerol ester was much slower than the oleate ester and only 21% of the 14C was recovered as free eicosanoic acid (Michael and Coots, 1971). This finding is further supported by the in vitro experiment conducted with the source substance Oleic acid, monoester with oxybis(propanediol) (CAS No. 49553-76-6). The study shows that approximately 94% of the substance is hydrolysed by an intestinal fluid simulant within 4 h at 37 °C. The main isomer of Oleic acid, monoester with oxybis(propanediol) is fully hydrolysed within 1 h of hydrolysis, whereas other positional isomers of the test item have a lower rate of hydrolysis (Jensen, 2013).
After hydrolysis of the target substance, the first hydrolysis product isooctadecanoic acid can be expected to be metabolised by oxidative processes typical for fatty acids. Fatty acids are degraded by mitochondrial β-oxidation which takes place in most animal tissues and uses an enzyme complex for a series of oxidation and hydration reactions, resulting in the cleavage of acetate groups in the form of acetyl-CoA. The alkyl chain length is reduced by 2 carbon atoms during each β-oxidation cycle. Alternative pathways for oxidation can be found in the liver (ω-oxidation) and the brain (α-oxidation). Iso-fatty acids such as isooctadecanoic acid have been found to be activated by acyl coenzyme A synthetase of rat liver homogenates and to be metabolised to a large extent by ω-oxidation. Each C2-unit resulting from β-oxidation enters the citric acid cycle as acetyl-CoA, through which they are completely oxidized to CO₂ (CIR, 1983, 1987; IOM, 2005; Lehninger, 1998; Stryer, 1996; Matulka, 2009). The second hydrolysis product diglycerol is assumed to be rapidly excreted and metabolism via cleavage of the ether bond to glycerol will not occur as for the related triglycerol (Michael and Coots, 1971). In this study the authors concluded that polyglycerols like triglycerol were not catabolized and that ether linkages within the molecule are inert of normal enzymatic hydrolysis.
The potential metabolites following enzymatic degradation of the target substance were also predicted using the QSAR OECD Toolbox (OECD, 2017). This QSAR tool predicts the primary and secondary metabolites of the parent compound that may result from enzymatic activity in the liver, in the skin and by the micro-flora in the GIT. Between 0 and 19 hepatic metabolites, depending on the exact structure taken for the prediction, and between 0 and 6 dermal metabolites were predicted for the representative constituents of Isooctadecanoic acid, mixed esters with oxybis[propanediol]. The number of potential metabolites decreases with increasing esterification degree. Thus, for the most complex representative structure accounted for in the profiling exercise, i.e. the isooctadecanoic acid tetraester with diglycerol, only acid-catalysed hydrolysis is predicted but no enzymatic metabolism of the parent compound. This result is fully in line with the general trend of enzymatic hydrolysis rates already discussed above.
As can be expected, the typical hepatic metabolic transformation of the lower molecular weight constituents is the cleavage of the ester bonds yielding the isooctadecanoic acid and diglycerol or esters with reduced esterification degree. Moreover, introduction of a hydroxyl function at the branched end of the isooctadecanoic acid moieties is also predicted, accounting for additional oxidation processes. Finally, oxidation of diglycerol to structures containing an additional carboxyl group is predicted. Metabolites formed in the skin are hydrolysis products, i.e. isooctadecanoic acid and diglycerol. No addition of a hydroxyl groups to any alkyl chain is calculated. Following the first reaction step, hydrolysis products may be metabolised further. No metabolite resulting from cleavage of the ether bond in diglycerol is anticipated. The resulting liver and skin metabolites are the products of α-, β- or ω-oxidation (i.e. addition of a hydroxyl group). In the case of ω-oxidation, it is followed by further oxidation to the aldehyde, which is then oxidised to the corresponding carboxylic acid. The ester bond may also remain intact, in which case a hydroxyl group is added to an alkyl chain. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II enzymes. The metabolites formed in the skin are expected to enter the blood circulation and have the same fate as the hepatic metabolites. Between 0 and 152 metabolites were predicted to result from all kinds of microbiological metabolism for the four representative constituents considered. Again, the number of metabolites decreases with increasing esterification degree and hence for the tri- and tetra-esters, no metabolites originating from microbial processes are predicted as the molecules become too large to be bioavailable. This rather high number of potential metabolites calculated for the mono- and di-esters includes many minor variations in the C-chain length and number of carbonyl and hydroxyl groups, reflecting the diversity of many microbial enzymes identified. Not all of these reactions are expected to take place in the human GIT. In conclusion, the results of the OECD Toolbox simulation support the information on metabolism routes retrieved in the literature.
Excretion
As a consequence of the enzymatic hydrolysis anticipated for Isooctadecanoic acid, mixed esters with oxybis[propanediol], it is considered to be excreted only to a minor extent. Diglycerol is assumed to be metabolised only to a certain degree and therefore to be excreted almost quantitatively in the urine (Michael and Coots, 1971). Isooctadecanoic acid will be metabolised for energy generation or stored as lipids in adipose tissue or used for further physiological processes, e.g. incorporation into cell membranes (Lehninger, 1998; Stryer, 1996), as discussed in detail above. Therefore, the fatty acid component of the parent compound is not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as CO2 or stored.
A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and in the CSR.
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