Ethoxylates of aliphatic alcohols (>C6): Human health tier II assessment
28 June 2019
- Chemicals in this assessment
- Grouping Rationale
- Import, Manufacture and Use
- Existing Worker Health and Safety Controls
- Health Hazard Information
- Risk Characterisation
- NICNAS Recommendation
Chemicals in this assessment
This assessment was carried out by staff of the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) using the Inventory Multi-tiered Assessment and Prioritisation (IMAP) framework.
The IMAP framework addresses the human health and environmental impacts of previously unassessed industrial chemicals listed on the Australian Inventory of Chemical Substances (the Inventory).
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Stage One of the implementation of this framework, which lasted four years from 1 July 2012, examined 3000 chemicals meeting characteristics identified by stakeholders as needing priority assessment. This included chemicals for which NICNAS already held exposure information, chemicals identified as a concern or for which regulatory action had been taken overseas, and chemicals detected in international studies analysing chemicals present in babies’ umbilical cord blood.
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Seven chemicals in this group were previously assessed in Tranche 4 and recommended for classification under the Hazardous Chemicals Information System (HCIS) (Safe Work Australia). These chemicals are- alcohols, C12-14, ethoxylated (CAS No. 68439-50-9), poly(oxy-1,2-ethanediyl), .alpha.-isodecyl-.omega.-hydroxy- (CAS No. 61827-42-7), alcohols, C13-15, ethoxylated (CAS No. 64425-86-1), alcohols, C12-13, ethoxylated (CAS No. 66455-14-9), alcohols, C12-15, ethoxylated (CAS No. 68131-39-5), alcohols, C12-18, ethoxylated (CAS No. 68213-23-0), alcohols, C12-16, ethoxylated (CAS No. 68551-12-2). This assessment contains updated information and additional chemicals.
The chemicals in this group are structurally related alcohol ethoxylates (AEs), ethoxylated ethers of aliphatic alcohols, where the alky chain length is 6 carbons or higher. Ethoxylates of shorter chain alcohols (C<6) do not show the same degree of surfactancy compared to the chemicals in this group. Hence, they are not included in this assessment.
In addition to linear aliphatic alcohol ethoxylates, this assessment also includes branched/secondary and unsaturated AEs. For the unsaturated straight chain chemicals, as the point of saturation is remote from the carbon where the ethoxy unit is attached, they are expected to have similar mode of action as the linear AEs. No good data are available to look at the impact of these structural variations but they form part of the composition of group members derived from natural fatty acid sources. Therefore, these are included in the assessment. Also included within the group are higher chain fatty alcohols such as tallow as they are not expected to have vastly different physicochemical or toxicological properties from the rest of the group. These chemicals contain homologues with various lengths of the polyethylene glycol moieties and various lengths and degrees of unsaturation of the fatty alcohol moieties.
Commercially available AEs generally consist of a mixture of various AE homologues of varying carbon chain lengths and degree of ethoxylation. The chemicals contain a hydrophobic alkyl chain attached via an ether linkage to a hydrophilic ethylene oxide (EO) chain that gives them their characteristic surfactant properties. The hydrophobic alkyl and the hydrophilic EO chains can vary in length depending on method of production and source of the precursor chemicals (HERA, 2009). Some of the tested chemicals in the group had information available on the average distributions of the alkyl chain lengths and ethylene oxide units. These data are used to help understand the effects of the variations of the alkyl and ethoxylates chain lengths in the assessment. Where available, the number of ethylene oxide repeat units in the chemicals is represented as an average.
Although most of chemicals of this group are polymers according to the definition in the Industrial Chemicals (Notification and Assessment) Act (1989), the individually named members do not necessarily meet the polymer of low concern (PLC) criteria as the number-average molecular weight (NAMW) >1000 Da. Lower molecular weight forms of these chemicals (MW <500) are expected to be used in commercial, domestic and cosmetic products.
The chemicals are used extensively as non-ionic surfactants in a wide range of cosmetic and domestic products. Some chemicals have additional functions and some had no information on uses available.
The chemicals in this group are expected to have similar physicochemical and toxicological properties, which depend on the alkyl chain length and the number of EO units.
Whilst, the primary focus of this assessment is on skin and eye irritation hazard end points; generally speaking, the AEs are not expected to be systemically toxic. Some ethylene glycol ethers are considered to be of concern for a range of adverse health effects, including repeated dose effects, irritation, haemolysis, bone marrow damage, liver and kidney damage, central nervous system (CNS) depression, and developmental and reproductive toxicity (US EPA, 2010). Effects have been mostly observed with shorter chain alkyl glycol ethers (methyl, ethyl, butyl, propyl, isopropyl and phenyl ethers) which are not included in this assessment. Systemic toxicity was shown to decrease with an increasing degree of ethoxylation. Additionally, ethanol, 2-(hexyloxy) (CAS No. 112-25-4) has no evidence of respiratory irritation or haemolysis (OECD, 2004; NICNASa).
Since the chemicals are homologues of various carbon chain lengths, it is possible that some, such as the coco derivative (CAS No. 61791-13-7) may contain shorter (C<6) alkyl chain. However, it is not possible to quantify how much of the shorter chain lengths are present, if at all, in the listed chemicals. Also, the dataset suggests a lack of systemic toxicity for chemicals with potential short chain presence in this group, indicating that even if they are present, the toxicity of the chemicals in this group is not affected by the shorter chain alkyl groups as seen in this assessment.
Import, Manufacture and Use
The following chemicals have Australian industrial uses reported under previous mandatory and/or voluntary calls for information.
Domestic use as cleaning and washing agents, and additives:
- alcohols, C10-16, ethoxylated (CAS No. 68002-97-1);
- alcohols, C12-15, ethoxylated (CAS No. 68131-39-5); and
- alcohols, C12-18, ethoxylated (CAS No. 68213-23-0).
According to industry information, the following chemicals have domestic and commercial uses:
Pigment dispersers or emulsifiers in paints (up to 0.2 %) and tinctures (up to 3 %)
- C11-15-secondary, ethoxylated (CAS No. 68131-40-8);
- alcohols, C16-18, ethoxylated (CAS No. 68439-49-6);
- alcohols, C16-18 and C18-unsaturated, ethoxylated (CAS No. 68920-66-1);
- poly(oxy-1,2-ethanediyl), .alpha.-tridecyl-.omega.-hydroxy-, branched (CAS No. 69011-36-5);
- alcohols, C11-14-iso-, C13 rich, ethoxylated (CAS No. 78330-21-9);
- alcohols, C12-C14-secondary, ethoxylated (CAS No. 84133-50-6);
- poly(oxy-1,2-ethanediyl), .alpha.-dodecyl-.omega.-hydroxy- (CAS No. 9002-92-0); and
- poly(oxy-1,2-ethanediyl), .alpha.-(9Z)-9-octadecen-1-yl-.omega.-hydroxy- (CAS No. 9004-98-2).
Adhesives, sealants and cleaning products
- alcohols, C12-C14-secondary, ethoxylated (CAS No 84133-50-6);
- alcohols, C6-12, ethoxylated (CAS No 68439-45-2); and
- alcohols, C9-11, ethoxylated (CAS No 68439-49-6).
- poly(oxy-1,2-ethanediyl), .alpha.-octadecyl-.omega.-hydroxy- (CAS No 9005-00-9)
- alcohols, C12-C14-secondary, ethoxylated (CAS No 84133-50-6);
Automotive aftermarket products including waxes and rubbing compounds
- Alcohols, C16-18, ethoxylated (CAS No 68439-49-6);
- Poly(oxy-1,2-ethanediyl), .alpha.-dodecyl-.omega.-hydroxy- (CAS No 9002-92-0); and
- Alcohols, C9-11-iso-, C10 rich, ethoxylated (CAS No 78330-21-9).
Polyethylene glycol isodecyl ether (CAS No. 61827-42-7) has reported commercial use as a lubricant and additive.
No specific Australian use, import, or manufacture information has been identified for the rest of the chemicals within the group.
The following international uses have been identified through the European Union Registration, Evaluation and Authorisation of Chemicals (EU REACH) dossiers; the Organisation for Economic Cooperation and Development Screening Information Dataset Initial Assessment Report (OECD SIAR); Galleria Chemica; Substances in Preparations in Nordic Countries (SPIN) database; the European Commission Cosmetic Substances and Ingredients (CosIng) database; United States (US) Personal Care Products Council International Nomenclature Cosmetic Ingredients (INCI) directory; and other data sources via eChemPortal including the US Environmental Protection Agency (EPA) Aggregated Computational Toxicology Resource (ACToR), and the US National Library of Medicine's Hazardous Substances Data Bank (HSDB).
The chemicals have reported use as surfactants. Generally, chemicals with fewer ethoxylate units function as emulsifying agents and, as the number of units increases, they function as solubilising or cleansing agents.
Some of the chemicals have no reported cosmetic use at all; whereas some have functions in addition to being surfactants such as being used as solvents or humectants, emulsion stabilisers, refatting agents, masking agents, fragrance or skin-conditioning agents in cosmetic products.
Most of alcohol ethoxylates have reported use in:
- rinse off (0.001 to 32 %) and leave on (0.00003 to 25 %) cosmetic products; and
- as odour agents.
A few of the chemicals have reported use in baby products (CIR 2012; CIR, 2016). The concentration used range from 0.03 to 4 %.
The chemicals have reported domestic use including in:
- cleaning and washing agents (up to 50 %);
- hard surface cleaners (up to 40 %);
- colouring agents;
- paints, lacquers and varnishes;
- preservatives; and
The chemicals have reported commercial use:
- in cutting fluids; and
- as process regulators.
The chemicals have reported site-limited use as complexing and flocculating agents.
Some of the chemicals have reported non-industrial use including in:
- food additives; and
The chemicals of this group are synthesised through processes which may result in 1,4-dioxane as an impurity. This impurity (listed under dioxane) is controlled through listing in the Poisons Standard (The Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP)) in Schedule 6, with schedule labelling requirements applying above 100 ppm (Appendix G, SUSMP 2018).
No known restrictions have been identified.
Existing Worker Health and Safety Controls
The following chemicals from this group:
- alcohols, C12-14, ethoxylated (CAS No. 68439-50-9);
- poly(oxy-1,2-ethanediyl), .alpha.-isodecyl-.omega.-hydroxy- (CAS No. 61827-42-7);
- alcohols, C13-15, ethoxylated (CAS No. 64425-86-1);
- alcohols, C12-13, ethoxylated (CAS No. 66455-14-9);
- alcohols, C12-15, ethoxylated (CAS No. 68131-39-5);
- alcohols, C12-18, ethoxylated (CAS No. 68213-23-0); and
- alcohols, C12-16, ethoxylated (CAS No. 68551-12-2)
are listed on the Hazardous Chemicals Information System (HCIS) (Safe Work Australia) and classified as hazardous, with the listed hazard category and hazard statement for human health:
- Acute toxicity – Category 4; H302 (Harmful if swallowed)
- Eye damage – Category 1; H318 (Causes serious eye damage)
- Skin irritation – Category 2; H315 (Causes skin irritation)
This listing resulted from the Tranche 4 IMAP assessment.
The rest of the chemicals from this group are not listed on the HCIS.
No specific exposure standards are available.
No specific exposure standards are available.
Health Hazard Information
The data available (HERA, 2009; CIR, 2012) relate to the chemicals with a carbon chain length distribution of C6 to C22. The alcohol ethoxylate group is defined for assessment purposes by the basic structure (Cx-yEOn). The numbers following 'C' indicate the range of carbon chain units. The number following 'EO' indicates the average number of ethoxylate units. The unit ranges reported in the toxicological studies represent the total span of all chemicals tested for each endpoint. The chemicals usually contain a distribution of alkyl chain lengths as well as ethoxy unit chain lengths.
The chemicals in this group are synthesised from linear alcohols (primary or secondary) or branched alcohols. The commercial AEs may also contain un-reacted alcohol as reaction by-products at about 5 % but with variations between different commercial products (HERA, 2009). Available data on linear and branched chain alcohols show that they have low acute and systemic toxicity and exhibit similar patterns of absorption, metabolism, and excretion to alcohol ethoxylates. They are also shown to have no skin sensitisation potential. A potential for skin and eye irritation exists with alcohols >11 carbon chain length (OECD, 2006; OECD, 2006a).
Alcohol ethoxylates, ranging from C12–15 and EO3–10, were readily absorbed from the gastrointestinal tract and rapidly excreted in the urine, faeces and in expired air following oral administration in rats (SCCP, 2007; HERA, 2009; CIR, 2012; CIR, 2016).
Similar results were found following oral administration in humans. Human studies of alcohol ethoxylates (C12 or C13; EO6) demonstrated that they are readily absorbed across the gastrointestinal tract after ingestion and are rapidly excreted in the urine (75 %), faeces (5 %) and in expired air (4 %) within 24 hours after dosing. The chemicals were completely eliminated from the body within 144 hours of dosing. Based on the toxicokinetics, the chemicals are not expected to bioaccumulate within the body (SCCP, 2007; HERA, 2009; CIR, 2012; CIR, 2016).
The primary degradation pathway for most AEs appears to be hydrolysis of the ether linkage followed by oxidation of the alkyl chain to form lower molecular weight poly ethylene glycol (PEG) like compounds and carbon dioxide and water (CIR, 2012). PEGs are not further metabolised and rapidly excreted unchanged in the urine and faeces (CIR, 2012). Metabolism was found to be a function of alkyl and ethoxy chain lengths, with an increase in the proportion excreted via the faeces and expired air with longer chain lengths (SCCP, 2007; HERA, 2009; CIR, 2012; CIR, 2016).
The chemicals can be absorbed through the skin and mucosa following dermal administration and the absorbed dose is rapidly excreted via the urine, faeces or expired air (CIR, 2012). The chemicals are poorly absorbed through human skin as compared to rat skin. In rats, 50 % of the administered dose was excreted in urine, indicating that less of the total administered dose was absorbed dermally as compared to the oral administration (HERA, 2009). Shorter chain ethoxylates were absorbed more readily then the longer chain ones (CIR, 2016). The maximum systemically available dose after dermal application of C12EO6 in humans was determined to be less than 2 % at 144 hours (HERA, 2009). Following dermal administration, the chemicals were rapidly metabolised to carbon dioxide in expired air. The percentage of the chemical in expired air decreased; whereas percentages excreted in faeces and urine increased; with increases in the number of ethoxylate units (CIR, 2016).
As a general rule, the dermal penetration of long chain alcohols is likely to be low and the dermal penetration of the alcohol ethoxylates (particularly branched ones) is likely to be even lower (OECD, 2006). These chemicals are large molecules and have low likelihood to penetrate the skin and enter the circulation. However, some of them may enhance penetration of other ingredients through the skin due to their surfactant properties (CIR, 2016).
Some of the chemicals in this group are currently classified with hazard category ‘Acute toxicity – Category 4’ and hazard statement ‘H302 (Harmful if swallowed)’ in the HCIS (refer to the Existing Work Health and Safety Controls section). Based on the available data, the degree of ethoxylation appears to impact the acute oral toxicity, which was highest for chemicals with EO units between 5 and 15. However, moderate acute oral toxicity cannot be ruled out for the chemicals not meeting this criteria and a hazard classification is recommended (unless data for the specific chemical are available to indicate otherwise) (refer to the Recommendation section).
Based on the available animal (rats, mice and guinea pigs) studies, the chemicals in this group are expected to have low to moderate acute oral toxicity (REACHa-h; OECD, 2005; HERA, 2009; CIR, 2012). The LD50 in rats ranged from 600 mg/kg bw to greater than 20 g/kg bw. Observed sub-lethal effects for the chemical with the highest toxicity (C15–16 and EO10) included diarrhoea, pilo-erection, ataxia, abnormal posture, difficult laboured breathing, salivation, lacrimation, bloody noses and lethargy.
Data from HERA assessment studies show that the chemicals with ethoxylate chains (EO) between 5 and 15 units were more toxic by the oral route than those with less than 4 or greater than 21 units. No relationship between the alcohol chain length and toxicity was observed (HERA, 2009).
The chemicals of this group exhibit low acute dermal toxicity.
The chemicals (C9 to C15 with 3–13 EO units) were of low acute toxicity in rats and rabbits following dermal exposure. The LD50 ranged from 2000 to 5000 mg/kg bw. Sub-clinical effects included wet appearance of the fur, little or no urine, laboured breathing, lethargy, diarrhoea, ataxia, muscle tremours and decreased activity. There was no relationship between the alcohol chain length or number of ethoxylate groups and toxicity. Very high dermal doses of the chemicals (>16000 mg/kg bw) applied dermally for 24 hours in rabbits led to severe skin irritation, ataxia and lung lesions (HERA, 2009; CIR, 2012).
The chemicals of this group are of low acute inhalation toxicity.
In a guideline study (Test Guideline (TG) 403), a single static inhalation exposure to substantially saturated vapour (equivalent to 131.58 ppm - calculated) of C6EO1-2.5 (CAS No. 112-59-4), resulted in no mortality or other signs of inhalation toxicity in Sprague-Dawley (SD) rats (REACHa).
In non-guideline studies reported in HERA (2009) for the chemical (C9-11EO5), the LC50 values in rats exceeded the saturated vapour concentration in air. Treatment related effects observed in animals included laboured breathing, inactivity and bloody nasal discharge. No mortality was reported.
Corrosion / Irritation
Some of the chemicals in this group are currently classified with hazard category ‘Skin irritation – Category 2’ and hazard statement ‘H315 (Causes skin irritation)’ in the HCIS (refer to the Existing Work Health and Safety Controls section). Based on the available data, hazard classification is recommended for the remaining chemicals in this group (unless data for the specific chemical are available to indicate otherwise) (refer to the Recommendation section).
Overall, the chemicals in this group are reported to be moderate to severe skin irritants in animal studies. The degree of irritation was reported to be dependent on the type of patch (occluded vs semi-occluded), exposure time (ranging from 4 hours up to 4 weeks) and the concentration used. Undiluted chemicals were moderately to severely irritating, 1–10 % was mildly irritating and 0.1 % and 0.5 % were non-irritating. There was also a general trend between the severity of irritation and the degree of ethoxylation. Chemicals with 3 and less ethoxylate units appeared to be more irritating than chemicals with higher degree of ethoxylation. No trend in irritation potential with respect to the length of carbon chain could be established.
The dermal irritation potential of a number of chemicals (ranging from C9–14 and EO3–20) in the group was tested according to OECD Test Guideline (TG) 404 in numerous tests when applied undiluted to intact rabbit skin for 4 hours under fully occluded conditions. The chemicals ranged from slightly irritating (C13EO20, C12-14EO15), moderately irritating (C12-14EO6, C13EO6, C13EO5-6.5) to extremely irritating (C12-14EO6, C12-14EO3, C13EO3). Overall, well defined erythema and oedema, and dry skin occurred from the chemicals that were severely irritating. The exposed areas were free of irritation within 6 days (HERA, 2009). These data suggest a possible trend between irritation and degree of ethoxylation, with 3 and less than 3 ethoxylate units more irritating than chemicals with higher ethoxylate units.
The dermal irritation potential of the chemical with the generic CAS No. 68439-46-3 (C9-C11 with 3-8 EO units) was evaluated in several Draize tests using albino rabbits. The undiluted chemical was severely irritating. The chemical was slightly to moderately irritating at 10 %, slightly to mildly irritating at 1 % and minimally to non-irritating at 0.1 % (vehicle not specified) (CIR, 2012).
The dermal irritation potential of the chemical with the generic CAS No. 66455-14-9 (C12-C13 with 1-7 EO units) was evaluated as a single occlusive patch in several Draize tests in NZW or albino rabbits (CIR, 2012). In 1 study, the undiluted chemical (C12-C13 with unspecified EO units) was applied to intact and abraded sites which were graded at 24 hours, 72 hours and 7 days. Mean erythema scores of 2, 2.2 and 2.5/4 and mean oedema scores of 1, 2 and 2/4 were reported at 24, 72 and 7 days, respectively. Moderate irritation along with necrosis and cracking of the skin was observed. In a similar study with the undiluted C12-C13EO2, moderate irritation with no necrosis was observed. Other Draize tests using albino rabbits showed that undiluted C12-C13EO3 was severely to extremely irritating; whereas, undiluted C12-C13EO7 was mildly to severely irritating, possibly indicating a trend that alcohol ethoxylates become less irritating with increasing ethoxylation degree. The chemical (C12-C13EO7) was moderately irritating at 10 %, mildly irritating at 1 % and mildly to non-irritating at 0.1 % (vehicle not specified). Dilute preparations (between 1 and 10 %, vehicle not specified) of group members (CAS Nos. 68131-39-5 and 68951-67-7) with a range of carbon chain length from C12-15 and EO3-18) caused mild to moderate irritation in rabbits Draize studies. The undiluted chemicals were moderately to severely irritating (CIR, 2012).
Diluted preparations (between 1 and 10 %, vehicle not specified) of chemical group members (CAS Nos. 68439-50-9, 68131-39-5 and 64425-86-1) with a range of carbon chain length from C9-15 and EO7-18) caused mild to severe irritation in guinea pigs and rabbits after repeated application (5 times a week) over 4 and a half weeks (HERA, 2009).
Some of the chemicals in this group are currently classified with hazard category ‘Eye damage – Category 1’ and hazard statement ‘H318 (Causes serious eye damage)’ in the HCIS (refer to the Existing Work Health and Safety Controls section). Based on the available data, this hazard classification is recommended for the remaining chemicals in this group (unless data are available for the specific chemical to indicate otherwise) (refer to the Recommendation section).
Overall, available data indicates that undiluted AEs can produce varying degrees of eye irritation ranging from moderate to severe irritancy. The severity of irritation was found to be concentration dependent, with up to 1 % minimally irritating and concentrations in the range of 1 to 10 % slightly to moderately irritating. In most cases, following exposure, the eyes of the treated animals recovered a few days after exposure. Further tests showed that rinsing the eye 30 seconds after application with tap water may reduce the severity of the effects. No clear relationship could be established between the number of EO units or carbon chain length and eye irritation potency.
In studies reported in HERA (2009), chemicals tested covered the range of C7 to C15 with EO units from 2 to 20. Most studies were preformed using the Draize test and scored using the eye irritation index (EII) method from 0-110. An EII between 0.5 to 15 was considered minimally irritating and an EII value in the range >25 to 50 was considered moderately to severely irritating. The majority of the undiluted chemicals tested were either moderate or severe irritants whereas diluted chemicals at concentrations of 0.1 % were generally not irritating. No pattern in the animals that recorded irritant responses could be determined from a wide database covering a range of degree of ethoxylation and alkyl chain lengths. Similar lack of pattern was reported between linear and branched AEs with similar chain lengths and ethoxylation units. Some of the tested chemicals (covering the range of C12 to 14 and EO units 5 to 10) caused irreversible damage to the eye, causing conjunctivitis and corneal opacity. Vascularisation of the cornea was observed when undiluted analogue chemicals (C7-9 or 14-15 and EO 6 or 11) were applied to the eyes of rabbits. As this is considered a permanent effect, the studies were terminated and the animals were sacrificed. The chemicals were considered to be severely irritating to the eye. Further tests determined that the irritancy of the chemicals (covering the range of C9 to C18 with 3 to 20 EO units) could be reduced by rinsing the eye 30 seconds after instillation. The degree of irritation was shown to be concentration dependent as lower concentrations were less irritating. Up to 1 % concentrations were non-irritating and concentrations between 1 to 10 % were slightly to moderately irritating (HERA, 2009).
Similar results were reported in a multitude of Draize tests (using albino and NZW rabbits) in the CIR evaluation (2012) which covered the range of C9 to C15 with EO units from 1 to 18. The degree of irritation was reported to be concentration dependent with severe irritation seen if the rabbits eyes were not rinsed. One chemical (an unsaturated 18 carbon chain with 20 EO units, CAS No. 9004-98-2) at 5 % produced only mild, transient conjunctival redness and chemosis. In several Draize tests, the chemicals (CAS Nos. 68439-46-3, 66455-14-9, 68131-39-5 and 68951-67-7, with variable carbon chain lengths (C9-15) and EO (1-18) units) were severely to extremely irritating as undiluted, moderately to non-irritating at 10 %, non-irritating to mildly irritating at 1 % and non-irritating as 0.1 % solutions (CIR, 2012).
Based on the available data, all the chemicals in the group should be considered to be severe eye irritants when undiluted unless data on the specific chemical are available to indicate otherwise.
Observation in humans
The undiluted chemicals tested negative for skin irritation in a battery of standard human patch tests with several chemicals that covered a variable range of carbon chain length (11–18) and EO units (3–20) under occlusive patches. In some cases, mild erythema was observed that cleared very quickly (HERA, 2009; CIR, 2012).
Based on available data, the chemicals in this group are not skin sensitisers.
The skin sensitisation potential of the chemicals (covering C9 to C21 with 2 to 21 EO units) was evaluated in several Buehler tests, guinea pig maximisation tests and local lymph node assay (LLNA).
In a LLNA (OECD Test Guideline (TG) 429), female CBA/Ca mice (n = 6/dose) were treated topically with the chemical (diethylene glycol monohexyl ether, CAS No. 112-59-4, 250 µL, 99 % purity) on the dorsum of both ears at concentrations of 5, 25 or 75 % or vehicle (acetone in olive oil) once daily for 3 consecutive days. The stimulation index (SI) scores of 0.4, 1.0, and 0.7 at 5, 25 and 75 %, respectively, were obtained. The SI scores of less than 3 indicate that the chemical is a non-sensitiser in the LLNA (REACHa).
Observation in humans
The chemicals are neither primary skin irritants or sensitisers when tested under clinical settings.
The undiluted chemicals tested negative for skin irritation in a battery of standard human patch tests with several chemicals that covered a variable range of carbon chain length (11–18) and EO units (3–20) under occlusive patches. In some cases, mild erythema was observed that cleared very quickly (HERA, 2009; CIR, 2012).
The chemicals (CAS Nos. 66455-14-9 (C12-15EO7) and 68131-39-5 (C12-15EO7-9)) were not found to induce dermal sensitisation in human repeated insult patch tests (HRIPT) at concentrations between 1 and 25 %. Mild erythema, dryness and itching were observed in some subjects in the tests (HERA, 2009; CIR, 2012). Similar negative results were reported in other HRIPT studies tested at a concentration of 1 % that covered chemicals with a range of carbon chain lengths between 12 to 13 and EO units between 6.5 to 12. In additional HRIPT tests, it was reported that the chemical (C12EO9) tested negative at up to 20 % in an aerosol cream and the chemical (C12EO23) tested negative in an HRIPT at up to 25 % solution (HERA, 2009; CIR, 2012).
Repeated Dose Toxicity
The chemicals in this group are not expected to cause serious damage to health from repeated oral exposure.
In several 90-day oral feeding studies in rats (similar to OECD TG 407), the NOAEL was established between 50 and 700 mg/kg bw/day (calculated from dietary levels) for group members (CAS Nos. 68439-50-9 and 68131-39-5, ranging from C12–15 with EO7). Effects observed at higher concentrations included reduction in mean body weights, and increases in relative liver and kidney weights. These changes were considered to be adaptive and related to the poor palatability of the test chemicals. No treatment related histopathological changes were reported (SCCS, 2007; HERA 2009; CIR, 2012).
Similar effects were seen in longer-term studies. Alcohols, C12-13, ethoxylated (CAS No. 66455-14-9; EO6.5) and alcohols, C14-15, ethoxylated (CAS No. 68951-67-7, EO7, not listed on AICS) were given to rats in 1- and 2-year chronic feeding studies at levels between 0.1 and 1 %. The NOAEL was established between 50 and 192 mg/kg bw/day (calculated from dietary level). Effects observed at higher levels included reduction in mean body weights, and increase in relative liver and kidney weights. These changes were considered to be adaptive and may be due to poor palatability of the test chemicals. No treatment related lesions were observed (SCCS, 2007; HERA, 2009; CIR, 2012).
Repeated oral or inhalation doses of certain short chain monoethylene glycol ethers such as 2-butoxyethanol (CAS No. 111-76-2), and its acetate (CAS No. 112-07-2) may cause haemolytic effects in laboratory animals and effects on the liver, stomach and kidneys. However, humans appear to be the least sensitive species for haemolytic effects (NICNAS, 1996; OECD, 2004; NICNASb). Exposure to these (less potent) chemicals is not expected to be sufficient to cause haemolysis and associated organ toxicity.
The chemicals of this group are not expected to cause serious damage to health from repeated dermal exposure.
In a 90-day study (OECD TG 411), Fischer rats were exposed to the chemical (C9–11 with 6 EO units, CAS No. 68439-46-3) at 1, 10 or 25 % concentration, 3 days/week. The application site was shaved but not covered. There were no significant treatment related effects at any concentration. Dry and flaky skin was observed in the 10 and 25 % dose groups. Increased relative kidney weights were observed in the 25 % dose groups. However, no histological lesions were observed. The NOAEL was established at 10 %, equivalent to 80 mg/kg bw/day (HERA, 2009).
No data are available.
Based on the data available, the chemicals in this group are not considered to be genotoxic.
The group members (CAS Nos. 68439-50-9, 68131-39-5 and 64425-86-1) and several analogue chemicals (ranging from C12–18 and EO3–21) produced negative results in several in vitro and in vivo tests for gene mutation and clastogenicity. Negative results were reported in bacterial reverse mutation tests for mutagenicity against Salmonella typhimurium (strains TA98, TA100, TA102, TA104, TA1535, TA1537 and TA1538) and Escherichia coli (strains WP2 and WP2uvrA pKM101), with or without metabolic activation. Negative results were also reported in chromosomal aberration tests in Chinese hamster V79, Chinese hamster ovary, mouse lymphoma and rat liver cell lines (SCCP, 2007; HERA, 2009; CIR, 2012).
These chemicals did not induce chromosomal damage in Chinese hamster or Tunstall Wistar rat bone marrow cells after acute oral doses ranged between 250 and 3400 mg/kg bw (HERA, 2009).
Based on the data available, the chemicals in this group are not considered to be carcinogenic.
Two chemicals, alcohols, C12-13, ethoxylated (CAS No. 66455-14-9; EO6.5) and alcohols, C14-15, ethoxylated (CAS No. 68951-67-7, EO7, not listed on AICS) were administered at up to 1 % in the diet to rats for 1 and 2 years, respectively. No treatment related histopathological effects or increased tumour incidences were observed in either study (HERA, 2009; CIR, 2012).
The chemicals are synthesised through processes which may result in 1,4-dioxane as an impurity. This impurity is classified as a Carcinogen—Category 3 (R40—Limited evidence of a carcinogenic effect). However, it is reported that cosmetic industry uses additional purification steps to remove the 1,4-dioxane residual in PEG before blending into cosmetic formulations (CIR, 2012).
Reproductive and Developmental Toxicity
Based on the data available, the chemicals of this group are not considered to cause reproductive or developmental toxicity.
In a 2-generation reproductive and developmental toxicity study, the chemical (C14-15EO7) was administered in the diet of Charles River CD rats (n=25/sex/group, at doses of 0, 25, 50 or 250 mg/kg bw/day). The NOAEL for reproductive toxicity was established as 250 mg/kg bw/day (or 0.5 % of the diet). No treatment related effects were reported with respect to fertility, gestation, or viability indices or other histopathological parameters. The NOAEL for developmental toxicity was established as 50 mg/kg bw/day based on reduced pup body weights in the second generation at 250 mg/kg bw/day (HERA 2009; CIR, 2012).
In a 2-generation reproductive and developmental toxicity study, the chemical (C9-11EO6) was applied dermally to Fischer 344 rats (n=30/sex/group, at doses of 0, 10, 100 or 250 mg/kg bw/day, 3 times a week except mating periods). No treatment related effects were reported with respect to mating, fertility, gestation, or viability indices and mean gestational length in both generations. No effects on testicular weights or sperm counts were observed in the male rats. The NOAEL for reproductive toxicity was established as 250 mg/kg bw/day. The NOAEL for developmental toxicity was >250 mg/kg bw/day, based on no effects seen in growth and development in the offspring up to the highest dose tested (HERA 2009; CIR, 2012).
In a 2-generation study, the chemical (C12EO6) was administered in the diet of female rabbits at doses of 0, 50, 100 or 200 mg/kg bw/day from gestation days 2 to 16. Ataxia and a slight decrease in body weight were observed at 100 and 200 mg/kg bw/day, indicating maternal toxicity. Nine rabbits in the control group and 31 in the treatment groups died during the study (details not available). There were no treatment related effects on implantations, number of live foetuses and spontaneous abortions. The NOAEL for maternal toxicity was reported as >50 mg/kg bw/day (HERA, 2009).
Although certain short chain monoethylene glycol ethers such as 2-ethoxyethanol (CAS No. 110-80-5) are known reproductive toxicants, the ability of the glycol ethers to cause testicular toxicity decreases with increasing chain length, with effects not observed with chain lengths greater than C2 (OECD, 2004).
In addition, no reproductive effects were observed in several repeat dose toxicity studies (refer to the Repeated dose toxicity section above).
Other Health Effects
Critical Health Effects
The critical human health effects for risk characterisation are acute oral toxicity and skin and eye irritation. The irritant effects are similar to those produced by other surfactants, and the severity of irritation appears to increase directly with concentration and generally decrease with an increasing number of ethoxylate units.
Public Risk Characterisation
Although data on the use of all the chemicals within the group in products in Australia are not available, a few of the chemicals are reported to be used in domestic cleaning and washing products. International use data, considered representative of Australian use, suggest widespread and repeated exposure of the public to these chemicals through the use of rinse-off and leave-on cosmetics and domestic products. Therefore, considering the range of cosmetics and domestic products that may contain these chemicals, the main routes of public exposure are expected to be through the skin and eyes, although incidental ocular and oral exposure can also occur. Considering the wide range of domestic products that the chemicals might be used in, there is a possibility of public exposure to the chemicals in this group through secondary exposure via the environment. However, this exposure is considered to be at much diluted concentrations and; hence, not considered to be comparable to direct exposure.
The Cosmetic Ingredient Review (CIR) Panel determined that cosmetic use concentrations of alcohol ethoxylates are safe when formulated to be non-irritating; however, there is a potential for dermal irritation with some of the chemicals within the group (CIR, 2012; CIR, 2016).
In addition, a quantitative risk assessment of consumer cleaning products containing the chemicals concluded that these chemicals are not of any significant systemic human health concern (HERA, 2009). The margin of exposure calculated in this assessment was based on a worst case scenario and large enough to account for any uncertainties or inter and intra-species extrapolation. However, where high concentrations of the chemical are used, irritant effects on exposure could occur, and eye irritation from accidental eye contact cannot be ruled out at some known use concentrations.
The chemicals are synthesised through processes that might result in 1,4-dioxane as a residual by-product, although it is not expected to be present in any significant amount. The concentration of 1,4-dioxane (listed under dioxane) is controlled through listing in the Poisons Standard (SUSMP) in Schedule 6, with labelling requirements applying at above 100 ppm (Appendix G, SUSMP 2018). It is urged that industry should continue to use additional purification steps to remove 1,4-dioxane from the chemicals before blending them into cosmetic formulations (CIR, 2012).
The chemicals of this group are not currently listed in the Poisons Standard (SUSMP, 2018) and there are no restrictions on the use of these chemicals in Australia.
The available data on some of the chemicals can be extrapolated to support the safety of all the chemicals in this group. There is potential for dermal and ocular effects to occur from use of these chemicals at irritating concentrations. Overall, the chemicals are not considered to pose an unreasonable risk to public health when used at low concentrations or when formulated to be non-irritating.
The total surfactant concentration in the products should be considered when determining label instructions, especially where direct dermal and ocular exposures are expected, or when packaging presents the possibility of accidental ingestion. The irritant effects could be mitigated by labelling (such as warning statement- If in eyes wash out immediately with water etc.) and concentration controls. Any controls for these chemicals should be considered as part of a broader review of the management of surfactants in the SUSMP.
Occupational Risk Characterisation
During product formulation, oral, dermal and ocular exposure of workers to the chemicals may occur, particularly where manual or open processes are used. These may include transfer and blending activities, quality control analysis, and cleaning and maintenance of equipment. Worker exposure to the chemicals at higher concentrations is expected. The level and route of exposure will vary depending on the method of application and work practices employed.
Given the critical systemic acute and local health effects, the chemicals could pose an unreasonable risk to workers unless adequate control measures to minimise dermal and ocular exposure are implemented. The chemical should be appropriately classified and labelled to ensure that a person conducting a business or undertaking (PCBU) at a workplace (such as an employer) has adequate information to determine appropriate controls.
The data available support an amendment to the hazard classification in the HCIS (Safe Work Australia) (refer to the Recommendation section).
Further risk management is required. Sufficient information is available to recommend that risks to public health and safety from the potential use of the chemical in cosmetics and/or domestic products be managed through changes to poisons scheduling, and risks for workplace health and safety be managed through changes to classification and labelling. It is recommended that the chemicals be considered as part of a broader review of the management of surfactants in the SUSMP.
Assessment of the chemicals is considered to be sufficient provided that risk management recommendations are implemented and all requirements are met under workplace health and safety and poisons legislation as adopted by the relevant state or territory.
The public can be exposed to these chemicals through their presence in domestic (such as laundry and cleaning) or cosmetic products. However, the chemicals are not contact sensitisers and not expected to be irritating at low concentrations. There is potential for dermal and ocular irritation to occur from use of these chemicals at higher concentrations depending on the use pattern. A different class of surfactant chemicals (such as sodium lauryl sulfate and its salts) have recently been listed in Schedule 6 of the Poisons Standard.
No specific regulatory controls are recommended on the chemicals in this group as part of this assessment. NICNAS recommends that formulators of products containing these chemicals should take into account the total surfactant concentration in the products when determining label instructions, especially where direct dermal and ocular exposures are expected, or when packaging presents the possibility of accidental ingestion. The irritant effects can be mitigated by labelling (such as warning statement—If in eyes wash out immediately with water etc.) and concentration controls. Any controls for these chemicals should be considered as part of a broader review of the management of surfactants in the SUSMP.
Work Health and Safety
Unless data on specific chemicals are available, the critical health effects cannot be ruled out for any chemical as they can be formulated with variable degree of ethoxylation and alkyl chain lengths. Chemicals with the same generic CAS number may include a range of ethoxylate levels which may affect the toxicological properties.
The chemicals are recommended for classification and labelling aligned with the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) as below.
The classification for the majority of chemicals should include the note that ‘The chemical is a substance of unknown or variable composition, complex reaction product, or biological material (UVCB). The hazards of the chemical may depend on the composition. For more information refer to the assessment report published on the website of the National Industrial Chemical Notification and Assessment Scheme'.
This assessment does not consider classification of physical hazards and environmental hazards.
From 1 January 2017, under the model Work Health and Safety Regulations, chemicals are no longer to be classified under the Approved Criteria for Classifying Hazardous Substances system.
|Hazard||Approved Criteria (HSIS)a||GHS Classification (HCIS)b|
|Acute Toxicity||Not Applicable||Harmful if swallowed - Cat. 4 (H302)|
|Irritation / Corrosivity||Not Applicable||Causes serious eye damage - Cat. 1 (H318) Causes skin irritation - Cat. 2 (H315)|
a Approved Criteria for Classifying Hazardous Substances [NOHSC:1008(2004)].
b Globally Harmonized System of Classification and Labelling of Chemicals (GHS) United Nations, 2009. Third Edition.
* Existing Hazard Classification. No change recommended to this classification
Advice for consumers
Products containing the chemical should be used according to label instructions.
Advice for industry
Control measures to minimise the risk from oral, dermal and ocular exposure to the chemicals should be implemented in accordance with the hierarchy of controls. Approaches to minimise risk include substitution, isolation and engineering controls. Measures required to eliminate or minimise risk arising from storing, handling and using a hazardous chemical depend on the physical form and the manner in which the chemical is used. Examples of control measures which may minimise the risk include, but are not limited to:
- minimising manual processes and work tasks through automating processes;
- work procedures that minimise splashes and spills;
- regularly cleaning equipment and work areas; and
- using protective equipment that is designed, constructed, and operated to ensure that the worker does not come into contact with the chemicals.
Guidance on managing risks from hazardous chemicals are provided in the Managing Risks of Hazardous Chemicals in the Workplace—Code of Practice available on the Safe Work Australia website.
Personal protective equipment should not solely be relied upon to control risk and should only be used when all other reasonably practicable control measures do not eliminate or sufficiently minimise risk. Guidance in selecting personal protective equipment can be obtained from Australian, Australian/New Zealand or other approved standards.
Obligations under workplace health and safety legislation
Information in this report should be taken into account to assist with meeting obligations under workplace health and safety legislation as adopted by the relevant state or territory. This includes, but is not limited to:
- ensuring that hazardous chemicals are correctly classified and labelled;
- ensuring that (material) safety data sheets ((m)SDS) containing accurate information about the hazards (relating to both health hazards and physicochemical (physical) hazards) of the chemical are prepared; and
- managing risks arising from storing, handling and using a hazardous chemical.
Your work health and safety regulator should be contacted for information on the work health and safety laws in your jurisdiction.
Information on how to prepare an (m)SDS and how to label containers of hazardous chemicals are provided in relevant codes of practice such as the Preparation of Safety Data Sheets for Hazardous Chemicals— Code of Practice and Labelling of Workplace Hazardous Chemicals—Code of Practice, respectively. These codes of practice are available from the Safe Work Australia website.
A review of the physical hazards of the chemical has not been undertaken as part of this assessment.
Cosmetic Ingredient Review (CIR) 2012. Review Expert Panel. Safety assessment of alkyl PEG ethers as used in cosmetics. International Journal of Toxicology, 31 (suppl 2): 169S-244S.
Cosmetic Ingredient Review (CIR) 2016. Review Expert Panel. Safety assessment of alkyl PEG/PPG ethers as used in cosmetics. International Journal of Toxicology, 35 (suppl 1): 60S-89S.
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