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EC number: 262-108-6 | CAS number: 60209-82-7
- 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
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- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
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- Nanomaterial catalytic activity
- Endpoint summary
- Stability
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- 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
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- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
Description of key information
There are no experimental studies available in which the toxicokinetic behaviour of isodecyl pivalate (CAS 60209-82-7) has been assessed.
In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2008), assessment of the toxicokinetic behaviour of the substance is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physicochemical and toxicological properties according to the relevant Guidance (ECHA, 2008) and taking into account available information on the analogue substances from which data was used for read-across to cover data gaps.
The physicochemical properties and molecular weight of isodecyl pivalate suggest oral absorption. However, the substance is anticipated to undergo enzymatic hydrolysis in the gastrointestinal tract and absorption of the ester hydrolysis products is also relevant. The absorption rate of the hydrolysis products is considered to be high. Due to the limited information available, absorption via inhalation is assumed to be as high as via the oral route in a worst case approach. The dermal absorption potential of isodecyl pivalate is predicted to be low. The hydrolysis products of isodecyl pivalate are anticipated to distribute systemically. There is no indication that the substance isodecyl pivalate is activated to reactive intermediates under the relevant test conditions. The branched C10 fatty acid resulting from the oxidation of the corresponding alcohol and the highly branched pivalic acid resulting from hydrolysis of the ester, are unlikely to be used for energy generation and storage, since saturated aliphatic, branched-chain acids are described to be subjected to omega-oxidation due to steric hindrance by the methyl groups at uneven position, which results in the formation of various diols, hydroxyl acids, ketoacids or dicarbonic acids. These metabolites may be conjugated to glucuronides or sulphates, which subsequently can be excreted via urine or bile or cleaved in the gut with the possibility of reabsorption (entero-hepatic circulation). The alcohol component of the ester may also be conjugated to form a more water-soluble molecule and excreted via the urine. In an alternative pathway, the alcohol may be conjugated with e.g. glutathione and excreted directly, bypassing further metabolism steps.
Key value for chemical safety assessment
- Bioaccumulation potential:
- no bioaccumulation potential
Additional information
There are no experimental studies available in which the toxicokinetic behaviour of isodecyl pivalate (CAS 60209-82-7) has been assessed.
In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2008), assessment of the toxicokinetic behaviour of the substance is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physicochemical and toxicological properties according to the relevant Guidance (ECHA, 2008) (ECHA, 2008) and taking into account available information on the analogue substances from which data was used for read-across to cover data gaps.
Isodecyl pivalate is UVCB substance of complex composition derived from pivalic acid (neopentanoic acid) and isodecyl alcohol, the main components being structural isomers of C15H30O2. The molecular weight is about 242 g/mol. It is a liquid at 20°C (Stearinerie Dubois Fils 2012). The water solubility was measured as < 0,05 mg/l. The Log Pow was measured as 3,54 (Stearinerie Dubois Fils) and the vapour pressure was estimated to be 0,17 Pa at 20°C (Nagel, 2011)
Absorption
Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters to provide information on this potential are the molecular weight, octanol/water coefficient (log Pow) value and water solubility (ECHA, 2008). The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2008).
Oral
The molecular weight of isodecyl pivalate is lower than 500 g/mol, indicating that the substance is available for absorption (ECHA, 2008). A log Pow >3 in combination with the low water solubility suggests that any absorption will likely happen via micellar solubilisation (ECHA, 2008).
The available acute oral toxicity data on the read-across substances isopropyl laurate (CAS 10233-13-3) and isopropyl myristate (CAS 110-27-0) consistently showed LD50 values > 2000 mg/kg bw and no systemic effects (Dufour, 1991; Reijnders, 1988). In the subacute (90-day) repeated dose toxicity study performed with the read-across substances ethyl oleate (CAS 111-62-6) and isostearyl neopentanoate (CAS 58958-60-4), no toxicologically relevant effects were noted up to and including the highest dose level of 5500 mg/kg bw/day (Bookstaff, 2004) and 3460 mg/kg bw/day (Keller Abbott, 1983), respectively. This indicates that the test substance isodecyl pivalate will also have a low potential for toxicity, although no assumptions can be made regarding the absorption potential based on the experimental data.
The potential of a substance to be absorbed in the (GI) tract may be influenced by chemical changes taking place in GI fluids as a result of metabolism by GI flora, by enzymes released into the GI tract or by hydrolysis. These changes will alter the physicochemical characteristics of the substance and hence predictions based upon the physico-chemical characteristics of the parent substance may no longer apply (ECHA, 2008).
In general, alkyl esters are readily hydrolysed in the gastrointestinal (GI) tract, blood and liver to the corresponding alcohol and fatty acid by the enzymatic activity of ubiquitous carboxylesterases. There are indications that the hydrolysis rate in the intestine by action of pancreatic lipase is lower for alkyl esters than for triglycerides, the natural substrate of this enzyme. The hydrolysis rate of linear esters increases with increasing chain length of either the alcohol or acid. Branching reduces the ester hydrolysis rate, compared with linear esters. (Mattson and Volpenhein, 1969, 1972; WHO, 1999).
The substance isodecyl pivalate is therefore anticipated to be enzymatically hydrolysed to isodecyl alcohol (isoC10) and pivalic acid (C5).
Free fatty acids and alcohols are readily absorbed by the intestinal mucosa. Within the epithelial cells, fatty acids are (re-)esterified with glycerol to triglycerides. In general, short-chain or unsaturated fatty acids are more readily absorbed than long-chain, saturated fatty acids. In rats given a single dose of radiolabelled octadecanol via duodenal cannula, 56.6 ± 14% of the administered material was absorbed within 24 h. As for fatty acids, the rate of absorption is likely to increase with decreasing chain length (Greenberger et al., 1966; IOM, 2005; Mattson and Volpenhein, 1962, 1964; OECD, 2006; Sieber, 1974).
In conclusion, based on the available information, the physicochemical properties and molecular weight of isodecyl pivalate suggest oral absorption. However, the substance is anticipated to undergo enzymatic hydrolysis in the gastrointestinal tract and absorption of the ester hydrolysis products is also relevant. The absorption rate of the hydrolysis products is considered to be high.
Dermal
The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 favour dermal uptake, while for those above 500 the molecule may be too large. Dermal uptake is anticipated to be low, if the water solubility is < 1 mg/L; low to moderate if it is between 1-100 mg/L; and moderate to high if it is between 100-10000 mg/L. Dermal uptake of substances with a water solubility > 10000 mg/L (and log Pow < 0) will be low, as the substance may be too hydrophilic to cross the stratum corneum. Log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if water solubility is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2008).
The substance isodecyl pivalate is almost insoluble in water, indicating a low dermal absorption potential (ECHA, 2008). The molecular weight of 242 g/mol indicates a potential for dermal absorption. The log Pow is > 3, which means that the uptake into the stratum corneum can not be excluded (ECHA, 2008).
The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2004):
log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW
The Kp is thus 0.752 cm/h. Considering the water solubility (0.0005 mg/cm³), the dermal flux is estimated to be ca. 3.8E-05 mg/cm²/h.
If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2008).
The experimental animal and human data on isodecyl pivalate and read-across substances show that no significant skin irritation occurred, which excludes enhanced penetration of the substance due to local skin damage (Dufour, 1991; Laine, 1997).
Overall, based on the available information, the dermal absorption potential of isodecyl pivalate is predicted to be low.
Inhalation
As the vapour pressure of isodecyl pivalate is very low (0.17 Pa at 20 °C), the volatility is also low. Therefore, the potential for exposure and subsequent absorption via inhalation during normal use and handling is considered to be negligible.
If the substance is available as an aerosol, the potential for absorption via the inhalation route is increased. While droplets with an aerodynamic diameter < 100 μm can be inhaled, in principle, only droplets with an aerodynamic diameter < 50 μm can reach the bronchi and droplets < 15 μm may enter the alveolar region of the respiratory tract (ECHA, 2008).
As for oral absorption, the molecular weight, log Pow and water solubility are suggestive of absorption across the respiratory tract epithelium either by micellar solubilisation.
Esterases present in the lung lining fluid may also hydrolyse the substance, hence making the resulting alcohol and acid available for inhalative absorption.
An acute inhalation toxicity study was performed with the read-across substance isopropyl laurate (CAS 10233-13-3), in which rats were exposed nose-only to > 5.3 mg/L (analytical value) of an aerosol for 4 hours (Van Huygevoort, 2010). No mortality occurred and no toxicologically relevant effects were observed. Thus, the test substance is not acutely toxic by the inhalation route, but no firm conclusion can be drawn on respiratory absorption.
Due to the limited information available, absorption via inhalation is assumed to be as high as via the oral route in a worst case approach.
Distribution and Accumulation
Distribution of a compound within the body depends on the physicochemical 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 extracellular concentration, particularly in fatty tissues (ECHA, 2008).
The substance isodecyl pivalate will mainly be absorbed in the form of the hydrolysis products. The fraction of ester absorbed unchanged will undergo enzymatic hydrolysis by ubiquitous esterases, primarily in the liver (Fukami and Yokoi, 2012). Consequently, the hydrolysis products are the most relevant components to assess. Both hydrolysis products are expected to be distributed widely in the body.
After being absorbed, fatty acids are (re-)esterified along with other fatty acids into triglycerides and released in chylomicrons. Fatty acids of carbon chain length ≤ 12 may be transported as the free acid bound to albumin directly to the liver via the portal vein, instead of being re-esterified. Chylomicrons are transported in the lymph to the thoracic duct and eventually to the venous system. Upon 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 oxidised for energy or they are released into the systemic circulation and returned to the liver (IOM, 2005; Johnson, 1990; Johnson, 2001; Lehninger, 1993; Stryer, 1996).
Absorbed alcohols are likewise transported via the lymphatic system. Twenty-four hours after intraduodenal administration of a single dose of radiolabelled octadecanol to rats, the percent absorbed radioactivity in the lymph was 56.6 ± 14. Thereof, more than half (52-73%) was found in the triglyceride fraction, 6-13% as phospholipids, 2-3% as cholesterol esters and 4-10% as unchanged octadecanol. Almost all of the radioactivity recovered in the lymph was localized in the chylomicron fraction. Thus, the alcohol is oxidised to the corresponding fatty acid and esterified in the intestine as described above (Sieber, 1974).
Taken together, the hydrolysis products of isodecyl pivalate are anticipated to distribute systemically. Long-chain alcohols are rapidly converted into the corresponding fatty acids by oxidation and distributed in form of triglycerides, which can be used as energy source or stored in adipose tissue. Stored fatty acids underlie a continuous turnover as they are permanently metabolised for energy and excreted as CO2. Bioaccumulation of fatty acids takes place, if their intake exceeds the caloric requirements of the organism.
Metabolism
The metabolism of isodecyl pivalate initially occurs via enzymatic hydrolysis of the ester resulting in isodecyl alcohol (isoC10) and pivalic acid (C5). The esterases catalysing the reaction are present in most tissues and organs, with particularly high concentrations in the GI tract and the liver (Fukami and Yokoi, 2012). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the body. After oral ingestion, esters of alcohols and fatty acids undergo enzymatic hydrolysis already in the gastrointestinal tract. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin may enter the systemic circulation directly before entering the liver where hydrolysis will generally take place.
The branched isodecyl alcohol will mainly be metabolised to the corresponding carboxylic acid via the aldehyde as a transient intermediate (Lehninger, 1993). The stepwise process starts with the oxidation of the alcohol by alcohol dehydrogenase to the corresponding aldehyde, where the rate of oxidation increases with increased chain-length. Subsequently, the aldehyde is oxidised to carboxylic acid, catalysed by aldehyde dehydrogenase. Both the alcohol and the aldehyde may also be conjugated with e.g. glutathione and excreted directly, by passing further metabolism steps (WHO, 1999).
A major metabolic pathway for linear and branched fatty acids is the beta-oxidation for energy generation. In this multi-step process, the fatty acids are at first esterified into acyl-CoA derivatives and subsequently transported into cells and mitochondria by specific transport systems. In the next step, the acyl-CoA derivatives are broken down into acetyl-CoA molecules by sequential removal of 2-carbon units from the aliphatic acyl-CoA molecule. Further oxidation via the citric acid cycle leads to the formation of H2O and CO2 (Lehninger, 1993). Branched-chain acids can be metabolised via the same beta-oxidation pathway as linear, depending on the steric position of the branch, but at lower rates (WHO, 1999). The alpha-oxidation pathway is a major metabolic pathway for branched-chain fatty acids where a methyl substituent at the beta-position blocks certain steps in the beta-oxidation (Mukherji, 2003). Generally, a single carbon unit is cleaved off the branched acid in an additional step before the removal of 2-carbon units continues. Alternative pathways for long-chain fatty acids include the omega-oxidation at high dose levels (WHO, 1999). The fatty acid can also be conjugated (by e.g. glucuronides, sulfates) to more polar products that are excreted in the urine.
The potential metabolites following enzymatic metabolism of the substance were predicted using the QSAR OECD toolbox (OECD, 2011). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. Five hepatic metabolites and 6 dermal metabolites were predicted for the substance. Primarily, the ester bond is broken both in the liver and in the skin and the hydrolysis products may be further metabolised. Besides hydrolysis, the resulting liver and skin metabolites are all the product of alpha-, beta- or omega-oxidation (= addition of hydroxyl group). In the case of omega-oxidation, it is followed by further oxidation to the aldehyde, which is then oxidised to the corresponding carboxylic acid. In a few cases the ester bond remains intact, and only fatty acid oxidation products are found, which result in the addition of one hydroxyl group to the molecule. 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. Fifty-one metabolites were predicted to result from all kinds of microbiological metabolism of the substance. Most of the metabolites were found to be a consequence of fatty acid oxidation and associated chain degradation of the molecule. The results of the OECD Toolbox simulation support the information retrieved in the literature.
There is no indication that the substance isodecyl pivalate is activated to reactive intermediates under the relevant test conditions. The experimental studies performed on genotoxicity (Ames test, gene mutation in mammalian cells in vitro, chromosome aberration assay in mammalian cells in vitro) using isodecyl pivalate and several read-across substances were negative, with and without metabolic activation (Anonymous, 2007; Buskens, 2010; Buskens, 2010; Gloxhuber, 1981; Haddouk, 2007; Verspeek-Rip, 2010; Verspeek-Rip, 2010). The result of the skin sensitisation studies performed with the read-across substances isopropyl myristate (CAS 110-27-0) and Fatty acids, C16-18, 2-ethylhexyl esters (CAS 91031-48-0) were likewise negative (Clouzeau, 1991; Potokar, 1984).
Excretion
The branched C10 fatty acid resulting from the oxidation of the corresponding alcohol and the highly branched pivalic acid resulting from hydrolysis of the ester, are unlikely to be used for energy generation and storage, since saturated aliphatic, branched-chain acids are described to be subjected to omega-oxidation due to steric hindrance by the methyl groups at uneven position, which results in the formation of various diols, hydroxyl acids, ketoacids or dicarbonic acids. In contrast to the products of beta-oxidation, these metabolites may be conjugated to glucuronides or sulphates, which subsequently can be excreted via urine or bile or cleaved in the gut with the possibility of reabsorption (entero-hepatic circulation) (WHO, 1998).
In addition, the alcohol component of the ester may also be conjugated to form a more water-soluble molecule and excreted via the urine (WHO, 1999). In an alternative pathway, the alcohol may be conjugated with e.g. glutathione and excreted directly, bypassing further metabolism steps.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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