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Scheduling delegate's final decisions, July 2016

Scheduling medicines and poisons

27 October 2016

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4.3 2,4-Dinitrophenol

Part A - Final decisions on matters referred to an expert advisory committee

4. Scheduling proposals referred to the July 2016 meeting of the Advisory Committee on Medicines Scheduling (ACMS#18)

4.3 2,4-Dinitrophenol

Note

  • Red strikethrough text indicates text that has been deleted.
  • Green italicised text indicates text that has been added.
Referred scheduling proposal

An application was submitted to list 2,4-dinitrophenol in Schedule 10 due to there being no appropriate therapeutic use and its high toxicity that it is a danger to health warrants prohibition of sale, supply and use.

Scheduling application

General application.

The applicant's proposed amendments to the SUSMP are as follows:

Schedule 10 - New Entry

2,4-DINITROPHENOL for human use.

The applicant's reasons for the request are:

  • 2,4-dinitrophenol is a highly toxic substance when ingested, inhaled or absorbed through the skin;
  • 2,4-dinitrophenol inhibits efficient energy (ATP) production in cells and leads to rapid consumption of energy without generating ATP and consequently increased fat metabolism, increased oxygen consumption and production of heat;
  • In the 1930s, 2,4-dinitrophenol was used as a weight loss agent in the treatment of obesity. Adverse effects included cataracts, renal failure and deaths due to hyperthermia;
  • The US FDA banned therapeutic use of 2,4-dinitrophenol for weight loss in 1938;
  • In the late 1990s, 2,4-dinitrophenol was promoted to the body building community as a 'fat burner'. There has been renewed interest in the use of 2,4-dinitrophenol among body builders and individuals who are anorexic or bulimic;
  • There have been reports of intentional overdoses with 2,4-dinitrophenol;
  • There has been a recent increase in deaths associated with the use of 2,4-dinitrophenol, particularly in the UK;
  • In late 2015, a young woman died in South Australia after the voluntary consumption of around 50 tablets of an unspecified strength of 2,4-dinitrophenol;
  • Users of 2,4-dinitrophenol are sourcing the substance and tablets/capsules via the internet;
  • The current human use of 2,4-dinitrophenol is not under medical supervision and presents a significant risk to health; and
  • 2,4-Dinitrophenol for human use presents such a danger to health as to warrant prohibition of sale, supply and use.
Substance summary

Developed in the late 19th century, 2,4-dinitrophenol is a synthetic organic disubstituted nitro derivative of phenol, produced by hydrolysis of 2,4-dinitrochlorobenzene. It is used non-medically in manufacturing dyes, as a wood preservative, insecticide and as an indicator. 2,4-Dinitrophenol is a chemical intermediate in the production of sulfur dyes and is also used as an antiseptic, as a herbicide (such as Dinoseb (2,4-dinitro-6-sec-butylphenol) and Dinoterb (2-(2-methyl-2-propanyl)-4,6-dinitrophenol)), as a photographic developer and in the manufacture of explosives.

All dinitrophenols are highly toxic when ingested, inhaled or absorbed through the skin. 2,4-Dinitrophenol inhibits efficient energy adenosine triphosphate (ATP) production in cells and leads to rapid consumption of energy without generating ATP and consequently increased fat metabolism, increased oxygen consumption and production of heat.

The mechanism of action of dinitrophenols involves the uncoupling of mitochondrial oxidative phosphorylation resulting in increased metabolism of lipids. This effect led to use of 2,4-dinitrophenol in weight loss tablets in the early 1930s. Adverse effects including cataracts, renal failure and deaths due to hyperthermia were attributed to use of 2,4-dinitrophenol. It was banned for weight loss purposes by the US Food and Drugs Administration (FDA) in 1938. The epidemiological features of the cataracts suggest an idiosyncratic reaction more than toxicity. There has been renewed interest in the use of 2,4-Dinitrophenol as a 'fat burner' among body builders. There have been reports of misuse of 2,4-Dinitrophenol by anorexic and bulimic individuals and in intentional overdoses.

The use of high doses as a dieting aid has been associated with severe side-effects, including death. 2,4-Dinitrophenol is rapidly absorbed through the gastrointestinal tract, respiratory tract and intact skin. Potential symptoms of overexposure include: marked fatigue, tremendous thirst, profuse sweating, flushing of face, nausea, vomiting, abdominal pain, diarrhoea, restlessness, anxiety, excitement, rise in body temperature, tachycardia, hyperpnoea, dyspnoea, cyanosis, muscle cramps, kidney and liver injury.

Acute oral exposure to 2,4-dinitrophenol has resulted in hyperthermia, nausea, vomiting, sweating, dizziness and headache. Subacute oral exposure can cause weight loss. Chronic oral exposure can lead to formation of cataracts and skin lesions and effects on the bone marrow, central nervous system and cardiovascular system.

There has been an increase in the number of deaths associated with use of 2,4-dinitrophenol since 2001. The main effects seen in patients who die as a result of poisoning with 2,4-dinitrophenol include profuse sweating, tachycardia, tachypnoea and hyperthermia.

2,4-Dinitrophenol is a yellow crystalline solid. It is volatile with steam and is soluble in most organic solvents as well as aqueous alkaline solutions. The chemical structure of 2,4-dinitrophenol is shown in Figure 4.3 and a summary of its chemical properties are described in Table 4.3.

Figure 4.3: Structure of 2,4-Dinitrophenol

Figure 4.3: Structure of 2,4-Dinitrophenol

Table 4.3 General chemical information 2,4-dinitrophenol
IUPAC name 2,4-Dinitrophenol
Molecular formula HOC6H3(NO2)2
Molecular weight 184.106 g/mol
CAS No. 51-28-5
Specific questions raised by the delegate

The delegate asked the committee (based on toxicity, morbidity and evidence of misuse) whether 2,4-dinitrophenol should be listed in Schedule 10 or whether another schedule was more appropriate.

Current scheduling status

2,4-Dinitrophenol (CAS No. 51-28-5) is not specifically scheduled in the SUSMP.

There are three class entries for dinitrophenols in the SUSMP as follows:

Schedule 7

DINITROPHENOLS except when included in Schedule 4 or 6.

Schedule 6

DINITROPHENOLS and their homologues in preparations containing 5 per cent or less of such compounds except:

  1. when included in Schedule 4; or
  2. when separately specified in this Schedule.

Schedule 4

DINITROPHENOLS for therapeutic use.

Appendix E, Part 2 - A, G1, E1, S1

Appendix F, Part 3 except when for therapeutic use - 1, 4, 8

Appendix J, Part 2 - 1

Relevant scheduling history

2,4-Dinitrophenol (CAS No. 51-28-5) is not specifically scheduled in the SUSMP.

In January 1955, dinitrophenols were considered by the National Drugs and Poisons Schedule Committee (NDPSC) and included Schedule 4 and in Schedule 6 for agricultural and horticultural purposes. In November 1955 dinitrophenols were included in Schedule 7 by the NDPSC. In May 1956, dinitrophenols were included in Schedule 1 (substances which are extremely dangerous to human life), Schedule 2 and Schedule 4. In February and April 1963 the NDPSC recommended amendment to Schedule 6 and 7 for dinitrophenols and amended the Schedule 4 entry to include the words 'for therapeutic use'. The Schedule 2 entry was deleted in November 1969. In February 1979, first aid statements A, B, F were included. In February 1983, the first aid statement Q was added.

International regulations

US FDA banned therapeutic use of 2,4-dinitrophenol for weight loss in 1938.

The United Kingdom's Food Standards Agency identifies DNP as "an industrial chemical known to have serious short-term and long-term effects, which can be extremely dangerous to human health." and advises "consumers not to take any product containing DNP at any level. This chemical is not suitable for human consumption."

Pre-meeting public submissions

No submissions were received.

Summary of ACMS advice to the delegate

The committee advised that the proposal to include 2,4-dinitrophenol in Schedule 10 was appropriate.

The ACMS advised an implementation date of 1 February 2017.

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; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice comprised the following:

  • Serious and common adverse effects causing significant toxicity, including death;
  • Legitimate industrial uses - pesticide, wood preservative, dyes, photographic developer, and explosive;
  • No legitimate therapeutic use;
  • Serious evidence of misuse; and
  • Education at state level is needed due to the high toxicity of the substance.
Delegate's considerations

The delegate considered the following in regards to this application:

  • Scheduling proposal;
  • ACMS advice;
  • Public submissions received;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling Policy Framework (SPF 2015); and
  • Other relevant information.
Delegate's interim decision

The delegate notes and accepts the ACMS advice and reasons to create a new Schedule 10 entry for 2,4-dinitrophenol for human use. Schedule 10 is the most appropriate schedule for 2,4-dinitrophenol owing to its range of serious acute and chronic adverse effects causing significant toxicity and morbidity. Furthermore, although there are legitimate uses of 2,4-dinitrophenol - pesticide, wood preservative, dyes, photographic developer, and explosive - there are no legitimate therapeutic uses. There is also evidence of serious misuse of 2,4-dinitrophenol.

The proposed implementation date is 1 February 2017.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (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; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

Schedule 10 - New Entry

2,4-DINITROPHENOL for human use.

Schedule 7 - Amend Entry

DINITROPHENOLS except when included in Schedule 4, 6 or 10.

Public submissions on the interim decision

No public submissions were received regarding the interim decision for 2,4-dinitrophenol.

Delegate's final decision

The delegate has confirmed the interim decision as no new evidence has been received to alter the interim decision. The delegate has confirmed that the final decision and reasons for the final decision are in keeping with those for the interim decision.

The implementation date is 1 February 2017.

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