:2,4-Dinitrophenol

{{Infobox drug

| drug_name =

| INN =

| image = 2,4-Dinitrophenol.svg

| image2 = 2,4-Dinitrophenol.jpg

| width = 120px

| alt =

| caption = Chemical structure (top) and sample of pure compound (bottom)

| pronounce =

| tradename =

| Drugs.com =

| MedlinePlus =

| routes_of_administration = Oral

| bioavailability =

| protein_bound =

| metabolism = Nitro reduction

| metabolites =

| onset =

| elimination_half-life = Unknown

| duration_of_action=

| excretion =

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = C02496

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 273386

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C6H4N2O5/c9-6-2-1-4(7(10)11)3-5(6)8(12)13/h1-3,9H

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = UFBJCMHMOXMLKC-UHFFFAOYSA-N

| CAS_number = 51-28-5

| PubChem = 1493

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 42017

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = Q13SKS21MN

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB04528

| smiles = O=[N+]([O-])c1cc(ccc1O)[N+]([O-])=O

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 1448

| class = Uncoupling agents

| IUPAC_name =

| C=6 | H=4 | N=2 | O=5

| legal_status = Banned for human consumption in many countries

}}

2,4-Dinitrophenol (2,4-DNP or simply DNP) is an organic compound with the formula HOC₆H₃(NO₂)₂. It has been used in explosives manufacturing and as a pesticide and herbicide.

In humans, DNP causes dose-dependent mitochondrial uncoupling, causing the rapid loss of ATP as heat and leading to uncontrolled hyperthermia—up to {{convert|44|C}}—and death in case of overdose. Researchers noticed its effect on raising the basal metabolic rate in accidental exposure and developed it as one of the first weight 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.

Chemical properties

File:Synthesis 2,4-Dinitrophenol.svg and nitric acid via 2-Nitrophenol and 4-Nitrophenol]]

DNP has the chemical formula HOC₆H₃(NO₂)₂. As a solid, it is a yellow, crystalline and has a sweet, musty odor. It sublimates, is volatile with steam, and is soluble in most organic solvents as well as aqueous alkaline solutions.{{Cite book |title=The Merck index : an encyclopedia of chemicals, drugs, and biologicals |date=1989 |publisher=Merck |editor=Budavari, Susan |display-editors=etal |isbn=978-0-911910-28-5 |edition=11th |location=Rahway, NJ |page=[https://archive.org/details/merckindexency00buda/page/1900 1900] |oclc=21297020 |url=https://archive.org/details/merckindexency00buda/page/1900 |url-access=limited}} DNP is a member of the dinitrophenols chemical family.{{cite journal |last1=Sousa |first1=Daniela |last2=Carmo |first2=Helena |last3=Roque Bravo |first3=Rita |last4=Carvalho |first4=Félix |last5=Bastos |first5=Maria de Lourdes |last6=Guedes de Pinho |first6=Paula |last7=Dias da Silva |first7=Diana |title=Diet aid or aid to die: an update on 2,4-dinitrophenol (2,4-DNP) use as a weight-loss product |journal=Archives of Toxicology |date=April 2020 |volume=94 |issue=4 |pages=1071–1083 |doi=10.1007/s00204-020-02675-9|pmid=32078021 |s2cid=211194992 }}

DNP can be produced by hydrolysis of 2,4-dinitrochlorobenzene. Other routes of DNP synthesis include nitration of monochlorobenzene, nitration of benzene with nitrogen dioxide and mercurous nitrate, oxidation of 1,3-dinitrobenzene,{{sfn|Shea et al.|1983|p=2}} and nitration of phenol with nitric acid.{{Cite journal|last1=Khabarov|first1=Yu. G.|last2=Lakhmanov|first2=D. E.|last3=Kosyakov|first3=D. S.|last4=Ul'yanovskii|first4=N. V.|date=1 October 2012|title=Synthesis of 2,4-dinitrophenol|journal=Russian Journal of Applied Chemistry|language=en|volume=85|issue=10|pages=1577–1580|doi=10.1134/S1070427212100163|s2cid=98830371|issn=1608-3296}}

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.{{Cite book|url=https://books.google.com/books?id=e4_S46UcI2AC&pg=PT399|title=Encyclopaedia of Occupational Health and Safety: Guides, indexes, directory|last=Stellman|first=Jeanne Mager|date=1998|publisher=International Labour Organization|isbn=978-92-2-109817-1|language=en}} DNP forms explosive salts with strong bases as well as ammonia, and emits toxic fumes of nitrogen dioxide when heated to decomposition.{{cite book|title=Dangerous properties of industrial materials|last=Sax|first=N.Irving|author2=Bruce, Robert D|publisher=John Wiley & Sons|year=1989|isbn=0-442-27368-1|edition=7th|volume=3|url=https://archive.org/details/dangerouspropert00saxn}} DNP's explosive strength is 81% that of TNT, based on the Trauzl lead block test.{{Cite book|url=https://books.google.com/books?id=4TIkDAAAQBAJ&pg=PT340|title=Explosives|last1=Meyer|first1=Rudolf|last2=Köhler|first2=Josef|last3=Homburg|first3=Axel|year=2016|publisher=John Wiley & Sons|isbn=978-3-527-68961-3|language=en}}

Uses

=Industrial=

Historically, DNP has been used as an antiseptic and as a non-selective bioaccumulating pesticide.{{cite web|url=https://www.epa.gov/sites/production/files/2016-09/documents/2-4-dinitrophenol.pdf|title=2,4-Dinitrophenol|publisher=Environmental Protection Agency|access-date=15 October 2017}}

DNP was particularly useful as a herbicide alongside other closely related dinitrophenol herbicides like 2,4-dinitro-o-cresol (DNOC), dinoseb and dinoterb.{{Cite book|title=Reproductive and developmental toxicology|date=2011|publisher=Academic Press|editor=Gupta, Ramesh C.|isbn=978-0-12-382032-7|location=London|page=509|oclc=717387050}} Since 1998 DNP has been withdrawn from agricultural use.{{Cite book|url=https://books.google.com/books?id=RYt0Wzb60b4C&pg=PA1088|title=Sittig's Handbook of Toxic and Hazardous Chemicals and Carcinogens|last=Pohanish|first=Richard P.|year= 2011|publisher=William Andrew|isbn=978-1-4377-7870-0|language=en}} Currently, there are no actively registered pesticides containing DNP in the United States or Europe.{{cite web |title=Toxicological Profile for Dinitrophenols |url=https://www.atsdr.cdc.gov/ToxProfiles/tp64.pdf |website=Agency for Toxic Substances and Disease Registry |publisher=U.S. Department of Health and Human Services |date=August 2021}}{{Cite book|url=https://books.google.com/books?id=--rEAgAAQBAJ&pg=PA296|title=Sittig's Handbook of Pesticides and Agricultural Chemicals|last=Pohanish|first=Richard P.|year=2014|publisher=William Andrew|isbn=978-1-4557-3157-2|language=en}} Dinoseb is used industrially as a polymerisation inhibitor during styrene production. In 2023, the Home Office said it could not determine any legitimate industrial uses for DNP in the United Kingdom.{{Cite web |title=Q. Dinitrophenol |url=https://www.parallelparliament.co.uk/question/136690/dinitrophenol |access-date=2023-02-07 |website=www.parallelparliament.co.uk}}

It is a chemical intermediate in the production of sulfur dyes,Gerald Booth "Nitro Compounds, Aromatic" in "Ullmann's Encyclopedia of Industrial Chemistry" 2007; Wiley-VCH, Weinheim. {{doi|10.1002/14356007.a17_411}} wood preservatives and picric acid.{{Cite book|url=https://books.google.com/books?id=2B4VqK18VOUC&pg=PA132|title=Organic Chemistry of Explosives|last1=Agrawal|first1=Jai Prakash|last2=Hodgson|first2=Robert|year= 2007|publisher=John Wiley & Sons|isbn=978-0-470-05935-7|language=en}} A precursor to 2,4,6-trinitrotoluene (TNT), DNP has also been used to make photographic developers and explosives. DNP is classified as an explosive in the United Kingdom{{Cite book|url=https://books.google.com/books?id=rnXUDAAAQBAJ&pg=PA452|title=Bretherick's Handbook of Reactive Chemical Hazards|last=Urben|first=Peter|year=2017|publisher=Elsevier|isbn=978-0-08-101059-4|language=en}} and the United States.{{Cite news|url=https://www.federalregister.gov/documents/2017/12/28/2017-28010/commerce-in-explosives-2017-annual-list-of-explosive-materials|title=Commerce in Explosives; 2017 Annual List of Explosive Materials|date=28 December 2017|work=Federal Register|access-date=22 July 2018}}

=In humans=

File:Histogram of DNP (dinitrophenol) doses reported on online forums.png of DNP doses reported on online forums and the subreddit /r/DNP]]

DNP raises energy expenditure by 30 to 40 percent and causes a weight loss of {{convert|0.7-0.9|kg}} per week.{{cite journal |last1=Christoffersen |first1=Berit Østergaard |last2=Sanchez-Delgado |first2=Guillermo |last3=John |first3=Linu Mary |last4=Ryan |first4=Donna H. |last5=Raun |first5=Kirsten |last6=Ravussin |first6=Eric |title=Beyond appetite regulation: Targeting energy expenditure, fat oxidation, and lean mass preservation for sustainable weight loss |journal=Obesity |date=April 2022 |volume=30 |issue=4 |pages=841–857 |doi=10.1002/oby.23374 |pmid=35333444 |language=en |issn=1930-7381|pmc=9310705 }} Although DNP is no longer in clinical use as a weight loss drug due to its dangerous side effects, its mechanism of action remains under investigation as a potential approach for treating obesity and non-alcoholic fatty liver disease.{{cite journal |last1=Ost |first1=Mario |last2=Keipert |first2=Susanne |last3=Klaus |first3=Susanne |title=Targeted mitochondrial uncoupling beyond UCP1 – The fine line between death and metabolic health |journal=Biochimie |date=March 2017 |volume=134 |pages=77–85 |doi=10.1016/j.biochi.2016.11.013|pmid=27916644 |s2cid=6867183 }} Researchers developed a prodrug, 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.{{cite journal |last1=Harrison |first1=Stephen A. |last2=Loomba |first2=Rohit |last3=Dubourg |first3=Julie |last4=Ratziu |first4=Vlad |last5=Noureddin |first5=Mazen |title=Clinical Trial Landscape in NASH |journal=Clinical Gastroenterology and Hepatology |date=July 2023 |volume=21 |issue=8 |pages=2001–2014 |doi=10.1016/j.cgh.2023.03.041|pmid=37059159 |s2cid=258115543 }}

DNP is used by bodybuilders, fitness enthusiasts, and people with an eating disorder to lose weight. The user profile is similar to that of anabolic steroids; many perceive it to be effective and with manageable risks.{{cite journal |last1=Petróczi |first1=Andrea |last2=Ocampo |first2=Jorge A. Vela |last3=Shah |first3=Iltaf |last4=Jenkinson |first4=Carl |last5=New |first5=Rachael |last6=James |first6=Ricky A. |last7=Taylor |first7=Glenn |last8=Naughton |first8=Declan P. |title=Russian roulette with unlicensed fat-burner drug 2,4-dinitrophenol (DNP): evidence from a multidisciplinary study of the internet, bodybuilding supplements and DNP users |journal=Substance Abuse Treatment, Prevention, and Policy |date=14 October 2015 |volume=10 |issue=1 |pages=39 |doi=10.1186/s13011-015-0034-1 |language=en |issn=1747-597X|doi-access=free |pmid=26466580 |pmc=4607104 }} Despite health warnings from regulators, DNP is readily available online sometimes under other names such as Dinosan, Dnoc, Solfo Black, Nitrophen, Aldifen, and Chemox. DNP is often sold in tablets containing 100 to 200 mg and may be sold alongside other substances such as anabolic steroids and thyroxine. It may also be found as a contaminant in other bodybuilding supplements not advertised as containing DNP. 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.{{cite journal |last1=McVeigh |first1=Jim |last2=Germain |first2=Jennifer |last3=Van Hout |first3=Marie Claire |title=2,4-Dinitrophenol, the inferno drug: a netnographic study of user experiences in the quest for leanness |journal=Journal of Substance Use |date=2017 |volume=22 |issue=2 |pages=131–138 |doi=10.3109/14659891.2016.1149238|s2cid=147770507 |url=https://e-space.mmu.ac.uk/624834/1/DNP%2520final%2520submission.pdf }} According to a study published in 2023, the most commonly reported doses were between 150 and 300 mg/day.{{cite journal |last1=Abdelati |first1=Ali |last2=Burns |first2=Michele M. |last3=Chary |first3=Michael |title=Sublethal toxicities of 2,4-dinitrophenol as inferred from online self-reports |journal=PLOS ONE |date=2023 |volume=18 |issue=9 |pages=e0290630 |doi=10.1371/journal.pone.0290630 |language=en |issn=1932-6203|doi-access=free |pmid=37703241 |pmc=10499234 |bibcode=2023PLoSO..1890630A }} Between 2010 and 2020, reports of overdoses were higher in Australasia, Europe and North America than in Asia, Africa, and South or Central America.

It is also used as a suicide method.

Biochemistry

= Mechanism of action =

File:Nitro reduction of 2,4-Dinitrophenol (DNP).png of DNP]]

In living cells, DNP acts as a protonophore, an agent that can shuttle protons (hydrogen cations) across biological membranes. It dissipates the proton gradient across the mitochondrial membrane, collapsing the proton motive force that the cell uses to produce most of its ATP chemical energy. Instead of producing ATP, the energy of the proton gradient is lost as heat. 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 for uncoupling oxidative phosphorylation. The phosphorylation of adenosine diphosphate (ADP) by ATP synthase gets disconnected or uncoupled from oxidation.{{cn|date=September 2023}}

DNP raises the basal metabolic rate (BMR) and lowers T4 (thyroid hormone) levels by increasing T4 metabolism and reducing thyroid hormone secretion. Because it binds to thyroxine-binding globulin, overall thyroid function may not be affected. DNP cannot substitute for thyroid hormone in myxedema.{{cite book |last1=Weiss |first1=Roy E. |last2=Refetoff |first2=Samuel |title=Endocrinology: Adult and Pediatric |date=2016 |publisher=W.B. Saunders |isbn=978-0-323-18907-1 |page=1397 |chapter=Chapter 78 - Thyroid Function Testing|edition=Seventh }}

=Pharmacokinetics=

Information about pharmacokinetics and pharmacodynamics of DNP in humans is limited.{{cite journal |last1=Meyer |first1=Lyndsey F. |last2=Rajadhyaksha |first2=Pooja M. |last3=Shah |first3=Dhaval K. |title=Physiologically-based pharmacokinetic model for 2,4-dinitrophenol |journal=Journal of Pharmacokinetics and Pharmacodynamics |date=1 June 2022 |volume=49 |issue=3 |pages=325–336 |doi=10.1007/s10928-022-09806-y |pmid=35089483 |s2cid=246361178 |url=https://link.springer.com/article/10.1007/s10928-022-09806-y |language=en |issn=1573-8744|url-access=subscription }} DNP is metabolized via nitro reduction. Its major metabolites are {{ill| 2-amino-4-nitrophenol|de|2-Amino-4-nitrophenol}} and 4-amino-2-nitrophenol. In overdoses, symptom onset can be as soon as 3 hours and the average time to death was 14 hours.

=As a pollutant=

Although many militaries are replacing traditional 2,4,6-trinitrotoluene (TNT)-based explosives for insensitive munitions, DNP is a degradation byproduct of the IMX-101 insensitive munition used by the United States Army.{{cite journal |last1=Richard |first1=Thomas |last2=Weidhaas |first2=Jennifer |title=Biodegradation of IMX-101 explosive formulation constituents: 2,4-Dinitroanisole (DNAN), 3-nitro-1,2,4-triazol-5-one (NTO), and nitroguanidine |journal=Journal of Hazardous Materials |date=15 September 2014 |volume=280 |pages=372–379 |doi=10.1016/j.jhazmat.2014.08.019 |pmid=25181681 |bibcode=2014JHzM..280..372R |url=https://www.sciencedirect.com/science/article/abs/pii/S030438941400675X |issn=0304-3894|url-access=subscription }}

While the Meisenheimer charge transfer reaction is effective at detecting TNT, it is not effective at detecting many other explosives including DNP. Researchers are studying colorimetric detection and other methods for DNP to find if water or solids such as soils are contaminated with DNP.{{cite journal |last1=Chen |first1=Lili |last2=Cheng |first2=Zihan |last3=Peng |first3=Xinyue |last4=Qiu |first4=Guoqiao |last5=Wang |first5=Li |title=Eu-Doped MOF-based high-efficiency fluorescent sensor for detecting 2,4-dinitrophenol and 2,4,6-trinitrophenol simultaneously |journal=Analytical Methods |date=2022 |volume=14 |issue=1 |pages=44–51 |doi=10.1039/D1AY01747K |pmid=34889337 |s2cid=244787652 |url=https://pubs.rsc.org/en/content/articlehtml/2022/ay/d1ay01747k |language=en|url-access=subscription }}{{cite journal |last1=Feng |first1=Hai-Tao |last2=Zheng |first2=Yan-Song |title=Highly Sensitive and Selective Detection of Nitrophenolic Explosives by Using Nanospheres of a Tetraphenylethylene Macrocycle Displaying Aggregation-Induced Emission |journal=Chemistry - A European Journal |date=3 January 2014 |volume=20 |issue=1 |pages=195–201 |doi=10.1002/chem.201302638|pmid=24285612 }}{{cite journal |last1=Adegoke |first1=Oluwasesan |last2=Daeid |first2=Niamh Nic |title=Polymeric-coated Fe-doped ceria/gold hybrid nanocomposite as an aptasensor for the catalytic enhanced colorimetric detection of 2,4-dinitrophenol |journal=Colloids and Surfaces A: Physicochemical and Engineering Aspects |date=October 2021 |volume=627 |pages=127194 |doi=10.1016/j.colsurfa.2021.127194|s2cid=237672987 |url=https://discovery.dundee.ac.uk/en/publications/b4b76b52-2712-4e14-a573-f75fbb3dd94b }}{{cite journal |last1=Dinesh |first1=Bose |last2=Aadhav |first2=Anantharamakrishnan |last3=Devi |first3=K. S. Shalini |last4=Krishnan |first4=Uma Maheswari |title=Electrocatalytic reduction of 2,4 dinitrophenol on carbon black-modified glassy carbon electrode and its selective recognition in cold beverages |journal=Carbon Letters |date=1 June 2022 |volume=32 |issue=4 |pages=1017–1029 |doi=10.1007/s42823-022-00334-w |s2cid=247942852 |url=https://link.springer.com/article/10.1007/s42823-022-00334-w |language=en |issn=2233-4998|url-access=subscription }} UiO-66-NH2 can be used to bind to and remove DNP from solution.{{cite journal |last1=Xu |first1=Zhuang |last2=Wen |first2=Yuquan |last3=Tian |first3=Li |last4=Li |first4=Guangtao |title=Efficient and selective adsorption of nitroaromatic explosives by Zr-MOF |journal=Inorganic Chemistry Communications |date=March 2017 |volume=77 |pages=11–13 |doi=10.1016/j.inoche.2017.01.025}}

Adverse effects

DNP has a low therapeutic index, meaning that the dosage at which toxicity occurs is not much larger than that required to produce a desired effect. Individual tolerance to DNP's harmful short- and long-term effects varies greatly. The most common adverse effect reported is a rash, which could be maculopapular, urticarial, angioedema, or an exfoliative dermatitis. Cataracts can form, causing a permanent loss of vision in days to months of usage, and permanent deafness has also been reported. Other adverse effects reported include peripheral neuritis, agranulocytosis, and neutropaenia. Negative effects on the central nervous system, cardiovascular system, and bone marrow can occur. In animal studies, DNP acted as a teratogen, mutagen, and carcinogen and caused developmental and reproductive harm. 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.{{cite journal |last1=Zack |first1=F. |last2=Gummesson |first2=A. |last3=Büttner |first3=A. |title=Morphologische Befunde als Hinweise auf eine 2,4-Dinitrophenol-Intoxikation |journal=Rechtsmedizin |date=1 October 2022 |volume=32 |issue=5 |pages=386–390 |doi=10.1007/s00194-021-00552-y |s2cid=245336193 |url=https://link.springer.com/article/10.1007/s00194-021-00552-y |language=de |issn=1434-5196|url-access=subscription }} 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.

=Overdose=

Overdose is extremely dangerous; cases reported to poison control centers had a 11.9 percent fatality rate between 2010 and 2020.{{Cite journal|last1=Gziut|first1=Tomasz|last2=Thomas|first2=Simon H. L.|date=2021-11-23|title=International trends in systemic human exposures to 2,4 dinitrophenol reported to poisons centres|journal=Clinical Toxicology|volume=60|issue=5|language=en|pages=628–631|doi=10.1080/15563650.2021.2005797|pmid=34812657|s2cid=244490656|issn=1556-3650|doi-access=free}} Although the largest number of overdose deaths occurred in the 1910s and 1920s when the chemical was in more widespread industrial use, the substance's use as a dieting aid has caused a number of fatalities in the twenty-first century: at least 50 overdose deaths were reported worldwide between 2010 and 2020. Although the lowest published fatal ingested dose is 4.3 mg/kg,{{Cite book|chapter-url=https://books.google.com/books?id=8WYHBAAAQBAJ&pg=PA259|title=Oxford Desk Reference: Toxicology|last1=Bateman|first1=Nick|last2=Jefferson|first2=Robert|last3=Thomas|first3=Simon|last4=Thompson|first4=John|last5=Vale|first5=Allister|year= 2014|publisher=Oxford University Press|isbn=978-0-19-102248-7|language=en|pages=258–259|chapter=Dinitrophenol}} a typical overdose death occurs at a higher level of exposure, around 20-50 mg/kg.

The first symptoms to appear are nausea, vomiting, abdominal pain, and perhaps diarrhea. The typical overdose syndrome seen with DNP and other phenols is a combination of hyperthermia, tachycardia, diaphoresis, and tachypnoea. 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 {{convert|44|C}}. The disruption of metabolism also leads to the accumulation of potassium and phosphate, potentially contributing to toxicity. DNP can cause T wave and ST segment abnormalities; heart muscle, kidney, and liver damage have been found on autopsy. 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.{{cite journal |last1=Potts |first1=A. J. |last2=Bowman |first2=N. J. |last3=Seger |first3=D. L. |last4=Thomas |first4=S. H. L. |title=Toxicoepidemiology and predictors of death in 2,4-dinitrophenol (DNP) toxicity |journal=Clinical Toxicology |date=3 June 2021 |volume=59 |issue=6 |pages=515–520 |doi=10.1080/15563650.2020.1826505|pmid=33021407 |s2cid=222159746 }}

There is no antidote to DNP and management strategies are based on expert opinion and case studies. Treatment for overdose is supportive, and often involves aggressive cooling using methods such as ice baths and intravenous fluids. Grundlingh et al. recommend administering activated charcoal if the patient presents within an hour of ingestion and using intravenous vasopressors or inotropes to control blood pressure if necessary. Intravenous methylthioninium chloride can treat methaemoglobinaemia. Benzodiazepines can help control seizures and dantrolene has been used in an attempt to control hyperthemia. Cardiopulmonary resuscitation (CPR) has been used on people who died of DNP overdoses but has no known successful outcomes.

History

During World War I, munitions workers in France fell ill and some died from DNP exposure.{{cite journal |last1=Colman |first1=Eric |title=Dinitrophenol and obesity: An early twentieth-century regulatory dilemma |journal=Regulatory Toxicology and Pharmacology |date=2007 |volume=48 |issue=2 |pages=115–117 |doi=10.1016/j.yrtph.2007.03.006|pmid=17475379 }} Stanford University academic Maurice L. Tainter learned of DNP's effect in raising the metabolic rate and causing weight loss and pioneered its use as a weight loss drug. Although he was aware of DNP's narrow therapeutic index, Tainter tried the drugs on obese patients and published successful results in 1933; average weight loss was {{convert|20|lbs}} 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. Tainter argued that DNP was highly effective in raising the metabolic rate (up to 50 percent) and avoided the negative circulatory effects of desiccated thyroid, another weight loss drug in use at the time.

File:Dinitrophenol (DNP) chamber of horrors.jpg publication "Chamber of Horrors"]]

Other physicians were less optimistic about the adverse effects of DNP, and in 1935 the American Medical Association's Council on Chemistry and Pharmacy declined to list DNP in the New and Nonofficial Remedies on the grounds that its benefits did not exceed its risks to health. Reports of cataracts forming during DNP usage administered by a physician appeared the same year; in 1936 an ophthalmologist based in San Francisco estimated that 2,500 American women had gone blind from DNP use. 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.{{cite book |last1=Swann |first1=John P. |title=Perspectives on Twentieth-century Pharmaceuticals |date=2010 |publisher=Peter Lang |isbn=978-3-03910-920-3 |pages=289, 292, 299, 301|language=en |chapter=Reducing with dinitrophenol : self-medication, and the challenge of regulating a dangerous pharmaceutical before the US Food, Drug, and Cosmetic Act}}

DNP's risks were highlighted in the "Chamber of Horrors", an exhibit assembled by the Food and Drug Administration to explain the limitations of existing American drug regulations. In 1938, the Food, 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. Nevertheless, it continued to be used for weight loss. William F. Loomis and Fritz Albert Lipmann discovered DNP's mechanism of action and reported it in a 1948 publication.

Reports of its use increased in the twenty-first century after the drug became available on the Internet.{{cite journal |last1=Yen |first1=May |last2=Ewald |first2=Michele Burns |title=Toxicity of Weight Loss Agents |journal=Journal of Medical Toxicology |date=2012 |volume=8 |issue=2 |pages=145–152 |doi=10.1007/s13181-012-0213-7 |language=en |issn=1937-6995|doi-access=free |pmid=22351299 |pmc=3550246 }}

Legal status

DNP is banned for human consumption in many countries. Because it has some legitimate uses, in many jurisdictions, DNP is legal to sell, but not for human consumption.{{cite news|first=Alana |last=Hippensteele |title=Pharmacy Fact: Miracle Weight Loss Drug Successfully Burns Fat, Also 'Cooks' Internal Organs |url=https://www.pharmacytimes.com/view/pharmacy-fact-miracle-weight-loss-drug-successfully-burns-fat-also-cooks-internal-organs |access-date=17 September 2023 |work=Pharmacy Times |date=7 May 2021 |language=en}} In Australia, all dinitrophenols were classified as Schedule 1 dangerous drugs in 1956. In February 2017, DNP was reclassified as Schedule 10, "Substances of such a danger to health as to warrant prohibition of sale, supply and use".{{cite news |last1=Casey |first1=Scott |title=2,4-Dinitrophenol – effective but dangerous fat burner |url=https://www.australianpharmacist.com.au/24-dinitrophenol-effective-but-dangerous-fat-burner/ |access-date=17 September 2023 |work=Australian Pharmacist |date=10 December 2019 |language=en-AU}} Since 1 October 2023, DNP has been classified as a regulated poison in the United Kingdom.{{Cite web |last=Wickware |first=Carolyn |title=Government to change law to reclassify so-called 'diet drug' as a poison |url=https://pharmaceutical-journal.com/article/news/government-to-change-law-to-reclassify-so-called-diet-drug-as-a-poison |access-date=2023-01-29 |website=The Pharmaceutical Journal |date=27 January 2023 |language=en-US}} It is a prohibited substance (class F4) in Brazil.{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-07-24 |title=RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |url-status=live |archive-url=https://web.archive.org/web/20230827163149/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |archive-date=2023-08-27 |access-date=2023-08-27 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-07-25}} In the United States, DNP is classified as an investigational new drug; it received orphan drug status for Huntington's disease.{{cite journal |last1=Geisler |first1=John G. |title=2,4 Dinitrophenol as Medicine |journal=Cells |date=23 March 2019 |volume=8 |issue=3 |pages=280 |doi=10.3390/cells8030280 |issn=2073-4409|doi-access=free |pmid=30909602 |pmc=6468406 }} DNP has been banned by the World Anti-Doping Association since 2015.{{cite web |title=DNP: Is it really all that dangerous? |url=https://www.opss.org/article/dnp-it-really-all-dangerous |website=opss |access-date=18 September 2023 |language=en}}

Petróczi et al. recommend against campaigns informing people of the risks of DNP because it could increase use of the drug. However, Sousa et al. argue that publicity campaigns in the United Kingdom in the early and mid-2010s reduced DNP usage. In 2015, Interpol and the World Anti-Doping Agency released an orange notice warning of the dangers of DNP.

In 1941, the Eastman Kodak Company, a bulk distributor of DNP, was investigated after some of its product was found in illegal diet pills. 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.{{cite journal |last1=Grundlingh |first1=Johann |last2=Dargan |first2=Paul I. |last3=El-Zanfaly |first3=Marwa |last4=Wood |first4=David M. |title=2,4-Dinitrophenol (DNP): A Weight Loss Agent with Significant Acute Toxicity and Risk of Death |journal=Journal of Medical Toxicology |date=1 September 2011 |volume=7 |issue=3 |pages=205–212 |doi=10.1007/s13181-011-0162-6 |language=en |issn=1937-6995|doi-access=free |pmid=21739343 |pmc=3550200 }} In 2018, a seller in the United Kingdom was convicted of manslaughter for selling DNP for human consumption. The conviction was sent to retrial in 2020 by the English Court of Appeal, where the seller was, once again, convicted of gross negligence manslaughter.{{cite news|url=https://www.bbc.co.uk/news/uk-england-shropshire-51806951 |title=Eloise Parry: Man convicted over diet pill death|work=BBC News|date=9 March 2020}}