o-Toluidine

Overview

o-Toluidine (ortho-toluidine) is an organic compound with the chemical formula C7H9N.o-Toluidine is primarily used in the manufacture of dyes. o-Toluidine is highly toxic to humans when absorbed through the skin, inhaled as vapor, or swallowed. Acute (short-term) exposure of humans to o-toluidine affects the blood (i.e., methemoglobinemia), with clinical signs of central nervous system depression. The chronic (long-term) effects in workers exposed to o-toluidine include anemia, anorexia, weight loss, skin lesions, central nervous system depression, cyanosis, and methemoglobinemia. Animal studies indicate that chronic exposure to o-toluidine causes effects on the spleen, liver, urinary bladder, and blood. Occupational exposure to dyestuffs (including o-toluidine) is associated with an increased risk of bladder cancer. 2-Methylaniline hydrochloride (the hydrochloride salt of o-toluidine) was carcinogenic in rats and mice. o-Toluidine has been classified by EPA as a Group B2, probable human carcinogen.

Toluidine Isomers

Toluidine has three isomers: o-toluidine, m-toluidine and p-toluidine, while o-toluidine is the situ substitution product and m-toluidine is the shift substitution product.
O-toluidine is an important intermediate for the production of dyes and pigments and can be used to prepare direct red 62, red base RL, red base G, juvenile base GBC, alkaloid, peptone AS-D, acid red 35,158 265, solvent red 124, diazo group of azo dyes and coupling component, pigment yellow 14, yellow 17, Blue 19; raw materials of pesticide like Tricyclazole, insecticide Chlordimeform, chloromethiuron; acetochlor; raw materials of Thiofide; raw material of saccharin; corrosion inhibitor and other raw materials. In organic synthesis, o-toluidine are also used in synthesis of heterocyclic compounds indole and its derivatives.

Chemical and Physical Properties

O-toluidine is a clear colorless or light yellow liquid, may become reddish brown on exposure to air and light, and white precipitate at the presence of formaldehyde. It is slightly soluble in water, soluble in dilute acid, alcohol and ether.
relative density: 1.004(20℃);
melting point:-16.3℃ (β),-24.4℃(α);
boiling point: 199.7℃;
Flash point 185°F;
spontaneous ignition point: 482.2℃;
vapor density: 3.69.
Its vapor can form explosive mixture with air. The maximum allowable concentration in air is 5ppm. O-toluidine is flammable when exposed to heat or flame. It will, when heated, emit toxic gases toxic similar to that of aniline. Once it enters human body, it will cause the formation of hemoglobin, resulting in the occurrence of neurological disorders and cyanosis.
It has about the same density as water and is very slightly soluble in water. Vapors are heavier than air. Confirmed carcinogen.
The chemical properties of the toluidines are quite similar to those of aniline and toluidines have properties in common with other aromatic amines. Due to the amino group bonded to the aromatic ring, the toluidines are weakly basic.

Synthesis Method

o-Toluidine can be synthesized from toluene. The direct aromatic amination is very effective when done with a parent nitrenium ion, but o-toluidine can also be synthesized in other ways. For example, by the amination of toluene with methylhydroxylamine or hydroxylammonium salts in presence of aluminum trichloride.[22] The reaction using a nitrenium ion is not regionselective and multiple structural isomers will be present in the product. Figure 2 shows a very general synthesis reaction of o-toluidine and the other products (p-toluidine and m-toluidine). To obtain pure o-toluidine, the isomers need to be separated.
1. In the dilute acid medium, o-nitrotoluene heated together with iron powder and water to synthesize o-toluidine.
 
2. O-nitrotoluene is preheated with hydrogen in the induction heater and hydrogenated in the presence of copper catalyst to prepare o-toluidine. 

3.Toluene is aminated by ammonia sodium with the rhodium-carbon catalyst to produce o-toluidine.
4.Aniline is alkylated with methanol under the catalysis of ferric nitrate and germanium dioxide to produce the finished product o-toluidine.

Hazard Occasions

• O-toluidine is toxic, the inhalation of its vapor or absorbtion through the skin or ingestion can cause poisoning. It is one of the known carcinogens.
• O-toluidine is flammable with a fire point of 482℃, and can form explosive mixture with air. The allowable concentration in air in the United States is 2ppm (9mg/m3).

Toxicity

O-toluidine has a toxicity similar to aniline. The inhalation of its vapor or absorbtion through the skin or ingestion can cause poisoning. Once it enters human body, it will cause the formation of hemoglobin, resulting in the occurrence of neurological disorders, anoxia, headach, acratia, dizziness, drowsiness, cyanosis and hematuresis under microscope. Contact with eyes and skin may cause dermatitis and eye burns. It is one of the known carcinogens.
(Toxicity studies on animals: acute P.O. toxicity on rat LD50: 670 mg/kg, acute P.O. toxicity on mice LD50: 520 mg/kg
Skin irritation on rabbit 10 mg x 24 h, severe. Eye irritation on rabbit 0.75 mg x 24 h, severe.)

Transportation

Organic poison;
Dangerous Goods Code: 84182.UN No.：1708/6270/6.1-02/335.
Domestic commodity number: 61750；
Container in transportation must be marked “Poisonous”.

Storage

Stored in glass bottles or metal barrels to prevent mechanical damage. Place it in a cool, dry, well ventilated place. It is best to use the open or attached warehouse. No fireworks, far away from the fire site. Avoid light. Sealed preservation. Separate it from oxidizer.

Identification

Determination in air: analysis by silica adsorption, propyl alcohol treatment and gas chromatography.

Applications

o-Toluidine is used or applied in different circumstances. It is used the most for dye, especially for coloring hair. The other usages of o-toluidine are specific determination of glucose in blood and the most recent one, the separation of toxic metal ions, which is still in the research phase.

• Dye

o-Toluidine has been used as a dye precursor since the 19th century, when synthetic dye was produced.In the years that followed, the aromatic amine functioned as a precursor of many dyes and pigments for consumer goods. But when the carcinogenicity of o-toluidine for animals was recognized, and that it potentiality could be carcinogenic for humans, the production of o-toluidine and its use in dye manufacturing has been largely banned in the Western world and in many parts of the East. But there are still a few dyes that are based on this compound. The most known compounds are petroleum products and yellow organic pigments. It is also an essential compound in the production of 4-chloro-o-toluidine and 4-amino-2′,3-dimethylazobenzene, which are also dyes.

Specific determination of glucose

o-Toluidine can also be used for measuring serum glucose concentration, in the form of acetic acid–o-toluidine.[26] The o-toluidine reaction for the estimation of glucose concentration in the serum gained massive popularity in the 1970s. This method was mostly used by clinical laboratories. Because of the potential health hazard, the laboratories now have a modified method by using alternative compounds.

Separation of toxic metal ions

The increasing level of heavy metals in the environment is a serious environmental problem. Various methods have been developed to remove these metals from aqueous systems, but these methods have limitations. Because of the limitations, researchers prompted to exploit inorganic materials as ion exchangers. These inorganic ion exchangers are able to obtain specific metal ions/anions or organic molecules. Following research in 2010,[27] there has been a synthesis and analytical application on a new thermally stable composite cation exchange material: poly-o-toluidine stannic molybdate. This material showed a high selectivity for Pb2+ and Hg2+ metal ions.

First-aid

If it enters the eyes, immediately rinse with water or eye drops; on the contact with the skin, immediately wash it off with soap and water; if it inhaled, immediately remove the patient from the scene to the fresh air; practice artificial respiration if necessary; if it is swallowed, drink plenty of water and induce vomiting followed by gastric lavage, and immediately send the patient to hospital for treatment. Methylene blue is a specific antidote to it.

Protective Measures

Suitable protective clothing should be equipped during the peration to prevent skin contact. Wear protective glasses to prevent contact with skin and eyes. Immediately remove permeable clothing, such as wetted or contaminated,. The operating site shall be provided with a safety signal indicator, eyewash and flushing equipment.

The Detection of blood glucose

Methods of determination of the glucose include oxidase method and o-toluidine condensation method and Folin-Wushi method. Among them, o-toluidine condensation method are most commonly used. This method has a high specificity for detecting glucose and is not affected by other substances other than glucose. The theoretical basis is that glucose in hot acetic acid solution can be condensed with o-toluidine to form a blue-green Schiff's base and the color depth is proportional to the glucose content. O-toluidine is added into the serum and glucose standard liquid. Then compare their optical density and calculate the serum glucose content. The normal level of fasting serum glucose is 70~100mg /dl.

Fire Extinguishant

Fog water, foam, carbon dioxide, sand.

Occupational Standard

TWA 22 mg/m3; STEL 44 mg/m3.

Chemical Properties

Light-yellow liquid, becomes reddishbrown on exposure to air and light. Soluble in alcohol and ether; very slightly soluble in water. Combustible.

Chemical Properties

o-Toluidine is a colorless to pale yellow liquid with a weak, pleasant, aromatic odor.

Chemical Properties

O-Toluidine is a light yellow to reddish brown liquid. On exposure to light and atmospheric air, the compound quickly turns a dark color. The compound has extensive use in a large number of industries around the world. For instance, as an intermediate in the manufacture of azo and indigo dyes, pigments, sulfur dyes, pesticides, pharmaceutical products, rubber and vulcanizing chemicals, and similar products.

Physical properties

Colorless to pale yellow liquid with an aromatic, aniline-like odor. Becomes reddish-brown on exposure to air and light. Odor threshold concentration is 250 ppb (quoted, Amoore and Hautala, 1983).

Occurrence

O-Toluidine has been reported to be a component of tar produced by low-temperature carbonization of coal and has been detected in gasoline fractions from arlan petroleum, tobacco leaf extracts, and in the aroma components of black tea (Anon. 1972). Patrianakos and Hoffmann (1979) detected it in tobacco smoke. It is a metabolite of prilocaine anesthetic in rats (Akerman et al 1966) and humans (Hjelm et al 1972; Struck et al 1969). It is a possible contaminant of bootleg methaqualone (Goldfarb and Finelli 1974) but is not a methaqualone metabolite (Nowak et al 1966). It is also a metabolite of the dye Poncean 3R (Lindstrom et al 1969).O-Toluidine has been detected as a contaminant in injectables stored in polystyrene (Ahmad, 1982).

Uses

It was used in determination of glucose in biological materials.It was used as precursor in the synthesis of poly(o-toluidine) and copper nanoparticle composite material.

Uses

o-Toluidine is used in the manufacture ofvarious dyes, in printing textiles blue-blackand as an intermediate in rubber chemicals,pesticides, and pharmaceuticals.

Uses

A carcinogenic and toxic aromatic amine contained in hair dye, henna and dyed hair samples.
o-Toluidine, is a methemoglobin-inducing chemical and a human carcinogen. Commercial production of o-toluidine was first reported in the United States in 1922. o-Toluidine and its hydrochloride salt are used primarily as intermediates in the manufacture of dyes and pigments for printing textiles, in color photography, and as biologic stains. In addition, o-toluidine is used as an intermediate for rubber vulcanizing chemicals, pharmaceuticals, and pesticides. Other minor uses include intermediate for organic synthesis and clinical laboratory reagent for glucose analysis (IARC, 2000, 2010; Woo and Lai, 2012).

Definition

ChEBI: An aminotoluene in which the amino substituent is ortho to the methyl group.

Production Methods

The production of O-toluidine is based on the catalytic hydrogenation of O-nitrotoluene or the amination of toluene with methylhydroxylamine in the presence of aluminum trichloride (Windholz 1983). It is available as a technical grade with a minimum of 99.5% purity containing m-toluidine (0.4% maximum) and/or ptoluidine (0.1% maximum) as impurities (Anon. 1978). The stabilized technical grade may also contain less than 0.5% of unidentified stabilizing agents to prevent darkening.

Synthesis Reference(s)

Journal of the American Chemical Society, 113, p. 1054, 1991 DOI: 10.1021/ja00003a056
The Journal of Organic Chemistry, 43, p. 731, 1978 DOI: 10.1021/jo00398a046
Chemical and Pharmaceutical Bulletin, 34, p. 3905, 1986 DOI: 10.1248/cpb.34.3905

General Description

A clear colorless or light yellow liquid. May become reddish brown on exposure to air and light. Flash point 185°F. Has about the same density as water and is very slightly soluble in water. Vapors are heavier than air. Confirmed carcinogen.

Air & Water Reactions

Becomes reddish brown upon exposure to air and light [Hawley]. Slightly soluble in water.

Reactivity Profile

o-Toluidine neutralizes acids in exothermic reactions to form salts plus water. May be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen may be generated in combination with strong reducing agents, such as hydrides. Emits very toxic oxides of nitrogen when heated to decomposition. Undergoes a hypergolic reaction with red fuming nitric acid [Kit and Evered, 1960, p. 239, 242].

Health Hazard

Absorption of toxic quantities by any route causes cyanosis (blue discoloration of lips, nails, skin); nausea, vomiting, and coma may follow. Repeated inhalation of low concentrations may cause pallor, low-grade secondary anemia, fatigability, and loss of appetite. Contact with eyes causes irritation.

Health Hazard

Exposures to O-toluidine cause toxicity and poisoning to animals and occupational workers. It is highly toxic to animals and humans and is rapidly absorbed by oral, dermal, and inhalation by mammals. The acute oral LD50 to rats ranges from 900 to 940 mg/kg. The compound is known to cause adverse effects in workers, which include headache, irritation of skin, eye, kidneys, bladder, and hematuria. O-Toluidine has caused hepatocellular adenoma and carcinoma in experimental laboratory mice and rats. Occupational workers exposed to O-toluidine have also demonstrated bladder cancer although the role of aniline cannot be ruled out. However, the IARC working group, because of insuffi cient data, classify O-toluidine as a Group 2B agent, meaning possibly carcinogenic to humans, while the NIOSH classify this compound as an occupational carcinogen, and the ACGIH label it as a suspected human carcinogen under A2 class.

Health Hazard

Acute O-toluidine poisoning can cause painful hematuria (Goldbarb and Finelli, 1974) and methemoglobinemia (Hjelm et al 1972 and Struck et al 1969) in humans. Conflicting reports have resulted from evaluating the role of the compound in causing bladder or other cancers. Olt and Langner (1983) reported no increase in men engaged in the production of organic dyes, but Rubino et al (1982) strongly implicated O-toluidine in deaths due to bladder cancer in similar types of men.

Health Hazard

o-Toluidine is a cancer-causing compound.Its acute toxicity in test species was lowto moderate. Severe poisoning may occur athigh doses. It may enter the body by inhala tion of its vapors, ingestion, or absorptionthrough skin contact. The target organs arekidneys, liver, blood, cardiovascular system,skin, and eyes. The toxic symptoms includemethemoglobinemia, anemia, and reticulo cytosis, which are similar to aniline. Thisproduces anoxia (lack of oxygen), cyanosis,headache, weakness, drowsiness, dizziness,increase in urine volume, and hematuria.The pure liquid on skin contact can causeirritation and dermatitis. Contact with eyescan cause burns.
LD50 value, oral (mice): 520 mg/kg
o-Toluidine is a suspected human carcinogen. The evidence of carcinogenicity inhuman is inadequate. It caused tumors in thekidney, bladder, and lungs in rats, mice, andrabbits resulting from oral and subcutaneousadministration.
Brennan and Schiestl (1999) have reportedo-toluidine and o-anisidine induced free radicals and intrachromosomal recombination inSaccharomyces cerevisiae. The toxicity andrecombination induced by these compoundswere reduced by free radical scavenger andantioxidant N-acetyl cysteine.

Fire Hazard

Special Hazards of Combustion Products: Toxic oxides of nitrogen and flammable vapors may form in fire.

Flammability and Explosibility

Non flammable

Chemical Reactivity

Reactivity with Water: No reaction; Reactivity with Common Materials: No reactions; Stability During Transport: Stable; Neutralizing Agents for Acids and Caustics: Not pertinent; Polymerization: Not pertinent; Inhibitor of Polymerization: Not pertinent.

Industrial uses

O-Toluidine is used as an intermediate of the manufacturing of triphenylmethane dyes and safranine colors (Northcott 1978; Windholz 1983). It is an antioxidant in rubber manufacturing and a pharmaceutical intermediate. It has been used as a laboratory reagent in glucose analysis and also used in the preparation of ion exchange resins and making various colors fast to acid.

Safety Profile

Confirmed carcinogen with experimental neoplastigenic and tumorigenic data. Poison by ingestion and intraperitoneal routes. Moderately toxic by skin contact. Human systemic effects by inhalation: urine volume increase, hematuria, and blood methemoglobinemiacarboxyhemoglobinemia. An experimental teratogen. Human mutation data reported. A skin and severe eye irritant. Human mucous membrane effects. Can produce severe systemic disturbances. The main portal of entry into the body is the respiratory tract, particularly in cases of industrial exposure. The symptoms produced are headache, weakness, difficulty in breathing, air hunger, psychic dsturbances, and marked irritation of the kidneys and bladder. The literature does not yield any good data for comparing the toxicity of the o-, m-, and p-isomers. Their behavior is generally comparable to that of aniline. It has been determined experimentally that a concentration of about 100 ppm is the maximum endurable for 1 hour without serious consequences and that 6-23 ppm is endurable for several hours without serious disturbances. Flammable when exposed to heat or flame. Hypergolic reaction with red fuming nitric acid. Can react with oxidizing materials. To fight fire, use foam, CO2, dry chemical. When heated to decomposition it emits highly toxic fumes of NOx. See also ANILINE.

Potential Exposure

o-Toluidine is used as an intermediate in the manufacture of dyes; as an intermediate in pharmaceutical manufacture; in textile printing; in rubber accelerators; in production of o-aminoazotoluene

Carcinogenicity

o-Toluidine and o-toluidine hydrochloride are reasonably anticipatedto be human carcinogens based on sufficient evidence of carcinogenicity from studies in experimental animals.

Source

As o+p-toluidine, detected in distilled water-soluble fractions of 87 octane gasoline and Gasohol at concentrations of 0.80 and 0.19 mg/L, respectively (Potter, 1996). o-Toluidine was detected in 77% of 65 gasoline (regular and premium) samples (62 from Switzerland, 3 from Boston, MA). At 25 °C, concentrations ranged from 13 to 18,000 μg/L in gasoline and 10 to 1,400 μg/L in water-soluble fractions. Average concentrations were 6.1 mg/L in gasoline and 0.47 mg/L in water-soluble fractions (Schmidt et al., 2002).

Environmental Fate

Biological. Heukelekian and Rand (1955) reported a 5-d BOD value of 1.40 g/g which is 55.1% of the ThOD value of 2.54 g/g.
Chemical/Physical. Kanno et al. (1982) studied the aqueous reaction of o-toluidine and other substituted aromatic hydrocarbons (aniline, toluidine, 1- and 2-naphthylamine, phenol, cresol, pyrocatechol, resorcinol, hydroquinone, and 1-naphthol) with hypochlorous acid in the presence of ammonium ion. They reported that the aromatic ring was not chlorinated as expected but was cleaved by chloramine forming cyanogen chloride. As the pH was lowered, the amount of cyanogen chloride formed increased (Kanno et al., 1982).
o-Toluidine will not hydrolyze because it does not contain a hydrolyzable functional group (Kollig, 1993).

Metabolism

Absorption of O-toluidine from the gastrointestinal tract in rats is rapid with peak blood values at 1 h; blood values were near zero in 24 h (Sencyuk and Rucinska 1984a). The urine was the main excretory route; > 92% in 24 h (Cheever et al 1980). At an oral dose of 20 mg/kg, 26% was excreted in the urine in 24 h as O-toluidine (Senczuk and Rucinska 1984b). Kulkarni et al (1983) demonstrated that N-hydroxy-O-toluidine and O-nitrosotoluene are urinary metabolites of otoluidine. Other urinary metabolites in rats have included conjugated aminomethylphenols (Cheever et al 1980), azoxytoluene, N-acetyl-O-toluidine, N-acetyl-oaminobenzylalcohol, 4-amino-m-cresol, N-acetyl-4-amino-m-cresol, anthranilic acid, N-acetylanthranilic acid (Son et al 1980). Sulfate conjugates predominate over glucuronides by a ratio of 6:1. Thus, in rats, the major metabolic routes are N-acetylation and 4-hydroxylation. Human urinary metabolites (after administration of prilocaine) included O-toluidine,P-hydroxy-O-toluidine, and O-hydroxy-toluidine (Hjelm et al 1972). The primary metabolism of O-toluidine takes place in the endoplasmic reticulum. Exposure to O-toluidine enhances the microsomal activity of aryl hydrocarbon hydroxylase (particularly in kidney), NADPH-cyto-chrome c reductase and the content of cytochrome P-450 (Gnojkowski et al 1984).

Shipping

UN1708 Toluidines, liquid, Hazard Class: 6.1; Labels: 6.1-Poisonous materials.

Purification Methods

In general, methods similar to those for purifying aniline can be used, e.g. distillation from zinc dust, at reduced pressure, under nitrogen. Berliner and May [J Am Chem Soc 49 1007 1927] purified it via the oxalate. Twice-distilled o-toluidine is dissolved in four times its volume of diethyl ether, and the equivalent amount of oxalic acid needed to form the dioxalate is added as its solution in diethyl ether. (If p-toluidine is present, its oxalate precipitates and can be removed by filtration.) Evaporation of the ethereal solution gives crystals of o-toluidine dioxalate [Beilstein 12 III 1494, 12 IV 1817]. These are filtered off, recrystallised five times from water containing a small amount of oxalic acid (to prevent hydrolysis), then treated with dilute aqueous Na2CO3 to liberate the amine which is separated, dried (CaCl2) and distilled under reduced pressure. The benzoyl derivative has m 144o (from EtOH). [Beilstein 12 H 772, 12 I 372, 12 II 429, 12 III 1837, 12 IV 1744.]

Incompatibilities

Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides.

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. Controlled incineration (oxides of nitrogen are removed from the effluent gas by scrubbers and/or thermal devices).