Mercaptoacetate salts: Human health tier II assessment
04 July 2014
- 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
|Chemical Name in the Inventory||CAS Number|
|Acetic acid, mercapto-, calcium salt (2:1)||814-71-1|
|Acetic acid, mercapto-, monosodium salt||367-51-1|
|Acetic acid, mercapto-, monoammonium salt||5421-46-5|
|Acetic acid, mercapto-, calcium salt (1:1)||29820-13-1|
|Acetic acid, mercapto-, monopotassium salt||34452-51-2|
|Acetic acid, mercapto-, strontium salt||38337-95-0|
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).
The framework was developed with significant input from stakeholders and provides a more rapid, flexible and transparent approach for the assessment of chemicals listed on the Inventory.
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.
Stage Two of IMAP began in July 2016. We are continuing to assess chemicals on the Inventory, including chemicals identified as a concern for which action has been taken overseas and chemicals that can be rapidly identified and assessed by using Stage One information. We are also continuing to publish information for chemicals on the Inventory that pose a low risk to human health or the environment or both. This work provides efficiencies and enables us to identify higher risk chemicals requiring assessment.
The IMAP framework is a science and risk-based model designed to align the assessment effort with the human health and environmental impacts of chemicals. It has three tiers of assessment, with the assessment effort increasing with each tier. The Tier I assessment is a high throughput approach using tabulated electronic data. The Tier II assessment is an evaluation of risk on a substance-by-substance or chemical category-by-category basis. Tier III assessments are conducted to address specific concerns that could not be resolved during the Tier II assessment.
These assessments are carried out by staff employed by the Australian Government Department of Health and the Australian Government Department of the Environment and Energy. The human health and environment risk assessments are conducted and published separately, using information available at the time, and may be undertaken at different tiers.This chemical or group of chemicals are being assessed at Tier II because the Tier I assessment indicated that it needed further investigation.
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This group of six chemicals consists of some salts of mercaptoacetic acid (CAS No. 68-11-1). These salts dissociate in solution to form the mercaptoacetate anion and the respective metallic cations (calcium, ammonium, potassium, strontium or sodium, all of which have low toxicity). The toxicological properties of these salts are considered to be similar and have been grouped together for assessment, as any toxicity is expected to result from the presence of the mercaptoacetate anion.
The Organisation for Economic Co-operation and Development's (OECD) Screening Information Dataset Initial Assessment Profile (OECD SIAP, 2009) assessed mercaptoacetic acid and its ammonium salt together, with additional data for the sodium salt used to fill any data gaps. Similarly, the REACH dossier for ammonium mercaptoacetate (REACH a) used data on mercaptoacetic acid and the sodium salt in a read-across procedure, supporting the grouping of these chemicals together for assessment.
The cations Na+, Ca2+ and K+ are generally considered to be of low concern with regards to industrial chemicals, with a number of salts containing these cations identified as 'Stage One chemicals identified as low concern to human health' (NICNAS, 2012). Similarly, a number of salts containing NH4+ are also on this list. The strontium cation (Sr2+) is also unlikely to contribute to toxicity as assessed previously for strontium chloride (CAS No. 10476-85-4) and strontium carbonate (CAS No. 1633-05-2), which were both identified as 'Chemicals considered not posing an unreasonable risk to the health of workers and public health on the basis of the Tier I assessment' (NICNAS, 2013).
Mercaptoacetic acid has been assessed separately (NICNAS), but where data are unavailable for the salts, or further evidence is required, mercaptoacetic acid has been used as an analogue.
Import, Manufacture and Use
No specific Australian use, import, or manufacturing information has been identified for any of the chemicals.
The following international uses have been identified through the review article of Burnett et al. (2009): European Union Registration, Evaluation and Authorisation of Chemicals (EU REACH) dossiers, the Organisation for Economic Cooperation and Development Screening Information Dataset Initial Assessment Profile (OECD SIAP), 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, US Household Products Database, 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).
Some of the chemicals have reported cosmetic use as:
- hair perming/hair waving products (ammonium salt);
- hair straightening products (ammonium salt); and
- depilatory/hair removal creams and liquids (calcium salts, potassium salt, sodium salt).
The chemicals have reported commercial use in leather processing (depilatory).
The chemicals have reported site-limited use including in:
- manufacturing pharmaceuticals;
- sensitive detection reagent for iron, molybdenum, silver and tin; and
- corrosive inhibitors.
No known restrictions have been identified for any of the chemicals.
The mercaptoacetates are listed on the following (Galleria Chemica):
- EU Cosmetic Directive 88/233/EEC Annex III: List of substances which cosmetic ingredients must not contain except subject to the restrictions laid down (reference 2a; thioglycolic acid and its salts);
- Canada: List of prohibited and restricted cosmetic ingredients (The Cosmetic Ingredient "Hotlist"), March 2011;
- New Zealand: Cosmetic Products Group Standard—Schedule 5: Components cosmetic products must not contain except subject to the restrictions and conditions laid down; and
- Association of Southeast Asian Nations (ASEAN): Cosmetic Directive Annex III, part 1: List of substances which cosmetic products must not contain except subject to restrictions and conditions.
In these directives the maximum allowable concentration of the mercaptoacetates (measured as mercaptoacetic acid) in preparations is limited according to the type of cosmetic product:
- Hair products for waving or straightening:
(a) General use (≤ 8 %; pH 7 to 9.5);
(b) Professional use (≤ 11 %; pH 7–9.5);
- Depilatories (≤ 5 %; pH 7–12.7); and
- Hair rinse-off products (≤ 2 %; pH 7–9.5).
Labelling requirements are specified for all these uses.
Existing Worker Health and Safety Controls
The chemicals are not listed on the Hazardous Substances Information System (HSIS) (Safe Work Australia).
No specific exposure standards are available for the chemicals in this group.
The following exposure standards have been identified for calcium di(mercaptoacetate) (CAS No. 814-71-1), ammonium mercaptoacetate (CAS No. 5421-46-5) and sodium mercaptoacetate (CAS No. 367-51-1) (Galleria Chemica):
- TWA: 5–10 mg/m³ in different countries such as USA (California, Tennessee), Spain, Ireland, Canada (British Colombia, Ontario, Quebec).
TWA of 1 mg/m³ has been identified for strontium mercaptoacetate (CAS No. 38337-95-0) in Bulgaria, based on strontium and its compounds (Galleria Chemica).
No exposure standards have been identified for calcium mercaptoacetate (1:1) (CAS No. 29820-13-1) or potassium mercaptoacetate (CAS No. 34452-51-2).
Health Hazard Information
No data are available on the systemic availability of these chemicals through oral, dermal or inhalation routes. Physical chemistry parameters (small, ionisable and water-soluble molecules with a very low log Kow), and results from toxicological studies suggest ready absorption via oral and inhalation routes (OECD, 2009). Cosmetic formulations containing these chemicals have shown low dermal penetration (≤ 1 %) (OECD, 2009; REACH a).
Dermal absorption of 14C-labelled ammonium mercaptoacetate (CAS No. 5421-46-5; 11 % solution) was tested on Sprague Dawley rats (skin exposed for 30 minutes, washed off and followed with a neutralisation step). Radiolabelled 14C was detected in the wash solution at 96.1–96.8 %. Mean absorption was 0.24–0.27 % of the dose (Burnett et al., 2009). A study on excised pig skin found that a 30-minute exposure to ammonium mercaptoacetate (13 % in a hair product formulation) resulted in dermal absorption of only 0.8 % (REACH a).
Dermal absorption of 35S-labelled sodium mercaptoacetate (CAS No. 367-51-1) was tested in male rabbits. A 25 % solution (330 mg/kg bw) was applied to the skin. After one hour, 5–8 % of 35S was detected in the urine. This increased to 30–40 % after five hours. At a higher dose (660 mg/kg bw), similar excretion as a percentage of dose was observed (Burnett et al., 2009; REACH a,b).
In a study investigating urinary excretion of ammonium mercaptoacetate in rabbits, 22.7 % and 23.5 % of oral doses 65 or 131 mg/kg bw, respectively had been excreted by 72 hours (REACH a). When 35S-labelled sodium mercaptoacetate was administered by intraperitoneal injection to rats or rabbits in a number of studies at doses ranging from 70 to 200 mg/kg bw, 59–95 % of the chemical was excreted in the first 24 hours (REACH a,b).
Based on the data available for ammonium mercaptoacetate (CAS No. 5421-46-5) and sodium mercaptoacetate (CAS No. 367-51-1), a hazard classification is warranted for the entire group of chemicals.
Two oral gavage studies testing the acute oral toxicity of ammonium mercaptoacetate (71 % solution) on Wistar rats established an LD50 of 35–142 mg/kg bw. In these studies, all rats died at the highest dose of either 142 or 200 mg/kg bw, but no mortalities were observed at lower doses of 25 or 35 mg/kg bw. The clinical signs of toxicity included hair loss (alopecia), discolouration of the stomach and intestine, emphysema and black discolouration of the lungs, discolouration and excessive fluid in the bladder and dilation of the bladder (OECD, 2009; REACH a).
Two further oral gavage studies (using methodology similar to OECD TG 423) with sodium mercaptoacetate have been reported. In the first, administering sodium mercaptoacetate (98 % purity) resulted in an LD50 of 50–200 mg/kg bw. In the second, the salt (45.9 % purity) resulted in an LD50 of 92–229 mg/kg bw. Clinical signs in the second test included lung haemorrhage, and discolouration of the liver and kidneys (OECD, 2009; REACH a).
No data are available for other salts of mercaptoacetate.
Based on the data available for ammonium mercaptoacetate (CAS No. 5421-46-5) and sodium mercaptoacetate (CAS No. 367-51-1) (LD50 > 200–2000 mg/kg bw), a hazard classification is warranted for all chemicals in this group.
Dermal LD50s derived for ammonium mercaptoacetate (71 % solution) were > 1430 mg/kg bw in rats (OECD TG 402) and > 200 mg/kg bw in rabbits (national guideline US 16 CFR 1500.40), based on no mortalities at the highest dose of either 200 or 1430 mg/kg bw (REACH a).
In guideline studies (OECD TG 402), the dermal LD50 for sodium mercaptoacetate was 1000–2000 mg/kg bw (OECD, 2009). As discussed earlier in the Toxicokinetics section, dermal absorption of the analogue 35S-labelled sodium mercaptoacetate was tested in male rabbits. When a dose of 330 mg/kg bw was applied to the skin of five rabbits, no mortalities were observed. When a higher dose of 660 mg/kg bw was applied to three rabbits, all of the animals died, i.e. LD50 330–660 mg/kg bw (Burnett et al., 2009).
No data are available for the other mercaptoacetate salts.
Data are not available for any of the mercaptoacetate salts. Based on available data for the analogue mercaptoacetic acid (CAS No. 68-11-1) (LC50 < 2 mg/L/4-h), a hazard classification is recommended for all chemicals in this group.
The free mercaptoacetic acid is classified as hazardous with the risk phrase ‘Toxic by inhalation’ (T; R23) in HSIS (Safe Work Australia).
The inhalation LC50 (4 hours) for mercaptoacetic acid was established as 1094 mg/m3 (1.09 mg/L/4-h) in female rats and 1981 mg/m3 (1.98 mg/L/4-h) in male rats, in a test with the chemical as a vapour, according to OECD TG 403 (OECD, 2009; REACH b). Clinical signs of toxicity included irregular and laboured breathing, irritation of the respiratory tract, ruffled coat, reduced mobility, leg tremors and paralysis.
Another inhalation toxicity study of seven hours in rats resulted in no mortalities at a concentration of 2.4 mg/L (600 ppm) (OECD, 2009; REACH b).
Corrosion / Irritation
Based on the limited data available for some salts of mercaptoacetate, all chemicals in this group should be classified for respiratory tract irritation.
Ammonium mercaptoacetate (CAS No. 5421-46-5) and sodium mercaptoacetate (CAS No. 367-51-1) have been shown to cause respiratory tract irritation: 'Respiratory tract irritation was observed in rats exposed to a high concentration of a vapour/aerosol mixture, but not when exposed to saturated vapour only' (OECD, 2009). However, no details are given on these studies.
Irritation of the respiratory tract was observed in rats exposed to the vapours of mercaptoacetic acid (CAS No. 68-11-1) (REACH b). Mercaptoacetic acid is of limited value as an analogue due to its corrosive properties.
Based on the data available for some salts of mercaptoacetate, all chemicals in this group should be classified for skin irritation.
Most reliable data on skin irritation are for ammonium mercaptoacetate (CAS No. 5421-46-5), but data are also available for calcium di(mercaptoacetate), potassium and sodium mercaptoacetate (CAS Nos. 814-71-1, 34452-51-2 and 367-51-1, respectively) (Burnett et al., 2009; OECD, 2009; REACH a).
A study conducted according to OECD TG 404 found that ammonium mercaptoacetate (71 % solution) was only slightly irritating to rabbit skin after a four hour exposure (mean erythema and oedema scores of 0.66 and 0, respectively). However, a second study conducted with exposure for 24 hours (according to a national guideline 16 CFR 1500.41) found the ammonium salt to be highly irritating (erythema and oedemas scores were 3 and 2.33 respectively, on intact skin after 72 hours) (REACH a).
Calcium di(mercaptoacetate) (99.8 % purity) and sodium mercaptoacetate (98 %) were found to be moderately irritating to rabbit skin (Burnett et al., 2009). Potassium mercaptoacetate (43 %) was found to be mildly irritating to rabbit skin (Burnett et al., 2009). Erythema and oedema scores are not available.
Based on the data available for ammonium mercaptoacetate (CAS No. 5421-46-5) and calcium di(mercaptoacetate) (CAS No. 814-71-1), all chemicals in this group should be classified for eye irritation.
A study conducted according to OECD TG 405 on three rabbits with ammonium mercaptoacetate (71 % solution), gave mean (24, 28 and 72 h) eye irritation scores of 0, 0, 0.9 and 0.7 for cornea, iritis, redness of the conjunctivae and chemosis. All the effects were fully reversible within 72 hours (REACH a). In a similar test (in accordance with the US CFR 1500.42 guideline), the mean eye irritation scores were 0, 0 and 2.6 for cornea, iritis and redness of the conjunctivae, respectively. Discharge was also noted in 3/6 animals (REACH a). Burnett et al. (2009) reviewed the literature for eye irritation studies with ammonium mercaptoacetate at likely concentrations in consumer products (5.0–17.5 % solutions) and found effects from no irritation to moderate irritation. These studies imply that the ammonium salt is slightly irritating to the eye.
Calcium di(mercaptoacetate) (CAS No. 814-71-1) in its pure powder form was found to be an extreme eye irritant, while a 10 % solution only produced very mild irritation (Burnett et al., 2009). No data are available on the eye irritant scores.
No data are available for other mercaptoacetate salts.
Observation in humans
A number of human skin irritation and sensitisation (repeated insult patch testing on the skin of the arm or back) studies have been conducted with ammonium mercaptoacetate (CAS No. 5421-46-5) at concentrations from 14.4–18 % in solution, and one study with a hair waving/perming product containing ammonium mercaptoacetate at 4.4 % (REACH a).
A number of people had to be withdrawn from these studies due to skin reactions within the first few applications in the induction phase. The majority of reactions were slight with just noticeable redness or erythema (which scored > 0 or < 1 out of 4). However, there were usually also a number of cases of mild erythema (score 1/4) or moderate erythema (score 2/4) (REACH a).
When asthmatic patients were exposed to mists of ammonium mercaptoacetate (71 %) at various dilutions (1:10 to 1:100000), 13/14 patients had symptoms representative of respiratory irritation (Burnett et al., 2009). The irritation of the throat (pharyngeal irritation) lasted from 0.5–2 hours. Eight non-asthmatic patients (control group who had not suffered previously from hayfever or eczema) exposed to the same scenarios did not suffer from respiratory irritation.
No data are available for any of the chemicals.
The mercaptoacetate salts are considered to be skin sensitisers.
Local lymph node assays with mice (OECD TG 429) reported positive results for skin sensitisation for the following salts (Burnett et al., 2009; OECD, 2009):
- ammonium mercaptoacetate (CAS No. 5421-46-5; 70 % solution): EC3 of 0.65 %;
- calcium di(mercaptoacetate) (CAS No. 814-71-1; original purity not reported): EC3 not calculated, sensitisation at 30 %;
- potassium mercaptoacetate (CAS No. 34452-51-2; 43 % solution): EC3 not calculated, sensitisation at ³ 25 %; and
- sodium mercaptoacetate (CAS No. 367-51-1; 98 % purity): EC3 of 6 %.
Epicutaneous tests on guinea pigs showed mild to weak sensitisation following induction phases using 10 % or 30 % ammonium mercaptoacetate (Burnett et al., 2009). However, in a number of guinea pig maximisation tests with hair product formulations containing 1.14–10.98 % ammonium mercaptoacetate, no skin sensitisation was observed (Burnett et al., 2009).
Observation in humans
Although details are not provided, the OECD SIAP report (OECD, 2009) states that a number of cases of skin sensitisation have been reported for hairdressers working with formulations containing the salts of mercaptoacetic acid, particularly ammonium mercaptoacetate (CAS No. 5421-46-5). In addition, dermatologists also report positive results for skin sensitisation in some patients with ammonium mercaptoacetate. Only limited information is available on respiratory sensitisation effects of some salts in this group (i.e. in asthmatic patients).
A whole series of occupational exposure scenarios with hairdressers, beauticians or their clients are outlined in the review article by Burnett et al. (2009). These studies suggest that allergic contact dermatitis in response to ammonium mercaptoacetate is an important issue, particularly for workers in these industries. Subjects will have been previously exposed to the salts, and also other chemicals, including the free mercaptoacetic acid (CAS No. 68-11-1) and esters of mercaptoacetic acid, in various combinations in hair product formulations. In many of the listed studies, the subjects selected for sensitisation testing were already suffering from dermatitis (of the hands) or other atopic effects (asthma, hay fever). Although these are not ideal conditions to test the sensitisation potential of specific chemicals, the sheer number of cases/weight of evidence suggests that these salts are skin sensitisers.
A number of human skin irritation and sensitisation (repeat insult patch testing on the skin of the arm or back) studies have been conducted with ammonium mercaptoacetate at concentrations from 14.4–18 % in solution, and one study with a hair waving/perming product containing ammonium mercaptoacetate at 4.4 % (REACH a). Of the subjects who completed the induction and challenge phases, the proportion who had a reaction during either of those phases varied from 9–47 %. Two cases of likely allergic contact dermatitis arose during the four studies (REACH a).
When asthmatic patients were exposed to mists of ammonium mercaptoacetate (71 %) at various dilutions (up to 1:10), 13/14 patients had symptoms including 'asthmatic breathing, an uncontrollable paroxysmal cough, pharyngeal irritation, and blocked nasal passages or nasal drip' (Burnett et al., 2009). Whereas hairdressers with occupational rhinitis (irritation and inflammation of the mucous membrane of the nose) were exposed to ammonium mercaptoacetate (0.06 % solution), only 1/31 had a positive reaction to the salt at this concentration (Burnett et al., 2009).
Repeated Dose Toxicity
Based on the data available for sodium mercaptoacetate (CAS No. 367-51-1), the chemicals in this group may cause serious damage to health from repeated oral exposure. A hazard classification is warranted under GHS to indicate specific target organ toxicity from repeated oral exposure. However, according to the Approved Criteria, a hazard classification is not warranted.
A 90-day oral gavage repeated dose toxicity study (OECD TG 408) exposed rats to sodium mercaptoacetate daily (7 mg/kg bw/d or 20 mg/kg bw/d, n = 10/sex/dose; 60 mg/kg bw/d, n = 16/sex/dose). The no observed adverse effect level (NOAEL) was 20 mg/kg bw/d based on mortalities at 60 mg/kg bw/d (1/16 males died, 1/16 females had to be euthanised). The liver of each of these animals was discoloured. Other signs of toxicity at the highest dose included higher mean absolute and relative liver weights (accompanied by histopathological changes, particularly microscopic vacuolation in the area near the portal vein of the liver), microscopic vacuolation of the heart and kidneys, excessive salivation and piloerection (erection of the hair of the skin) (OECD, 2009; REACH a,b). In blood plasma, there were dose-related increases in the concentration of fatty acids (36–178 % increase), urea (60–70 % increase) and lactate (80–107 % increase), and dose-related decreases in both glucose (17–32 % decrease) and β-hydroxybutyrate (78–80 % decrease). Changes were significant in blood plasma at 60 mg/kg bw/day in male rats and from 20 mg/kg bw/day in female rats. These observations of blood biochemistry, in conjunction with microscopic histopathological changes in the liver, are consistent with a mode of toxic action where β-oxidation of fatty acids is inhibited, leading to higher concentrations of triglycerides in the liver (REACH a,b).
In an oral gavage study, rats were dosed with sodium mercaptoacetate during the 10-week premating phase of a reproductive toxicity study. No effects were seen for male or female adult rats at doses of 10 and 20 mg/kg bw/d (n = 25/sex/dose). The lowest observed effect level (LOEL) was 40 mg/kg bw/d based on microscopic observation of vacuolation in the liver in 2/25 males and 6/25 females. Observations of biochemistry showed significant decreases in urea in males and decreases in fatty acids in females at this dose. As the reproductive test continued, 4/6 (pregnant) females with the microvacuolation of the liver were found dead and 2/6 had to be euthanised (REACH a,b).
In a similar oral gavage test (premating phase of a reproductive toxicity test) rats were administered sodium mercaptoacetate at doses of 20, 40 or 80 mg/kg bw/d (14 animals/sex/dose). A NOAEL of 40 mg/kg bw/d and a lowest observed adverse effect level (LOAEL) of 80 mg/kg bw/d were established based on mortalities at 80 mg/kg bw/d (1/14 female, 2/14 male) in the 10-week premating period (OECD, 2009; REACH a,b).
Based on the data available for sodium mercaptoacetate (CAS No. 367-51-1), the chemicals in this group are not considered to cause serious damage to health from repeated dermal exposure.
In two, 13-week studies (similar to OECD TG 411), sodium mercaptoacetate was applied to the skin of rats (Fischer) and mice (B6C3F1) for five days/week (five dose levels, 10 animals/sex/dose). NOAELs for systemic toxicity were established as ³ 180 mg/kg bw/d and ³ 360 mg/kg bw/d for rats and mice, respectively, which was the highest dose tested in each case. No mortalities occurred. The studies resulted in either no weight or histopathological changes in major organs (rats), or these changes were only observed in a few animals at the highest dose (mice). However, local effects were observed at the site of application. Skin irritation was noted in all rats at all treatment levels, including at the lowest dose of 11.25 mg/kg bw/d. Skin thickening and ulceration were also observed, but were only prevalent at higher doses. In mice, microscopic changes at the treatment site resulted in hyperplasia at concentrations ³ 45 mg/kg bw/d (OECD, 2009; REACH a, b).
No data are available for the chemicals in this group or for mercaptoacetic acid.
Based on the weight of evidence in available, well-conducted in vitro and in vivo genotoxicity studies using ammonium mercaptoacetate (CAS No. 5421-46-5), sodium mercaptoacetate (CAS No. 367-51-1), or mercaptoacetic acid (CAS No. 68-11-1), the chemicals in this group are not considered genotoxic.
Negative results were reported for ammonium mercaptoacetate in a number of in vitro genotoxicity tests (bacterial reverse mutation assay—Ames test; and mammalian cell gene mutation assay with mouse lymphoma cells). Some positive results for cytotoxicity were observed in these tests but were not deemed significant. No in vivo tests are reported for this salt (OECD, 2009; REACH a).
Negative results were reported for sodium mercaptoacetate in an in vitro genotoxicity test (bacterial reverse mutation assay—Ames test) and for some in vivo genotoxicity tests (chromosome aberration study using a micronucleus assay on mouse bone marrow at doses up to and including 250 mg/kg bw (OEC TG 474); and sex-linked recessive lethal mutation test with Drosophila melanogaster) (OECD, 2009; REACH a).
In another chromosome aberration study using a micronucleus assay on mouse bone marrow (similar to OECD TG 474), negative results were reported for males at all doses up to and including 360 mg/kg bw and for females at doses between 22.5–280 mg/kg bw. However, positive results were reported for females at the highest dose of 360 mg/kg bw/d (OECD, 2009; REACH a).
Negative results were reported for the analogue mercaptoacetic acid in an in vitro mammalian chromosome aberration test (OECD TG 473) with human lymphocytes. Additionally, negative results were reported for an in vivo chromosome aberration study at doses up to and including 1000 mg/kg bw for males and 500 mg/kg bw for females (micronucleus assay on mouse bone marrow; OECD TG 474) (OECD, 2009; REACH b).
Only limited data are available for sodium mercaptoacetate (CAS No. 367-51-1). Therefore, it is not possible to make a conclusion on the carcinogenic potential of the chemicals in this group.
In a non-guideline study, sodium mercaptoacetate was not carcinogenic to mice when their skin was treated with a 1 % or 2 % solution in acetone twice weekly from seven weeks of age until their death. The average lifespan and the incidence of tumours in the mice were similar for control and treated groups (50 mice/sex/dose) (OECD, 2009; REACH a).
Reproductive and Developmental Toxicity
Based on the data available for sodium mercaptoacetate (CAS No. 367-51-1) and ammonium mercaptoacetate (CAS No. 5421-46-5), the chemicals in this group are not considered to have reproductive or developmental toxicity.
A two-generation reproductive study (OECDE TG 416) exposed rats to sodium mercaptoacetate via oral gavage doses of 10, 20 or 40 mg/kg bw/d (25 rats/sex/dose). Doses were given daily to the parental (F0) males and females throughout a 10-week premating period, the mating period (up to three weeks), gestation and lactation (up to 21 days). The F0 generation was sacrificed once the litters had weaned. At 22 days of age, eight male and eight female F1 generation animals were selected for further study and doses applied as above. They were mated after 9–11 weeks. The NOEL for F0 parental toxicity was established as 20 mg/kg bw/d, based on microscopic vacuolation of the liver in the region of the portal vein in 2/25 male and 6/25 female rats at the highest dose of 40 mg/kg bw/d. Four of these females died. Fatty acid concentrations in the blood were also significantly lower in this highest dose group for females. It is stated that 'sodium thioglycolate is known to induce fatty liver via an inhibition of the β-oxidation of fatty acids' (REACH a,b). The no observed effect level (NOEL) for fertility and gestation was 20 mg/kg bw/d in females. The NOEL for male fertility and mating was ³ 40 mg/kg bw/d (no effects at the highest dose). The NOEL for developmental toxicity was 20 mg/kg bw/d. At the higher dose, the pregnant female rats did not nest or nurse properly, which may have caused pups to die (REACH a,b).
Another reproductive study is available with sodium mercaptoacetate (according to OECD TG 421; single generation) in rats dosed at 20, 40 and 80 mg/kg bw/d. The NOEL for parental toxicity (F0) was 20 mg/kg bw/d based on deaths of pregnant rats in the gestation phase, due to late delivery at 40 mg/kg bw/d and above. At the highest dose 2/12 males died during the prebreeding phase; and 7/12 females died or had to be sacrificed early in the prebreeding, late gestation or early lactation stages. The NOEL for male reproductive toxicity (F0) was ³ 80 mg/kg bw/d, based on no effects at the highest dose. The NOEL for pups (F1 generation) was 40 mg/kg bw/d, based on the death of an entire litter of pups at 80 mg/kg bw/d, which may or may not have been related to adverse maternal effects (REACH a,b).
In a developmental toxicity study (OECD TG 414), ammonium mercaptoacetate was administered to pregnant rats at concentrations of 3, 15 or 75 mg/kg bw/d (gestation days 6–15). The NOAEL for maternal toxicity was 15 mg/kg bw/d based on two mortalities on gestation day 20 at the highest dose. The NOAEL for developmental toxicity was 75 mg/kg bw/d based on no teratogenic effects in pups, even at maternal toxic doses (OECD, 2009; REACH a).
Sodium mercaptoacetate was administered to the skin of pregnant rats (6 h/d, gestation days 6–19 at doses of 50, 100 or 200 mg/kg bw/d) or rabbits (6 h/d; gestation days 6–29 at doses of 10, 15, 25 or 65 mg/kg bw/d). In rabbits, the NOAEL for maternal toxicity was 65 mg/kg bw/d (no systemic toxicity at any dose tested; skin irritant effects at all doses at the application site). In rats, a NOAEL for maternal toxicity could not be established due to local effects observed at the lowest dose. At 200 mg/kg bw/d there was one mortality and a reduction in the mean body weight gain. At all doses there were changes in feeding habits, water intake and local irritant effects at the application site. A LOAEL for maternal toxicity in rats was established as 50 mg/kg bw/d. The NOAEL for developmental toxicity was > 65 mg/kg bw/d in rabbits (no teratogenic effects at highest dose) and 100 mg/kg bw/d in rats based on lower body weight of foetuses (REACH a,b).
No data are available for the other mercaptoacetate salts in this group.
Other Health Effects
Critical Health Effects
The critical health effects for risk characterisation of mercaptoacetate salts in this group include acute toxicity; skin, eye and respiratory tract irritation; skin sensitisation and harmful effects following repeated oral exposure.
Public Risk Characterisation
Although use in cosmetic/domestic products in Australia is not known, the chemicals in this group are reported to be used in cosmetic products overseas, with concentrations regulated to be ≤ 11 % (measured as mercaptoacetic acid).
Canada, New Zealand and the European Union have restricted the use concentrations of these chemicals in cosmetics. Currently, there are no restrictions on using these chemicals in Australia. Considering the range of cosmetic products that may contain the chemical, the main route of public exposure is expected to be through the skin. In the absence of any regulatory controls, the characterised critical health effects have the potential to pose an unreasonable risk under the uses identified. The risks could be mitigated by implementing concentration limits and restricting uses to limit exposure.
Occupational Risk Characterisation
During product formulation, dermal, ocular and inhalation exposure of workers to these 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. The level and route of exposure will vary depending on the method of application and work practices employed.
Given the critical health effects, the chemicals in this group may pose an unreasonable risk to workers unless adequate control measures to minimise dermal, ocular and inhalation exposure to the chemical are implemented. The chemicals should be appropriately classified and labelled to ensure that a person conducting a business or undertaking (PCBU), e.g. employer, at a workplace, has adequate information to determine appropriate controls.
Based on the available data, all chemicals in this group are recommended to be classified as hazardous.
Further risk management is required. Sufficient information is available to recommend that risks to public health and safety from the potential use of these chemicals in cosmetics be managed through scheduling, and risks for workplace health and safety be managed through classification and labelling.
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.
Given the risk characterisation, it is recommended that the concentration of these chemicals in cosmetic products be restricted by appropriate scheduling to mitigate risks. Maximum concentrations allowed in the EU are provided under Restrictions.
Matters to be taken into consideration include acute toxicity, irritation, skin sensitisation and harmful effects from repeated oral exposure. Exemptions to scheduling may be applicable at low concentrations.
Work Health and Safety
The chemicals in this group are recommended for classification and labelling under the current approved criteria and adopted GHS as below. This assessment does not consider classification of physical hazards and environmental hazards.
|Hazard||Approved Criteria (HSIS)a||GHS Classification (HCIS)b|
|Acute Toxicity||Toxic if swallowed (T; R25) Harmful in contact with skin (Xn; R21) Toxic by inhalation (T; R23)||Toxic if swallowed - Cat. 3 (H301) Toxic in contact with skin - Cat. 3 (H311) Fatal if inhaled - Cat. 2 (H330)|
|Irritation / Corrosivity||Irritating to eyes (Xi; R36) Irritating to skin (Xi; R38) Irritating to respiratory system (Xi; R37)||Causes serious eye irritation - Cat. 2A (H319) Causes skin irritation - Cat. 2 (H315) May cause respiratory irritation - Specific target organ tox, single exp Cat. 3 (H335)|
|Sensitisation||May cause sensitisation by skin contact (Xi; R43)||May cause an allergic skin reaction - Cat. 1 (H317)|
|Repeat Dose Toxicity||May cause damage to organs through prolonged or repeated exposure - Cat. 2 (H373)|
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 these chemicals should be used according to the instruction on the label.
Advice for industry
Control measures to minimise the risk from dermal, ocular or inhalation exposure to the chemical 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:
- using closed systems or isolating operations;
- using local exhaust ventilation to prevent the chemical from entering the breathing zone of any worker;
- health monitoring for any worker who is at risk of exposure to the chemical if valid techniques are available to monitor the effect on the worker’s health;
- air monitoring to ensure control measures in place are working effectively and continue to do so;
- 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 chemical.
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.
Approved Criteria for Classifying Hazardous Substances [NOHSC: 1008(2004)] Third edition. Accessed at http://www.nohsc.gov.au/pdf/Standards/approved_criteriaNOHSC1008_2004.pdf.
Burnett CL, Bergfeld WF, Belsito DV, Klaassen CD, Marks JG Jr, Shank RC, Slaga TJ, Snyder PW, Cosmetic Ingredient Review Expert Panel & Andersen FA 2009. Final amended report on the safety assessment of ammonium thioglycolate, butyl thioglycolate, calcium thioglycolate, ethanolamine thioglycolate, ethyl thioglycolate, glyceryl thioglycolate, isooctyl thioglycolate, isopropyl thioglycolate, magnesium thioglycolate, methyl thioglycolate, potassium thioglycolate, sodium thioglycolate, and thioglycolic acid. International Journal of Toxicology 28(4S) pp. 68–133.
ChemIDPlus Advanced. Accessed May 2013 at http://chem.sis.nlm.nih.gov/chemidplus.
Galleria Chemica. Accessed May 2013 at http://jr.chemwatch.net/galleria/.
Globally Harmonised System of Classification and Labelling of Chemicals (GHS) United Nations, 2009. Third edition. Accessed at http://www.unece.org/trans/danger/publi/ghs/ghs_rev03/03files_e.html.
Hazardous Substances Data Bank (HSDB). National Library of Medicine. Accessed May 2013 at http://toxnet.nlm.nih.gov.
National Industrial Chemicals Notification and Assessment Scheme (NICNAS) 2012. Inventory Multi-Tiered Assessment and Prioritisation Framework: Identification of chemicals of low concern to human health. Australian Government Department of Health and Ageing. Accessed May 2013 at http://www.nicnas.gov.au.
National Industrial Chemicals Notification and Assessment Scheme (NICNAS) 2013. Inventory Multi-Tiered Assessment and Prioritisation Framework: Tranche 2 - Tier 1 Human Health Risk Assessments. Table 1. Australian Government Department of Health and Ageing. Accessed May 2013 at http://www.nicnas.gov.au/Industry/Existing_Chemicals/Chemicals_On_AICS/IMAP%20Assessments%20Tranche%202.asp.
National Industrial Chemicals Notification and Assessment Scheme (NICNAS). Human health assessment for acetic acid, mercapto-. CAS registry number: 68-11-1. Australian Government Department of Health and Ageing. Accessed May 2013 at http://www.nicnas.gov.au.
OECD 2009. SIAP on thioglycolic acid and its ammonium salt. Accessed May 2013 at http://webnet.oecd.org/Hpv/ui/handler.axd?id=f8a7ff9a-73c7-437f-a0ec-5485bed83646.
REACH Dossier (a). Ammonium mercaptoacetate (5421-46-5). Accessed May 2012 at http://echa.europa.eu/web/guest/information-on-chemicals/registered-substances.
REACH Dossier (b). Mercaptoacetic acid (68-11-1). Accessed May 2012 at http://echa.europa.eu/web/guest/information-on-chemicals/registered-substances.
Safe Work Australia (SWA). Hazardous Substances Information System (HSIS). Accessed May 2013 at http://hsis.safeworkaustralia.gov.au/HazardousSubstance.