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EC number: 939-592-9 | CAS number: 67254-71-1
- 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
Endpoint summary
Administrative data
Link to relevant study record(s)
Description of key information
Absorption: > 75% via the gastrointestinal tract
Distribution: approx. 1% in the liver and < 1% in the kidney
Metabolism: Fast hepatic metabolism dominated by one or more hydroxylation and/or dehydrogenation steps in alkyl and/or ethoxy (EO) chains. In addition, hydrolysis of ether groups and shortening of alkyl and/or ethoxy (EO) moieties. Breakdown ultimately leading to carbon dioxide and water.
Excretion: The majority was excreted via urine and faeces depending on the amount of ethoxy (EO) units, minor portions in expired carbon dioxide. Metabolism of longer alkyl chains gave rise to a higher percentage of carbon dioxide into expired air and a lower percentage in urine.
Assumed dermal absorption: 2%
Key value for chemical safety assessment
- Bioaccumulation potential:
- no bioaccumulation potential
- Absorption rate - oral (%):
- 75
- Absorption rate - dermal (%):
- 2
Additional information
Limited data on the toxicokinetic behaviour of member substances of the Alcohol Ethoxylates (AE) category are available. In order to assess the toxicokinetic behaviour, investigations compiled and evaluated in a voluntary industry programme carrying out Human and Environmental Risk Assessments are considered (HERA, 2009). The studies were performed with AE carrying > 2.5 EO (as opposed to the definition of the member substances of the AE category with < 2.5 EO). However, in the absence of adequate and reliable toxicokinetic investigations with AE category member substances and considering conclusive trends in physico-chemical properties of the AE substances, the information derived from the AE with > 2.5 EO is considered appropriate to demonstrate the absorption, distribution, metabolism and excretion (ADME) behaviour also expected for the substances in the AE category. In addition a comparative in vitro metabolism investigation conducted on selected AE test substances is summarised and discussed.
Experimental ADME investigations
Oral absorption, distribution, metabolism and excretion of three 14C-labelled ethoxylated dodecanols (C12) with 3, 6 and 10 EO units attached (C12EO3, C12EO6 and C12EO10) were determined in female Wistar rats. The tracer was located in the alkyl chain without any further specification. Following administration, the rats were placed in a metabolism chamber for 4 days and the faeces, urine and expired air were monitored for 14C activity. At the end of the study period, animals were sacrificed and various tissues and organs were removed and analysed for radioactivity. In summary, 14C was excreted by the rats mainly in the urine after oral or intraperitoneal administration of the test compounds. The relative proportions of compounds found in the urine, faeces, air and carcass did not differ with the route of application and the recoveries were close to 100% for all routes. Small proportions were recovered as 14CO2 and in the faeces. These proportions increased with increasing number of ethoxy (EO) units. The results suggest an almost complete absorption from the alimentary tract. There were indications that some of the longer ethoxy (EO) chain-containing compounds may be excreted via the bile or excreted into the intestine by other routes. Each test compound gave rise to two distinct polar metabolites in the urine and no parent compound was recovered. It was hypothesised that the alcohol chain was oxidised and the ethoxy (EO) chain residue remained intact. No further details on the metabolic breakdown are provided.
In another study, the elimination and resorption of 14C labelled octadecanol (C18) with 10 EO units (C18EO10) was monitored over 72 h after a single oral gavage application at doses of 20, 40, 100, 200, 500 and 1000 mg/kg bw to Wistar rats. From the 40, 200 and 1000 mg/kg bw dose group (four male rats) one animal was placed in a closed metabolism cage to monitor exhaled 14CO2 whereas the other rats were kept in a non-closed system. Urine and faeces were monitored daily over 4 days and gastrointestinal tract, liver, oesophagus, kidney and blood were monitored for 14C activity. Most of the administered compound was resorbed in the intestine (about 80 - 90%) of that approx. 30% was excreted via the bile and 2% was excreted as 14CO2 in air. Within 72 h about 98 - 99% of the compound was eliminated with 90% being excreted within the first 24 h. The test compound was excreted in the urine and in the faeces (about 40 - 50%) to equal amounts. Very low levels of residual radioactivity (about 1%) were noted in the liver and to an even lower extent in the kidney. No dose-dependent differences in elimination were observed. The test substance was excreted rapidly even at high doses. The highest dose did not cause any symptoms of toxicity within the test rats.
In a further study, 14C-labelled C12-15EO6 and C12-15EO7 were applied orally to rats to evaluate the intake (absorption) and excretion. The label was either in the hydroxyl bearing carbon (of the EO-chain) or the α-carbon of the alkyl moiety. The orally dosed material was absorbed quickly and extensively (> 75% of the dose). In most of the experiments about half of the 14C was excreted promptly in the urine; smaller amounts appeared in the faeces and CO2. Much of the 14C in the faeces probably resulted from biliary excretion.
The mammalian absorption, distribution and excretion of AE containing linear and branched carbon chains were comparable. When rats were administered C12EO6 (linear), C13EO6 (branched) and C15EO7 (branched) the distribution in the rat was similar with the major portion of the radioactivity appearing in the urine (52 - 55%) and smaller amounts in the faeces (23 - 27%) and expired CO2 (2 - 3%) for all three compounds.
In a study with human volunteers, the absorption, distribution and excretion of 14C labelled C12EO6 (linear) and C13EO6 (branched) was examined in males given a capsule with the test compound. The behaviour of the two compounds in the males was comparable and most of the radioactivity was recovered after 24 h in the urine, 75% for both compounds.
In summary, the biggest structural component determining the absorption, distribution and excretion of AE was found not to be the degree of branching of the alkyl chain but rather the length of the ethoxy (EO) chain with more of the AE being excreted via the faeces and expired in air as the ethoxy (EO) chain length increased. In addition, the length of the alkyl chain may have determined how AE were distributed in the rat. An oral gavage study with 14C labelled C14-18EO10 (linear) indicated that AE with longer alkyl chains were excreted at a higher proportion into expired air and less into the urine and faeces (about 40 - 50%).
Metabolism
The major degradation pathway of AE substances as assessed in the HERA report appears to be the degradation of the ether group to form poly- and oligo ethylene glycol-like compounds and alcohols. By degradation of the ether group between the alkyl and the ethoxy (EO) chains and oxidation of the resulting alcohols, fatty acids are produced in addition to the poly- and oligo ethylene glycol-like compounds. All breakdown products are finally metabolised to carbon dioxide and water. Studies with radio-labelled compounds showed that both the alkyl and the ethoxy (EO) groups are sites of attack. Thus, also the poly- and oligo ethylene glycol-like compounds will be degraded to various ethoxy (EO) chain lengths. AE substances labelled either with 14C in the α-carbon of the alkyl group or the hydroxyl-bearing position of the ethoxy (EO) chain showed that distribution and excretion of ethoxy (EO) chains of varying length was similar but the metabolism of their alkyl chains was a function of carbon chain length. Metabolism of the alkyl chain seemed to change as the alkyl chain length increased with longer alkyl chains giving rise to a higher percentage of CO2 into expired air, and a lower percentage in urine.
Aliphatic alcohols are eliminated in humans by three pathways: oxidation, conjugation and elimination of the unchanged alcohol into the expired air and urine. Which route constituted a major pathway was depending on physical and chemical factors of the alcohol, including the number of carbon atoms (the alkyl chain length), the nature of the alcoholic hydroxyl group and the extent of branching of the alkyl chain.
A comparative in vitro metabolism investigation using selected AE test substances was performed. The AE test substances were characterised by well-defined length of their C-chain and the number of ethoxy (EO) groups (i.e. the length of the ‘EO tail’). Tetraethylene glycol monooctyl ether (C8EO4), pentaethylene glycol monodecyl ether (C10EO5), tetraethylene glycol monododecyl ether (C12EO4), octaethylene glycol monohexadecyl ether (C16EO8) and triethylene glycol monooctadecyl ether (C18EO3) were investigated using rat, hamster and human liver S9 fraction (over 60 min) and cryopreserved hepatocytes of rat, hamster and human (over 120 min) with initial test concentrations of 1 µM and 10 µM. Samples were analysed using an Liquid Chromatography/Q Exactive™ orbitrap-Mass Spectrometry (LC/QE-orbitrap-MS) setup (Tolonen and Lassila, 2022). Concentrations as function of time were measured and disappearance rates, half-lives and hepatic clearances were calculated to identify whether the metabolising capacity of the selected systems varies in a substance-specific manner. No disappearance was observed without cofactors (experiments in liver S9 fraction) or in buffer incubations without hepatocytes for any of the AE test substances. The data showed that the AE test substances were readily metabolised. This is in agreement with the observations reported in the previous section. The excretion rates observed in various HERA studies (e.g. 75% in 24 h for C12EO6 (linear) and C13EO6 (branched) in male human volunteers) could only be obtained with a high rate of metabolisation.
Even the longest half-life determined in the in vitro metabolism investigation for human hepatocytes (85 min for octaethylene glycol monohexadecyl ether (C16EO8)) leads to almost complete metabolisation within 24 h after exposure. Half-lives tended to increase with increasing length of the C-chain and increasing number of ethoxy (EO) groups. The main metabolic routes of the investigated AE test substances turned out to be qualitatively similar in hepatocytes and in liver S9 fraction. Similar metabolic pathways were identified. The metabolites were analysed for all AE test substances and quantified. Based on the qualitative and quantitative analysis the metabolic route (i.e. chemical conversions) could be deduced. The metabolism in hepatocytes proceeded further with additional hydroxylation reactions and shortening of the ethoxy (EO) ‘tails’ of the investigated AE substances. The main metabolites detected in liver S9 fraction were most abundant in the earlier time points of the hepatocyte experiments and tended to be transformed to further metabolites. The main metabolic routes for all investigated AE test substances were mono and di-hydroxylations in the alcohol moiety (i.e. alkyl chain) and further oxidation reactions (e.g. dehydrogenations) resulting in the formation of carboxylic (fatty) acids. Moreover, metabolites originating from oxidation reactions in the ethoxy (EO)-moiety and shortening of the ethoxy (EO) ‘tail’ via consecutive losses of ethoxy (EO) groups were detected. For some of the substances, low abundance of glucuronide- and sulfo- conjugates were also observed after hydroxylation of the fatty acid chain. The metabolite profiles between the species were qualitatively similar although some quantitative differences were observed.
Dermal penetration
The dermal penetration rate for AE was investigated in a dermal penetration study with 14C-labelled C12EO6 in two human volunteers (HERA, 2009) and calculated according to the following equation:
Kp = dermal flux / (exposure time x concentration of test solution)
Kp = 0.022 mg/cm² / (24 hours x 100 mg/cm³) = 0.0000092 cm/h
This penetration rate is derived from measured data and assumes - conservatively - 2% absorption within the first 24 h following dermal application. In the study, however, the maximum systemically available C12EO6 after 144 h exposure was determined to be 1.82%. It should be noted that the study was performed only on few test subjects and that reporting was limited. The study clearly demonstrated that AE substances penetrate poorly through human skin and clearly less readily than through rat skin. The human study was therefore judged to represent more reliably the systemic availability of AE in humans following dermal exposure to AE-containing cleaning products. It should also be noted that rat studies have shown that short chain AE (C8-C14 with 3 - 7 ethoxy (EO) units) penetrate the skin more readily than longer chained AE (i.e., > C14, > 7 ethoxy (EO) units) (HERA, 2009). Thus, calculating dermal exposures to the whole range of AE substances on the basis of a dermal penetration rate derived from a short chain AE such as C12EO6 can be considered as a conservative scenario.
Summary
100% of the 14C-labelled AE are assumed to be absorbed via the gastrointestinal tract after oral ingestion and distributed widely in the body. Only minor amounts of the AE are directly absorbed via the skin (2%).
The majority of the absorbed dose is rapidly excreted via urine and faeces and minor parts via expired CO2 with more of the AE being excreted via the faeces and expired in air as the ethoxy (EO) chain length increased. Moreover, the length of the alkyl chain is assumed to have an impact on AE with longer alkyl chains being excreted at a higher proportion into expired air and less into the urine and faeces.
A maximum of 1% of the administered dose was found in liver and kidneys, respectively.
Metabolisation is shown to be rapid and complete. The most likely pathway of AE metabolism is expected to be the hydrolysis of the ether linkage and subsequent oxidation of the alcohols to finally form C2-fragments and shorter alkyl chains and ultimately carbon dioxide and water. The lower molecular weight polyethylene glycol-like compounds are further broken down via ether hydrolysis or are subjected to renal excretion.
Reference
HERA (2009). Human & Environmental Risk Assessment on ingredients of European household cleaning products, Alcohol Ethoxylates. Version 2.0, September, 2009 (www.heraproject.com/RiskAssessment.cfm?SUBID=34, last accessed 2021-04-13)
Tolonen and Lassila (2022). METABOLIC STABILITY AND METABOLITE IDENTIFICATION FOR C8EO4, C10EO5, C12EO4, C16EO8, AND C18EO3 IN RAT, HAMSTER AND HUMAN HEPATOCYTES AND LIVER S9 FRACTIONS, Testing Facility: Admescope Ltd, Oulu, Finland, Sponsor: Alcohol Ethoxylates (AE) consortium, Study No.: ADM-21-3833a+b
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