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DiazinonFrom Wikipedia, the free encyclopedia

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Diazinon

IUPAC name[hide]

O,O-Diethyl O-[4-methyl-6-(propan-2-yl)pyrimidin-2-yl]

phosphorothioate

Other names[hide]

Diethoxy-[(2-isopropyl-6-methyl-4-pyrimidinyl)oxy]-

thioxophosphorane

Identifiers

CAS number 333-41-5
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PubChem 3017

ChemSpider

2909

UNII YUS1M1Q929

KEGG D07856

ChEBI CHEBI:34682

ChEMBL CHEMBL388560

ATCvet code QP53AF03

Jmol-3D images Image 1

SMILES

[show]

InChI

[show]

Properties

Molecular formula C12H21N2O3PS

Molar mass 304.35 g mol1

Appearance Colorless to dark brown

liquid

Density

1.116-1.118 g/cm3at 20 C[1]

Solubilityinwater

40 mg/L[2]

log P

3.81 (octanol/water)[3]

Except where noted otherwise, data are given for materials in

theirstandard state(at 25 C (77 F), 100 kPa)

(verify)(what is: / ?)

Infobox references

Diazinon(IUPACname: O,O-Diethyl O-[4-methyl-6-(propan-2-yl)pyrimidin-2-yl]phosphorothioate,INN-Dimpylate), a colorless to dark brown liquid, is a thiophosphoric acid esterdeveloped in 1952 byCiba-Geigy,a Swiss chemical company (laterNovartisand thenSyngenta). It is anonsystemicorganophosphateinsecticideformerly used to controlcockroaches,silverfish,ants,andfleasin residential, non-food buildings. Diazinon was heavily used during the 1970s and early1980s for general-purpose gardening use and indoor pest control. A bait form was used to controlscavengerwaspsin the western U.S. Diazinon is used in flea collars for domestic pets in Australia andNew Zealand. Residential uses of diazinon were outlawed in the U.S. in 2004 but it is still approved foragricultural uses. An emergency antidote isatropine.[4]

Contents[hide]
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History[edit]

Diazinon was developed in 1952 by the Swiss company Ciba-Geigy as a replacement for the insecticideDDT. Diazinon became available for mass use in 1955, as DDT production tapered. Prior to 1970diazinon had issues with contaminants in the solution. However, by the 1970s, alternative purificationmethods were utilized to reduce residual materials. After this, diazinon became an all-purpose indoorand outdoor commercial pest control product. In 2004, U.S. residential use of diazinon was outlawed,except for agricultural purposes and cattle ear tags .

Structure and reactivity[edit]

The structure of diazinon contains a thiophosphoric ester. The phosphorus center is the reactive site ofthe chemical. However, no known mechanisms currently exist. A novel mechanism does exist, whichproposes that the sulfur is protonated in acidic medium via a hydronium ion which ultimately delivers ahydroxide group to the phosphorus center and can react readily.

The form of diazinon varies widely as it can be in dusts, granules, liquids, concentrates,microencapsulations, wettable powders, and seed dressings. Its appearance varies depending onpurity, ranging from a dark brown (industrial grade), to a colorless liquid (pure). Indicative of itsfunctionality of a thiophosphoric ester, the chemical has a pronounced smell similar to that of diethylether.

Diazinon is relatively stable under standard ambient temperature and pressure but is susceptible to formtoxic phosphine gas upon heating. Furthermore, diazinon can oxidize into toxic phosphorus oxides if inthe presence of a strong oxidizing agent.

Synthesis[edit]

According to the German Patent bureau, the industrial synthesis of diazinon is as follows:

-isobutyrylaminocrotonic acid amine was cyclized with NaOR (R is either a hydrogen oraliphatic chain of 1 to 8 carbons) in a mixture of 0 to 100% by weight of water and an alcoholhaving 1 to 8 carbon atoms, above 90C (but below the boiling point of the mixture used).Sodium pyrimidinolate was precipitated out in an inert solvent, such as benzene, withsimultaneous removal of the water formed. The potassium salt is then reacted withdiethylthiophosphoryl chloride by heating for several hours. When the reaction finished, the

potassium chloride formed was washed with water and the solvent was removed underreduced pressure leaving diazinon.

Metabolism and mechanism of action[edit]

Diazinon functions as an acetylcholinesterase (AChE) inhibitor. This enzyme breaks down theneurotransmitter acetylcholine (ACh) into [choline] and an acetate group. (1) The inhibition of theAChE causes an abnormal accumulation of ACh in the synaptic cleft. When Diazinon enters thebody, it is oxidatively degenerated to diaxozon, an organophosphate compound that is much morepoisoning than diazinon and causes mainly the inhibition of AChE (6). The activation of diazinon(Reaction 1) is located in the liver microsomal enzyme system and requires O2andNADPH.Additionally it can also be degenerated via oxidation in the microsomal enzyme system (Reaction2). Both reactions are possible, and likely are catalyzed nonspecifically by the same mixed functionoxidase. Once formed diazoxon is biotransformed again as it is degenerated. Diazoxon is

degenerated due to the very effective hydrolyases in the microsomal and other sub cellular factionswithin the liver (Reaction 3). Mammalian specie degenerate diazoxon at a much slower rate though(with a half-life of 2 to 6 weeks). Insects lack this hydrolysis step which allows for the toxic speciesto accumulate rapidly. The detoxification of diazoxon is processed through the mircosomal mixedfunction oxidase system. Although not fully known, it is believed that this is the cause for theselectivity of diazinon against insects. After the hydrolysis or oxidation diazinon is furtherdegenerated (Reaction 4).
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The mechanism, described above of the biotransformation of Diazinon

Toxicity and effects on animals: Diazinon is considered to be of relatively high toxicity forvertebrates. The common method of administering diazinon is absorption although inhalation ispossible as well. The observed toxification symptoms conform to other acetylcholinesteraseinhibitors. Symptoms are as follows:

Colics Diarrhea and/or Vomiting Vertigo Headaches Miosis Bradycardia Sudden Drop in blood pressure Convulsion Apnea

Lethal Dose Observations

LD50

214 mgkg1 (human, oral, TDLo) (2,3)

66 mgkg1 (rat, oral, LD50) (2,4)

17 mgkg1 (mouse, oral, LD50) (2,5)

Symptoms in humans[edit]

Intoxication of diazinon produces the following signs and symptoms:

Eyes, ears, nose, and throat

Small pupils (unreactive to light) Tearing, increased

Cardiovascular
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Low or high blood pressure Slow or rapid heart rate

Respiratory

Breathing difficulty

Chest tightness

Nervous system Anxiety Convulsions Coma Dizziness Excitability Headache Weakness

Tremor

Twitching Skin

Irritation

Redness Sweating

Gastrointestinal Abdominal cramps

Diarrhea

Loss of appetite

Nausea

Vomiting

Typically treatments will vary depending on exposure and method of administration of the toxin.Critical biomarkers such as urine samples, blood content and heart rates are measured whiledetoxifying the patient. Common treatments for patients suffering from diazinon poisoning include:

Assisted Breathing Intravenous fluids (IV) Irrigation (washing of the skin and eyes) Medicinal Treatments; including the antidotesatropineandoxime.[5] Gastric Lavage

Patients that continue to improve over the first 4 to 6 hours (after medical treatment) usuallyrecover unscathed. Prolonged treatment often is needed to reverse the poisoning, includingintensive care hospitalization and long-term therapy. Some toxicity may persist for weeks ormonths, or even longer.

Efficacy and side effects[edit]

Diazinon is a contact insecticide which kills insects by altering normal neurotransmission within thenervous system of the insect. As mentioned above, diazinon inhibits the enzymeacetylcholinesterase (AChE), which hydrolyzes the neurotransmitter acetylcholine (ACh) incholinergic synapses and neuromuscular junctions. This results in abnormal accumulation of AChwithin the nervous system. Diazinon, although a thiophosphoric ester, shares a commonmechanism of toxicity with other organophosphate insecticides such as chlorpyrifos, malathion andparathion, and is not very effective against the organophosphate-resistant insect populations.

Symptoms of acute diazinon exposure develop in minutes to hours following exposure, dependingof the exposure pathway. The initial symptoms of humans are nausea, dizziness, salivation,headache, sweating, lacrimation, and rhinorrhea. The symptoms can progress to vomiting,abdominal cramps, diarrhea, muscle twitching, weakness, tremor, a lack of coordination andmiosis. Furthermore, some studies have even reported some psychiatric side effects as wellincluding memory loss, confusion, and depression.

Because diazinon is fat soluble, there is potential for delayed toxicity if significant amounts ofdiazinon are stored in fatty tissues. Intermediate syndrome generally occurs within 2496 hours
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after exposure. Intermediate syndrome in humans is characterized by difficulty breathing andmuscular weakness, often in the face neck and proximal limb muscles. Cranial nerve palsies anddepressed tendon reflexes have also been reported.

Studies have suggested that exposure to some organophosphate pesticides can result in long-termneurological problems including organophosphate-induced delayed neuropathy (weakness orparalysis as well as paresthesia in the extremities); however, reports of these symptoms following

diazinon exposures are rare. Human poisoning victims have shown increased levels of serumamylase and glucose as well as elevated urinary diastase levels accompanied by symptomsconsidered to be indicative of acute pancreatitis.

SaccharinFrom Wikipedia, the free encyclopedia


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(Redirected fromSodium saccharin)

Saccharin[1]

IUPAC name[hide]

2H-16,2-benzothiazol-1,1,3-trione

Other names[hide]

Benzoic sulfimide

Ortho sulphobenzamide

Identifiers

CAS number 81-07-2

PubChem 5143

ChemSpider 4959

UNII FST467XS7D
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KEGG D01085

ChEBI CHEBI:32111

ChEMBL CHEMBL310671


SMILES

[show]

InChI

[show]

Properties

Molecular formula C7H5NO3S


Appearance White crystalline solid

Density 0.828 g/cm3

Melting point 228.8-229.7 C

Solubilityinwater 1 g per 290 mL




Infobox references

Saccharin[2]is anartificial sweetenerwith effectively nofood energywhich is approximately 300 times

as sweet as sucrose or table sugar, but has a bitter or metallic aftertaste,especially at highconcentrations. It is used to sweeten products such as drinks, candies, cookies, medicines, andtoothpaste.

Origins[edit]

Saccharin derives its name from the word "saccharine", meaning of, relating to, or resembling sugar. [3]

Properties[edit]
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Sodium salt of saccharin: A white powder

Saccharin is unstable when heated but it does not react chemically with other food ingredients. As such,it stores well. Blends of saccharin with other sweeteners are often used to compensate for eachsweetener's weaknesses and faults. A 10:1cyclamate:saccharin blend is common in countries where

both these sweeteners are legal; in this blend, each sweetener masks the other's off-taste. Saccharin isoften used together withaspartamein diet carbonated soft drinks, so that some sweetness remainsshould the fountain syrup be stored beyond aspartame's relatively short shelf-life. Saccharin is believedto be an important discovery, especially fordiabetics,as it goes directly through the humandigestivesystemwithout being digested. Although saccharin has nofood energy,it may trigger the releaseofinsulinin humans and rats, presumably as a result of its taste, but this is not conclusive as the samestudy states "No statistically significant changes in plasma insulin were found."[4][5][6]This is similar foraspartame (another artificial sweetener).[7]

In its acid form, saccharin is not water-soluble. The form used as an artificial sweetener is usuallyitssodiumsalt.Thecalciumsalt is also sometimes used, especially by people restricting their dietarysodium intake. Both salts are highly water-soluble: 0.67 grams per milliliter water at roomtemperature.[8][9]

History[edit]

Saccharin, historical wrapping;Sugar Museum (Berlin)

Saccharin was produced first in 1878 byConstantin Fahlberg,a chemist working oncoal tarderivativesinIra Remsen's laboratory at theJohns Hopkins University.(As discussed below, the relativecontributions of Fahlberg and Remsen to the discovery were later contested, with no final resolution insight; the 1879 paper announcing the discovery lists both names as authors, with Fahlberg's name first.)Fahlberg noticed a sweet taste on his hand one evening, and connected this with the compound that hehad been working on that day.[10][11]Fahlberg and Remsen published articles on benzoic sulfimide in1879 and 1880.[8][12]In 1884, then working on his own in New York City, Fahlberg applied for patents inseveral countries, describing methods of producing this substance that he named saccharin.[13]Twoyears later he began production of the substance in a factory in a suburb of Magdeburg, Germany.Fahlberg would soon grow wealthy, while Remsen merely grew irritated, believing that he deservedcredit for substances produced in his laboratory. On the matter, Remsen commented, "Fahlberg is a

scoundrel. It nauseates me to hear my name mentioned in the same breath with him."

[14]

Although saccharin was commercialized not long after its discovery, it was not until sugar shortagesduringWorld War Ithat its use became widespread. Its popularity further increased during the 1960sand 1970s among dieters, since saccharin is acalorie-free sweetener. In the United States, saccharin isoften found in restaurants inpinkpackets; the most popular brand is "Sweet'n Low".

Government regulation[edit]Starting in 1907, theUSDAbegan investigating saccharin as a direct result of thePure Food and DrugAct.Harvey Wiley,then the director of the bureau of chemistry for the USDA, viewed it as an illegalsubstitution of a valuable ingredient (sugar) by a less valuable ingredient. In a clash that had careerconsequences, Wiley told PresidentTheodore Rooseveltthat "Everyone who ate that sweet corn wasdeceived. He thought he was eating sugar, when in point of fact he was eating a coal tar product totallydevoid of food value and extremely injurious to health." But Roosevelt himself was a consumer ofsaccharin, and, in a heated exchange, Roosevelt angrily answered Wiley by stating, "Anybody who sayssaccharin is injurious to health is an idiot."[15]The episode proved the undoing of Wiley's career.
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edia.org/wiki/File:S%C3%BC%C3%9Fstoff_Saccharin_Zucker-Museum.jpghttp://en.wikipedia.org/wiki/File:Saccharin-Na_substance_photo.jpghttp://en.wikipedia.org/wiki/File:S%C3%BC%C3%9Fstoff_Saccharin_Zucker-Museum.jpghttp://en.wikipedia.org/wiki/File:S%C3%BC%C3%9Fstoff_Saccharin_Zucker-Museum.jpghttp://en.wikipedia.org/wiki/File:Saccharin-Na_substance_photo.jpghttp://en.wikipedia.org/wiki/Sodium_saccharin#cite_note-15http://en.wikipedia.org/wiki/Theodore_Roosevelthttp://en.wikipedia.org/wiki/Harvey_Wileyhttp://en.wikipedia.org/wiki/Pure_Food_and_Drug_Acthttp://en.wikipedia.org/wiki/Pure_Food_and_Drug_Acthttp://en.wikipedia.org/wiki/USDAhttp://en.wikipedia.org/w/index.php?title=Saccharin&action=edit&section=4http://en.wikipedia.org/wiki/Sweet%27n_Lowhttp://en.wikipedia.org/wiki/Pinkhttp://en.wikipedia.org/wiki/Caloriehttp://en.wikipedia.org/wiki/World_War_Ihttp://en.wikipedia.org/wiki/Sodium_saccharin#cite_note-14http://en.wikipedia.org/wiki/Sodium_saccharin#cite_note-13http://en.wikipedia.org/wiki/Sodium_saccharin#cite_note-Fahlberg-8http://en.wikipedia.org/wiki/Sodium_saccharin#cite_note-Fahlberg-8http://en.wikipedia.org/wiki/Sodium_saccharin#cite_note-10http://en.wikipedia.org/wiki/Sodium_saccharin#cite_note-10http://en.wikipedia.org/wiki/Johns_Hopkins_Universityhttp://en.wikipedia.org/wiki/Ira_Remsenhttp://en.wikipedia.org/wiki/Coal_tarhttp://en.wikipedia.org/wiki/Constantin_Fahlberghttp://en.wikipedia.org/wiki/Sugar_Museum_(Berlin)http://en.wikipedia.org/w/index.php?title=Saccharin&action=edit&section=3http://en.wikipedia.org/wiki/Sodium_saccharin#cite_note-Fahlberg-8http://en.wikipedia.org/wiki/Sodium_saccharin#cite_note-Fahlberg-8http://en.wikipedia.org/wiki/Calciumhttp://en.wikipedia.org/wiki/Salt_(chemistry)http://en.wikipedia.org/wiki/Sodiumhttp://en.wikipedia.org/wiki/Sodium_saccharin#cite_note-7http://en.wikipedia.org/wiki/Sodium_saccharin#cite_note-6http://en.wikipedia.org/wiki/Sodium_saccharin#cite_note-4http://en.wikipedia.org/wiki/Sodium_saccharin#cite_note-4http://en.wikipedia.org/wiki/Insulinhttp://en.wikipedia.org/wiki/Food_energyhttp://en.wikipedia.org/wiki/Digestive_systemhttp://en.wikipedia.org/wiki/Digestive_systemhttp://en.wikipedia.org/wiki/Diabetes_mellitushttp://en.wikipedia.org/wiki/Aspartamehttp://en.wikipedia.org/wiki/Cyclamate


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In 1911, the Food Inspection Decision 135 stated that foods containing saccharin were adulterated.However, in 1912, Food Inspection Decision 142 stated that saccharin was not harmful.

More controversy was stirred in 1969 with the discovery of files from the FDA's investigations of 1948and 1949. These investigations, which had originally argued against saccharin use, were shown toprove little about saccharin being harmful to human health. In 1972, the USDA made an attempt tocompletely ban the substance.[16][full citation needed]However, this attempt was also unsuccessful, and the

sweetener continued to be widely used in the United States. It is now the most popular artificialsweetener aftersucraloseandaspartame.

In the European Union, saccharin is also known by theE number(additive code) E954.

The current status of saccharin is that i t is allowed in most countries, and countries like Canada areconsidering lifting their previous ban of it as a food additive.[17]The claims that it is associated withbladder cancer were shown to be unfounded in experiments on primates.[18](It is, however, prohibited tomail saccharin tablets or packets to France.)[19]

Saccharin was formerly on California's list of chemicals known to the state to cause cancer for thepurposes ofProposition 65,but it was delisted in 2001.[20]

Warning label addition and removal[edit]In 1958, the United States Congress amended theFood, Drugs, and Cosmetic Act of 1938with

theDelaney clauseto mandate that theFood and Drug Administrationnot approve substances that"induce cancer in man, or, after tests, [are] found to induce cancer in animals." Studies in laboratory ratsduring the early 1970s linked saccharin with the development of bladder cancer in rodents. As aconsequence, all food containing saccharin was labeled with a warning meeting the requirement oftheSaccharin Study and Labeling Act of 1977.[21]

However, in 2000, the warning labels were removed because scientists learned that rodents, unlikehumans, have a unique combination of high pH, high calcium phosphate, and high protein levels in theirurine.[22][23]One or more of the proteins that are more prevalent in male rats combine with calciumphosphate and saccharin to produce microcrystals that damage the lining of the bladder. Over time, therat's bladder responds to this damage by over-producing cells to repair the damage, which leads totumor formation. Since this does not occur in humans, there is no elevated risk of bladder cancer.

The delisting of saccharin led to legislation, known as the Sweetness Act; which was signed into law onDecember 21, 2000, repealing the warning label requirement for products containing saccharin. [citationneeded]

In 2001, the U.S.Food and Drug Administrationand the state ofCaliforniareversed their positionson saccharin, declaring it safe for consumption.[24]The FDA's decision followed a 2000 determination bythe U.S. Department of Health and Human Services' National Toxicology Program to remove saccharinfrom its list of carcinogens.

The EPA has officially removed saccharin and its salts from their list of hazardous constituents andcommercial chemical products. In a December 14, 2010 release, the EPA stated that saccharin is nolonger considered a potential hazard to human health.[25]

Chemistry[edit]

Saccharin can be produced in various ways.[26]The original route by Remsen & Fahlberg startswithtoluene;another route begins with o-chlorotoluene.[27]Sulfonation bychlorosulfonic acidgivesthe orthoandparasubstitutedsulfonyl chlorides.The orthoisomer is separated and converted tothesulfonamidewithammonia.Oxidation of the methyl substituent gives the carboxylic acid, which

cyclicizes to give saccharin free acid:[28]
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In 1950, an improved synthesis was developed at theMaumee Chemical CompanyofToledo,Ohio.In this synthesis,anthranilic acidsuccessively reacts withnitrous acid(fromsodiumnitriteandhydrochloric acid),sulfur dioxide,chlorine,and thenammoniato yield saccharin:[28]

The free acid of saccharin has a lowpKaof about 2 (the acidic hydrogen being that attachedto the nitrogen).[29][30]Saccharin can be used to prepare exclusivelydisubstitutedaminesfromalkyl halidesvia a nucleophilic substitution,[31]followed byGabrielsynthesis.
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AspartameFrom Wikipedia, the free encyclopedia(Redirected fromAspertame)

Aspartame[1]

IUPAC name[hide]

N-(L--Aspartyl)-L-phenylalanine,

1-methyl ester
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Identifiers

CAS number 22839-47-0

ChemSpider 118630

UNII Z0H242BBR1

DrugBank DB00168

KEGG C11045

ChEBI CHEBI:2877

ChEMBL CHEMBL171679


SMILES

[show]

InChI

[show]

Properties

Molecular formula C14H18N2O5


Density 1.347 g/cm3

Melting point 246247 C

Boiling point decomposes

Solubilityinwater sparingly soluble

Solubility slightly soluble inethanol

Acidity(pKa) 4.56.0[2]

Hazards

NFPA 704

110

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Infobox references

Aspartame(APM;/sprtem/or/sprtem/)is an artificial, non-saccharidesweetenerused asasugar substitutein some foods and beverages. In the European Union, it is codified as E951.Aspartame is amethylesterof theaspartic acid/phenylalaninedipeptide.It was first sold under thebrand nameNutraSweet;It was first synthesized in 1965 and the patent expired in 1992.

Thesafety of aspartamehas been the subject of several political and medicalcontroversies,congressional hearingsand Internet hoaxes[3][4][5]since its initial approval for use in foodproducts by theU.S. Food and Drug Administration(FDA) in 1981.[6]:2TheEuropean Food SafetyAuthorityconcluded in its 2013 re-evaluation that aspartame and its breakdown products are safe forhuman consumption at current levels of exposure,[7]corroborating other medical reviews.[8]However,because its breakdown products includephenylalanine,aspartame must be avoided by people with thegenetic conditionphenylketonuria(PKU).

Chemistry[edit]Aspartame is amethylesterof thedipeptideof the naturalamino acidsL-aspartic acidand L-phenylalanine.Under stronglyacidicoralkalineconditions, aspartame maygeneratemethanolbyhydrolysis.Under more severe conditions, thepeptide bondsare alsohydrolyzed,resulting in the free amino acids.[9]

While known aspects of synthesis are covered by patents, many details are proprietary.[10]Twoapproaches to synthesis are used commercially. In the chemical synthesis, the two carboxyl groups ofaspartic acid are joined into an anhydride, and the amino group is protected by a compound that willprevent further reactions of that group. Phenylalanine is methylated and combined with the N-protectedaspartic anhydride, then the blocking group is removed from aspartic acid by acid hydrolysis. Thedrawback of this technique is that a byproduct, the bitter tasting -form, is produced when the wrongcarboxyl group from aspartic acid links to phenylalanine. A process using anenzyme from Bacillusthermoproteolyticusto catalyze the condensation of the chemically altered amino acids will produce high

yields without the -form byproduct. A variant of this method, which has not been used commercially,uses unmodified aspartic acid, but produces low yields. Methods for directly producing aspartyl-phenylalanine by enzymatic means, followed by chemical methylation, have also been tried, but notscaled for industrial production.[11]

Properties and use[edit]

Beta-aspartame differs from aspartame based upon which carboxyl group of aspartate binds to the

nitrogen of phenylalanine.

Aspartame, anartificial sweetener,is approximately 200 times sweeter thansucrose,or table sugar.Due to this property, even though aspartame produces four kilocalories of energy per gram whenmetabolized, the quantity of aspartame needed to produce a sweet taste is so small that its caloriccontribution is negligible.[8]The taste of aspartame and other artificial sweeteners differs from that oftable sugar in the times of onset and how long the sweetness lasts, though aspartame comes closest tosugar's taste profile among approved artificial sweeteners.[10]The sweetness of aspartame lasts longerthan sucrose, so it is often blended with other artificial sweeteners such as acesulfame potassiumtoproduce an overall taste more like sugar.[12]Aspartame can be synthesized from its constituent amino

acids, L-phenylalanineandL-aspartate.Like many otherpeptides,aspartame mayhydrolyze(break down) into its constituent amino acids underconditions of elevated temperature or highpH.This makes aspartame undesirable as a baking
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sweetener, and prone to degradation in products hosting a high pH, as required for a long shelf life. Thestability of aspartame under heating can be improved to some extent by encasing it in fats orinmaltodextrin.The stability when dissolved in water depends markedly onpH.At room temperature, itis most stable at pH 4.3, where itshalf-lifeis nearly 300 days. At pH 7, however, itshalf-lifeis only a fewdays. Most soft-drinks have a pH between 3 and 5, where aspartame is reasonably stable. In productsthat may require a longer shelf life, such assyrupsforfountain beverages,aspartame is sometimesblended with a more stable sweetener, such assaccharin.[13]

Aspartame's major decomposition products are itscyclicdipeptide(in a2,5-diketopiperazine,or DKP,form), the de-esterified dipeptide (aspartyl-phenylalanine), and its constituentcomponents,phenylalanine,[14]aspartic acid,[15]andmethanol.[16]At 180 C, aspartame undergoesdecomposition to form a diketopiperazine derivative.[17]

In products such aspowdered beverages,theaminein aspartame can undergo aMaillard reactionwiththealdehydegroups present in certainaroma compounds.The ensuing loss of both flavor andsweetness can be prevented by protecting the aldehyde as anacetal.

Descriptive analysesof solutions containing aspartame report a sweet aftertaste as well as bitter andoff-flavor aftertastes.[18]

Discovery and approval[edit]

Aspartame was discovered in 1965 by James M. Schlatter, a chemist working forG.D. Searle &Company.Schlatter hadsynthesizedaspartame as an intermediate step in generating a tetrapeptide ofthe hormonegastrin,for use in assessing an anti-ulcerdrug candidate.[19]He accidentally discovered itssweet taste when he licked his finger, which had become contaminated with aspartame, to lift up a pieceof paper.[8][20][21]

In 1975, prompted by issues regardingFlagylandAldactone,a U.S. FDA task force team reviewed 25studies submitted by the manufacturer, including 11 on aspartame. The team reported "seriousdeficiencies in Searle's operations and practices".[6]The FDA sought to authenticate 15 of the submittedstudies against the supporting data. In 1979, theCenter for Food Safety and Applied Nutrition(CFSAN)concluded, since many problems with the aspartame studies were minor and did not affect theconclusions, the studies could be used to assess aspartame's safety.[6]

In 1980, the FDA convened a Public Board of Inquiry (PBOI) consisting of independent advisorscharged with examining the purported relationship between aspartame andbrain cancer.The PBOI

concluded aspartame does not causebraindamage, but it recommended against approving aspartameat that time, citing unanswered questions about cancer in laboratory rats.[6]:9496[22]

Citing data from a Japanese study that had not been available to the members of the PBOI,[23]and afterseeking advice from an expert panel that found fault with statistical analyses underlying the PBOI'shesitation, yet argued against approval,[6]:53FDA commissioner Hayes approved aspartame for use indry goods.[6]In 1983, the FDA further approved aspartame for use in carbonated beverages, and for usein other beverages, baked goods, and confections in 1993. In 1996, the FDA removed all restrictionsfrom aspartame, allowing it to be used in all foods.

Several European Union countries approved aspartame in the 1980s, with EU-wide approval in 1994.The European CommissionScientific Committee on Foodreviewed subsequent safety studies andreaffirmed the approval in 2002. TheEuropean Food Safety Authorityreported in 2006 that thepreviously establishedAcceptable daily intakewas appropriate, after reviewing yet another set ofstudies.[24]

Compendial status[edit]

British Pharmacopoeia[25] United States Pharmacopeia[26]

Safety and approval controversies[edit]Main article:Aspartame controversy

Aspartame has been found to be safe for human consumption by more than ninety countriesworldwide,[27][28]with FDA officials describing aspartame as "one of the most thoroughly tested andstudied food additives the agency has ever approved" and its safety as "clear cut",[29]but has been thesubject of several controversies, hoaxes[3]and health scares.[30]

Initially aspartame was approved by theU.S. Food and Drug Administration(FDA) in 1974, however,problems with Searle's safety testing program, including testing of aspartame, were discovered
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