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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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2.2 Quinine and its salts

Referred scheduling proposal

An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a new entry for quinine in Schedule 6 of the Poisons Standard, with exemption concentration cut-offs and skin sensitisation warning labels.

Scheduling application

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

Schedule 6 – New Entry

QUININE in hair preparations except when the maximum concentration in ready-for-use hair preparations is 0.5 per cent or less of quinine base in rinse-off products or 0.2 per cent or less of quinine base in leave-in products.

Appendix F, Part 3 – New Entry

QUININE

Warning Statement: 28 (Repeated exposure may cause sensitisation).

The applicant's reasons for the request are:

  • Quinine and its salts are skin sensitisers;
  • Quinine and its salts have moderate acute oral toxicity;
  • Quinine and its salts are reported to be used in cosmetic products overseas and are therefore likely to be used in similar products in Australia; and
  • Quinine and its salts have international restrictions on their use - the maximum concentration allowed in ready-for-use hair preparations is 0.5% (as quinine base) in rinse-off products and 0.2% (as quinine base) in leave-on products.

Current scheduling status and relevant scheduling history

Quinine is currently listed in Schedules 4, 5 and 7 in the Poisons Standard as follows:

Schedule 7

QUININE for veterinary use except when included in Schedule 5.

Schedule 5

QUININE in preparations for veterinary use containing 1 per cent or less of quinine.

Schedule 4

QUININE for human therapeutic use except when the maximum recommended daily dose is 50 mg or less of quinine.

In March 1980, the Poisons Schedule Committee (PSC) considered a new entry in Schedule 3 for quinine after several cases of children's deaths due to accidental overdose. The committee decided to agree to this proposal.

In November 1985, the PSC discussed the need for additional warnings as accidental children's deaths were still occurring. The committee agreed and quinine was included in Appendix F, Part 1 - Warning Statements (21 – WARNING – May be fatal to children) and Part 2 - Poisons Required to be Labelled with Warning Statements (Quinine ... 21). This was amended to Appendix F, Part 1 (8 – WARNING – May be fatal to children) and Part 3 (Quinine … 8) in the SUSDP No. 5 as part of amendments to that Appendix.

In November 1986 the DPSC agreed to an exemption of liquids containing 40 mg/L or less of quinine from Schedule 3. The committee did not support a proposal to remove the "warning – may be fatal to children" statement from paediatric products.

In May 1990, the DPSC discussed placing quinine and its salts in Schedule 4 following reports of fatal cases of thrombocytopenia. The committee agreed that there was insufficient specific data to warrant the up-schedule and decided the scheduling remains appropriate. It was noted that the committee recommended that the PSA educate pharmacists on the risks.

In August 1992, the DPSC discussed down-scheduling low-dose quinine to Schedule 2. However, due to the risks previously discussed, the committee agreed that the scheduling remains appropriate. The committee agreed to change the current Schedule 3 entry with the exemption of 40 mg/L or 40 mg/kg or less of quinine that exempts soft drinks and low dose liquid and solid homoeopathic preparations.

In May 1993, the DPSC again discussed down-scheduling quinine from Schedule 3 to Schedule 2 and agreed that due to the risks, the current scheduling remained appropriate.

In February 1996, the NDPSC recommended the rescheduling of quinine from Schedule 3 to Schedule 4 due to quinine's potential to cause thrombocytopenia and reports of haemolytic uraemic syndrome. This was agreed in the May 1996 NDPSC meeting, and the appropriate amendments to the Poisons Standard were made.

In May 1998, the NDPSC discussed down-scheduling individual dosage units containing 15 mg or less of quinine up to a maximum daily dose of 50 mg of quinine from Schedule 4 to Schedule 2. The committee discussed prior meetings decisions and agreed that the current scheduling remains appropriate.

In June 2005, the NDPSC approved quinine for veterinary use and placed it in Schedule 7 and Schedule 5.

In June 2006, the NDPSC agreed to amend the Schedule 4 entry on international harmonisation grounds. The committee agreed to amend the entry to reflect therapeutic use instead of internal use.

Australian regulatory information

Quinine is listed in the Australia New Zealand Food Standards Code in Schedules 15 and 19. Quinine has a maximum permitted level as a food additive (Schedule 15) and a maximum level as a natural toxicant (Schedule 19) of:

Table 2.2.1: Permissible ingredients and requirements applying to quinine 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
4187 QUININE ARSENITE H

Only for use as an active homoeopathic ingredient.

Quinine is a mandatory component of Quinine arsenite.

The maximum recommended daily dose must be no more than 50 mg of quinine.

4188 QUININE SULFATE DIHYDRATE H

Only for use as an active homoeopathic ingredient.

Quinine is a mandatory component of quinine sulfate dihydrate.

The maximum recommended daily dose must be no more than 50 mg of quinine.

Quinine is listed in 4 products on the Australian Register of Therapeutic Goods (ARTG) as an active ingredient.

Quinine is in two veterinary medicines (fish tank anti-protozoal medication products) that contain 1% quinine and are captured by Schedule 5.
In the last 20 years, there have been 575 adverse events reports in the Database of Adverse Events Notification (DAEN) - Medicines: 334 cases with a single suspected medicine and 14 cases of death as a reported outcome.

According to the TGA Ingredient Database, quinine is available for use as follows:

  • Quinine is available for use as an Active Ingredient in: Biologicals, Export Only, Over the Counter, Prescription Medicines;
  • Quinine is available for use as an Excipient Ingredient in: Biologicals, Devices, Prescription Medicines;
  • Quinine is available for use as an Equivalent Ingredient in: Listed Medicines; and
  • Quinine salts are available for use as an Active Ingredient or Excipient Ingredient in a range of areas, but not available as an Equivalent Ingredient.

International regulations

Quinine is currently listed in:

  • EU Cosmetics Regulation 1223/2009 Annex III—List of substances which cosmetic products must not contain except subject to the restrictions and conditions laid down
  • New Zealand Cosmetic Products Group Standard—Schedule 5: Components cosmetic products must not contain except subject to the restrictions and conditions laid down
  • Association of Southeast Asian Nations (ASEAN) Cosmetic Directive Annex III—List of substances which cosmetic products must not contain except subject to restrictions and conditions laid down

For all of the above, the maximum concentration allowed in ready-for-use hair preparations is 0.5% (as quinine base) in rinse-off products and 0.2% (as quinine base) in leave-on products.

Substance summary

Quinine and its salts have key/expected uses in cosmetics, food flavourings, therapeutic and veterinary medicines.

Chemical structure of CAS 130-95-0
130-95-0
quinine (INCI); cinchonan-9-ol, 6'-methoxy-, (8.alpha.,9R)- (CAS); quinine anhydrous
Chemical structure of CAS 549-56-4
549-56-4
cinchonan-9-ol, 6'-methoxy-, (8.alpha.,9R)-, sulfate (1:1) (salt) (CAS); quinine sulfate (1:1)
Chemical structure of CAS 804-63-7
804-63-7
cinchonan-9-ol, 6'-methoxy-, (8.alpha.,9R)-, sulfate (2:1) (salt) (CAS); quinine sulfate (2:1)
Chemical structure of CAS 6119-70-6
6119-70-6
methoxy-, (8.alpha.,9R)-, sulfate(2:1) (salt), dihydrate (CAS); quinine sulfate (2:1) dihydrate
Chemical structure of CAS 6183-68-2
6183-68-2
cinchonan-9-ol, 6'-methoxy-, (8.alpha.,9R)-, sulfate (1:1) (salt), heptahydrate (CAS); quinine sulfate (1:1) heptahydrate
Chemical structure of CAS 60-93-5
60-93-5
cinchonan-9-ol, 6'-methoxy-, dihydrochloride, (8.alpha.,9R)- (CAS); quinine dihydrochloride
Chemical structure of CAS 130-89-2
130-89-2
cinchonan-9-ol, 6'-methoxy-, monohydrochloride, (8.alpha.,9R)- (CAS); quinine monohydrochloride
Chemical structure of CAS 619-47-7
6119-47-7
cinchonan-9-ol, 6'-methoxy-, monohydrochloride, dihydrate, (8.alpha.,9R)- (CAS); quinine hydrochloride dihydrate
Chemical structure of CAS 7549-43-1
7549-43-1
cinchonan-9-ol, 6'-methoxy-, hydrochloride, (8.alpha.,9R)- (CAS); quinine hydrochloride (unspecified)

Figure 2.2.1: Chemical structures, alternative names and CAS numbers for quinine and its salts

The following information was extracted from the Human Health Tier II Assessment report for Quinine and its salts, publicly available from the NICNAS website.

Table 2.2.2: Acute toxicity end-points for Quinine
Toxicity Species Quinine SPF (2015) Classification
Acute oral toxicity
LD50 (mg/kg bw)
Human 29–114 mg/kg bw (quinine, CAS No. 130-95-0) Schedule 6
Rat 456 mg/kg bw, equivalent to 351 mg/kg bw quinine base (quinine sulfate (1:1), CAS No. 549-56-4)
Rabbit 641 mg/kg bw (quinine dihydrochloride, CAS No. 60-93-5)
Mouse 660 mg/kg bw (quinine dihydrochloride, CAS No. 60-93-5)
Rat 1392 mg/kg bw (quinine dihydrochloride, CAS No. 60-93-5)
Guinea pig 1800 mg/kg bw (quinine, CAS No. 130-95-0)
Acute dermal toxicity
LD50 (mg/kg bw)
N/A No data available N/A
Acute inhalational toxicity
LC50 (mg/m3/4h)
N/A No data available N/A
Skin irritation Guinea pig Not irritating up to 25% concentration (quinine monohydrochloride, CAS No. 130-89-2) N/A
Eye irritation in vitro bovine corneal opacity and permeability (BCOP) test method (OECD TG 437) Not irritating up to 20% concentration (quinine, CAS No. 130-95-0), but further testing is required based on the outcome of this test N/A
Skin sensitisation
(Guinea pig maximisation test and human case reports)
Guinea pig Sensitisation reactions observed in 80–95% of exposed animals, reported as a 'grade V allergen or potent contact allergen' (quinine monohydrochloride, CAS No. 130-89-2) Schedule 6
Human Skin sensitisation in humans assessed by patch testing and oral challenge test

Acute toxicity

Quinine and its salts are considered to have moderate acute oral toxicity in animals. No data are available for acute dermal and acute inhalation toxicity.
The reported oral median lethal dose (LD50) values were:

  • 1800 mg/kg bw in guinea pigs exposed to quinine;
  • 641, 660 and 1392 mg/kg bw in rabbits, mice and rats, respectively, exposed to quinine dihydrochloride; and
  • 456 mg/kg bw in rats exposed to quinine sulfate (1:1), which is reported to equate to 351 mg/kg bw quinine base.

In humans, ingestion of 2–8 g of quinine has been reported to be fatal in adults. This equates to a dose of approximately 29–114 mg/kg bw in a 70 kg person.

Irritation

Quinine and its salts are not considered to cause skin irritation at concentrations up to 25%.
For eye irritation, only in vitro data are available and the outcome is that no prediction of eye irritancy can be made without additional testing.

Sensitisation

Quinine and its salts are considered to cause skin sensitisation.

In a guinea pig maximisation test conducted similar to OECD TG 406, animals (n = 20/group) were exposed to quinine hydrochloride at 0.25% in distilled water for intradermal induction; pre-treated with sodium lauryl sulfate before being exposed to quinine hydrochloride at 20% in petrolatum for epicutaneous induction; and challenged 21 days later with 1, 5 or 10% quinine hydrochloride in petrolatum by topical application for 24 and 48 hours. Quinine was reported to be a grade V allergen or potent contact allergen, since sensitisation was observed in 80–95% of animals exposed to quinine at 5 or 10% at both 24 and 48 hour time-points.

Observation in humans

Human case reports support the potential for skin sensitisation.

In five case studies in males (aged 25 – 40 years), exposure to quinine (indirectly from a contraceptive pessary used by their wives, which contained quinine, or directly through use of a hair lotion that contained quinine or via consumption of bitter flavoured beverages) caused present or past contact dermatitis (skin rash and inflammation). Patch testing using 1% quinine sulfate (n = 1) or 2% quinine sulfate (n = 4) resulted in positive reactions in all patients, confirming that quinine is a contact allergen.

Recurrent contact dermatitis was reported in a 15-month old child exposed on the upper chest for three months to a topical respiratory decongestion balm. Patch testing confirmed an allergy to quinine, one of the components of the topical balm.

In a 26-year old man, examination of asymptomatic swelling and redness led to a fixed eruption diagnosis (adverse skin reaction), secondary to quinine consumption of tonic beverages. An oral challenge test using tonic water, and a patch test using 1% quinine hydrochloride were both positive. Severe redness and swelling of the lips was observed four days after the man drank tonic water; a large blister with redness was observed at the patch test site two days after exposure to quinine hydrochloride. Eleven other cases (n = 6 males, n = 5 females, 23–57 years old) of fixed eruption attributed to quinine in tonic beverages have also been reported and confirmed by oral challenges or patch testing.

Other hypersensitivity reactions have also been reported in humans, including anaphylactic shock, anaphylactoid reactions, urticaria (hives, upper dermis swelling), angio-oedema (swelling below the dermis layer), serious skin rashes, facial swelling, bronchospasm and pruritus (severe skin itching).

Irritant dermatitis was reported in process workers in a factory manufacturing quinine sulfate (1:1), but with potential exposure to up to 13 different quinine or quinidine (the stereoisomer of quinine) products. Employees with a current or past history of skin disorders were examined
(n = 23, from a total of 73 employees), and skin disorders from 15 of the 23 employees were deemed to be work-related. Exposure to quinine was deemed the cause of skin disorders in 13 of the 15 work-related cases, with development of symptoms typically occurring 4 to 8 weeks post-exposure (range 2 weeks to 8 months). However, negative results were observed during patch testing and medical opinion based on clinical examination suggested that the effects were caused by irritation, rather than allergy. For the majority of workers, the effects were reversed following cessation of exposure, or spontaneously cleared even with continued exposure.

Repeat-dose toxicity

Quinine and its salts are not considered to cause serious systemic health effects from repeated oral exposure. No data are available for repeated dermal and repeated inhalation exposure.

Genotoxicity

Quinine and its salts are not considered to be genotoxic.

Carcinogenicity

The available data are insufficient to derive a conclusion on carcinogenicity of quinine and its salts.

Reproduction and developmental toxicity

Quinine and its salts are not expected to cause developmental toxicity. The limited available data in female rats and pregnant women indicate quinine and its salts have no reproductive toxicity in females, but no test data are available on males.

Public exposure

Although specific use in cosmetic products in Australia is not known, quinine and its salts are reported to be used in cosmetic products overseas as denaturants, hair conditioning agents, masking agents and fragrance ingredients.

Pre-meeting submissions

Three (3) public submissions were received, all in support of the proposal to align concentration limits for quinine and its salts with international (EU) standards.

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

Summary of ACCS-ACMS advice to the delegate

The committee recommended that a new Schedule 6 entry for QUININE be created in the Poisons Standard as follows:

Schedule 6 – New Entry

QUININE in cosmetic preparations except:

  1. in rinse-off hair preparations containing 0.5 per cent or less of quinine; or
  2. in leave-on hair preparations containing 0.2 per cent or less of quinine.

Appendix F, Part 3 – New Entry

QUININE

Warning Statement: 28 (Repeated exposure may cause sensitisation).

Index – Amend Entry

QUININE
cross reference: QUININE (CAS No. 130-95-0), QUININE SULFATE (1:1) (CAS No. 549-56-4), QUININE SULFATE (2:1) (CAS No. 804-63-7), QUININE SULFATE (2:1) DIHYDRATE (CAS No. 6119-70-6), QUININE SULFATE (1:1) HEPTAHYDRATE (CAS No. 6183-68-2), QUININE DIHYDROCHLORIDE (CAS No. 60-93-5), QUININE MONOHYDROCHLORIDE (CAS No. 130-89-2), QUININE HYDROCHLORIDE DIHYDRATE (CAS No. 6119-47-7), QUININE HYDROCHLORIDE (UNSPECIFIED) (CAS No. 7549-43-1)

Schedule 7
Schedule 6
Schedule 5
Schedule 4
Appendix F, Part 3

The committee also recommended an implementation date of 1 February 2018.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice were:

  • The potential risks of quinine are skin sensitisation and moderate acute oral toxicity.
  • Other than therapeutics and its use as a food additive, the only reported use of quinine is in hair cosmetics (both leave-on and rinse-off).
  • No cosmetic products are reported to exceed the proposed cut-off concentrations of quinine or its salts. Schedule 6 would allow for appropriate labelling and packaging of the product to provide appropriate protections for users and consumers.
  • The proposed exemption concentration cut-offs will align with the maximum permitted concentrations in comparable countries, many of which are among our major trading partners – EU, ASEAN and NZ.
  • A Schedule 6 entry for quinine with ready for use cut-off levels (rinse-off products 0.5% and leave-in products 0.2%) would bring Australia in line with international restrictions on its use.

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 to create a new Schedule 6 entry for quinine in the Poisons Standard. The proposed Schedule entry is as follows:

Schedule 6 – New Entry

QUININE in cosmetic preparations except:

  1. in rinse-off hair preparations containing 0.5 per cent or less of quinine; or
  2. in leave-on hair preparations containing 0.2 per cent or less of quinine.

Appendix F, Part 3 – New Entry

QUININE

Warning Statement: 28 (Repeated exposure may cause sensitisation).

Index – Amend Entry

QUININE

cross reference: QUININE (CAS No. 130-95-0), QUININE SULFATE (1:1) (CAS No. 549-56-4), QUININE SULFATE (2:1) (CAS No. 804-63-7), QUININE SULFATE (2:1) DIHYDRATE (CAS No. 6119-70-6), QUININE SULFATE (1:1) HEPTAHYDRATE (CAS No. 6183-68-2), QUININE DIHYDROCHLORIDE (CAS No. 60-93-5), QUININE MONOHYDROCHLORIDE (CAS No. 130-89-2), QUININE HYDROCHLORIDE DIHYDRATE (CAS No. 6119-47-7), QUININE HYDROCHLORIDE (UNSPECIFIED) (CAS No. 7549-43-1)

Schedule 7
Schedule 6
Schedule 5
Schedule 4
Appendix F, Part 3

The proposed implementation date is 1 February 2018, as this is the earliest possible implementation date.

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; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the interim decision are:

  • The potential risks of quinine are skin sensitisation and moderate acute oral toxicity.
  • Other than therapeutics and its use as a food additive, the only reported use of quinine is in hair cosmetics (both leave-on and rinse-off).
  • No cosmetic products are reported to exceed the proposed cut-off concentrations of quinine or its salts. Schedule 6 would allow for appropriate labelling and packaging of the product to provide appropriate protections for users and consumers.
  • The proposed exemption concentration cut-offs will align with the maximum permitted concentrations in comparable countries, many of which are among our major trading partners – EU, ASEAN and NZ.
  • A Schedule 6 entry for quinine with ready for use cut-off levels (rinse-off products 0.5% and leave-in products 0.2%) would bring Australia in line with international restrictions on its use.

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