Table of Contents

Fluorine, chlorine, bromine, iodine and the more recently discovered radioactive element astatine, make up the family of elements known as the halogens. Except for astatine, the physical and chemical properties of these elements have been exhaustively studied. They occupy group VII in the periodic table, and they display an almost perfect gradation in physical properties.

The family relationship of the halogens is illustrated also by the similarity in the chemical properties of the elements, a similarity which is associated with the arrangement of seven electrons in the outer shell of the atomic structure of each of the elements in the group. All the members form compounds with hydrogen, and the readiness with which union occurs decreases as the atomic weight increases. In like manner, the heats of formation of the various salts decrease with the increasing atomic weights of the halogens. The properties of the halogen acids and their salts show as striking a relationship; the similarity is apparent in organic halogen compounds, but, as the compound becomes chemically more complex, the characteristics and influences of other components of the molecule may mask or modify the gradation of properties.

Uses

Halogens are used in the chemical, water and sanitation, plastics, pharmaceutical, pulp and paper, textile, military and oil industries. Bromine, chlorine, fluorine and iodine are chemical intermediates, bleaching agents and disinfectants. Both bromine and chlorine are used in the textile industry for bleaching and shrink-proofing wool. Bromine is also used in gold mining extraction processes and in oil- and gas-well drilling. It is a fire retardant in the plastics industry and an intermediate in the manufacture of hydraulic fluids, refrigerating and dehumidifying agents, and hair-waving preparations. Bromine is also a component of military gas and fire-extinguishing fluids.

Chlorine is used as a disinfectant for refuse and in the purification and treatment of drinking water and swimming pools. It is a bleaching agent in laundries and in the pulp and paper industry. Chlorine is used in the manufacture of special batteries and chlorinated hydrocarbons, and in the processing of meat, vegetables, fish and fruit. In addition, it acts as a flame retardant. Chlorine dioxide is utilized in the water and sanitation and swimming pool industries for water purification, taste and odour control. It is a bleaching agent in the food, leather, textile, and pulp and paper industries, as well as an oxidizing agent, bactericide and antiseptic. It is used in cleaning and detanning leather and in bleaching cellulose, oils and beeswax. Nitrogen trichloride was formerly used as a bleach and “improver” for flour. Iodine is also a disinfectant in the water and sanitation industry, and acts as a chemical intermediate for inorganic iodides, potassium iodide, and organic iodine compounds.

Fluorine, fluorine monoxide, bromine pentafluoride and chlorine trifluoride are oxidizers for rocket fuel systems. Fluorine is also used in the conversion of uranium tetrafluoride to uranium hexafluoride, and chlorine trifluoride is used in nuclear reactor fuel and for cutting oil-well tubes.

Calcium fluoride, found in the mineral fluorspar, is the primary source of fluorine and its compounds. It is used in ferrous metallurgy as a flux to increase fluidity of the slag. Calcium fluoride is also found in the optical, glass and electronics industries.

Hydrogen bromide and its aqueous solutions are useful for manufacturing organic and inorganic bromides and as reducing agents and catalysts. They are also used in the alkylation of aromatic compounds. Potassium bromide is used to manufacture photographic papers and plates. Large quantities of phosgene gas are required for numerous industrial syntheses, including the manufacture of dye-stuffs. Phosgene is also used in military gas and in pharmaceuticals. Phosgene is found in insecticides and fumigants.

Hazards

The similarity which these elements exhibit in chemical properties is apparent in the physiological effects associated with the group. The gases (fluorine and chlorine) and the vapours of bromine and iodine are irritants of the respiratory system; inhalation of relatively low concentrations of these gases and vapours gives an unpleasant, pungent sensation, which is followed by a feeling of suffocation, coughing and a sensation of constriction in the chest. The damage to the lung tissue which is associated with these conditions may cause the lungs to become overloaded with fluid, resulting in a condition of pulmonary oedema which may well prove fatal.

Fluorine and its compounds

Sources

The majority of fluorine and its compounds is obtained directly or indirectly from calcium fluoride (fluorspar) and phosphate rock (fluorapatite), or chemicals derived from them. The fluoride in phosphate rock limits the usefulness of this ore and, therefore, the fluoride must be removed almost completely in the preparation of elemental phosphorus or food-grade calcium phosphate, and partially in the conversion of fluorapatite to fertilizer. These fluorides are recovered in some cases as aqueous acid or as calcium or sodium salts of the liberated fluoride (probably a mixture of hydrogen fluoride and silicon tetrafluoride), or released to the atmosphere.

Fire and explosion hazards

Many of the fluorine compounds present a fire and explosion hazard. Fluorine reacts with nearly all materials, including metal containers and piping if the passivating film is broken. The reaction with metals can produce hydrogen gas. Absolute cleanliness is required in conveying systems to prevent localized reactions and subsequent fire hazards. Special lubricant-free valves are used to prevent reactions with lubricants. Oxygen difluoride is explosive in gaseous mixtures with water, hydrogen sulphide or hydrocarbons. When heated, many fluorine compounds produce poisonous gases and corrosive fluoride fumes.

Health hazards

Hydrofluoric acid. Skin contact with anhydrous hydrofluoric acid produces severe burns that are felt immediately. Concentrated aqueous solutions of hydrofluoric acid also cause early sensation of pain, but dilute solutions may give no warning of injury. External contact with liquid or vapour causes severe irritation of eyes and eyelids that may result in prolonged or permanent visual defects or total destruction of eyes. Fatalities have been reported from skin exposure to as little as 2.5% of total body surface.

Quick treatment is essential, and should include washing copiously with water on the way to the hospital, then soaking in an iced solution of 25% magnesium sulphate if possible. Standard treatment for mild to moderate burns involves application of a calcium gluconate gel; more severe burns may require injection in and around the affected area with 10% calcium gluconate or magnesium sulphate solution. Sometimes local anaesthesia may be needed for pain.

Inhalation of concentrated hydrofluoric acid mists or anhydrous hydrogen fluoride may cause severe respiratory irritation, and as little as 5 minutes’ exposure is usually fatal within 2 to 10 hours from haemorrhagic pulmonary oedema. Inhalation may also be involved in skin exposures.

Fluorine and other fluorinated gases. Elemental fluorine, chlorine trifluoride and oxygen difluoride are strong oxidizers and may be highly destructive. At very high concentrations, these gases may have an extremely corrosive effect on animal tissue. However, nitrogen trifluoride is strikingly less irritating. Gaseous fluorine in contact with water forms hydrofluoric acid, which will produce severe skin burns and ulceration.

Acute exposure to fluorine at 10 ppm causes slight skin, eye and nasal irritation; exposure above 25 ppm is intolerable, although repeated exposures may cause acclimatization. High exposures may cause delayed pulmonary oedema, haemorrhage and kidney damage, and possibly be fatal. Oxygen difluoride has similar effects.

In an acute rat inhalation study with chlorine trifluoride, 800 ppm for 15 minutes and 400 ppm for 25 minutes were fatal. The acute toxicity is comparable to that of hydrogen fluoride. In a long-term study in two species, 1.17 ppm caused respiratory and eye irritation, and in some animals, death.

In long-term repeated inhalation animal studies with fluorine, toxic effects on the lungs, liver and testicles were observed at 16 ppm, and irritation of mucous membranes and lungs observed at 2 ppm. Fluorine at 1 ppm was tolerated. In a subsequent multi-species study, no effects were observed from 60-minute exposures at concentrations up to 40 ppm.

There are sparse data available on industrial exposure of workers to fluorine. There is even less experience of long-term exposure to chlorine trifluoride and oxygen difluoride.

Fluorides

Ingestion of quantities of soluble fluorides in the range of 5 to 10 grams is almost certainly fatal to human adults. Human fatalities have been reported in connection with the ingestion of hydrogen fluoride, sodium fluoride and fluosilicates. Non-fatal illnesses have been reported due to ingesting these and other fluorides, including the sparingly soluble salt, cryolite (sodium aluminium fluoride).

In industry, fluoride-bearing dusts play a part in a considerable proportion of cases of actual or potential fluoride exposure, and dust ingestion may be a significant factor. Occupational fluoride exposure may be largely due to gaseous fluorides, but, even in these cases, ingestion can rarely be ruled out completely, either because of contamination of food or beverages consumed in the workplace or because of fluorides coughed up and swallowed. In exposure to a mixture of gaseous and particulate fluorides, both inhalation and ingestion may be significant factors in fluoride absorption.

Fluorosis or chronic fluorine intoxication has been widely reported to produce fluoride deposition in skeletal tissues of both animals and humans. The symptoms included increased radiographic bone opacity, formation of blunt excrescences on the ribs, and calcification of intervertebral ligaments. Dental mottling is also found in cases of fluorosis. The exact relationship between fluoride levels in urine and the concurrent rates of osseous fluoride deposition is not fully understood. However, provided urinary fluoride levels in workers are consistently no higher than 4 ppm, there appears to be little need for concern; at a urinary fluoride level of 6 ppm more elaborate monitoring and/or controls should be considered; at a level of 8 ppm and above, it is to be expected that skeletal deposition of fluoride will, if exposure is allowed to continue for many years, lead to increased osseous radio-opacity.

The fluoborates are unique in that absorbed fluoborate ion is excreted almost completely in the urine. This implies that there is little or no dissociation of fluoride from the fluoborate ion, and hence virtually no skeletal deposition of that fluoride would be expected.

In one study of cryolite workers, about half complained of lack of appetite, and shortness of breath; a smaller proportion mentioned constipation, localized pain in the region of the liver, and other symptoms. A slight degree of fluorosis was found in cryolite workers exposed for 2 to 2.5 years; more definite signs were found in those exposed nearly 5 years, and signs of moderate fluorosis appeared in those with more than 11 years of exposure.

Fluoride levels have been associated with occupational asthma among workers in aluminium reduction potrooms.

Calcium fluoride. The hazards of fluorspar are due primarily to the harmful effects of the fluorine content, and chronic effects include diseases of teeth, bones and other organs. Pulmonary lesions have been reported among persons inhaling dust containing 92 to 96% calcium fluoride and 3.5% silica. It was concluded that calcium fluoride intensifies the fibrogenic action of silica in the lungs. Cases of bronchitis and silicosis have been reported amongst fluorspar miners.

Environmental Hazards

Industrial plants using quantities of fluorine compounds, such as iron and steelworks, aluminium smelters, superphosphate factories and so on, may emit fluorine-containing gases, smokes or dusts into the atmosphere. Cases of environmental damage have been reported in animals grazing on contaminated grass, including fluorosis with dental mottling, bone deposition and wasting; etching of window glass in neighbouring houses has also occurred.

Bromine and its compounds

Bromine is widely distributed in nature in the form of inorganic compounds such as minerals, in seawater and in salt lakes. Small amounts of bromine are also contained in animal and vegetable tissues. It is obtained from salt lakes or boreholes, from seawater and from the mother liquor remaining after the treatment of potassium salts (sylnite, carnallite).

Bromine is a highly corrosive liquid, the vapours of which are extremely irritating to the eyes, skin and mucous membranes. On prolonged contact with tissue, bromine may cause deep burns which are long in healing and subject to ulceration; bromine is also toxic by ingestion, inhalation and skin absorption.

A bromine concentration of 0.5 mg/m³ should not be exceeded in case of prolonged exposure; in a bromine concentration of 3 to 4 mg/m³, work without a respirator is impossible. A concentration of 11 to 23 mg/m³ produces severe choking, and it is widely considered that 30 to 60 mg/m³ is extremely dangerous for humans and that 200 mg/m³ would prove fatal in a very short time.

Bromine has cumulative properties, being deposited in the tissues as bromides and displacing other halogens (iodine and chlorine). Long-term effects include disorders of the nervous system.

Persons exposed regularly to concentrations three to six times higher than the exposure limit for 1 year complain of headache, pain in the region of the heart, increasing irritability, loss of appetite, joint pains and dyspepsia. During the fifth or sixth year of work there may be loss of corneal reflexes, pharyngitis, vegetative disorders and thyroid hyperplasia accompanied by thyroid dysfunction. Cardiovascular disorders also occur in the form of myocardial degeneration and hypotension; functional and secretory disorders of the digestive tract may also occur. Signs of inhibition of leucopoiesis and leucocytosis are seen in the blood. The blood concentration of bromine varies between 0.15 mg/100 cm³ to 1.5 mg/100 cm³ independently of the degree of intoxication.

Hydrogen bromide gas is detectable without irritation at 2 ppm. Hydrobromic acid, its 47% solution in water, is a corrosive, faintly yellow liquid with a pungent smell, which darkens on exposure to air and light.

The toxic action of hydrobromic acid is two to three times weaker than that of bromine, but more acutely toxic than hydrogen chloride. Both the gaseous and aqueous forms irritate the mucous membranes of the upper respiratory tract at 5 ppm. Chronic poisoning is characterized by upper respiratory inflammation and digestive problems, slight reflex modifications and diminished erythrocyte counts. Olfactory sensitivity may be reduced. Contact with the skin or mucous membranes may cause burns.

Bromic acid and hypobromous acid. The oxygenated acids of bromine are found only in solutions or as salts. Their action on the body is similar to that of hydrobromic acid.

Ferroso-ferric bromide. Ferroso-ferric bromides are solid substances used in the chemical and pharmaceutical industries and in the manufacture of photographic products. They are produced by passing a mixture of bromine and steam over iron filings. The resultant hot, syrupy brome salt is tipped into iron containers, where is solidifies. Wet bromine (that is, bromine containing more than about 20 ppm of water) is corrosive to most metals, and elemental bromine has to be transported dry in hermetically sealed monel, nickel or lead containers. To overcome the corrosion problem, bromine is frequently transported in the form of ferroso-ferric salt.

Bromophosgene. This is a decomposition product of bromochloromethane and is encountered in the production of gentian violet. It results from the combination of carbon monoxide with bromine in the presence of anhydrous ammonium chloride.

The toxic action of bromophosgene is similar to that of phosgene (see Phosgene in this article).

Cyanogen bromide. Cyanogen bromide is a solid used for gold extraction and as a pesticide. It reacts with water to produce hydrocyanic acid and hydrogen bromide. Its toxic action resembles that of hydrocyanic acid, and it probably has similar toxicity.

Cyanogen bromide also has a pronounced irritant effect, and high concentrations may cause pulmonary oedema and lung haemorrhages. Twenty ppm for 1 minute and 8 ppm for 10 minutes is intolerable. In mice and cats, 70 ppm causes paralysis in 3 minutes, and 230 ppm is fatal.

Chlorine and its inorganic compounds

Chlorine compounds are widely found in nature, comprising about 2% of the earth’s surface materials, especially in the form of sodium chloride in sea water and in natural deposits as carnallite and sylvite.

Chlorine gas is primarily a respiratory irritant. In sufficient concentration, the gas irritates the mucous membranes, the respiratory tract and the eyes. In extreme cases difficulty in breathing may increase to the point where death can occur from respiratory collapse or lung failure. The characteristic, penetrating odour of chlorine gas usually gives warning of its presence in the air. Also, at high concentrations, it is visible as a greenish-yellow gas. Liquid chlorine in contact with skin or eyes will cause chemical burns and/or frostbite.

The effects of chlorine may become more severe for up to 36 hours after exposure. Close observation of exposed individuals should be a part of the medical response programme.

Chronic exposure. Most studies indicate no significant connection between adverse health effects and chronic exposure to low concentrations of chlorine. A 1983 Finnish study did show an increase in chronic coughs and a tendency for hypersecretion of mucous among workers. However, these workers showed no abnormal pulmonary function in tests or chest x rays.

A 1993 Chemical Industry Institute of Toxicology study on the chronic inhalation of chlorine exposed rats and mice to chlorine gas at 0.4, 1.0 or 2.5 ppm for up to 6 hours a day and 3 to 5 days/week for up to 2 years. There was no evidence of cancer. Exposure to chlorine at all levels produced nasal lesions. Because rodents are obligatory nasal breathers, how these results should be interpreted for humans is not clear.

Chlorine concentrations considerably higher than current threshold values may occur without being immediately noticeable; people rapidly lose their ability to detect the odour of chlorine in small concentrations. It has been observed that prolonged exposure to atmospheric chlorine concentrations of 5 ppm results in disease of the bronchi and a predisposition to tuberculosis, while lung studies have indicated that concentrations of 0.8 to 1.0 ppm cause permanent, although moderate, reduction in pulmonary function. Acne is not unusual in persons exposed for long periods of time to low concentrations of chlorine, and is commonly known as “chloracne”. Tooth enamel damage may also occur.

Oxides

In all, there are five oxides of chlorine. They are dichlorine monoxide, chlorine monoxide, chlorine dioxide, chlorine hexoxide and chlorine heptoxide; they have mainly the same effect on the human organism and require the same safety measures as chlorine. The one most used in industry is chlorine dioxide. Chlorine dioxide is a respiratory and eye irritant similar to chlorine but more severe in degree. Acute exposures by inhalation cause bronchitis and pulmonary oedema, the symptoms observed in affected workers being coughing, wheezing, respiratory distress, nasal discharge, and eye and throat irritation.

Nitrogen trichloride is a powerful irritant to the skin and mucous membranes of the eyes and respiratory tract. The vapours are as corrosive as chlorine. It is highly toxic when ingested.

The mean lethal concentration (LC₅₀) of nitrogen trichloride in rats is 12 ppm according to one study involving exposing the rats at concentrations from 0 to 157 ppm for 1 hour. Dogs fed on flour bleached with nitrogen trichloride rapidly develop ataxia and epileptiform convulsions. Histological examination of experimental animals has shown cerebral cortex necrosis and Purkinje cell disorders in the cerebellum. The red cell nucleus may also be affected.

Nitrogen trichloride may explode as the result of an impact, exposure to heat, supersonic waves, and even spontaneously. The presence of certain impurities may increase the explosion hazard. It will also explode on contact with traces of certain organic compounds—in particular, turpentine. Decomposition results in highly toxic chlorinated decomposition products.

Phosgene. Commercially, phosgene (COCl₂) is manufactured by the reaction between chlorine and carbon monoxide. Phosgene is also formed as an undesirable by-product when certain chlorinated hydrocarbons (especially dichloromethane, carbon tetrachloride, chloroform, trichloroethylene, perchloroethylene and hexachloroethane) come into contact with an open flame or hot metal, as in welding. The decomposition of chlorinated hydrocarbons in closed rooms can result in the accumulation of harmful concentrations of phosgene, as for example from the use of carbon tetrachloride as a fire-extinguishing material, or tetrachloroethylene as a lubricant in the machining of high-grade steel.

Anhydrous phosgene is not corrosive to metals, but in the presence of water it reacts to from hydrochloric acid, which is corrosive.

Phosgene is one of the most poisonous gases used in industry. The inhalation of 50 ppm for a short time is fatal to test animals. For humans, prolonged inhalation of 2 to 5 ppm is dangerous. An additional hazardous property of phosgene is the lack of all warning symptoms during its inhalation, which may merely cause light irritation of the mucous membranes of the respiratory tract and eye at concentrations of 4 to 10 ppm. Exposure to 1 ppm for extended periods can cause delayed pulmonary oedema.

Light cases of poisoning are followed by temporary bronchitis. In serious cases, delayed pulmonary oedema can occur. This can occur after a latent period of several hours, usually 5 to 8, but seldom more than 12. In most cases, the patient remains conscious until the end; death is caused by asphyxiation or heart failure. If the patient survives the first 2 to 3 days, the prognosis is generally favourable. High concentrations of phosgene cause immediate acid damage to the lung and rapidly cause death by suffocation and termination of circulation through the lungs.

Environmental protection

Free chlorine destroys vegetation and, as it may occur in concentrations causing such damage under unfavourable climatic conditions, its release into the surrounding atmosphere should be prohibited. If it is not possible to utilize the liberated chlorine for the production of hydrochloric acid or the like, every precaution must be taken to bind the chlorine, for instance by means of a lime scrubber. Special technical safety measures with automatic warning systems should be installed, in the factories and in the surroundings, wherever there is a risk that appreciable quantities of chlorine may escape to the surrounding atmosphere.

From the point of view of environmental pollution, particular attention should be paid to cylinders or other vessels used for the transport of chlorine or its compounds, to measures for the control of possible hazards, and to steps to be taken in case of emergency.

Iodine and its compounds

Iodine does not occur free in nature, but iodides and/or iodates are found as trace impurities in deposits of other salts. Chilean saltpetre deposits contain enough iodate (about 0.2% sodium iodate) to make its commercial exploitation feasible. Similarly, some naturally occurring brines, especially in the United States, contain recoverable quantities of iodide. Iodide in ocean water is concentrated by some seaweeds (kelp), the ash of which was formerly a commercially important source in France, the United Kingdom and Japan.

Iodine is a powerful oxidizing agent. An explosion may result if it contacts materials such as acetylene or ammonia.

Iodine vapour, even in low concentrations, is extremely irritating to the respiratory tract, eyes and, to a lesser extent, the skin. Concentrations as low as 0.1 ppm in the air may cause some eye irritation upon prolonged exposure. Concentrations higher than 0.1 ppm cause increasingly severe eye irritation along with irritation of the respiratory tract and, ultimately, pulmonary oedema. Other systemic injury from the inhalation of iodine vapour is unlikely unless the exposed person already has a thyroid disorder. Iodine is absorbed from the lungs, converted to iodide in the body, and then excreted, mainly in urine. Iodine in crystalline form or in strong solutions is a severe skin irritant; it is not easily removed from the skin and, after contact, tends to penetrate and cause continuing injury. Skin lesions caused by iodine resemble thermal burns except that iodine stains the burned areas brown. Ulcers that are slow to heal may develop because of iodine remaining fixed to the tissue.

The probable mean lethal oral dose of iodine is 2 to 3 g in adults, due to its corrosive action on the gastrointestinal system. In general, iodine-containing materials (both organic and inorganic) appear to be more toxic than analogous bromine- or chlorine-containing materials. In addition to “halogen-like” toxicity, iodine is concentrated in the thyroid gland (the basis for treating thyroid cancer with ¹³¹I), and therefore metabolic disturbances are likely to result from overexposure. Chronic absorption of iodine causes “iodism”, a disease characterized by tachycardia, tremor, weight loss, insomnia, diarrhoea, conjunctivitis, rhinitis and bronchitis. In addition, hypersensitivity to iodine may develop, characterized by skin rashes and possibly rhinitis and/or asthma.

Radioactivity. Iodine has an atomic number of 53 and an atomic weight ranging from 117 to 139. Its only stable isotope has a mass of 127 (126.9004); its radioactive isotopes have half-lives from a few seconds (atomic weights of 136 and higher) to millions of years (¹²⁹I). In the reactions that characterize the fission process in a nuclear reactor, ¹³¹I is formed in abundance. This isotope has a half-life of 8.070 days; it emits beta and gamma radiation with principal energies of 0.606 MeV (max) and 0.36449 MeV, respectively.

Upon entering the body by any route, inorganic iodine (iodide) is concentrated in the thyroid gland. This, coupled with the abundant formation of ¹³¹I in nuclear fission, makes it one of the most hazardous materials that can be released from a nuclear reactor either deliberately or by accident.

Halogens and compounds tables

Table 1 - Chemical information.

Table 2 - Health hazards.

Table 3 - Physical and chemical hazards.

Table 4 - Physical and chemical properties.

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The heterocyclic compounds are used as chemical intermediates and solvents in the pharmaceutical, chemical, textile, dye-stuffs, petroleum and photography industries. Several compounds also function as vulcanization accelerators in the rubber industry.

Acridine and benzanthrone are used as starting materials and intermediates in the manufacture of dyes. Benzanthrone is also used in the pyrotechnics industry. Propyleneimine is used in flocculants in petroleum refining and as a modifier for rocket propellant fuels. It has been used in oil additives as a modifier for viscosity control, for high-pressure performance, and for oxidation resistance. 3-Methylpyridine and 4-methylpyridine serve as waterproofing agents in the textile industry. 4-Methylpyridine is a solvent in the synthesis of pharmaceuticals, resins, dye-stuffs, rubber accelerators, pesticides and waterproofing agents. 2-Pyrrolidone is also used in pharmaceutical preparations and functions as a high-boiling solvent in petroleum processing. It is found in specialty printing inks and in certain floor polishes. 4,4'-Dithiodimorpholine is used in the rubber industry as a staining protector and a vulcanizing agent. In the rubber industry, 2-vinylpyridine is made into a terpolymer that is used in adhesives for bonding tire cord to rubber.

Several heterocyclic compounds—morpholine, mercaptobenzothiazole, piperazine, 1,2,3-benzotriazole and quinoline—function as corrosion inhibitors for copper and industrial water treatment. Mercaptobenzothiazole is also a corrosion inhibitor in cutting oils and petroleum products, and an extreme-pressure additive in greases. Morpholine is a solvent for resins, waxes, casein and dyes, and a defoaming agent in the paper and paperboard industries. In addition, it is found in insecticides, fungicides, herbicides, local anaesthetics, and antiseptics. 1,2,3-Benzotriazole is a restrainer, developer and antifogging agent in photographic emulsions, a component of military aircraft de-icing fluid, and a stabilizing agent in the plastics industry.

Pyridine is utilized by numerous industries as both a chemical intermediate and a solvent. It is used in the manufacture of vitamins, sulpha drugs, disinfectants, dye-stuffs and explosives, and as a dyeing assistant in the textile industry. Pyridine is also useful in the rubber and paint industries, oil and gas well drilling, and in the food and non-alcoholic beverage industries as a flavouring agent. The vinylpyridines are utilized for the production of polymers. Sulpholane, a solvent and a plasticizer, is used for the extraction of aromatic hydrocarbons from oil refinery streams, for textile finishing, and as a component of hydraulic fluid. Tetrahydrothiophene is a solvent and a fuel gas odorant used in fire safety stench warning systems in underground mines. Piperidine is used in the manufacture of pharmaceuticals, wetting agents and germicides. It is a hardening agent for epoxy resins and a trace constituent of fuel oil.

Hazards

Acridine is a powerful irritant which, in contact with the skin or mucous membrane, causes itching, burning, sneezing, lacrimation and irritation of the conjunctiva. Workers exposed to acridine crystal dust in concentrations of 0.02 to 0.6 mg/m³ complained of headache, disturbed sleep, irritability and photosensitization, and presented oedema of the eyelids, conjunctivitis, skin rashes, leucocytosis and increased red cells sedimentation rates. These symptoms did not appear at an acridine airborne concentration of 1.01 mg/m³. When heated, acridine emits toxic fumes. Acridine, and a large number of its derivatives have been shown to possess mutagenic properties and to inhibit DNA repair and cell growth in several species.

In animals, near-lethal doses of aminopyridines produce increased excitability to sound and touch, and cause tremor, clonic convulsions and tetany. They also cause contraction of skeletal muscle and smooth muscle, producing vasconstriction and increased blood pressure. It has been reported that aminopyridines and some alkyl pyridines exert inotropic and chronotropic action on the heart. Vinyl pyridines cause less dramatic convulsions. Acute poisoning can occur either from inhalation of the dust or vapour at relatively low concentrations, or by skin absorption.

A common hazard of benzanthrone is skin sensitization due to exposure to benzanthrone dust. Sensitivity varies from person to person, but after exposure of between a few months and several years, sensitive persons, especially those who are blond or red-headed, develop an eczema which may be intense in its course and the acute phase of which may leave a hazel or slate-grey pigmentation, especially around the eyes. Microscopically, atrophy of the skin has been found. Skin disorders due to benzanthrone are more frequent in the warm season and are significantly aggravated by heat and light.

Morpholine is a moderately toxic compound by ingestion and by cutaneous application; undiluted morpholine is a strong skin irritant and a potent eye irritant. It does not appear to have chronic toxic effects. It is a moderate fire hazard when exposed to heat, and thermal decomposition results in the release of fumes containing nitrogen oxides.

Phenothiazine has harmful irritant properties, and industrial exposure may produce skin lesions and photosensitization, including photosensitized keratitis. As far as systemic effects are concerned, severe intoxication in therapeutic use has been reported to be characterized by haemolitic anaemia and toxic hepatitis. Because of its low solubility, the rate of its absorption from the gastrointestinal tract is dependent on particle size. A micronized form of the drug is absorbed rapidly. The toxicity of the substance varies a great deal from animal to animal, the oral LD₅₀ in rats being 5 g/kg.

Although phenothiazine oxidizes fairly easily when it is exposed to air, the risk of fire is not high. However, if involved in a fire, phenothiazine produces highly toxic sulphur and nitrogen oxides, which are dangerous lung irritants.

Piperidine is absorbed by inhalation and through the digestive tract and the skin; it produces a toxic response in animals similar to that obtained with the aminopyridines. Large doses block ganglionic conduction. Small doses cause both parasympathetic and sympathetic stimulation due to action on the ganglia. Increased blood pressure and heart rate, nausea, vomiting, salivation, laboured breathing, muscular weakness, paralysis and convulsions are signs of intoxication. This substance is highly flammable and evolves explosive concentrations of vapour at normal room temperatures. The precautions recommended for pyridine should be adopted.

Pyridine and homologues. Some information on pyridine is available from clinical reports of human exposure, primarily through medical treatments or through exposure to the vapour. Pyridine is absorbed through the gastrointestinal tract, through the skin and by inhalation. Clinical symptoms and signs of intoxication include gastrointestinal disturbance with diarrhoea, abdominal pain and nausea, weakness, headache, insomnia and nervousness. Exposures less than those required to produce overt clinical signs may cause varying degrees of liver damage with central lobular fatty degeneration, congestion and cellular infiltration; repeated low-level exposures cause cirrhosis. The kidney appears to be less sensitive to pyridine-induced damage than is the liver. In general, pyridine and its derivatives cause local irritation on contact with the skin, mucous membranes and cornea. The effects on the liver may occur at levels that are too low to elicit a response from the nervous system, and so no warning signs may be available to a potentially exposed worker. Further, although the odour of pyridine is easily detectable at vapour concentrations of less than 1 ppm, odour detection cannot be relied upon because olfactory fatigue occurs quickly.

Pyridine in both the liquid and vapour phase may constitute a severe fire and explosion hazard when exposed to flame; it may also react violently with oxidizing substances. When pyridine is heated to decomposition, cyanide fumes are released.

Pyrrole and pyrrolidine. Pyrrole is a flammable liquid and, when burning, gives off dangerous nitrogen oxides. It has a depressant action on the central nervous system and, in severe intoxication, is injurious to the liver. Few data are available about the degree of occupational risk that this substance presents. Fire protection and prevention measures should be adopted and means of extinguishing fire should be provided. Respiratory protective equipment should be available for persons fighting a fire involving pyrrole.

The human experience with pyrrolidine is not well documented. Prolonged administration in rats caused reduction of diuresis, inhibition of spermatogenesis, decreased haemoglobin content in blood, and nervous excitation. As with many nitrates, the acidity of the stomach can convert pyrrolidine into N-nitrosopyrrolidine, a compound which has been found to be carcinogenic in laboratory animals. Some workers may develop headaches and vomiting from exposure.

The liquid is capable of evolving flammable concentrations of vapour at ordinary working temperatures; consequently, open lights and other agencies liable to ignite the vapour should be excluded from areas in which it is used. When burning, pyrrolidine gives off dangerous nitrogen oxides, and persons exposed to these combustion products should be supplied with suitable respiratory protection. Bunding and sills should be provided to prevent the spread of liquid accidentally escaping from storage and process vessels.

Quinoline is absorbed through the skin (percutaneously). The clinical signs of toxicity include lethargy, respiratory distress, and prostration leading to coma. This substance is irritating to the skin and may cause pronounced permanent corneal damage. It is a carcinogen in several animal species but there are inadequate data available on the human cancer risk. It is moderately flammable but does not evolve a flammable concentration of vapour at a temperature below 99 °C.

Vinylpyridine. Brief exposure to the vapour has caused eye, nose and throat irritation and transient headache, nausea, nervousness and anorexia. Skin contact causes burning pain followed by severe skin burns. Sensitization may develop. The fire hazard is moderate, and decomposition by heat is accompanied by the release of dangerous cyanide fumes.

Safety and Health Measures

The normal safety precautions are required for handling the dusts and vapours of the chemicals in this grouping. Since skin sensitization is associated with a number of them, it is particularly important that adequate sanitary and washing facilities be provided. Care should be taken to assure that workers have access to clean eating areas.

Heterocyclic compounds tables

Table 1 - Chemical information.

Table 2 - Health hazards.

Table 3 - Physical and chemical hazards.

Table 4 - Physical and chemical properties.

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Aliphatic hydrocarbons are compounds of carbon and hydrogen. They may be saturated or unsaturated open chain, branched or unbranched molecules, the nomenclature being as follows:

• paraffins (or alkanes)—saturated hydrocarbons

• olefins (or alkenes)—unsaturated hydrocarbons with one or more double bond linkages

• acetylenes (or alkynes)—unsaturated hydrocarbons with one or more triple bond linkages

The general formulae are C_nH_2n+2 for paraffins, C_nH_2n for olefins, and C_nH_2n-2 for acetylenes.

The smaller molecules are gases at room temperature (C₁ to C₄). As the molecule increases in size and structural complexity it becomes a liquid with increasing viscosity (C₅ to C₁₆), and finally the higher molecular weight hydrocarbons are solids at room temperature (above C₁₆).

The aliphatic hydrocarbons of industrial importance are derived mainly from petroleum, which is a complex mixture of hydrocarbons. They are produced by the cracking, distillation and fractionation of crude oil.

Methane, the lowest member of the series, comprises 85% of natural gas, which may be tapped directly from pockets or reservoirs in the vicinity of petroleum deposits. Large amounts of pentane are produced by fractional condensation of natural gas.

Uses

The saturated hydrocarbons are used in industry as fuels, lubricants and solvents. After undergoing processes of alkylation, isomerization and dehydrogenation, they also act as starting materials for the synthesis of paints, protective coatings, plastics, synthetic rubber, resins, pesticides, synthetic detergents and a wide variety of petrochemicals.

The fuels, lubricants and solvents are mixtures which may contain many different hydrocarbons. Natural gas has long been distributed in the gaseous form for use as a town gas. It is now liquefied in large quantities, shipped under refrigeration and stored as a refrigerated liquid until it is introduced unchanged or reformed into a town gas distribution system. Liquefied petroleum gases (LPGs), consisting mainly of propane and butane, are transported and stored under pressure or as refrigerated liquids, and are also used to augment town gas supply. They are used directly as fuels, often in high-grade metallurgical work in which a sulphur-free fuel is essential, in oxypropane welding and cutting, and in circumstances where a heavy industrial demand for gaseous fuels would strain public supply. Storage installations for these purposes vary in size from about 2 tons to several thousands of tons. Liquefied petroleum gases are also used as propellants for many types of aerosols, and the higher members of the series, from heptane upwards, are used as motor fuels and solvents. Isobutane is used to control the volatility of gasoline and is a component of instrument calibration fluid. Isooctane is the standard reference fuel for octane rating of fuels, and octane is used in antiknock engine fuels. In addition to being a component of gasoline, nonane is a component of biodegradable detergent.

The principal use of hexane is as a solvent in glues, cements and adhesives for the production of footwear, whether from hide or from plastics. It has been used as a solvent for glue in the assembling of furniture, in adhesives for wallpaper, as a solvent for glue in the production of handbags and suitcases from hide and artificial hide, in the manufacture of raincoats, in the retreading of car tyres and in the extraction of vegetable oils. In many uses, hexane has been replaced by heptane because of the toxicity of n-hexane.

It is not possible to list all the occasions when hexane may be present in the working environment. It may be advanced as a general rule that its presence is to be suspected in volatile solvents and grease removers based on hydrocarbons derived from petroleum. Hexane is also used as a cleaning agent in the textile, furniture and leather industries.

Aliphatic hydrocarbons used as starting materials of intermediates for synthesis may be individual compounds of high purity or relatively simple mixtures.

Hazards

Fire and explosion

The development of large storage installations first for gaseous methane and later for LPGs has been associated with explosions of great magnitude and catastrophic effect, which have emphasized the danger when a massive leakage of these substances occurs. The flammable mixture of gas and air may extend far beyond the distances that are regarded as adequate for normal safety purposes, with the result that the flammable mixture may become ignited by a household fire or automobile engine well outside the specified danger zone. Vapour may thus be set alight over a very large area, and flame propagation through the mixture may reach explosive violence. Many smaller—but still serious—fires and explosions have occurred during the use of these gaseous hydrocarbons.

The largest fires involving liquid hydrocarbons have occurred when large quantities of liquid have escaped and flowed towards a part of the factory where ignition could take place, or have spread over a large surface and evaporated quickly. The notorious Flixborough (United Kingdom) explosion is attributed to a leak of cyclohexane.

Health hazards

The first two members of the series, methane and ethane, are pharmacologically “inert”, belonging to a group of gases called “simple asphyxiants”. These gases can be tolerated in high concentrations in inspired air without producing systemic effects. If the concentration is high enough to dilute or exclude the oxygen normally present in the air, the effects produced will be due to oxygen deprivation or asphyxia. Methane has no warning odour. Because of its low density, methane may accumulate in poorly ventilated areas to produce an asphyxiating atmosphere. Ethane in concentrations below 50,000 ppm (5%) in the atmosphere produces no systemic effects on the person breathing it.

Pharmacologically, the hydrocarbons above ethane can be grouped with the general anaesthetics in the large class known as the central nervous system depressants. The vapours of these hydrocarbons are mildly irritating to mucous membranes. The irritation potency increases from pentane to octane. In general, alkane toxicity tends to increase as the carbon number of alkanes increases. In addition, straight-chain alkanes are more toxic than the branched isomers.

The liquid paraffin hydrocarbons are fat solvents and primary skin irritants. Repeated or prolonged skin contact will dry and defat the skin, resulting in irritation and dermatitis. Direct contact of liquid hydrocarbons with lung tissue (aspiration) will result in chemical pneumonitis, pulmonary oedema, and haemorrhage. Chronic intoxication by n-hexane or mixtures containing n-hexane may involve polyneuropathy.

Propane causes no symptoms in humans during brief exposures to concentrations of 10,000 ppm (1%). A concentration of 100,000 ppm (10%) is not noticeably irritating to the eyes, nose or respiratory tract, but it will produce slight dizziness in a few minutes. Butane gas causes drowsiness, but no systemic effects during a 10-minute exposure to 10,000 ppm (1%).

Pentane is the lowest member of the series that is liquid at room temperature and pressure. In human studies a 10-min exposure to 5,000 ppm (0.5%) did not cause mucous membrane irritation or other symptoms.

Heptane caused slight vertigo in men exposed for 6 min to 1,000 ppm (0.1%) and for 4 min to 2,000 ppm (0.2%). A 4-min exposure to 5,000 ppm (0.5%) heptane caused marked vertigo, inability to walk a straight line, hilarity and incoordination. These systemic effects were produced in the absence of complaints of mucous membrane irritation. A 15-min exposure to heptane at this concentration produced a state of intoxication characterized by uncontrolled hilarity in some individuals, and in others it produced a stupor lasting for 30 min after the exposure. These symptoms were frequently intensified or first noticed at the moment of entry into an uncontaminated atmosphere. These individuals also complained of loss of appetite, slight nausea, and a taste resembling gasoline for several hours after exposure to heptane.

Octane in concentrations of 6,600 to 13,700 ppm (0.66 to 1.37%) caused narcosis in mice within 30 to 90 min. No deaths or convulsions resulted from these exposures to concentrations below 13,700 ppm (1.37%).

Because it is likely that in an alkane mixture the components have additive toxic effects, the US National Institute for Occupational Safety and Health (NIOSH) has recommended keeping a threshold limit value for total alkanes (C₅ to C₈) of 350 mg/m³ as a time-weighted average, with a 15-min ceiling value of 1,800 mg/m³. n-Hexane is considered separately because of its neurotoxicity.

n-Hexane

n-Hexane is a saturated, straight-chain aliphatic hydrocarbon (or alkane) with the general formula C_nH_2n+2 and one of a series of hydrocarbons with low boiling points (between 40 and
90 °C) obtainable from petroleum by various processes (cracking, reforming). These hydrocarbons are a mixture of alkanes and cycloalkanes with five to seven carbon atoms
(n-pentane, n-hexane, n-heptane, isopentane, cyclopentane, 2-methylpentane,
3-methylpentane, cyclohexane, methylcyclopentane). Their fractional distillation produces single hydrocarbons that may be of varying degrees of purity.

Hexane is sold commercially as a mixture of isomers with six carbon atoms, boiling at 60 to
70 °C. The isomers most commonly accompanying it are 2-methylpentane, 3-methylpentane, 2,3-dimethylbutane and 2,2-dimethylbutane. The term technical hexane in commercial use denotes a mixture in which are to be found not only n-hexane and its isomers but also other aliphatic hydrocarbons with five to seven carbon atoms (pentane, heptane and their isomers).

Hydrocarbons with six carbon atoms, including n-hexane, are contained in the following petroleum derivatives: petroleum ether, petrol (gasoline), naphtha and ligroin, and fuels for jet aircraft.

Exposure to n-hexane may result from occupational or non-occupational causes. In the occupational field it may occur through the use of solvents for glues, cements, adhesives or grease-removing fluids. The n-hexane content of these solvents varies. In glues for footwear and rubber cement, it may be as high as 40 to 50% of the solvent by weight. The uses referred to here are those that have caused occupational disease in the past, and in some instances hexane has been replace with heptane. Occupational exposure to n-hexane may occur also through the inhalation of petrol fumes in fuel depots or workshops for the repair of motor vehicles. The danger of this form of occupational exposure, however, is very slight, because the concentration of n-hexane in petrol for motor vehicles is maintained below 10% owing to the need for a high octane number.

Non-occupational exposure is found mainly among children or drug addicts who practise the sniffing of glue or petrol. Here the n-hexane content varies from the occupational value in glue to 10% or less in petrol.

Hazards

n-Hexane may penetrate the body in either of two ways: by inhalation or through the skin. Absorption is slow by either way. In fact measurements of the concentration of n-hexane in the breath exhaled in conditions of equilibrium have shown the passage from the lungs to the blood of a fraction of the n-hexane inhaled of from 5.6 to 15%. Absorption through the skin is extremely slow.

n-Hexane has the same skin effects previously described for other liquid aliphatic hydrocarbons. Hexane tends to vaporize when swallowed or aspirated into tracheobronchial tree. The result can be rapid dilution of alveolar air and a marked fall in its oxygen content, with asphyxia and consequent brain damage or cardiac arrest. The irritative pulmonary lesions occurring after the aspiration of higher homologues (e.g., octane, nonane, decane and so on) and of mixtures thereof (e.g., kerosene) do not appear to be a problem with hexane. Acute or chronic effects are almost always due to inhalation. Hexane is three times more acutely toxic than pentane. Acute effects occur during exposure to high concentrations of n-hexane vapours and range from dizziness or vertigo after brief exposure to concentrations of about 5,000 ppm, to convulsions and narcosis, observed in animals at concentrations of about 30,000 ppm. In humans, 2,000 ppm (0.2%) produces no symptoms in a 10-min exposure. An exposure of 880 ppm for 15 min can cause eye and upper respiratory tract irritation in humans.

Chronic effects occur after prolonged exposure to doses that do not produce obvious acute symptoms and tend to disappear slowly when the exposure ends. In the late 1960s and early 1970s, attention was drawn to outbreaks of sensorimotor and sensory polyneuropathy among workers exposed to mixtures of solvents containing n-hexane in concentrations mainly ranging between 500 and 1,000 ppm with higher peaks, although concentrations as low as 50 ppm could cause symptoms in some instances. In some cases, muscular atrophy and cranial nerve involvements such as visual disorders and facial numbness were observed. About 50% showed denervation and regeneration of the nerves, Tingling, numbness and weakness of distal extremities were complained of, mainly in the legs. Stumbling was often observed. Achilles tendon reflexes disappeared; touch and heat sensation were diminished. Conduction time was decreased in the motor and sensory nerves of the arms and legs.

The course of the disease is generally very slow. After the appearance of the first symptoms, a deterioration of the clinical picture is often observed through an aggravation of the motor deficiency of the regions originally affected and their extension to those which have hitherto been sound. This deterioration can occur for some months after exposure has ceased. The extension generally takes place from the lower to the upper limbs. In very serious cases ascending motor paralysis appears with a functional deficiency of the respiratory muscles. Recovery may take as long as 1 to 2 years. Recovery is generally complete, but a diminution of the tendon reflexes, particularly that of the Achilles tendon, may persist in conditions of apparent full well-being.

Symptoms in the central nervous system (defects of the visual function or the memory) have been observed in serious cases of intoxication by n-hexane and have been related to degeneration of the visual nuclei and the tracts of hypothalamic structures. These may be permanent.

With regard to laboratory tests, the most usual haematological and haemato-chemical tests do not show characteristic changes. This is also true of urine tests, which show increased creatinuria only in serious cases of paralysis with muscular hypotrophy.

The examination of the spinal fluid does not lead to characteristic findings, either manometric or qualitative, except for rare cases of increased protein content. It appears that only the nervous system shows characteristic changes. The electroencephalograph readings (EEG) are usually normal. In serious cases of disease, however, it is possible to detect dysrhythmias, widespread or subcortical discomfort and irritation. The most useful test is electromyography (EMG). The findings indicate myelinic and axonal lesions of the distal nerves. The motor conduction velocity (MCV) and the sensitive conduction velocity (SCV) are reduced, the distal latency (LD) is modified and the sensory potential (SPA) is diminished.

Differential diagnosis with respect to the other peripheral polyneuropathies is based on the symmetry of the paralysis, on the extreme rareness of sensory loss, on the absence of changes in the cerebrospinal fluid, and, above all, on the knowledge that there has been exposure to solvents containing n-hexane and the occurrence of more than one case with similar symptoms from the same workplace.

Experimentally, technical grade n-hexane has produced peripheral nerve disturbances in mice at 250 ppm and higher concentrations after 1 year of exposure. Metabolic investigations have indicated that in guinea-pigs n-hexane and methyl butyl ketone (MBK) are metabolized to the same neurotoxic compounds (2-hexanediol and 2,5-hexanedione).

The anatomical modifications of the nerves underlying the clinical manifestations described above have been observed, whether in laboratory animals or in sick human beings, through muscular biopsy. The first convincing n-hexane polyneuritis reproduced experimentally is due to Schaumberg and Spencer in 1976. The anatomical modifications of the nerves are represented by axonal degeneration. This axonal degeneration and the resulting demyelination of the fibre start at the periphery, particularly in the longer fibres, and tend to develop towards the centre, though the neuron does not show signs of degeneration. The anatomical picture is not specific to the pathology of n-hexane, for it is common to a series of nervous diseases due to poisons in both industrial and non-industrial use.

A very interesting aspect of n-hexane toxicology lies in the identification of the active metabolites of the substance and its relations with the toxicology of other hydrocarbons. In the first place it seems to be established that the nervous pathology is caused only by n-hexane and not by its isomers referred to above or by pure n-pentane or n-heptane.

Figure 1 shows the metabolic pathway of n-hexane and methyl n-butyl ketone in human beings. It can be seen that the two compounds have a common metabolic pathway and that MBK can be formed from n-hexane. The nervous pathology has been reproduced with 2-hexanol, 2,5-hexanediol and 2,5-hexanedione. It is obvious, as has been shown, moreover, by clinical experience and animal experiment, that MBK is also neurotoxic. The most toxic of the n-hexane metabolites in question is 2,5-hexanedione. Another important aspect of the connection between n-hexane metabolism and toxicity is the synergistic effect that methyl ethyl ketone (MEK) has been shown to have in the neurotoxicity of n-hexane and MBK. MEK is not by itself neurotoxic either for animals or for humans, but it has led to lesions of the peripheral nervous systems in animals treated with n-hexane or MBK that arise more quickly than similar lesions caused by those substances alone. The explanation is most likely to be found in a metabolic interference activity of MEK in the pathway which leads from n-hexane and MBK to the neurotoxic metabolites referred to above.

Figure 1. The metabolic pathway of n-hexane and methyl-n-butyl ketone  

MISSING

Safety and Health Measures

It is clear from what has been observed above that the association of n-hexane with MBK or MEK in solvents for industrial use is to be avoided. Whenever possible, substitute heptane for hexane.

With regard to TLVs in force for n-hexane, modifications of the EMG pattern have been observed in workers exposed to concentrations of 144 mg/ml (40 ppm) that have not been present in workers not exposed to n-hexane. The medical monitoring of exposed workers is based both on acquaintance with the data concerning the concentration of n-hexane in the atmosphere and on clinical observation, particularly in the neurological field. Biological monitoring for 2,5-hexanedione in the urine is the most useful indicator of exposure, although MBK will be a confounder. If necessary, measurement of n-hexane in exhaled air at the end of shift can confirm exposure.

Cycloparaffins (Cycloalkanes)

The cycloparaffins are alicyclic hydrocarbons in which three or more of the carbon atoms in each molecule are united in a ring structure and each of these ring carbon atoms is joined to two hydrogen atoms, or alkyl groups. The members of this have the general formula C_nH_2n. Derivatives of these cycloparaffins include compounds such as methylcyclohexane (C₆H₁₁CH₃). From the occupational safety and health point of view, the most important of these are cyclohexane, cyclopropane and methylcyclohexane.

Cyclohexane is used in paint and varnish removers; as a solvent for lacquers and resins, synthetic rubber, and fats and waxes in the perfume industry; as a chemical intermediate in the manufacture of adipic acid, benzene, cyclohexyl chloride, nitrocyclohexane, cyclohexanol and cyclohexanone; and for molecular weight determinations in analytical chemistry. Cyclopropane serves as a general anaesthetic.

Hazards

These cycloparaffins and their derivatives are flammable liquids, and their vapours will form explosive concentrations in air at normal room temperature.

They may produce toxic effects by inhalation and ingestion, and they have an irritant and defatting action on the skin. In general, the cycloparaffins are anaesthetics and central nervous system depressants, but their acute toxicity is low and, due to their almost complete elimination from the body, the danger of chronic poisoning is relatively slight.

Cyclohexane. The acute toxicity of cyclohexane is very low. In mice, exposure to 18,000 ppm (61.9 mg/l) cyclohexane vapour in air produced trembling in 5 min, disturbed equilibrium in 15 min, and complete recumbency in 25 min. In rabbits, trembling occurred in 6 min, disturbed equilibrium in 15 min, and complete recumbency in 30 min. No toxic changes were found in the tissues of rabbits after exposure for 50 periods of 6 h to concentrations of 1.46 mg/l (434 ppm). 300 ppm was detectable by odour and somewhat irritating to the eyes and mucous membranes. Cyclohexane vapour causes weak anaesthesia of brief duration but more potent than hexane.

Animal experimentation has shown that cyclohexane is far less harmful than benzene, its six-membered ring aromatic analogue, and, in particular, does not attack the haemopoietic system as does benzene. It is thought that the virtual absence of harmful effects in the blood-forming tissues is due, at least partially, to differences in the metabolism of cyclohexane and benzene. Two metabolites of cyclohexane have been determined—cyclohexanone and cyclohexanol—the former being partially oxidized to adipic acid; none of the phenol derivatives that are a feature of the toxicity of benzene have been found as metabolites in animals exposed to cyclohexane, and this has led to cyclohexane being proposed as a substitute solvent for benzene.

Methylcyclohexane has a toxicity similar to but lower than that of cyclohexane. No effects resulted from repeated exposures of rabbits at 1,160 ppm for 10 weeks, and only slight kidney and liver injury was observed at 3,330 ppm. Prolonged exposure at 370 ppm appeared to be harmless to monkeys. No toxic effects from industrial exposure or intoxication in humans by methylcyclohexane have been reported.

Animal studies show that the majority of this substance entering the bloodstream is conjugated with sulphuric and glucuronic acids and excreted in the urine as sulphates or glucuronides, and in particular the glucuronide of trans-4-methylcyclohexanol.

Saturated and alicyclic hydrocarbons tables

Table 1 - Chemical information.

Table 2 - Health hazards.

Table 3 - Physical and chemical hazards.

Table 4 - Physical and chemical properties.

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Halogenated aliphatic hydrocarbons are organic chemicals in which one or more hydrogen atoms has been replaced by a halogen (i.e., fluorinated, chlorinated, brominated or iodized). Aliphatic chemicals do not contain a benzene ring.

The chlorinated aliphatic hydrocarbons are produced by chlorination of hydrocarbons, by the addition of chlorine or hydrogen chloride to unsaturated compounds, by the reaction between hydrogen chloride or chlorinated lime and alcohols, aldehydes or ketones, and exceptionally by chlorination of carbon disulphide or in some other way. In some cases more steps are necessary (e.g., chlorination with subsequent elimination of hydrogen chloride) to obtain the derivative needed, and usually a mixture arises from which the desired substance has to be separated. Brominated aliphatic hydrocarbons are prepared in a similar manner, while for iodized and particularly for fluorinated hydrocarbons, other methods such as electrolytic production of iodoform are preferred.

The boiling point of substances generally increases with molecular mass, and is then further raised by halogenation. Amongst the halogenated aliphatics, only not very highly fluorinated compounds (i.e., up to and including decafluorobutane), chloromethane, dichloromethane, chloroethane, chloroethylene and bromomethane are gaseous at normal temperatures. Most other compounds in this group are liquids. The very heavily chlorinated compounds, as well as tetrabromomethane and triodomethane, are solids. The odour of hydrocarbons is often strongly enhanced by halogenation, and several volatile members of the group have not merely an unpleasant odour but also have a pronounced sweet taste (e.g., chloroform and heavily halogenated derivatives of ethane and propane).

Uses

The unsaturated halogenated aliphatic and alicyclic hydrocarbons are used in industry as solvents, chemical intermediates, fumigants and insecticides. They are found in the chemical, paint and varnish, textile, rubber, plastics, dye-stuff, pharmaceutical and dry-cleaning industries.

Industrial uses of the saturated halogenated aliphatic and alicyclic hydrocarbons are numerous, but their primary importance is their application as solvents, chemical intermediates, fire-extinguishing compounds, and metal-cleaning agents. These compounds are found in the the rubber, plastics, metalworking, paint and varnish, healthcare and textile industries. Some are components of soil fumigants and insecticides, and others are rubber-vulcanizing agents.

1,2,3-Trichloropropane and 1,1-dichloroethane are solvents and ingredients in paint and varnish removers, while methyl bromide is a solvent in aniline dyes. Methyl bromide is also used for degreasing wool, sterilizing food for pest control, and for extracting oils from flowers. Methyl chloride is a solvent and diluent for butyl rubber, a component of thermometric and thermostatic equipment fluid, and a foaming agent for plastics. 1,1,1-Trichloroethane is used primarily for cold type metal cleaning and as a coolant and lubricant for cutting oils. It is a cleaning agent for instruments in precision mechanics, a solvent for dyes, and a component of spotting fluid in the textile industry; in plastics, 1,1,1-trichloroethane is a cleaning agent for plastic moulds. 1,1-Dichloroethane is a solvent, cleaning agent and degreaser used in rubber cement, insecticide spray, fire extinguishers and gasoline, as well as for high-vacuum rubber, ore flotation, plastics and fabric spreading in the textile industry. Thermal cracking of 1,1-dichloroethane produces vinyl chloride. 1,1,2,2-Tetrachloroethane has varied functions as a non-flammable solvent in the rubber, paint and varnish, metal and fur industries. It is also a moth-proofing agent for textiles and is used in photographic film, the manufacture of artificial silk and pearls, and for estimating the water content of tobacco.

Ethylene dichloride has limited uses as a solvent and as a chemical intermediate. It is found in paint, varnish and finishing removers, and has been used as a gasoline additive to reduce lead content. Dichloromethane or methylene chloride is primarily used as a solvent in industrial and paint-stripping formulations, and in certain aerosols, including pesticides and cosmetic products. It serves as a process solvent in the pharmaceutical, plastics and foodstuff industries. Methylene chloride is also used as a solvent in adhesives and in laboratory analysis. The major use of 1,2-dibromoethane is in the formulation of lead-based antiknock agents for blending with gasoline. It is also used in the synthesis of other products and as a component of refractive-index fluids.

Chloroform is also a chemical intermediate, a dry-cleaning agent and a rubber solvent. Hexachloroethane is a degassing agent for aluminium and magnesium metals. It is used to remove impurities from molten metals and to inhibit the explosiveness of methane and the combustion of ammonium perchlorate. It is used in pyrotechnics, explosives and the military.

Bromoform is a solvent, fire retardant and flotation agent. It is used for mineral separation, rubber vulcanization and chemical synthesis. Carbon tetrachloride was formerly used as a degreasing solvent and in dry-cleaning, fabric spotting, and fire-extinguishing fluid, but its toxicity has led to discontinuing its use in consumer products and as a fumigant. Since a large part of its use is in the manufacture of chlorofluorocarbons, which in turn are eliminated from the great majority of commercial uses, the use of carbon tetrachloride will decrease still further. It is now used in semiconductor manufacture, cables, metal recovery and as a catalyst, an azeotropic drying agent for wet spark plugs, soap fragrance and for extracting oil from flowers.

Although replaced by tetrachloroethylene in most areas, trichloroethylene functions as a degreasing agent, solvent and paint diluent. It serves as an agent for removing basting threads in textiles, an anaesthetic for dental services and a swelling agent for dyeing polyester. Trichloroethylene is also used in vapour degreasing for metal work. It has been used in typewriter correction fluid and as an extraction solvent for caffeine. Trichloroethylene, 3-chloro-2-methyl-1-propene and allyl bromide are found in fumigants and in insecticides. 2-Chloro-1,3-butadiene is used as a chemical intermediate in the manufacture of artificial rubber. Hexachloro-1,3-butadiene is used as a solvent, as an intermediate in lubricant and rubber production, and as a pesticide for fumigation.

Vinyl chloride has been mainly used in the plastics industry and for the synthesis of polyvinyl chloride (PVC). However, it was formerly widely used as a refrigerant, extraction solvent and aerosol propellant. It is a component of vinyl-asbestos floor tiles. Other unsaturated hydrocarbons are primarily used as solvents, flame retardants, heat exchange fluids, and as cleaning agents in a wide variety of industries. Tetrachloroethylene is used in chemical synthesis and in textile finishing, sizing and desizing. It is also used for dry-cleaning and in the insulating fluid and cooling gas of transformers. cis-1,2-Dichloroethylene is a solvent for perfumes, dyes, lacquers, thermoplastics and rubber. Vinyl bromide is a flame retardant for carpet backing material, sleepwear and home furnishings. Allyl chloride is used for thermosetting resins for varnishes and plastics, and as a chemical intermediate. 1,1-Dichloroethylene is used in food packaging, and 1,2-dichloroethylene is a low-temperature extracting agent for heat-sensitive substances, such as perfume oils and caffeine in coffee.

Hazards

The production and use of halogenated aliphatic hydrocarbons involves serious potential health problems. They possess many local as well as systemic toxic effects; the most serious include carcinogenicity and mutagenicity, effects on the nervous system, and injury of vital organs, particularly the liver. Despite the relative chemical simplicity of the group, the toxic effects vary greatly, and the relation between structure and effect is not automatic.

Cancer. For several halogenated aliphatic hydrocarbons (e.g., chloroform and carbon tetrachloride) experimental evidence of carcinogenicity was observed rather a long time ago. The carcinogenicity classifications of of the International Agency for Research on Cancer (IARC) are given in the appendix to the Toxicology chapter of this Encyclopaedia. Some halogenated aliphatic hydrocarbons also exhibit mutagenic and teratogenic properties.

Depression of the central nervous system (CNS) is the most outstanding acute effect of many of the halogenated aliphatic hydrocarbons. Inebriation (drunkenness) and excitation passing into narcosis is the typical reaction, and for that reason many of chemicals in this group have been used as anaesthetics or even abused as a recreational drug. The narcotic effect varies: one compound may have very pronounced narcotic effects while another is only weakly narcotic. In severe acute exposure there is always the danger of death from respiratory failure or cardiac arrest, for the halogenated aliphatic hydrocarbons make the heart more susceptible to catecholamines.

The neurological effects of some compounds, such as methyl chloride and methyl bromide, as well as other brominated or iodized compounds in this group, are much more severe, particularly when there is repeated or chronic exposure. These central nervous system effects cannot simply be described as depression of the nervous system, since the symptoms can be extreme and include headache, nausea, ataxia, tremors, difficulty in speech, visual disturbances, convulsions, paralysis, delirium, mania or apathy. The effects may be long lasting, with only a very slow recovery, or there may be permanent neurological damage. The effects associated with different chemicals can go by a variety of names such as “methyl chloride encephalopathy” and “chloroprene encephalomyelitis”. The peripheral nerves may also be affected, such as is observed with tetrachloroethane and dichloroacetylene polyneuritis.

Systemic. Harmful effects on the liver, the kidney and other organs are common to virtually all the halogenated aliphatic hydrocarbons, though the extent of damage varies substantially from one member of the group to another. Since the signs of injury do not appear immediately, these effects have sometimes been referred to as delayed effects. The course of acute intoxication has often been described as biphasic: the signs of a reversible effect at an early stage of the intoxication (narcosis) as the first phase, with signs of other systemic injury not becoming apparent until later as the second phase. Other effects, such as cancer, may have extremely long latency periods. It is not always possible, however, to make a sharp distinction between the toxic effects of chronic or repeated exposure and the delayed effects of acute intoxication. There is no simple relation between the intensity of the immediate and the delayed effects of particular halogenated aliphatic hydrocarbons. It is possible to find substances in the group with a rather strong narcotic potency and weak delayed effects, and substances that are very dangerous because they may cause irreversible organ injuries without showing very strong immediate effects. Almost never is only a single organ or system involved; in particular, injury is rarely caused to the liver or kidneys alone, even by compounds which used to be regarded as typically hepatotoxic (e.g., carbon tetrachloride) or nephrotoxic (e.g., methyl bromide).

The local irritant properties of these substances are particularly pronounced in the case of some of the unsaturated members; surprising differences exist, however, even between very similar compounds (e.g., octafluoroisobutylene is enormously more irritating than the isomeric octafluoro-2-butene). Lung irritation may be a major danger in acute inhalation exposure to some compounds belonging to this group (e.g., allyl chloride), and a few of them are lacrimators (e.g., carbon tetrabromide). High concentrations of vapours or liquid splashes may be dangerous for the eyes in some instances; the injury caused by the most used members, however, recovers spontaneously, and only prolonged exposure of the cornea gives rise to persistent injury. Several of these substances, such as 1,2-dibromoethane and 1,3-dichloropropane, are definitely irritating and injurious to the skin, causing reddening, blistering and necrosis even on brief contact.

Being good solvents, all of these chemicals can damage the skin by degreasing it and making it dry, vulnerable, cracked and chapped, particularly on repeated contact.

Hazards of specific compounds

Carbon tetrachloride is an extremely hazardous chemical which has been responsible for deaths from poisoning of workers acutely exposed to it. It is classified as a Group 2B possible human carcinogen by IARC, and many authorities, such as British Health and Safety Executive, require the phasing out of its use in industry. Since a large part of the carbon tetrachloride use was in the production of chlorofluorocarbons, the virtual elimination of these chemicals further drastically limits the commercial uses of this solvent.

Most carbon tetrachloride intoxications have resulted from the inhalation of the vapour; however, the substance is also readily absorbed from the gastrointestinal tract. Being a good fat solvent, carbon tetrachloride removes fat from the skin on contact, which may lead to development of a secondary septic dermatitis. Since it is absorbed through the skin, care should be taken to avoid prolonged and repeated skin contact. Contact with the eyes may cause a transient irritation, but does not lead to serious injury.

Carbon tetrachloride has anaesthetic properties, and exposures to high vapour concentrations can lead to the rapid loss of consciousness. Individuals exposed to less than anaesthetic concentrations of carbon tetrachloride vapour frequently exhibit other nervous system effects such as dizziness, vertigo, headache, depression, mental confusion, and incoordination. It may cause cardiac arrhythmias and ventricular fibrillation at higher concentrations. At surprisingly low vapour concentrations, gastrointestinal disturbances such as nausea, vomiting, abdominal pain and diarrhoea are manifested by some individuals.

The effects of carbon tetrachloride on the liver and kidney must be given primary consideration in evaluating the potential hazard incurred by individuals working with this compound. It should be noted that the consumption of alcohol augments the injurious effects of this substance. Anuria or oliguria is the initial response, which is followed in a few days by a diuresis. The urine obtained during the period of diuresis has a low specific gravity, and usually contains protein, albumin, pigmented casts and red blood cells. Renal clearance of inulin, diodrast and p-aminohippuric acid are reduced, indicating a decrease in blood flow through the kidney as well as glomerular and tubular damage. The function of the kidney gradually returns to normal, and within 100 to 200 days after exposure, the kidney function is in the low-normal range. Histopathological examination of the kidneys reveals varying degrees of damage to the tubular epithelium.

Chloroform. Chloroform is also a dangerous volatile chlorinated hydrocarbon. It may be harmful by inhalation, ingestion and skin contact, and can cause narcosis, respiratory paralysis, cardiac arrest or delayed death due to liver and kidney damage. It may be misused by sniffers. Liquid chloroform may cause defatting of the skin, and chemical burns. It is teratogenic and carcinogenic for mice and rats. Phosgene is also formed by the action of strong oxidants on chloroform.

Chloroform is a ubiquitous chemical, used in many commercial products and formed spontaneously through the chlorination of organic compounds, such as in chlorinated drinking water. Chloroform in air may result at least partly from photochemical degradation of trichloroethylene. In sunlight it decomposes slowly to phosgene, chlorine and hydrogen chloride.

Chloroform is classified by IARC as a Group 2B possible human carcinogen, based on experimental evidence. The oral LD₅₀ for dogs and rats is about 1 g/kg; 14-day-old rats are twice as susceptible as adult rats. Mice are more susceptible than rats. Liver damage is the cause of death. Histopathological changes in the liver and kidney were observed in rats, guinea-pigs and dogs exposed for 6 months (7 h/day, 5 days/week) to 25 ppm in air. Fatty infiltration, granular centrilobular degeneration with necrotic areas in the liver, and changes in serum enzyme activities, as well as swelling of tubular epithelium, proteinuria, glucosuria and decreased phenolsulphonephtalein excretion, were reported. It appears that chloroform has little potential for causing chromosomal abnormalities in various test systems, so it is believed that its carcinogenicity arises from non-genotoxic mechanisms. Chloroform also causes various foetal abnormalities in test animals and a no-effect level has not yet been established.

Persons acutely exposed to chloroform vapour in air may develop different symptoms depending on the concentration and duration of exposure: headache, drowsiness, feeling of drunkenness, lassitude, dizziness, nausea, excitation, unconsciousness, respiratory depression, coma and death in narcosis. Death may occur due to respiratory paralysis or as a result of cardiac arrest. Chloroform sensitizes the myocardium to catecholamines. A concentration of 10,000 to 15,000 ppm of chloroform in inhaled air causes anaesthesia, and 15,000 to 18,000 ppm may be lethal. Narcotic concentrations in blood are 30 to 50 mg/100 ml; levels of 50 to 70 mg/100 ml blood are lethal. After transient recovery from heavy exposure, failure of liver functions and kidney damage may cause death. Effects on heart muscle have been described. Inhalation of very high concentrations may cause sudden arrest of the heart’s action (shock death).

Workers exposed to low concentrations in air for long periods and persons with developed dependance on chloroform may suffer from neurological and gastrointestinal symptoms resembling chronic alcoholism. Cases of various forms of liver disorders (hepatomegaly, toxic hepatitis and fatty liver degeneration) have been reported.

2-Chloropropane is a potent anaesthetic; it has not been widely used, however, because vomiting and cardiac arrhythmia have been reported in humans, and injury to liver and kidneys has been found in animal experiments. Splashes on the skin or into the eyes can result in serious but transient effects. It is a severe fire hazard.

Dichloromethane (methylene chloride) is highly volatile, and high atmospheric concentrations may develop in poorly ventilated areas, producing loss of consciousness in exposed workers. The substance does, however, have a sweetish odour at concentrations above 300 ppm, and consequently it may be detected at levels lower than those having acute effects. It has been classified by IARC as a possible human carcinogen. There is insufficient data on humans, but the animal data which are available are considered sufficient.

Cases of fatal poisoning have been reported in workers entering confined spaces in which high dichloromethane concentrations were present. In one fatal case, an oleoresin was being extracted by a process in which most of the operations were conducted in a closed system; however, the worker was intoxicated by vapour escaping from vents in the indoor supply tank and from the percolators. It was found that the actual loss of dichloromethane from the system amounted to 3,750 l per week.

The principal acute toxic action of dichloromethane is exerted on the central nervous system—a narcotic or, in high concentrations, an anaesthetic effect; this latter effect has been described as ranging from severe fatigue to light-headedness, drowsiness and even unconsciousness. The margin of safety between these severe effects and those of a less serious character is narrow. The narcotic effects cause loss of appetite, headache, giddiness, irritability, stupor, numbness and tingling of the limbs. Prolonged exposure to the lower narcotic concentrations may produce, after a latent period of several hours, shortness of breath, a dry, non-productive cough with substantial pain and possibly pulmonary oedema. Some authorities have also reported haematological disturbance in the form of reduction of the erythrocyte and haemoglobin levels as well as engorgement of the brain blood vessels and dilation of the heart.

However, mild intoxication does not seem to produce any permanent disability, and the potential toxicity of dichloromethane to the liver is much less than that of other halogenated hydrocarbons (in particular, carbon tetrachloride), although the results of animal experiments are not consistent in this respect. Nevertheless, it has been pointed out that dichloromethane is seldom used in a pure state but is often mixed with other compounds which do exert a toxic effect on the liver. Since 1972 it has been shown that persons exposed to dichloromethane have elevated carboxyhaemoglobin levels (such as 10% an hour after two hours’ exposure to 1,000 ppm of dichloromethane, and 3.9% 17 hours later) because of the in vivo conversion of dichloromethane to carbon monoxide. At that time exposure to dichloromethane concentrations not exceeding a time-weighted average (TWA) of 500 ppm could result in a carboxyhaemoglobin level in excess of that allowed for carbon monoxide (7.9% COHb is the saturation level corresponding to 50 ppm CO exposure); 100 ppm of dichloromethane would produce the same COHb level or concentration of CO in the alveolar air as 50 ppm of CO.

Irritation of the skin and eyes may be caused by direct contact, yet the chief industrial health problems resulting from excessive exposure are the symptoms of drunkenness and incoordination that result from dichloromethane intoxication and the unsafe acts and consequent accidents to which these symptoms may lead.

Dichloromethane is absorbed through the placenta and can be found in the embryonic tissues following exposure of the mother; it is also excreted via milk. Inadequate data on reproductive toxicity are available to date.

Ethylene dichloride is flammable and a dangerous fire hazard. It is classified in Group 2B—a possible human carcinogen—by IARC. Ethylene dichloride can be absorbed through the airways, the skin and the gastrointestinal tract. It is metabolized into 2-chloroethanol and monochloroacetic acid, both more toxic than the original compound. It has an odour threshold in humans that varies from 2 to 6 ppm as determined under controlled laboratory conditions. However, adaptation appears to occur relatively early, and after 1 or 2 minutes the odour at 50 ppm is barely detectable. Ethylene dichloride is appreciably toxic to humans. Eighty to 100 ml are enough to produce death within 24 to 48 hours. Inhalation of 4,000 ppm will cause serious illness. In high concentrations it is immediately irritating to the eyes, nose, throat and skin.

A major use of the chemical is in the manufacture of vinyl chloride, which is primarily a closed process. Leaks from the process can and do occur, however, producing a hazard for the worker so exposed. However, the most likely chance of exposure occurs during the pouring of containers of ethylene dichloride into open vats, where it is subsequently used for the fumigation of grain. Exposures also occur through manufacturing losses, application of paints, solvent extractions and waste-disposal operations. Ethylene dichloride rapidly photo-oxidizes in air and does not accumulate in the environment. It is not known to bioconcentrate in any food chains or to accumulate in human tissues.

The classification of ethylene chloride as a Group 2B carcinogen is based on the significant increases in tumour production found in both sexes in mice and rats. Many of the tumours, such as haemangiosarcoma, are uncommon types of tumours, rarely if ever encountered in control animals. The “time to tumour” in treated animals was less than in controls. Since it has caused progressive malignant disease of various organs in two species of animals, ethylene dichloride must be considered potentially carcinogenic in humans.

Hexachlorobutadiene (HCBD). Observations on occupationally induced disorders are scarce. Agricultural workers fumigating vineyards and simultaneously exposed to 0.8 to 30 mg/m³ HCBD and 0.12 to 6.7 mg/m³ polychlorobutane in the atmosphere exhibited hypotension, heart disorders, chronic bronchitis, chronic liver disease and nervous-function disorders. Skin conditions likely to be due to HCBD were observed in other exposed workers.

Hexachloroethane possesses a narcotic effect; however, since it is a solid and has a rather low vapour pressure under normal conditions, the hazard of a central nervous system depression by inhalation is low. It is irritating to skin and mucous membranes. Irritation has been observed from dust, and exposure of operators to fumes from hot hexachloroethane has been reported to cause blepharospasm, photophobia, lacrimation and reddening of the conjunctivae, but not corneal injury or permanent damage. Hexachloroethane may cause dystrophic changes in the liver and in other organs as demonstrated in animals.

IARC has placed HCBD into Group 3, non-classifiable as to carcinogenicity.

Methyl chloride is an odourless gas and therefore gives no warning. It is thus possible for considerable exposure to occur without those concerned becoming aware of it. There is also the risk of individual susceptibility to even mild exposure. In animals it has shown markedly differing effects in different species, with greater susceptibility in animals with more highly developed central nervous systems, and it has been suggested that human subjects may show an even greater degree of individual susceptibility. A hazard pertaining to mild chronic exposure is the possibility that the “drunkenness”, dizziness and slow recovery from slight intoxication may cause failure to recognize the cause, and that leaks may go unsuspected. This could result in further prolonged exposure and accidents. The majority of fatal cases recorded have been caused by leakage from domestic refrigerators or defects in refrigeration plants. It is also a dangerous fire and explosion hazard.

Severe intoxication is characterized by a latent period of several hours before the onset of symptoms such as headache, fatigue, nausea, vomiting and abdominal pain. Dizziness and drowsiness may have existed for some time before the more acute attack was precipitated by a sudden accident. Chronic intoxication from milder exposure has been less frequently reported, possibly because the symptoms may disappear rapidly with cessation of exposure. The complaints during mild cases include dizziness, difficulty in walking, headache, nausea and vomiting. The most frequent objective symptoms are a staggering gait, nystagmus, speech disorders, arterial hypotension, and reduced and disturbed cerebral electrical activity. Mild prolonged intoxication is liable to cause permanent injury of the heart muscle and the central nervous system, with a change of personality, depression, irritability, and occasionally visual and auditory hallucinations. Increased albumen content in the cerebrospinal fluid, with possible extrapyramidal and pyramidal lesions, may suggest a diagnosis of meningoencephalitis. In fatal cases, autopsy has shown congestion of lungs, liver and kidneys.

Tetrachloroethane is a powerful narcotic, and a central nervous system and liver poison. The slow elimination of tetrachloroethane from the body may be a reason for its toxicity. Inhalation of the vapour is ordinarily the chief source of tetrachloroethane absorption, although there is evidence that absorption through the skin may occur to some extent. It has been speculated that certain nervous-system effects (e.g., tremor) are caused chiefly by skin absorption. It is also a skin irritant and may produce dermatitis.

Most of the occupational exposures to tetrachloroethane have resulted from its use as a solvent. A number of fatal cases occurred between 1915 and 1920 when it was employed in the preparation of aeroplane fabric and in the manufacture of artificial pearls. Other fatal cases of tetrachloroethane intoxication have been reported in the manufacture of safety goggles, the artificial leather industry, the rubber industry and a non-specified war industry. Non-fatal cases have occurred in artificial silk manufacture, wool degreasing, penicillin preparation and the manufacture of jewellery.

Tetrachloroethane is a powerful narcotic, being two to three times as effective as chloroform in this respect for animals. Fatal cases among humans have resulted from the ingestion of tetrachloroethane, with death occurring within 12 hours. Non-fatal cases, involving loss of consciousness but no serious after-effects, have also been reported. In comparison with carbon tetrachloride, the narcotic effects of tetrachloroethane are much more severe, but the nephrotoxic effects are less marked. Chronic intoxication by tetrachloroethane can take two forms: central nervous system effects, such as tremor, vertigo and headache; and gastrointestinal and hepatic symptoms, including nausea, vomiting, gastric pain, jaundice and enlargement of the liver.

1,1,1-Trichloroethane is rapidly absorbed through the lungs and the gastrointestinal tract. It can be absorbed through the skin, but this is seldom of systemic importance unless it is confined to the skin surface beneath an impermeable barrier. The first clinical manifestation of overexposure is a functional depression of the central nervous system, commencing with dizziness, incoordination and impaired Romberg test (subject balances on one foot, with eyes closed and arms at his side), progressing to anaesthesia and respiratory centre arrest. The CNS depression is proportional to the magnitude of exposure and typical of an anaesthetic agent, hence the danger of epinephrine sensitization of the heart with the development of an arrhythmia. Transient liver and kidney injury has been produced following heavy overexposure, and lung injury has been noted at autopsy. Several drops splashed directly on the cornea can result in a mild conjunctivitis, which will resolve spontaneously within a few days. Prolonged or repeated contact with skin results in transient erythema and slight irritation, owing to the defatting action of the solvent.

Following the absorption of 1,1,1-trichloroethane a small percentage is metabolized to carbon dioxide while the remainder appears in the urine as the glucuronide of 2,2,2-trichloroethanol.

Acute exposure. Humans exposed to 900 to 1,000 ppm experienced transient, mild eye irritation and prompt, though minimal, impairment of coordination. Exposures of this magnitude may also induce headache and lassitude. Disturbances of equilibrium have been occasionally observed in “susceptible” individuals exposed to concentrations in the 300 to 500 ppm range. One of the most sensitive clinical tests of mild intoxication during the time of exposure is the inability to perform a normal modified Romberg test. Above 1,700 ppm, obvious disturbances of equilibrium have been observed.

The majority of the few fatalities reported in the literature have occurred in situations in which an individual was exposed to anaesthetic concentrations of the solvent and either succumbed as a result of respiratory centre depression or an arrhythmia resulting from epinephrine sensitization of the heart.

1,1,1-Trichloroethane is unclassifiable (Group 3) as to carcinogenicity accord to IARC.

The 1,1,2-trichloroethane isomer is used as a chemical intermediate and as a solvent. The principal pharmacologic response to this compound is depression of the CNS. It appears to be less acutely toxic than the 1,1,2- form. Although IARC considers it a nonclassifiable carcinogen (Group 3), some government agencies treat it as a possible human carcinogen (e.g., US National Institute of Occupational Safety and Health (NIOSH)).

Trichloroethylene. Although, under ordinary conditions of use, trichloroethylene is non-flammable and non-explosive, it may decompose at high temperatures to hydrochloric acid, phosgene (in the presence of atmosphere oxygen) and other compounds. Such conditions (temperatures above 300 °C) are found on hot metals, in arc welding and open flames. Dichloroacetylene, an explosive, flammable, toxic compound, may be formed in the presence of strong alkali (e.g., sodium hydroxide).

Trichloroethylene has primarily a narcotic effect. In exposure to high concentrations of vapour (above about 1,500 mg/m³) there may be an excitatory or euphoric stage followed by dizziness, confusion, drowsiness, nausea, vomiting and possibly loss of consciousness. In accidental ingestion of trichloroethylene a burning sensation in the throat and gullet precedes these symptoms. In inhalation poisonings, most manifestations clear with the breathing of uncontaminated air and elimination of the solvent and its metabolites. Nevertheless, deaths have occurred as a result of occupational accidents. Prolonged contact of unconscious patients with liquid trichloroethylene may cause blistering of the skin. Another complication in poisoning may be chemical pneumonitis and liver or kidney damage. Trichloroethylene splashed in the eye produces irritation (burning, tearing and other symptoms).

After repeated contact with liquid trichloroethylene, severe dermatitis may develop (drying, reddening, roughening and fissuring of the skin), followed by secondary infection and sensitization.

Trichloroethylene is classified as a Group 2A probable human carcinogen by IARC. In addition, the central nervous system is the main target organ for chronic toxicity. Two types of effects are to be distinguished: (a) narcotic effect of trichloroethylene and its metabolite trichloroethanol when still present in the body, and (b) the long-lasting sequellae of repeated over-exposures. The latter may persist for several weeks or even months after the end of the exposure to trichloroethylene. The main symptoms are lassitude, giddiness, irritability, headache, digestive disturbances, intolerance of alcohol (drunkenness after consumption of small quantities of alcohol, skin blotches due to vasodilation—”degreaser’s flush”), mental confusion. The symptoms may be accompanied by dispersed minor neurological signs (mainly of brain and autonomic nervous system, rarely of peripheral nerves) as well as by psychological deterioration. Irregularities of cardiac rhythm and minor liver involvement have rarely been observed. The euphoric effect of trichloroethylene inhalation may lead to craving, habituation and sniffing.

Allyl compounds

The allyl compounds are unsaturated analogues of corresponding propyl compounds, and are represented by the general formula CH₂:CHCH₂X, where X in the present context is usually a halogen, hydroxyl or organic acid radical. As in the case of the closely allied vinyl compounds, the reactive properties associated with the double bond have proved useful for the purposes of chemical synthesis and polymerization.

Certain physiological effects of significance in industrial hygiene are also associated with the presence of the double bond in the allyl compounds. It has been observed that unsaturated aliphatic esters exhibit irritant and lacrimatory properties which are not present (at least to the same extent) in the corresponding saturated esters; and the acute LD₅₀ by various routes tends to be lower for the unsaturated ester than for the saturated compound. Striking differences in these respects are found between allyl acetate and propyl acetate. These irritant properties, however, are not confined to the allyl esters; they are found in different classes of allyl compounds.

Allyl chloride (chloroprene) has flammable and toxic properties. It is only weakly narcotic but is otherwise highly toxic. It is very irritating to the eyes and upper respiratory tract. Both acute and chronic exposure can give rise to lung, liver and kidney injury. Chronic exposure has also been associated with decrease in the systolic pressure and in the tonicity of the brain blood vessels. In contact with the skin it causes mild irritation, but absorption through the skin causes deep-seated pain in the contact area. Systemic injury may be associated with skin absorption.

Animal studies give contradictory results with respect to carcinogenicity, mutagencity and reproductive toxicity. IARC has placed allyl chloride into a Group 3 classification—not classifiable.

Vinyl and vinylidene chlorinated compounds

Vinyls are chemical intermediates and are used primarily as monomers in the manufacture of plastics. Many of them can be prepared by the addition of the appropriate compound to acetylene. Examples of vinyl monomers include vinyl bromide, vinyl chloride, vinyl fluoride, vinyl acetate, vinyl ethers and vinyl esters. Polymers are high-molecular-weight products formed by polymerization, which can be defined as a process involving the combination of similar monomers to produce another compound containing the same elements in the same proportions, but with a higher molecular weight and different physical characteristics.

Vinyl chloride. Vinyl chloride (VC) is flammable and forms an explosive mixture with air at proportions between 4 and 22% by volume. When burning it is decomposed into gaseous hydrochloric acid, carbon monoxide and carbon dioxide. It is easily absorbed by the human organism through the respiratory system, from where it passes into the blood circulation and from there to the various organs and tissues. It is also absorbed through the digestive system as a contaminant of food and beverages, and through the skin; however, these two routes of entry are negligible for occupational poisoning.

The absorbed VC is transformed and excreted in various ways depending on the amount accumulated. If it is present in high concentrations, up to 90% of it may be eliminated unchanged by exhalation, accompanied by small amounts of CO₂; the rest undergoes biotransformation and is excreted with the urine. If present in low concentrations, the amount of monomer exhaled unchanged is extremely small, and the proportion reduced to CO₂ represents approximately 12%. The remainder is subjected to further transformation. The principal centre of the metabolic process is the liver, where the monomer undergoes a number of oxidative processes, being catalyzed partly by alcohol dehydrogenase, and partly by a catalase. The main metabolic pathway is the microsomal one, where VC is oxidated to chloroethylene oxide, an unstable epoxide which spontaneously transforms into chloroacetaldehyde.

Whichever the metabolic pathway followed, the final product is always chloroacetaldehyde, which consecutively conjugates with glutathion or cysteine, or is oxidated to monochloroacetic acid, which partly passes into the urine and partly combines with glutathion and cysteine. The main urinary metabolites are: hydroxyethyl cysteine, carboxyethyl cysteine (as such or N-acetylated), and monochloroacetic acid and thiodiglycolic acid in traces. A small proportion of metabolites are excreted with the gall into the intestine.

Acute poisoning. In humans, prolonged exposure to VC brings about a state of intoxication which may have an acute or chronic course. Atmospheric concentrations of about 100 ppm are not perceptible since the odour threshold is 2,000 to 5,000 ppm. If such high monomer concentrations are present, they are perceived as a sweetish, not unpleasant smell. Exposure to high concentrations results in a state of elation followed by asthenia, sensation of heaviness in the legs, and somnolence. Vertigo is observed at concentrations of 8,000 to 10,000 ppm, hearing and vision are impaired at 16,000 ppm, loss of consciousness and narcosis are experienced at 70,000 ppm, and concentrations of more than 120,000 ppm may be fatal to humans.

Carcinogenic action. Vinyl chloride is classified as a Group 1 known human carcinogen by IARC, and it is regulated as a known human carcinogen by numerous authorities throughout the world. In the liver, it may induce the development of an extremely rare malignant tumour known as angiosarcoma or haemangioblastoma or malignant haemangio-endothelioma or angiomatous mesenchymoma. The mean latency period is about 20 years. It evolves asymptomatically and becomes apparent only at a late stage, with symptoms of hepatomegaly, pain and decay of the general state of health, and there may be signs of concomitant liver fibrosis, portal hypertension, oesophageal varicose veins, ascites, haemorrhage of the digestive tract, hypochromic anaemia, cholestasia with an increase in alkaline phosphatasis, hyperbilirubinaemia, increase in BSP retention time, hyperfunction of the spleen characterized essentially by thrombocytopenia and reticulocytosis, and liver-cell involvement with a decrease in serum albumin and in fibrinogen.

Long-term exposure to sufficiently high concentrations gives rise to a syndrome called “vinyl chloride disease”. This condition is characterized by neurotoxic symptoms, modifications of the peripheral microcirculation (Raynaud’s phenomenon), skin changes of the scleroderma type, skeletal changes (acro-osteolysis), modifications in the liver and spleen (hepato-splenic fibrosis), pronounced genotoxic symptoms, as well as cancer. There may be skin involvement, including scleroderma on the back of the hand at the metacarpal and phalangeal joints and on the inside of the forearms. The hands are pale and feel cold, moist and swollen on account of a hard oedema. The skin may lose elasticity, be difficult to lift in folds, or covered by small papules, microvesicles and urticaroid formations. Such changes have been observed on the feet, neck, face and back, as well as the hands and arms.

Acro-osteolysis. This is a skeletal change generally localized at the distal phalanges of the hands. It is due to aseptic bone necrosis of ischaemic origin, induced by stenosing osseous arteriolitis. The radiologic picture shows a process of osteolysis with transverse bands or with thinned ungual phalanges.

Liver changes. In all cases of VC poisoning, liver changes can be observed. They may start with difficult digestion, a sensation of heaviness in the epigastric region, and meteorism. The liver is enlarged, has its normal consistency, and does not give particular pain when palpated. Laboratory tests are rarely positive. The liver enlargement disappears after removal from exposure. Liver fibrosis may develop in persons exposed for longer periods of time—that is, after 2 to 20 years. This fibrosis is sometimes isolated, but more often associated with an enlargement of the spleen, which may be complicated by portal hypertension, varicose veins at the oesophagus and cardia, and consequently by haemorrhages of the digestive tract. Fibrosis of the liver and spleen is not necessarily associated with an enlargement of these two organs. Laboratory tests are of little help, but experience has shown that a BSP test should be made, and the SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase), gamma GT and bilirubinaemia be determined. The only reliable examination is a laparoscopy with biopsy. The liver surface is irregular on account of the presence of granulations and sclerotic zones. The general structure of the liver is rarely changed, and the parenchyma is little affected, although there are liver cells with turbid swellings and liver-cell necrosis; a certain polymorphism of the cell nuclei is evident. The mesenchymal changes are more specific as there is always a fibrosis of the Glisson’s capsule extending into the portal spaces and passing into the liver-cell interstices. When the spleen is involved, it presents a capsular fibrosis with follicular hyperplasia, dilatation of the sinusoids and congestion of the red pulp. A discreet ascites is not infrequent. After removal from exposure the hepatomegaly and splenomegaly diminish, the changes of the liver parenchyma reverse, and the mesenchymal changes may undergo further deterioration or also cease their evolution.

Vinyl bromide. Although the acute toxicity of vinyl bromide is lower than that of many other chemicals in this group, it is considered a probable human carcinogen (Group 2A) by IARC and should be handled as a potential occupational carcinogen in the workplace. In its liquid state vinyl bromide is moderately irritant for the eyes, but not for the skin of rabbits. Rats, rabbits and monkeys exposed to 250 or 500 ppm for 6 hours per day, 5 days per week during 6 months did not reveal any damage. A 1-year experiment on rats exposed to 1,250 or 250 ppm (6 hours per day, 5 days per week) disclosed an increase in mortality, loss of body weight, angiosarcoma of the liver and carcinomas of Zymbal’s glands. The substance proved to be mutagenic in strains of Salmonella typhimurium with and without metabolic activation.

Vinylidene chloride (VDC). If pure vinylidene chloride is kept between -40 °C and +25 °C in the presence of air or oxygen, a violently explosive peroxide compound of undetermined structure is formed, which can detonate from slight mechanical stimuli or from heat. The vapours are moderately irritating to the eyes, and exposure to high concentrations may cause effects similar to drunkenness, which may progress to unconsciousness. The liquid is an irritant to the skin, which may be in part due to the phenolic inhibitor added to prevent uncontrolled polymerization and explosion. It also has sensitizing properties.

The carcinogenic potential of VDC in animals is still controversial. IARC has not classified it as a possible or probable carcinogen (as of 1996), but the US NIOSH has recommended the same exposure limit for VDC as for vinyl chloride monomer—that is, 1 ppm. No case reports or epidemiological studies relevant to the carcinogenicity to humans of VDC-vinyl chloride copolymers are available to date.

VDC has a mutagenic activity, the degree of which varies according to its concentration: at low concentration it has been found higher than that of vinyl chloride monomer; however, such activity seems to decrease at high doses, probably as a result of an inhibitory action on the microsomal enzymes responsible for its metabolic activation.

Aliphatic hydrocarbons containing bromine

Bromoform. Much of the experience in poisoning cases in humans has been from oral administration, and it is difficult to determine the significance of the toxicity of bromoform in industrial use. Bromoform has been used as a sedative and particularly as an antitussive for years, ingestion of quantities above the therapeutic dose (0.1 to 0.5 g) having caused stupor, hypotension and coma. In addition to the narcotic effect, a rather strong irritant and lacrimatory effect occurs. Exposure to bromoform vapours causes a marked irritation of the respiratory passages, lacrimation and salivation. Bromoform may injure the liver and the kidney. In mice, tumours have been elicited by intraperitoneal application. It is absorbed through the skin. On exposure to concentrations of up to 100 mg/m³ (10 ppm), complaints of headache, dizziness and pain in the liver region have been made, and alterations in the liver function have been reported.

Ethylene dibromide (dibromoethane) is a potentially dangerous chemical with an estimated minimum human lethal dose of 50 mg/kg. In fact, the ingestion of 4.5 cm³ of Dow-fume W-85, which contains 83% dibromoethane, proved to be fatal for a 55 kg adult female. It is classified as a Group 2A probable human carcinogen by IARC.

The symptoms induced by this chemical depend on whether there has been direct contact with the skin, inhalation of vapour, or oral ingestion. Since the liquid form is a severe irritant, prolonged contact with the skin leads to redness, oedema and blistering with eventual sloughing ulceration. Inhalation of its vapours results in respiratory system damage with lung congestion, oedema and pneumonia. Central nervous system depression with drowsiness also occurs. When death supervenes, it is usually due to cardiopulmonary failure. Oral ingestion of this material leads to injury of the liver with lesser damage to the kidneys. This has been found in both experimental animals and in humans. Death in these cases is usually attributable to extensive liver damage. Other symptoms which may be encountered following ingestion or inhalation include excitement, headache, tinnitus, generalized weakness, a weak and thready pulse and severe, protracted vomiting.

Oral administration of dibromoethane by stomach tube caused squamous cell carcinomas of the forestomach in rats and mice, lung cancers in mice, haemoangiosarcomas of the spleen in male rats, and liver cancer in female rats. No case reports in humans or definitive epidemiological studies are available.

Recently a serious toxic interaction has been detected in rats between inhaled dibromoethane and disulphiram, resulting in very high mortality levels with a high incidence of tumours, including haemoangiosarcomas of liver, spleen and kidney. Therefore the US NIOSH recommended that (a) workers should not be exposed to dibromoethane during the course of sulphiram therapy (Antabuse, Rosulfiram used as alcohol deterrents), and (b) no worker should be exposed to both dibromoethane and disulphiram (the latter being also used in industry as an accelerator in rubber production, a fungicide and an insecticide).

Fortunately the application of dibromoethane as a soil fumigant is ordinarily under the surface of the ground with an injector, which minimizes the hazard of direct contact with the liquid and vapour. Its low vapour pressure also reduces the possibility of inhalation of appreciable amounts.

The odour of dibromoethane is recognizable at a concentration of 10 ppm. Procedures set forth earlier in this chapter for the handling of carcinogens should be applied to this chemical. Protective clothing and nylon-neoprene gloves will help avoid skin contact and possible absorption. In case of direct contact with the skin surface, treatment consists of removal of covering garments and thorough washing of the skin with soap and water. If this is accomplished within a short time after the exposure, it constitutes adequate protection against development of skin lesions. Involvement of the eyes by either the liquid or vapour can be successfully treated by flushing with copious volumes of water. Since the ingestion of dibromoethane by mouth leads to serious liver injury, it is imperative that the stomach be promptly emptied and thorough gastric lavage be accomplished. Efforts to protect the liver should include such traditional procedures as a high-carbohydrate diet and supplementary vitamins, especially vitamins B, C and K.

Methyl bromide is among the most toxic organic halides and gives no odour warning of its presence. In the atmosphere it disperses slowly. For these reasons it is among the most dangerous materials encountered in industry. Entry to the body is mainly by inhalation, whereas the degree of skin absorption is probably insignificant. Unless severe narcosis results, it is typical for the onset of symptoms to be delayed by hours or even days. A few deaths have resulted from fumigation, where its continued use is problematic. A number have occurred due to leakage from refrigerating plants, or from the use of fire extinguishers. Lengthy skin contact with clothing contaminated by splashes can cause second-degree burns.

Methyl bromide may damage the brain, heart, lungs, spleen, liver, adrenals and kidneys. Both methyl alcohol and formaldehyde have been recovered from these organs, and bromide in amounts varying from 32 to 62 mg/300 g of tissue. The brain may be acutely congested, with oedema and cortical degeneration. Pulmonary congestion may be absent or extreme. Degeneration of the kidney tubules leads to uraemia. Damage to the vascular system is indicated by haemorrhage in the lungs and brain. Methyl bromide is said to be hydrolyzed in the body, with the formation of inorganic bromide. The systemic effects of methyl bromide may be an unusual form of bromidism with intracellular penetration by bromide. Pulmonary involvement in such cases is less severe.

An acneform dermatitis has been observed in persons repeatedly exposed. Cumulative effects, often with disturbances of the central nervous system, have been reported after repeated inhalation of moderate concentrations of methyl bromide.

Safety and Health Measures

The use of the most dangerous compounds of the group should be avoided entirely. Where it is technically feasible, they should be replaced by less harmful substances. For example, as far as practicable, less hazardous substances should be used instead of bromomethane in refrigeration and as fire extinguishers. In addition to the prudent safety and health measures applicable to volatile chemicals of similar toxicity, the following are also recommended:

Fire and explosion. Only the higher members of the series of halogenated aliphatic hydrocarbons are not flammable and not explosive. Some of them do not support combustion and are used as fire extinguishers. In contrast the lower members of the series are flammable, in some instances even highly flammable (for example, 2-chloropropane) and form explosive mixtures with air. Besides, in the presence of oxygen, violently explosive peroxide compounds may arise from some unsaturated members (for example, dichloroethylene) even at very low temperatures. Toxicologically dangerous compounds may be formed by thermal decomposition of halogenated hydrocarbons.

The engineering and hygiene measures of prevention should be completed by periodic health examinations and complementary laboratory tests aimed at the target organs, in particular the liver and kidneys.

Halogenated saturated hydrocarbons tables

Table 1 - Chemical information.

Table 2 - Health hazards.

Table 3 - Physical and chemical hazards.

Table 4 - Physical and chemical properties.

Halogenated unsaturated hydrocarbons tables

Table 5 - Chemical information.

Table 6 - Health hazards.

Table 7 - Physical and chemical hazards.

Table 8 - Physical and chemical properties.

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