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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March and July 2017

Scheduling medicines and poisons

15 September 2017

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2.4 Docusate sodium

An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a new Schedule 6 entry for docusate sodium in the Poisons Standard to restrict its use in cosmetic and domestic products.

Scheduling application

This was a general application. The applicant's proposed amendments to the Poisons Standard are:

Appendix B, Part 3 – Delete Entry

DOCUSATE SODIUM (DIOCTYL SODIUM SULFOSUCCINATE)

Schedule 6 – New Entry

DOCUSATE SODIUM except:

  1. in wash-off preparations containing 30 per cent or less of docusate sodium and, if containing more than 5 per cent of docusate sodium, when labelled with a warning to the following effect:

    IF IN EYES WASH OUT IMMEDIATELY WITH WATER;

  2. in leave-on preparations containing 1.5 per cent or less of docusate sodium;
  3. in toothpaste and oral hygiene preparations containing 5 per cent or less of docusate sodium;
  4. in other preparations for animal use containing 2 per cent or less of docusate sodium; or
  5. in other preparations containing 30 per cent or less of docusate sodium and, if containing more than 5 per cent of docusate sodium, when labelled with warnings to the following effect:

    IF IN EYES WASH OUT IMMEDIATELY WITH WATER; and

    IF SKIN OR HAIR CONTACT OCCURS, REMOVE CONTAMINATED CLOTHING AND FLUSH SKIN AND HAIR WITH RUNNING WATER.

Appendix E, Part 2 – New Entry

DOCUSATE SODIUM

Standard Statements: E1 (If in eyes wash out immediately with water), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

Appendix F, Part 3 – New Entry

DOCUSATE SODIUM

Warning Statements: 5 (Irritant); 72 (Do not use in the eyes); 79 (Will irritate eyes).

Safety Directions: 1 (Avoid contact with eyes); 4 (Avoid contact with skin).

Index – Amend Entry

DOCUSATE SODIUM

cross reference: DIOCTYL SODIUM SULFOSUCCINATE

Appendix B, Part 3

Schedule 6

The applicant's reasons for the request are:

  • While the US CIR Expert Panel concluded in 2013 that surfactant formulations containing docusate sodium would most likely produce irritation effects and recommended that products containing dialkyl sulfosuccinate salts (including docusate sodium) be formulated to be non-irritating, the available data do not provide sufficient evidence to determine a cut-off concentration at which exemptions may apply for either leave-on or rinse-off cosmetic formulations;
  • An exemption cut-off for domestic uses and rinse-off cosmetics could be assigned similar to that used for lauryl sulfate salts;
  • Inclusion of docusate sodium in Appendix B of the Poisons Standard is considered inappropriate, as docusate sodium cannot be considered to be of low toxicity based on the results of the NICNAS IMAP assessment;
  • Docusate sodium is reported to be used in domestic products in Australia;
  • Docusate sodium is reported to be used in cosmetic and domestic products overseas (CIR, 2013 that are potentially available for use in Australia; the updated REACH Dossier (December 2016) indicates consumer uses in cleaning applications, laundry detergents, paints and coatings;
  • Although there is no information to confirm the maximum use concentration of docusate sodium in cosmetic and domestic products in Australia, it is reported to be used in cosmetic and domestic products overseas at concentrations up to 4.4 and 5.0%, respectively (CIR, 2013);
  • Docusate sodium is a skin irritant and a severe eye irritant;
  • Docusate sodium is also reported to be a cumulative skin irritant based on effects observed in human irritation and skin sensitisation studies. In several four-day cumulative irritancy tests, application of products containing docusate sodium resulted in a primary irritation index (PII) range of 0.25-0.80 at 2.94% concentration, a PII range of 1.78-1.85 at 0.21% concentration and a PII of 0.04 at 0.084% concentration. In a 21-day cumulative irritancy test in seven volunteers, daily application of a product containing 1.13% of docusate sodium (84% purity) under occlusive conditions resulted in a total irritation score of 324/578, with the average score of 46.3/84 per subject (CIR, 2013; CIR, 1998);
  • Dermal irritation has been observed in humans (studies and case reports) following repeated application of products containing docusate sodium at <5% (CIR, 2013); and
  • The US CIR (2013) report stated, 'Diethylhexyl sodium sulfosuccinate (previously named dioctyl sodium sulfosuccinate) was reviewed by the CIR Expert Panel (Panel) in 1994, and a safe concentration limit of 0.42% was established. A petition to open the report to review new clinical data was received, and in 1998, the Panel amended the report to conclude that this ingredient is safe as used in cosmetic formulations. In the discussion, the Panel stressed that care should be taken to avoid irritancy, especially in those products intended for prolonged contact with the skin.' (CIR, 2013).

Current scheduling status and relevant scheduling history

Docusate sodium is currently listed in Appendix B of the Poisons Standard as follows:

Appendix B, Part 3: Substances considered not to require control by scheduling

DOCUSATE SODIUM (DIOCTYL SODIUM SULFOSUCCINATE)

Date of entry: February 1970
Reason for Entry – a, low toxicity
Area of Use – 7.1, general, any use

Docusate sodium (as dioctyl sodium sulphosuccinate) was considered for scheduling at the February 1970 meeting of the National Health and Medical Research Council Poisons Schedule Sub-committee. The product presented to the committee was a combination of bisacodyl and docusate sodium and was intended for use as a general purpose laxative. The sub-committee agreed that neither of the well-known actives required scheduling due to their low toxicity.

Australian regulatory information

Docusate sodium is listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 3 of 2017 as follows:

Table 2.4.1: Permissible ingredients and requirements applying to docusate sodium when contained in a medicine
Column 1 Column 2
Ingredient Name
Column 3
Purpose of the ingredient in the medicine
Column 4
Specific requirements(s) applying to the ingredient in Column 2
1900 DOCUSATE SODIUM E -

Docusate sodium is in 186 products on the ARTG, including medicines for constipation, pain relief, Parkinson's disease, anxiety, benign prostatic hyperplasia. Four (medicines to treat constipation) of the 186 products are listed medicines and 95 are non-prescription medicines (includes medicines for constipation and pain relief).

According to the TGA Ingredient Database, docusate sodium is available for use as an:

  • Active Ingredient in: Biologicals, Export Only, Over the Counter, Prescription Medicines; and
  • Excipient Ingredient in: Biologicals, Devices, Export Only, Listed Medicines, Over the Counter, Prescription Medicines.

In the last 20 years, there have been 81 reported adverse events related to docusate sodium in the Database of Adverse Events Notification (DAEN) - Medicines: 22 cases with a single suspected medicine (application site reaction (22), otitis externa (18) and ear pain (16)) and 1 case of death as a reported outcome.

Docusate sodium is present in 2 products registered by the Australian Pesticides and Veterinary Medicines Authority (APVMA), to treat the alimentary systems of dogs, cats and horses, containing up to 2.1% (21 mg/mL) docusate sodium.

International regulations

EU

Docusate sodium was registered under REACH as of 15 June 2012. The registration dossier was updated on 17 December 2016, following compliance checks by ECHA.

Docusate sodium is used in the following products in the EU: washing & cleaning products, lubricants and greases, polymers, metal working fluids, textile treatment products and dyes, pH regulators and water treatment products, hydraulic fluids and leather treatment products. This substance is also used as an intermediate in the manufacture of another substance.

Docusate sodium is used in the following areas: mining, agriculture, forestry and fishing, formulation of mixtures and/or re-packaging and municipal supply (e.g. electricity, steam, gas, water) and sewage treatment. It is used for the manufacture of: chemicals, textile, leather or fur, plastic products and food products.

USA-FDA

Docusate sodium is an approved ingredient for use in certain over-the-counter products including weight control and pediculicide drugs.

Canada

Docusate sodium is in 59 marketed over-the-counter products in Canada. Products include treatments for bloat and constipation.

New Zealand

Docusate sodium (as dioctyl sodium sulfosuccinate) is available for General Sale in NZ.

Substance summary

Docusate sodium is used in cosmetics, domestic products and in human therapeutic products (primarily as a laxative to treat constipation and as an ear wax remover) and animal therapeutic products (used to treat constipation and bloat).

Table 2.4.2: Chemical information for docusate sodium
Property Docusate sodium
Chemical structure chemical structure of docusate sodium
Molecular formula C20H37NaO7S
Molecular weight 444.6 g/mol
CAS number 577-11-7
CAS name butanedioic acid, sulfo-, 1,4-bis(2-ethylhexyl) ester, sodium salt
IUPAC and/or common and/or other names Sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate (IUPAC);
Diethylhexyl sodium sulfosuccinate (INCI);
Dioctyl sodium sulfosuccinate; succinic acid, sulfo-1,4-bis(2-ethylhexyl)ester, sodium salt.

The following information was extracted from the IMAP Human Health Tier II assessment report for docusate sodium publicly available from the NICNAS website. The US Cosmetic Ingredients Review (CIR) report is also publicly available.

Table 2.4.3: Acute toxicity end-points for docusate sodium
Toxicity Species Docusate Sodium SPF (2015) Classification
Acute oral toxicity
LD50 (mg/kg bw)
Rat 1900 - 4200 Schedule 5
Acute dermal toxicity
LD50 (mg/kg bw)
Rabbit (New Zealand White) >2000 Schedule 5
Acute inhalational toxicity
LC50 (mg/m3/4h)
Rat 20 mg/L
However, only very limited data available
Schedule 7
Skin irritation Rabbit (Russian and New Zealand White) Severe skin irritant Schedule 6
Human Cumulative skin irritant
Eye irritation Rabbit (Russian and New Zealand White) Severe eye irritant Schedule 6
Skin sensitisation (human repeated insult patch tests - HRIPTs) Human Not skin sensitising N/A

Acute oral toxicity

Based on the weight of evidence of results from animal tests following oral exposure, docusate sodium is considered to have low acute oral toxicity.

In a study in rats conducted according to Organisation for Economic Co-operation and Development (OECD) test guidelines, the median lethal dose (LD50) reported was >2100 mg/kg bw. In several other acute toxicity studies in rats, the oral LD50 values were reported to be between 3080 - 4200 mg/kg bw. In 2 other studies, no mortalities were reported up to the highest doses tested (LD50 values of >1300 and >1400 mg/kg bw, respectively). Although an LD50 value in rats of 1900 mg/kg bw was reported in 1 early study, only limited study details are available.

Acute dermal toxicity

Docusate sodium has low acute toxicity based on results from animal tests following dermal exposure.

In a study in New Zealand White (NZW) rabbits, the dermal LD50 value was reported to be
>10000 mg/kg bw. No mortalities were reported. Local effects of skin irritation were noted. In another study of limited reliability (due to low numbers of animals), the dermal LD50 in rabbits was reported to be 2525 mg/kg bw.

Acute inhalation toxicity

Limited inhalation data are available. Docusate sodium is reported to have a median lethal concentration (LC50) value of 20 mg/L in rats following 96-hours exposure. No further study details are available.

Skin irritation

Based on available experimental data, docusate sodium is considered to be a skin irritant. While effects indicative of corrosivity have been reported in several studies, these followed co-exposure to other substances, or exposure for prolonged exposure times.

In a skin irritation study conducted according to relevant OECD test guidelines, 0.5 mL of a 70% solution of docusate sodium was applied, under occlusive conditions, to the shaved skin of 3 white Russian rabbits for a 4 hour exposure period. A mean irritation score of 7.8 (out of a maximum score of 8) was reported based on observations recorded at 1, 24, 48 and 72 hours after exposure. Severe erythema and oedema were still observed in all animals after 14-days' observation, with formation of scars reported in 2/3 animals. While scar formation may indicate corrosive effects, the presence of 15% ethanol (denatured with 5% methanol) in the solution potentially increased the irritancy of the test substance was reported.

In another study conducted according to test guidelines, 0.5 mL of docusate sodium (>97% purity) was applied under occlusive conditions, to the shaved and intact skin of 6 NZW rabbits for 24-hours exposure. A primary irritation score of 3.83/4 was reported, with docusate sodium considered to be strongly irritating to the skin. Erythema and oedema were still observed after 72-hours observation. Reversibility was not assessed in this study.

In other studies, docusate sodium applied as a 2% patch on the skin of rabbits for 24 hours resulted in irritation scores of 3.7/8 (intact skin) and 1.7/8 (abraded skin), while 5% of docusate sodium applied to intact abdominal skin in rabbits produced a burn after two to four 24-hour applications, and 25% produced a burn after one 24-hour application. Additionally, application of 1, 5 and 25% of docusate sodium to abraded rabbit skin for three days caused moderate to severe irritation.

Eye irritation

Based on the available experimental data, docusate sodium is considered to be a severe eye irritant.

In an eye irritation study conducted according to relevant OECD test guidelines, 0.1 mL of a 70% solution of docusate sodium was applied to the right eye of 3 white Russian rabbits; the left eye served as the control. The test substance was washed out of the eye after 72-hours' exposure. An irritation index of 46.67/110 was reported based on mean irritation scores recorded at 1, 24, 48 and 72 hours after application. Effects, including turbidity of the cornea (reported as irreversible damage), were still visible after 21-days.

In another eye irritation study, 0.1 mL (equivalent to 0.1 g) of docusate sodium (>97% purity) was applied to the eyes of 3 NZW rabbits (exposure period not specified). Docusate sodium was reported to cause moderate eye irritation based on observations at 24, 48 and 72 hours after application. Effects on the cornea, iris and conjunctivae were still present after 72-hours observation. Reversibility was not assessed in this study.

A 10% solution of docusate sodium was also reported to have been used as a positive control in an eye irritancy test in rabbits, with severely irritating effects.

Sensitisation

While no skin sensitisation studies in animals are available, several repeat insult patch tests have been conducted in humans, with no significant effects indicative of skin sensitisation observed. However, skin irritation was reported in these studies, resulting from repeated exposure to docusate sodium.

Repeat-dose toxicity

Based on the available information from experimental studies, repeated oral exposure to docusate sodium is not considered to cause serious damage to health.

Based on the limited data available, repeated dermal exposure to docusate sodium is not considered to cause serious systemic health effects.

While several repeated inhalation toxicity studies in animals are available, these were conducted using formulated products containing docusate sodium, with very little information regarding the composition of the product. Therefore, any adverse effects reported in these studies cannot be solely attributed to docusate sodium being assessed in this report.

Genotoxicity

Although 2 well-conducted in vitro experimental studies are available, the results are inconclusive, and as no in vivo studies are available, there is insufficient evidence to determine the genotoxic potential of docusate sodium.

In an in vitro bacterial reverse mutation assay (Ames test), docusate sodium did not induce mutations in several strains of Salmonella typhimurium, either with or without metabolic activation, at test concentrations up to 5000 μ&mg/plate.

In an in vitro mammalian chromosome aberration test in Chinese hamster ovary (CHO) cells, a significantly increased frequency of cells with chromosomal aberrations was reported at concentrations ≥120 μg/mL, only in the presence of metabolic activation. No significant difference was observed in the absence of metabolic activation. While the study concluded that docusate sodium was able to induce chromosome aberrations in CHO cells, the authors noted that effects were observed at doses very close to the threshold of toxicity, and that aberration induction is likely to be associated with an indirect mechanism.

Carcinogenicity

No reliable data are available.

The only available carcinogenicity information is from a 6 month study investigating colorectal carcinogenesis in male rats. Animals were administered docusate sodium in the diet at 0 or 1%, in addition to a weekly single subcutaneous injection of 1,2-dimethylhydrazine (a chemical known to induce colon tumours in experimental animals). No statistically significant difference between test and control group animals were reported in regards to frequency or progression of tumours. However, due to the study design and the very limited study details available, these results are insufficient to determine the carcinogenic potential of docusate sodium.

Reproduction and developmental toxicity

Docusate sodium is the sodium salt of the diester of 2-ethylhexanol (2-EH) and sulfosuccinic acid, with hydrolysis of docusate sodium resulting in formation of 2-EH at a ratio of 2:1. Docusate sodium 2-EH has been assessed by NICNAS and is reported to cause developmental toxicity, but not teratogenicity, in rats following treatment via the oral route. These effects were noted in the absence of signs of marked maternal toxicity. The NOAEL for developmental toxicity was reported to be 130 mg/kg bw/day. Docusate sodium 2-EH is also classified as a Category 3 hazardous substance toxic to reproduction, with the risk phrase 'Possible risk of harm to the unborn child' (Xn; R63) in the HSIS (Safe Work Australia).

Available data on docusate sodium indicate that it is not a specific reproductive or developmental toxin. While some developmental effects were seen in a study using a very high dose of docusate sodium, this dose is outside the dose range considered relevant for developmental toxicity studies.

Observation in humans

In addition to being a potential skin and eye irritant following a single exposure, docusate sodium is reported to be a cumulative irritant based on effects observed in human irritation and skin sensitisation studies.

In 'mini-cumulative irritancy tests' in humans with 4 products containing docusate sodium at different concentrations, the following primary irritation index (PII) ranges were reported (CIR, 2013):

  • 0.25-0.80 for a product containing 3.5% solution of 84% of docusate sodium (chemical concentration = 2.94%);
  • 1.78 and 1.85 for two products containing 0.25% solution of 84% of docusate sodium (chemical concentration = 0.21%); and
  • 0.04 for a product containing 0.1% solution of 84% of docusate sodium (chemical concentration = 0.084%).

These PIIs indicate only mild skin irritation with cumulative exposure at concentrations up to ~3%.

In a 21-day cumulative irritancy test in 7 volunteers, daily application of a product containing 1.13% of docusate sodium (of 84% purity) under occlusive conditions resulted in a total irritation score of 324/578, with the average score of 46.3/84 per subject (CIR, 2013; CIR, 1998).

Skin irritation reactions were also reported in 6 patients following application of an orthopaedic plaster cast lined with a wool containing docusate sodium solution (CIR, 2013; CIR, 1998). Subsequent patch testing was conducted in these patients using the 4 chemicals used to manufacture the wool (the other three chemicals are not identified) at concentrations of 1, 10, and 100%. Application of docusate sodium produced positive irritancy reactions in all patients. The other 3 chemicals did not cause irritation. In a follow-up patch testing study, a product containing docusate sodium was applied to the skin of 18 volunteers (8 with normal skin and 10 with non-inflammatory skin disease). No irritation or allergic reactions were reported in any of the subjects exposed to docusate sodium at 1 and 10%. However, at 100%, docusate sodium produced skin irritation reactions in 12/18 volunteers.

In a separate study with 50 subjects, no irritation effects were reported following a single application of a formulation containing docusate sodium at 2.5% (occlusive patch) for a 24-hour period (CIR, 2013).

In a skin sensitisation patch test in humans, 0.3 g of a 2.5% solution of docusate sodium was applied to the back or forearms of 100 volunteers for 24-hour periods over 10 alternate days (induction phase). After one-week's rest, 0.3 g of a 1% solution was applied to different sites on the back or forearms of the volunteers for 24-hours (challenge phase). Observations were recorded after removal of the challenge patch. No sensitisation reactions were reported in any of the subjects at the challenge sites. However, mild erythema was reported in 19/100 individuals during the induction phase (REACH).

Docusate sodium was also reported not to induce skin sensitisation effects in several human repeated insult patch tests (HRIPTs) at concentration up to 5%. However, mild irritation reactions were reported in some individuals during the induction phase (CIR, 2013). Similar results were observed in a HRIPT of a 50/50 dilution in distilled water of an eyebrow pencil containing 2.5% of docusate sodium and another HRIPT of a product containing 0.1% of docusate sodium (reported as 84% purity) (CIR, 2013; CIR, 1998).

Public exposure

Currently, there are no restrictions in Australia on using this chemical in cosmetics or domestic products.

Considering the range of domestic, cosmetic and personal care products that may contain docusate sodium, the main route of public exposure is expected to be through the skin, inhalation from products applied as sprays or aerosols, and potential eye exposure from eye make-up products. Docusate sodium is also reported to be used in a cosmetic product that is likely to result in exposure to the mucous membrane. No further details on the product are available. Reported use of docusate sodium in a bath oil is also a potential concern in regards to all routes of exposure. Although concentration levels of docusate sodium used in consumer products in Australia are not known, docusate sodium is reported to be used in domestic products overseas at concentrations ranging from 0.01 - 5.0%. The maximum reported use concentration in cosmetic products overseas is at 4.4% in a leave-on eye make-up product. Docusate sodium is also reported to be used in leave-on skin moisturising products. Although use concentrations of docusate sodium are not specifically reported for these products, a concentration range of 0.0002 - 4.4% is reported for cosmetic products that are expected to result in dermal exposure. The concentration of docusate sodium used in bath oil is not reported (CIR, 2013).

The US Cosmetic Ingredients Review (CIR) Expert Panel evaluated the use of docusate sodium in cosmetic products in 1998 and 2013. Both reviews acknowledged that docusate sodium is a cumulative irritant and that 'care should be taken to avoid irritancy in formulations intended for prolonged contact with the skin', concluding that use of docusate sodium in cosmetics is 'safe in the present practices of use and concentration in cosmetics described...' and '...when formulated to be non-irritating' (CIR, 2013).

While docusate sodium is reported to be used at concentrations up to 0.25% in cosmetic products that may be aerosolised, there are insufficient data from inhalation exposure studies to determine the risk from use of these products. However, the CIR panel evaluated the risk of incidental inhalation exposure of docusate sodium from hair sprays, and concluded that, based on the available information (including docusate sodium and biological properties of docusate sodium), incidental inhalation is not considered to be a significant route of exposure that could lead to local respiratory or systemic effects.

Docusate sodium is a severe eye and skin irritant. Docusate sodium at 10% concentration was reported to cause severe eye irritation in rabbits. As the rinse off cosmetic products may lead to ocular exposure, concentration of docusate sodium in these products should be lowered to mild or non-irritating concentrations.

Docusate sodium is not a skin irritant at 2.5% concentration but a mild irritant at 5% concentration in humans. However, in a human patch test, a 2.5% solution of docusate sodium applied for 10 days produced mild erythema in 19/100 individuals. Docusate sodium caused mild skin irritation with cumulative exposure at concentrations up to ~3%, indicating concerns for use in leave-on cosmetic products at higher concentrations.

Pre-meeting public submissions

Two (2) public submissions were received, one (1) opposed and one (1) did not state a position.

Main points opposed:

  • Scheduling of this surfactant will not lead to a better risk management outcome;
  • The risks of surfactants are already well managed;
  • The public have a good understanding that surfactant based products such as shampoos, soaps and detergents are irritating to skin and eyes and will wash their hands and rinse their eyes in case of accidental contact, without being prompted by the label; and
  • If accidental eye contact did occur, attempting to read any instructions on the product label may prove to be problematic.

The other submission noted that more clarity was needed regarding restrictions for docusate sodium so that industry may comment. The submitter supported the current CIR recommendations that products containing dialkyl sulfosuccinate salts (including docusate sodium), be used in cosmetic products at concentrations up to 5.0% with the caution that manufacturers are aware that 'care should be taken to avoid irritancy, especially in those products intended for prolonged contact with the skin' (CIR, 2013).

The public submissions will be made available on the TGA website.

Summary of ACCS-ACMS advice to the delegate

The committee recommended that the current Appendix B (7.1 – any use) entry for docusate sodium in the Poisons Standard remained appropriate, and suggested that a review into the scheduling of all surfactants should take place.

Members agreed that the relevant matter under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance.

The reasons for the advice were:

  • There is no evidence of a public health risk.
  • Appendix B remains appropriate for docusate sodium in the absence of evidence relating to the human safety issues.

Delegate's considerations

The delegate considered the following regarding this proposal:

  • Scheduling proposal
  • ACCS-ACMS advice
  • Public Submissions received
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2015)
  • Other relevant information

Delegate's interim decision

The delegate's interim decision is that the current Appendix B (7.1, any use) entry for docusate sodium in the Poisons Standard remains appropriate.

The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of a substance.

The reasons for the interim decision are:

  • There is no evidence of a public health risk.
  • Appendix B remains appropriate for docusate sodium in the absence of evidence relating to the human safety issues.

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