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| Clinical data | |
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| Routes of administration | Oral |
| Drug class | Uncoupling agents |
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| Pharmacokinetic data | |
| Metabolism | Nitro reduction |
| Eliminationhalf-life | Unknown |
| Identifiers | |
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| ChemSpider |
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| UNII | |
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| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.000.080 |
| Chemical and physical data | |
| Formula | C6H4N2O5 |
| Molar mass | 184.107 g·mol−1 |
| 3D model (JSmol) | |
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2,4-Dinitrophenol (2,4-DNP or simplyDNP) is an organic compound with the formula HOC6H3(NO2)2. It has been used inexplosives manufacturing and as a pesticide and herbicide.
In humans, DNP causes dose-dependentmitochondrialuncoupling, causing the rapid loss ofATP as heat and leading to uncontrolledhyperthermia—up to 44 °C (111 °F)—and death in case of overdose. Researchers noticed its effect on raising thebasal metabolic rate in accidental exposure and developed it as one of the firstweight loss drugs in the early twentieth century. DNP was banned from human use by the end of the 1930s due to its risk of death and toxic side effects. DNP continues to be used after its ban and experienced a resurgence in popularity after it became available on the Internet.
DNP has the chemical formula HOC6H3(NO2)2. As a solid, it is a yellow, crystalline and has a sweet, musty odor.[1][2] It sublimates, is volatile with steam, and is soluble in mostorganic solvents as well as aqueous alkaline solutions.[2] DNP is a member of thedinitrophenols chemical family.[1]
DNP can be produced byhydrolysis of2,4-dinitrochlorobenzene.[1][3] Other routes of DNP synthesis includenitration ofmonochlorobenzene, nitration ofbenzene withnitrogen dioxide andmercurous nitrate,oxidation of1,3-dinitrobenzene,[4] and nitration ofphenol withnitric acid.[5]
A dust explosion is possible with DNP in powder or granular form in the presence of air. DNP may explosively decompose when submitted to shock, friction or concussion, and may explode upon heating.[6] DNP forms explosive salts withstrong bases as well asammonia, and emits toxic fumes ofnitrogen dioxide when heated to decomposition.[7] DNP'sexplosive strength is 81% that ofTNT, based on theTrauzl lead block test.[8]
Historically, DNP has been used as an antiseptic and as a non-selectivebioaccumulating pesticide.[9]
DNP was particularly useful as a herbicide alongside other closely related dinitrophenol herbicides like2,4-dinitro-o-cresol (DNOC),dinoseb anddinoterb.[10] Since 1998 DNP has been withdrawn from agricultural use.[11] Currently, there are no actively registered pesticides containing DNP in the United States or Europe.[12][13] Dinoseb is used industrially as apolymerisation inhibitor duringstyrene production. In 2023, theHome Office said it could not determine any legitimate industrial uses for DNP in the United Kingdom.[14]
It is a chemical intermediate in the production ofsulfur dyes,[3] wood preservatives[9] andpicric acid.[15] A precursor to2,4,6-trinitrotoluene (TNT), DNP has also been used to make photographic developers and explosives.[16][17] DNP is classified asan explosive in the United Kingdom[18] and the United States.[19]
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DNP raisesenergy expenditure by 30 to 40 percent and causes a weight loss of 0.7–0.9 kilograms (1.5–2.0 lb) per week.[21] Although DNP is no longer in clinical use as aweight loss drug due to its dangerous side effects, itsmechanism of action remains under investigation as a potential approach for treating obesity andnon-alcoholic fatty liver disease.[1][22][23] Researchers developed aprodrug,HU6, which is metabolized to DNP in the liver to provide more stable blood concentrations. HU6 completed a phase II trial in which it produced significant reductions in liver fat and body weight in overweight people with elevated liver fat, without serious adverse effects.[24]
DNP is used bybodybuilders, fitness enthusiasts, and people with aneating disorder to lose weight. The user profile is similar to that ofanabolic steroids; many perceive it to be effective and with manageable risks.[25] Despite health warnings from regulators, DNP is readily available online[25] sometimes under other names such as Dinosan, Dnoc, Solfo Black, Nitrophen, Aldifen, and Chemox.[17][25] DNP is often sold in tablets containing 100 to 200 mg[1] and may be sold alongside other substances such asanabolic steroids andthyroxine.[17] It may also be found as a contaminant in otherbodybuilding supplements not advertised as containing DNP.[25] Online message boards provide information on dosage and regimens for DNP use, and describe the risks of taking the compound and provide advice on how to mitigate hyperthermia.[17][25][26] According to a study published in 2023, the most commonly reported doses were between 150 and 300 mg/day.[20] Between 2010 and 2020, reports of overdoses were higher in Australasia, Europe and North America than in Asia, Africa, and South or Central America.[27]
It is also used as asuicide method.[17]
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In living cells, DNP acts as aprotonophore, an agent that can shuttleprotons (hydrogen cations) across biological membranes. It dissipates the proton gradient across themitochondrial membrane, collapsing theproton motive force that the cell uses to produce most of itsATP chemical energy. Instead of producing ATP, the energy of the proton gradient is lost as heat.[17] The inefficiency is proportional to the dose of DNP that is taken. As the dose increases and energy production is made more inefficient, metabolic rate increases (and more fat is burned) in order to compensate for the inefficiency and to meet energy demands. DNP is probably the best known agent foruncouplingoxidative phosphorylation. Thephosphorylation ofadenosine diphosphate (ADP) by ATP synthase gets disconnected or uncoupled from oxidation.[citation needed]
DNP raises thebasal metabolic rate (BMR) and lowersT4 (thyroid hormone) levels by increasing T4 metabolism and reducing thyroid hormone secretion. Because it binds tothyroxine-binding globulin, overall thyroid function may not be affected. DNP cannot substitute for thyroid hormone inmyxedema.[28]
Information aboutpharmacokinetics andpharmacodynamics of DNP in humans is limited.[23] DNP is metabolized vianitro reduction. Its major metabolites are2-amino-4-nitrophenol [de] and4-amino-2-nitrophenol.[16] In overdoses, symptom onset can be as soon as 3 hours and the average time to death was 14 hours.[16][17]
Although many militaries are replacing traditional2,4,6-trinitrotoluene (TNT)-based explosives forinsensitive munitions, DNP is a degradation byproduct of theIMX-101 insensitive munition used by theUnited States Army.[29]
While theMeisenheimer charge transfer reaction is effective at detecting TNT, it is not effective at detecting many other explosives including DNP. Researchers are studyingcolorimetric detection and other methods for DNP to find if water or solids such as soils are contaminated with DNP.[30][31][32][33]UiO-66-NH2 can be used to bind to and remove DNP from solution.[34]
DNP has a lowtherapeutic index, meaning that the dosage at which toxicity occurs is not much larger than that required to produce a desired effect.[17] Individual tolerance to DNP's harmful short- and long-term effects varies greatly.[1] The most common adverse effect reported is arash, which could bemaculopapular,urticarial,angioedema, or anexfoliative dermatitis.[17]Cataracts can form, causing a permanent loss of vision in days to months of usage, and permanent deafness has also been reported.[17][35] Other adverse effects reported includeperipheral neuritis,agranulocytosis, andneutropaenia.[17] Negative effects on thecentral nervous system,cardiovascular system, andbone marrow can occur.[1] In animal studies, DNP acted as ateratogen,mutagen, andcarcinogen and caused developmental and reproductive harm.[17] An unusually yellow coloring of the skin,mucous membranes,sclera, urine, stomach contents, and internal organs is an indication of DNP exposure, but does not occur in every case.[36] Contact with skin or inhalation can cause DNP poisoning. Symptoms are typically mild with dermal exposure, but inhalation can lead to systemic effects, the same way as oral exposure.[17]
Overdose is extremely dangerous;[17] cases reported topoison control centers had a 11.9 percent fatality rate between 2010 and 2020.[27] Although the largest number of overdose deaths occurred in the 1910s and 1920s when the chemical was in more widespread industrial use,[1] the substance's use as a dieting aid has caused a number of fatalities in the twenty-first century:[17] at least 50 overdose deaths were reported worldwide between 2010 and 2020.[27] Although the lowest published fatal ingested dose is 4.3 mg/kg,[17][16] a typical overdose death occurs at a higher level of exposure, around 20-50 mg/kg.[1]
The first symptoms to appear are nausea, vomiting, abdominal pain, and perhaps diarrhea.[16] The typical overdose syndrome seen with DNP and other phenols is a combination ofhyperthermia,tachycardia,diaphoresis, andtachypnoea.[16][17] Because of the heat produced during uncoupling, DNP overdose will overpower the body's attempt to maintain thermal homeostasis and cause an uncontrolled, fatal rise in body temperature up to as high as 44 °C (111 °F). The disruption of metabolism also leads to theaccumulation of potassium andphosphate, potentially contributing to toxicity. DNP can causeT wave andST segment abnormalities; heart muscle, kidney, and liver damage have been found on autopsy.[16][17] According to an analysis of United Kingdom and United States overdose cases, tachycardia,hyperpyrexia,acidosis, and agitation or confusion are independent predictors of overdose death.[37]
There is no antidote to DNP and management strategies are based on expert opinion and case studies.[17] Treatment for overdose is supportive, and often involves aggressive cooling using methods such as ice baths and intravenous fluids.[35][17] Grundlingh et al. recommend administeringactivated charcoal if the patient presents within an hour of ingestion and using intravenousvasopressors orinotropes to controlblood pressure if necessary. Intravenousmethylthioninium chloride can treatmethaemoglobinaemia.Benzodiazepines can help control seizures anddantrolene has been used in an attempt to control hyperthemia.[17]Cardiopulmonary resuscitation (CPR) has been used on people who died of DNP overdoses but has no known successful outcomes.[17]
DuringWorld War I, munitions workers in France fell ill and some died from DNP exposure.[38] Stanford University academicMaurice L. Tainter learned of DNP's effect in raising themetabolic rate and causing weight loss and pioneered its use as a weight loss drug.[1][38] Although he was aware of DNP's narrowtherapeutic index, Tainter tried the drugs on obese patients and published successful results in 1933; average weight loss was 20 pounds (9.1 kg) and most recipients did not report adverse effects. In 1934, Tainter estimated that at least 100,000 people had been treated with DNP in the United States during its first year on the market and there had been three reported fatalities connected to the drug.[38][1] Tainter argued that DNP was highly effective in raising the metabolic rate (up to 50 percent) and avoided the negative circulatory effects ofdesiccated thyroid, another weight loss drug in use at the time.[38]
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Other physicians were less optimistic about the adverse effects of DNP, and in 1935 theAmerican Medical Association's Council on Chemistry and Pharmacy declined to list DNP in theNew and Nonofficial Remedies on the grounds that its benefits did not exceed its risks to health.[38] Reports of cataracts forming during DNP usage administered by a physician appeared the same year; in 1936 anophthalmologist based inSan Francisco estimated that 2,500 American women had gone blind from DNP use.[38] Physician opinion turned against the drug, but many people bought direct-to-consumer preparations of DNP—marketed as a cosmetic rather than a drug to evade existing regulations.[38][39]
DNP's risks were highlighted in the "Chamber of Horrors", an exhibit assembled by theFood and Drug Administration to explain the limitations of existing American drug regulations. In 1938, theFood, Drug, and Cosmetic Act increased the FDA's ability to regulate drugs. DNP was deemed so toxic as to be banned for human consumption and in 1940 the FDA reported that there was no evidence of continued sale for this purpose.[39][38] Nevertheless, it continued to be used for weight loss.[35]William F. Loomis andFritz Albert Lipmann discovered DNP'smechanism of action and reported it in a 1948 publication.[38]
Reports of its use increased in the twenty-first century after the drug became available on the Internet.[35]
DNP is banned for human consumption in many countries.[1] Because it has some legitimate uses, in many jurisdictions, DNP is legal to sell, but not for human consumption.[25][40][41] In Australia, alldinitrophenols were classified asSchedule 1 dangerous drugs in 1956. In February 2017, DNP was reclassified asSchedule 10, "Substances of such a danger to health as to warrant prohibition of sale, supply and use".[40] Since 1 October 2023, DNP has been classified as a regulated poison in theUnited Kingdom.[42] It is a prohibited substance (class F4) inBrazil.[43] In theUnited States, DNP is classified as aninvestigational new drug; it receivedorphan drug status forHuntington's disease.[44] DNP has been banned by the World Anti-Doping Association since 2015.[45]
Petróczi et al. recommend against campaigns informing people of the risks of DNP because it could increase use of the drug.[25] However, Sousa et al. argue that publicity campaigns in theUnited Kingdom in the early and mid-2010s reduced DNP usage.[1] In 2015,Interpol and theWorld Anti-Doping Agency released an orange notice warning of the dangers of DNP.[25]
In 1941, theEastman Kodak Company, a bulk distributor of DNP, was investigated after some of its product was found in illegal diet pills.[39]Nicholas Bachynsky, a Texas physician, provided the drug to patients under the name "Mitcal". He was convicted of violating drug laws in 1986, but continued to work with DNP and was additionally convicted of fraud in 2008.[35][17] In 2018, a seller in theUnited Kingdom was convicted ofmanslaughter for selling DNP for human consumption. The conviction was sent to retrial in 2020 by theEnglish Court of Appeal, where the seller was, once again, convicted ofgross negligence manslaughter.[46]
