Arsenic(III) oxide

Toxicity

Symptoms of overdose include convulsions, muscle weakness and confusion.

Description

Arsenic trioxide, often denoted as As₂O₃ butmore correctly stated as As₄O₆, is an inorganic compound mainly used as the precursor for organoarsenic compounds. It can be obtained by the oxidation of arsenic-containing minerals in the air, such as roasting of orpiment.
2As₂S₃ + 9O₂ → As₄O₆ + 6SO₂

Chemical properties

WHITE POWDER AND FINE CHUNKS

Chemical properties

Arsenic trioxide is an amphoteric oxide that shows a marked preponderance for its acidic properties. It dissolves readily in alkaline solutions to give arsenites. It is the starting point for the manufacture of arsenic-based pesticides (sodium arsenite, sodium arsenate, sodium cacodylate); a starting point for the manufacture of certain arsenic-based pharmaceuticals (Neosalvarsan) and veterinary products. Arsenic trioxide has several applications: (i) a decolorizing agent for glasses and enamels; (ii) a preservative for wood, in animal hides; (iii) in hydrogen recombination poison for metallurgical studies, as a termite poison; (iv) as a starting material for the preparation of elemental arsenic, arsenic alloys, and to enhance electrical junctions in semiconductors; (v) as a cytostatic in the treatment of refractory promyelocytic (M3), a subtype of acute myeloid leukemia; (vi) arsenic trioxide is also used to treat leukemia in patients who have not responded to other medications; (vii) arsenic trioxide was mixed with copper II acetate to form the extremely toxic but exceedingly vibrant pigment, known as Paris green, for use as a rodenticide in the Paris subways; and (viii) in cases of suicide and murder. Humans can be exposed to arsenicin several ways, such as ingesting small amounts present in food and water or breathing air containing arsenic, breathing sawdust or burning smoke from wood treated with arsenic, living in areas with unusually high natural levels of arsenic in rock, working in a job that involves arsenic production or use, such as copper or lead smelting, wood treating, or pesticide application.

Chemical properties

Arsenic trioxide is a noncombustible, odorless, white powder or colorless crystalline solid.

Physical properties

This compound, also known as arsenious acid, is the hydrolyzed form of As2O3 and has the formula As(OH)3. As(OH)3 occurs in aqueous solutions and has not been isolated as a pure material, although this fact does not detract from the significance of As(OH)3. This compound is essentially the “hydroxide” of the arsenic ion but is not basic in character. The molecular weight of arsenous acid is 125.94 g/mol. As(OH)3 is a pyramidal molecule consisting of three hydroxyl groups connected by single bonds to arsenic. In contrast, the nominally related phosphorous species H3PO3 mainly adopts the structure HPO(OH)2 in which P(OH)3 is a very minor equilibrium component of such solutions (if it exists at all). The differing behaviors of the As and P compounds reflect a trend whereby high oxidation states are more stable for lighter members of main group elements than their heavier congeners like As where the +3 valance state dominates.
Arsenous acid [13464-58-9], AsH3O3, is known to exist only in solution. It is a weak acid with a dissociation constant of 8×10^-16 at 25°C. The free acid apparently has three OH groups attached directly to the arsenic atom and hence is not analogous to phosphorous acid. A number of complex arsenites are known, among which are copper acetate arsenite [12002-03-8], Cu2(C2H3O2)(AsO3), Paris green, and cupric hydrogen arsenite [10290-12-7], CuHAsO3, Scheele’s green. These have been used mainly as insecticides in the past.
As(OH)3 is a weak acid with a Pka of 9.2. The preparation of As(OH)3 involves a slow hydrolysis of hydolysis of arsenic trioxide in water. Addition of a base such as one of the alkali cations converts arsenous acid to the arsenite ions [AsO(OH)2]^-, [AsO2(OH)]^2-, and [AsO3]^3-. In other words, arsenous acid is “amphoteric” and easily forms anions in the presence of more cationic species like the alkali metals. Note that these anions are analogous to the mono, di and tri-basic anions of phosphate. Reactions attributed to aqueous arsenic trioxide are due to arsenous acid and its conjugate bases.

The Uses of Arsenic(III) oxide

It is a reductometric standard.

The Uses of Arsenic(III) oxide

Starting material for various arsenic compounds. Decolorizer and fining agent in manufacture of glass. In wood preservatives, weed killers, rodenticides.

The Uses of Arsenic(III) oxide

Arsenic trioxide is used as a precursor to forestry products, in colorless glass production, and in electronics. And it is also used as pigments, and preservatives for hides and wood, in the semiconductor industry to create light emitting diodes.

Indications

For induction of remission and consolidation in patients with acute promyelocytic leukemia (APL), and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression

Background

Arsenic trioxide is a chemotherapeutic agent of idiopathic function used to treat leukemia that is unresponsive to first line agents. It is suspected that arsenic trisulfide induces cancer cells to undergo apoptosis. In general, arsenic is known to be a naturally toxic substance capable of eliciting a variety of dangerous adverse effects. The enzyme thioredoxin reductase has recently been identified as a target for arsenic trioxide.

Definition

A colorless crystalline solid that is very poisonous (0.1 g would be a lethal dose). Analysis of the solid and vapor states suggests a dimerized structure of As₄O₆. An amphoteric oxide, arsenic(III) oxide is sparingly soluble in water, producing an acidic solution. It is formed when arsenic is burned in air or oxygen.

Definition

A salt of the hypothetical arsenic(III) acid, formed by reacting arsenic(III) oxide with alkalis. Arsenate(III) salts contain the ion AsO₃^3-. Copper arsenate(III) is used as an insecticide.

Definition

arsenolite: A mineral form of arsenic(III) oxide, As₄O₆.

Definition

Claudetite: a mineral form of arsenic(III) oxide, As₄O₆.

Preparation

Arsenic trioxide is obtained by roasting the mineral arsenopyrite, FeAsS, in air at 650 to 700°C. It is also obtained as a by-product during the smelting ofcopper and lead concentrates during the extraction of these metals from their ores that contain arsenic. The latter readily oxidizes to arsenic trioxide which is volatilized. The vapors are then condensed and collected. High purity-grade oxide can be obtained by resublimation of the crude trioxide or by pressure leaching and recrystallization. Arsenic trioxide may also be prepared by hydrolysis of arsenic trichloride, -tribromide or -trifluoride.

Reactions

In the processing of As2O3 the oxide is normally reduced withcarbon:
2As2O3+3C?→As4+3CO2
The reaction is endothermic and is carried out at 500–800℃.The elemental arsenic sublimes and is condensed out of the reaction gas by cooling.

brand name

Trisenox (Cephalon).

General Description

White or transparent, glassy amorphous lumps or crystalline powder. Slightly soluble in water, but dissolves very slowly; more soluble in hot water. Noncombustible. Corrosive to metals in the presence of moisture. Toxic by ingestion.

General Description

Arsenic trioxide is available in 10-mL vials for IV administrationas second-line therapy in the treatment of acutepromyelocytic leukemia (APL). The mechanism of theagent has not been well characterized; however, work hasindicated that the agent may cause the degradation of a proteinthat blocks myeloid differentiation. Acute lymphocyticleukemia is associated with a translocation in which thepromyelocytic leukemia (PML) gene is fused with theretinoic acid receptor gene (RAR), and the protein that resultsfrom this genetic rearrangement prevents myeloid differentiation.Arsenic trioxide is capable of degrading thisprotein and allowing the cells to differentiate. Additional effectshave included stimulation of apoptosis by decreasingBcl-2 activity and stimulation of caspase enzymes and p53.Angiogenesis is inhibited by the inhibition of VEGF at theprotein level.The agent is widely distributed after IV administration;however, the pharmacokinetics of the agenthave not been well characterized. Metabolism studies haveshown that the agent undergoes reduction to trivalent arsenicfollowed by methylation to give monomethylarsonicand dimethylarsinic acids, which are eliminated in theurine. Unlike most other antineoplastic agents, myelosuppressiondoes not occur in fact many patients (50%–60%)experience leukocytosis in which white blood cell count increases.APL differentiation syndrome is seen in many patients(30%) and presents as fever, shortness of breath,weight gain, pulmonary infiltrates, and pleural or pericardialeffusions. This may be fatal and is commonly treatedwith high-dose dexamethasone upon initial suspicion. Thepresentation of APL differentiation syndrome are identicalfor arsenic trioxide and retinoic acid. Additional adverse effectsinclude fatigue, a prolonged QT interval, dizziness,mild hyperglycemia, and mild nausea and vomiting.

Air & Water Reactions

Slightly soluble in water, but dissolves very slowly; more soluble in hot water [Merck].

Reactivity Profile

Arsenic(III) oxide reacts vigorously with fluorine at ordinary temperatures [Mellor 9:34 1946-47]. Dissolves in aqueous acids. Incompatible with tannic acid, infusions of cinchona and other vegetable astringent infusions and decoctions, and with iron in solution [Merck].

Hazard

A confirmed carcinogen.

Health Hazard

Material is considered super toxic; probable oral lethal dose (human) is less than 5 mg/kg, i.e., a taste (less than 7 drops) for a 70kg (150 lb.) person. Material causes acute gastrointestinal and central nervous system symptoms. Renal and hepatic damage have also been observed. Chronic exposure to material has led to nasal septum perforation, dermatological symptoms (lesions, necrosis, etc.) and an increase in the incidence of lung and lymphatic cancers. Appreciable exposure to respiratory irritant promoters such as metal oxide fumes elicits a carcinogenic response from Arsenic(III) oxide .

Health Hazard

Arsenic trioxide is readily absorbed by the digestive system. The toxic effects are also well known after inhalation of the dust or fumes and after skin contact. Initially, elimination is rapid (half-life of 1–2 days) by methylation to cacodylic acid and excretion in the urine, but a certain amount (30%–40% in the case of repeated exposure) is incorporated into the bones, muscles, skin, hair, and nails (all tissues rich in keratin) and eliminated over a period of weeks or months. The fi rst symptoms of acute arsenic poisoning by ingestion are digestive problems: vomiting, abdominal pains, and diarrhea often accompanied by bleeding. Sub-lethal doses can lead to convulsions, cardiovascular problems, infl ammation of the liver and kidneys, and abnormalities in the coagulation of the blood. These are followed by the appearance of characteristic white lines (Mees stripes) on the nails and by hair loss. Lower doses lead to liver and kidney problems and to changes in the pigmentation of the skin. Cases of acute arsenic poisoning after inhalation and after skin contact with arsenic trioxide are many. The fi rst signs are severe irritation, either of the respiratory tract or of the exposed skin, followed by longer-term neurological problems. Even dilute solutions of arsenic trioxide are dangerous on contact with the eyes. Ingesting or breathing low levels of inorganic arsenic for a long time can cause a darkening of the skin and the appearance of small “corns” or “warts” on the palms, soles, and torso. Skin contact with inorganic arsenic may cause redness and swelling. In brief, acute human exposures to arsenic in well water (typically containing more than 1200 μg/L) is known to cause many health effects, including abdominal pain, vomiting, diarrhea, muscular weakness and cramping, pain in arms and legs, skin changes or rashes, swelling of the eyelids, feet, and hands, and in serious poisoning, death.

Fire Hazard

Toxic fumes of Arsenic(III) oxide and arsine may be formed in fire situations. Contact with halide acids will form toxic volatile halides. Reduction in acid solutions will form arsine. Arsenic(III) oxide and excess zinc filings will explode on heating. Avoid sodium chlorate; fluorine; chlorine trifluoride; chromic oxide; aluminum chloride; phosphorus pentoxide; hydrogen fluoride; oxygen difluoride, tannic acid; infusion cinchona and other vegetable astringent infusions and decoctions; iron in solution. Arsenic(III) oxide is stable in air but slowly oxidizes in acid media.

Flammability and Explosibility

Not classified

Pharmacokinetics

Arsenic Trioxide is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy.

Clinical Use

Antineoplastic agent:
Acute promyelocytic leukaemia (APL)

Safety Profile

Confirmed human carcinogen with experimental neoplastigenic and tumorigenic data. Poison by ingestion, subcutaneous, and intravenous routes. Human systemic effects by ingestion: sleep changes, muscle weakness, hypermotiltty, darrhea, cardiac arrhythmias, coma, fatty degeneration of the liver, depressed renal function tests. An experimental teratogen. Other experimental reproductive effects. Mutation data reported. Reacts vigorously with Rb2C2, CIF3, F2, Hg, OF2, NaClO3. See also ARSENIC COMPOUNDS.

Potential Exposure

Arsenic trioxide, a primary raw material for other arsenic compounds, is used in manufacture of pesticides, glass, industrial chemicals, and drugs. It is an intermediate for insecticides, herbicides and fungicides. The material is used as a wood and tanning preservative and a decoloring and refining agent in glass manufacture. It is also used in pharmaceuticals and in the purification of synthetic gas.

Drug interactions

Potentially hazardous interactions with other drugs
Use with care in combination with other drugs known to cause QT interval prolongation.
Anti-arrhythmics: increased risk of ventricular arrhythmias with amiodarone and disopyramide.
Antibacterials: increased risk of ventricular arrhythmias with delamanid, erythromycin, levofloxacin and moxifloxacin.
Antidepressants: increased risk of ventricular arrhythmias with amitriptyline or clomipramine.
Antifungals: increased risk of ventricular arrhythmias with amphotericin.
Antimalarials: increased risk of ventricular arrhythmias with piperaquine with artenimol - avoid.
Antipsychotics: increased risk of ventricular arrhythmias with antipsychotics that prolong the QT interval and haloperidol; avoid with clozapine, increased risk of agranulocytosis.
Beta-blockers: increased risk of ventricular arrhythmias with sotalol.
Cytotoxics: increased risk of ventricular arrhythmias with vandetanib - avoid.
Diuretics: increased risk of ventricular arrhythmias if hypokalaemia occurs due to acetazolamide, loop diuretics or thiazide diuretics.
Lithium: increased risk of ventricular arrhythmias.

First aid

If this chemical gets into the eyes, remove anycontact lenses at once and irrigate immediately for at least30 min, occasionally lifting upper and lower lids. Seek medical attention immediately. If this chemical contacts theskin, remove contaminated clothing and wash immediatelywith large amounts of soap and water. Seek medical attention immediately. If this chemical has been inhaled, removefrom exposure, begin rescue breathing (using universal precautions, including resuscitation mask) if breathing hasstopped and CPR if heart action has stopped. Transferpromptly to a medical facility. When this chemical has beenswallowed, get medical attention.Note to physician: For severe poisoning, BAL [British AntiLewisite, Dimercaprol, dithiopropanol (C3H8OS2)] has beenused to treat toxic symptoms of certain heavy metals poisoning including arsenic. Although BAL is reported to have alarge margin of safety, caution must be exercised, becausetoxic effects may be caused by excessive dosage. Most canbe prevented by premedication with 1-ephedrine sulfate(CAS: 134-72-5). For milder poisoning penicillamine (notpenicillin) has been used, both with mixed success. Sideeffects occur with such treatment and it is never a substitutefor controlling exposure. It can only be done under strictmedical care.

Metabolism

Inorganic, lyophilized arsenic trioxide, when placed in solution, is immediately hydrolyzed to arsenous acid - this appears to be the pharmacologically active species of arsenic trioxide. Further metabolism involves the oxidation of arsenous acid to arsenic acid, and an oxidative methylation of arsenous acid to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) by methyltransferases in the liver. Both MMA and DMA have relatively long half-lives and can accumulate following multiple doses, the extent of which depends upon the dosing regimen in question.

Metabolism

When placed into solution, arsenic trioxide immediately forms the hydrolysis product arsenious acid (AsIII), which is the pharmacologically active species of arsenic trioxide. The metabolism of arsenic trioxide involves oxidation of AsIII to arsenic acid (AsV), as well as oxidative methylation to monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) by methyltransferases, primarily in the liver. Approximately 15% of the administered arsenic trioxide dose is excreted in the urine as unchanged AsIII. The methylated metabolites of AsIII (MMAV, DMAV) are primarily excreted in the urine.

storage

Color Code—Blue: Health Hazard/Poison: Store ina secure poison location. Prior to working with this chemicalyou should be trained on its proper handling and storage.Store in tightly closed containers in a cool, dry well-ventilated area away from contact with incompatible materials. Aregulated, marked area should be established where thischemical is handled, used, or stored in compliance withOSHA Standard 1910.1045.

Shipping

UN1561 Arsenic trioxide, Hazard Class: 6.1; Labels: 6.1-Poisonous materials

Purification Methods

It crystallises in an octahedral form (common form) from H2O or from dilute HCl (1:2), and is then washed, dried and sublimed (193o/760mm). Analytical reagent grade material is suitable for use as an analytical standard after it has been dried at 105o for 1-2hours or has been left in a desiccator for several hours over conc H2SO4. Alternatively: As2O3 (15g) is dissolved by heating in a mixture of H2O (60mL) and HCl (90g, s.g. 1.1), and crystallisation occurs on cooling, accompanied by brilliant flashes of light [Bandrowski Z Phys Chem 17 234 1895]. The amorphous form is a colourless transparent glass (m 200o) which is obtained when the vapour is slowly condensed below the vaporization temperature, and should be kept in a sealed tube because it changes to the octahedral form (m 275o) in the presence of moisture. [Rushton & Daniels J Am Chem Soc 48 384 1926.] A third monoclinic form, is obtained by heating the oxide in a sealed tube at 400o (the vitreous, amorphous form remains at the bottom of the tube) with the monoclinic form subliming onto the intermediate part of the tube at 200o (m 312o), and the octahedral form deposits at the top of the tube. The transition temperature between the last two forms is ~250o. POISONOUS (particularly the vapour, handle in a ventilated fume cupboard). [Schenk in Handbook of Preparative Inorganic Chemistry (Ed. Brauer) Academic Press Vol I p 600 1963.]

Incompatibilities

Sodium chlorate; sodium hydroxide, sulfuric acid; fluorine; chlorine trifluoride; chromic oxide; aluminum chloride; phosphorus pentoxide; hydrogen fluoride; oxygen difluoride; tannic acid; infusion cinchona and other vegetable astringent infusions and decoctions; iron in solution. Contact with acids or acid mists releases deadly arsine gas.

Waste Disposal

Consult with environmental regulatory agencies for guidance on acceptable disposal practices. Generators of waste containing this contaminant (≥100 kg/mo) must conform with EPA regulations governing storage, transportation, treatment, and waste disposal. Dissolve in a minimum of concentrated hydrochloric acid. Dilute with water until white precipitate forms. Add HCl to dissolve. Saturate with H2S; filter and wash precipitate and return to supplier. Alternatively, precipitate with heavy metals, such as lime or ferric hydroxide in lieu of H2S. If needed, seek professional environmental engineering assistance from the United States Environmental Protection Agency Environmental Response Team at (908) 548-8730 (24-hour response line).