Halogenated aliphatic hydrocarbons are organic chemicals in which one or more hydrogen atoms has been replaced by a halogen (i.e., fluorinated, chlorinated, brominated or iodized).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.