C HAPTER 16 Organohalide Compounds 16.1 INTRODUCTION Organohalide compounds are halogen-substituted hydrocarbons with a wide range of physical and chemical properties produced in large quantities as solvents, heat transfer fluids, chemical intermediates, and for other applications. They may be saturated (alkyl halides), unsaturated (alkenyl halides), or aromatic (aryl halides). The major means of synthesizing organohalide compounds are shown by examples in Chapter 13 and include substitution halogenation, addition halogenation, and hydrohalogenation reactions, illustrated in reactions 13.2.2, 13.2.3, and 13.2.4, respectively. Most organohalide compounds are chlorides (chlorocarbons and chlorohydrocarbons), but they also include compounds of fluorine, bromine, and iodine, as well as mixed halides, such as the chloro- fluorocarbons. The chemical reactivities of organohalide compounds vary over a wide range. The alkyl halides are generally low in reactivity, but may undergo pyrolysis in flames to liberate noxious products, such as HCl gas. Alkenyl halides may be oxidized, which in some cases produces highly toxic phosgene, as shown by the following example: (16.1.1) The toxicities of organohalide compounds vary widely. For example, dichlorodifluoromethane (Freon-12) is generally regarded as having a low toxicity, except for narcotic effects and the possibility of asphyxiation at high concentration. Vinyl chloride (see Section 16.3), however, is a known human carcinogen. The polychlorinated biphenyls (PCBs) are highly resistant to biodegra- dation and are extremely persistent in the environment. 16.1.1 Biogenic Organohalides Organohalides were once regarded as being produced exclusively by human activities. However, more recent investigations have shown that organisms including algae and fungi release a variety of organohalides, and more than 2000 compounds from these biogenic sources have now been identified. 1 Most of these compounds are organochlorine and organobromine species. Bottom-ice microalgae and Agarium cribrosum kelp in the Arctic have been shown to be significant producers of environmental organobromine as bromoform, HCBr 3 . 2 CC Cl H Cl Cl Cl C Cl O COO 2 + + HCl + Trichloroethylene Phosgene L1618Ch16Frame Page 327 Tuesday, August 13, 2002 5:41 PM Copyright © 2003 by CRC Press LLC 16.2 ALKYL HALIDES Alkyl halides are compounds in which halogen atoms are substituted for hydrogen on an alkyl group. The structural formulas of some typical alkyl halides are given in Figure 16.1. Most of the commercially important alkyl halides are derivatives of alkanes of low molecular mass. A brief discussion of the uses of the compounds listed in Figure 16.1 will provide an idea of the versatility of the alkyl halides. Volatile chloromethane (methyl chloride) was once widely used as a refrigerant fluid and aerosol propellant; most of it now is consumed in the manufacture of silicones. Dichlo- romethane is a volatile liquid with excellent solvent properties for nonpolar organic solutes. It has been applied as a solvent for the decaffeination of coffee and in paint strippers, as a blowing agent in urethane polymer manufacture, and to depress vapor pressure in aerosol formulations. Once commonly sold as a solvent and stain remover, carbon tetrachloride is now severely curtailed. Chloroethane is an intermediate in the manufacture of tetraethyllead (now virtually discontinued in motor fuel) and is an ethylating agent in chemical synthesis. Methyl chloroform (1,1,1-trichlo- roethane) used to be one of the more common industrial chlorinated solvents. Insecticidal 1,2- dibromethane has been used in large quantities to fumigate soil, grain, and fruit and as a lead scavenger in leaded gasoline. It is an effective solvent for resins, gums, and waxes and serves as a chemical intermediate in the syntheses of some pharmaceutical compounds and dyes. 16.2.1 Toxicities of Alkyl Halides The toxicities of alkyl halides vary a great deal with the compound. Although some of these compounds have been considered to be almost completely safe in the past, there is a marked tendency to regard each with more caution as additional health and animal toxicity study data become available. Perhaps the most universal toxic effect of alkyl halides is depression of the central nervous system. Chloroform, CHCl 3 , was the first widely used general anesthetic, although many surgical patients were accidentally killed by it. Figure 16.1 Some typical low-molecular-mass alkyl halides. HCCl H H F F Cl C Cl H H H H HCCCl Cl C Cl H H Cl Cl H H ClCCH Cl C Cl Cl Cl H H H H BrCCBr Chloromethane (fp -98˚C, bp -24˚C) Dichloromethane (methylene chloride, fp -97˚C, bp 40˚C) Carbon tetrachloride (fp -23˚C, bp 77˚C) Dichlorodifluoro- methane (“Freon 12,” fp -158˚C, bp -29˚C) Chloroethane(ethyl- ene chloride, fp -139˚C, bp 12˚C) 1,1,1-Trichloroethane (methyl chloroform, fp -33˚C, bp 74˚C) 1,2-Dibromoethane (ethylene dibromide, fp 9.3˚C, bp 131˚C) L1618Ch16Frame Page 328 Tuesday, August 13, 2002 5:41 PM Copyright © 2003 by CRC Press LLC 16.2.2 Toxic Effects of Carbon Tetrachloride on the Liver Of all the alkyl halides, carbon tetrachloride has the most notorious record of human toxicity, especially for its toxic effects on the liver. For many years it was widely used in consumer products as a degreasing solvent, in home fire extinguishers, and in other applications. However, numerous toxic effects, including some fatalities, were observed, and in 1970, the U.S. Food and Drug Administration (FDA) banned the sale of carbon tetrachloride and formulations containing it for home use. Carbon tetrachloride is toxic through both inhalation and ingestion. Toxic symptoms from inhalation tend to be associated with nervous system, whereas those from ingestion often involve the gastrointestinal tract and liver. Both the liver and kidney may be substantially damaged by carbon tetrachloride. The biochemical mechanism of carbon tetrachloride toxicity has been investigated in detail. The cytochrome P-450-dependent monooxygenase system acts on CCl 4 in the liver to produce the Cl 3 C · free radical: (16.2.1) There are two major processes that this radical may initiate. 3 The radical can bind with liver cell components, the ultimate effect of which is inhibition of lipoprotein secretion. This causes fatty tissue to accumulate in the liver, leading to fatty liver or steatosis. Formation of DNA adducts with the Cl 3 C· radical may initiate carcinogenesis. Another process that the Cl 3 C· radical may undergo is combination with molecular oxygen to yield the highly reactive Cl 3 COO· radical: (16.2.2) These radical species, along with others produced from their subsequent reactions, can react with biomolecules, such as proteins and DNA. The most damaging such reaction is lipid peroxidation , a process that involves the attack of chemically active species on unsaturated lipid molecules, followed by oxidation of the lipids through a free radical mechanism. It occurs in the liver and is a main mode of action of some hepatotoxicants, which can result in major cellular damage. The mechanism of lipid peroxidation may involve abstraction of the methylene hydrogens attached to doubly bonded carbon atoms in lipid molecules: (16.2.3) Reaction of the lipid radical with molecular oxygen yields peroxy radical species: Cl C Cl Cl Cl Cl C . Cl Cl OOCl C Cl Cl Cl C Cl Cl . + O 2 + + . CCl Cl Cl H CCl Cl Cl . CC H CC HH Lipid molecule, L Lipid radical, L . L1618Ch16Frame Page 329 Tuesday, August 13, 2002 5:41 PM Copyright © 2003 by CRC Press LLC (16.2.4) This species can initiate chain reaction sequences with other molecules as follows: (16.2.5) Once inititated, chain reactions such as these continue and cause massive alteration of the lipid molecules. The LOOH molecules are unstable and decompose to yield additional free radicals. The process terminates when free radical species combine with each other to form stable species. 16.2.3 Other Alkyl Halides Dichloromethane has long been regarded as one of the least acutely toxic alkyl halides. This compound has been used in large quantities as a degreasing solvent, paint remover, aerosol propellant additive, and grain fumigant. Because of the high volatility of dichloromethane, its most common route of exposure is through air. It can also be absorbed through the skin or ingested with food or water. As a result of its properites and widespread uses, human exposure to dichloromethane has been relatively high. Human fatalities have occurred from very high exposures to methylene chloride in paint-stripping operations. It is not known to be a human carcinogen, although there is concern that it may possibly be carcinogenic. Generally considered to be among the least toxic of the alkyl halides, 1,1,1-trichloroethane was once produced at levels of several hundred million kilograms per year. However, it is persistent in the atmosphere and is a strong stratospheric ozone-depleting chemical, so production has been severely curtailed and there is now little reason for concern over its toxicity. A much more toxic alkyl halide is 1,2-dibromoethane. It is a severe irritant, damaging the lungs when inhaled in high concentrations, and a potential human carcinogen. It was widely used until the early 1980s to kill insects and worms on grain, vegetables, and fruits such as mangoes, papayas, and citrus. As a result, human exposure was relatively high. But these uses were banned by the U.S. Environmental Protection Agency in 1984, and human exposure is now negligible. There is still the possibility of exposure through contaminated groundwater in areas where dibromoethane has been used. 16.2.4 Hydrochlorofluorocarbons Hydrochlorofluorocarbons (HCFCs) are now being produced in very large quantities as substi- tutes for ozone-depleting chlorofluorocarbons (CFCs). The two most common HCFCs are 1,1- dichloro-2,2,2-trifluoroethane (HCFC-123) and 1,1-dichloro-1-fluoroethane (HCFC-141b): + O 2 OO CC H . . CC H Lipid radical, L . radical, LOO . Lipid peroxy + + . CC H OO • CC H CC H OOH CC HH radical, LOO . Lipid peroxy Lipid radical, L . Lipid hydroper- oxide, LOOH Lipid molecule, L L1618Ch16Frame Page 330 Tuesday, August 13, 2002 5:41 PM Copyright © 2003 by CRC Press LLC As a result of their increased production and the consequent exposure of organisms to HCFCs, these compounds have been subjected to intense scrutiny for their potential toxicological effects. Studies with rat liver tissue indicate that both HCFC-123 and HCFC-141b are metabolized by cytochrome P-450 enzymes to produce reactive metabolites, probably with intermediate production of free radical species. Studies of human volunteers who had inhaled levels of 250, 500, and 1000 ppm HCFC-141b showed that the major metabolite excreted in urine was 2,2-dichloro-2-fluoroethyl glucuronide, hydrolyzed by the action of β -glucuronidase enzyme to give 2,2-dichloro-2-fluoroet- hanol, which was measured by gas chromatography 4 : 16.2.5 Halothane Extensive toxicological studies have been performed on halothane, because it is a commonly used anesthetic. In rare cases, repeated exposure to halothane has caused liver cell necrosis, resulting in fatal halothane hepatitis in humans. This condition has been classified as an immune hepatitis resulting from the bonding of trifluoroacetyl metabolite of halothane to proteins. 5 The sequence of processes by which this occurs begins with the cytochrome P-450 catalyzed oxidative dehalogenation of halothane, in which the bromine atom, the best leaving group of the halogens on the molecule, is lost to produce trifluoroacetylchloride: (16.2.6) 1,1-Dichloro-2,2,2- trifluoroethane (HCFC-123) HC Cl Cl CF F F FC Cl Cl CH H H 1,1-Dichloro-1- fluoroethane (HCFC-141b) O C O OH OH HO OH OCCF HCl HCl HO C C F HCl HCl 2,2-Dichloro-2-fluoroethyl glucuronide 2,2-Dichloro-2-fluoroethanol FC F F C Cl Cl Br FC F F C Cl Cl Br FC F F C O Cl Oxidative dehalogenation Cytochrome P– 450, {O} Trifluoroacetylchloride L1618Ch16Frame Page 331 Tuesday, August 13, 2002 5:41 PM Copyright © 2003 by CRC Press LLC This product can bind with proteins to produce neo-antigens that result in immune hepatitis. It can also hydrolyze to produce toxic trifluoroacetic acid: Halothane can also undergo reductive dehalogenation, (16.2.7) to generate a carbon-centered radical. As shown above for the Cl 3 C· radical generated from carbon tetrachloride, this radical species may be involved with lipid peroxidation and protein binding, resulting in liver damage to rats and presumably to humans. Evidence for the halothane metabolism outlined above has been found in products recovered from the breath and urine of humans subjected to halothane anesthetic during surgery. 6 As evidence of reductive metabolites, chlorotrifluoroethane and chlorodifluoroethylene, were found in breath samples and F – in urine. Trifluoroacetic acid and Br – in urine were evidence of oxidative metabolism. 16.3 ALKENYL HALIDES The alkenyl , or olefinic organohalides , contain at least one halogen atom and at least one carbon–carbon double bond. The most significant of these are the lighter chlorinated compounds, such as those illustrated in Figure 16.2. 16.3.1 Uses of Alkenyl Halides The alkenyl halides are used for numerous purposes. Some of the more important applications are discussed here. Vinyl chloride is consumed in large quantities to manufacture polyvinyl chloride plastic, a major polymer in pipe, hose, wrapping, and other products. Vinyl chloride is a highly flammable volatile gas with a sweet, not unpleasant odor. As shown in Figure 16.2, there are three possible dichloroethylene compounds, all clear, col- orless liquids. Vinylidene chloride forms a copolymer with vinyl chloride, used in some kinds of coating materials. The geometrically isomeric 1,2-dichloroethylenes are used as organic synthesis intermediates and as solvents. Trichloroethylene is an excellent solvent for organic substances and has some other properties that are favorable for a solvent. It is a clear, colorless, nonflammable, volatile liquid. It is an excellent FC F F C O OH Trifluoroacetic acid FC F F C Cl Cl Br FC F F C Cl Cl Reductive dehalogenation . FC F F C H H Cl Chlorotrifluoro- ethane CC F F Cl H Chlorodifluoro- ethylene L1618Ch16Frame Page 332 Tuesday, August 13, 2002 5:41 PM Copyright © 2003 by CRC Press LLC degreasing and dry-cleaning solvent and has been used as a household solvent and for food extraction (for example, in decaffeination of coffee). Tetrachloroethylene is a colorless, nonflammable liquid with properties similar to those of trichloroethylene. Its major use is for dry cleaning, and it has some applications for degreasing metals. The two chlorinated propene compounds shown are colorless liquids with pungent, irritating odors. Allyl chloride is an intermediate in the manufacture of allyl alcohol and other allyl com- pounds, including pharmaceuticals, insecticides, and thermosetting varnish and plastic resins. Dichloropropene compounds have been used as soil fumigants, as well as solvents for oil, fat, dry cleaning, and metal degreasing. Large quantities of chloroprene, a colorless liquid with an ethereal odor, are used to make neoprene rubber. Hexachlorobutadiene is a colorless liquid with an odor somewhat like that of turpentine. It is used as a solvent for higher hydrocarbons and elastomers, as a hydraulic fluid, in transformers, and for heat transfer. 16.3.2 Toxic Effects of Alkenyl Halides Because of their widespread use and disposal in the environment, the toxicities of the alkenyl halides are of considerable concern. They exhibit a wide range of acute and chronic toxic effects. Many workers have been exposed to vinyl chloride because of its use in polyvinyl chloride plastic manufacture. The central nervous system, respiratory system, liver, and blood and lymph systems are all affected by exposure to vinyl chloride. Among the symptoms of poisoning are fatigue, weakness, and abdominal pain. Cyanosis may also occur. Vinyl chloride was abandoned as an anesthetic when it was found to induce cardiac arrhythmias. The most notable effect of vinyl chloride is its carcinogenicity. It causes a rare angiosarcoma of the liver in chronically exposed individuals, observed particularly in those who cleaned autoclaves Figure 16.2 The more common low-molecular-mass alkenyl chlorides H CC H Cl H Cl H H Cl CC Cl H Cl Cl CC CC Cl Cl H H Cl Cl Cl CC Cl CC Cl H Cl H CC Cl H Cl CH H H CC H H Cl H CC H H CC Cl Cl Cl Cl CC Cl Cl Monochloroethylene (vinyl chloride) 1,1-Dichloroethylene (vinylidene chloride) Cis- 1,2-Dichloroethylene Trans- 1,2- Dichloroethylene Trichloroethylene (TCE) Tetrachloroethylene (perchloroethylene) C H H ClCC HH H 3-Chloropropene (allyl chloride) 1,2-Dichloropropene (allylene dichloride) 2-Chloro-1,3-butadiene (chloroprene) Hexachlorobutadiene L1618Ch16Frame Page 333 Tuesday, August 13, 2002 5:41 PM Copyright © 2003 by CRC Press LLC in the polyvinyl chloride fabrication industry. The carcinogenicity of vinyl chloride results from its metabolic oxidation to chloroethylene oxide by the action of the cytochrome P-450 monooxy- genase enzyme system in the liver as follows: (16.3.1) The epoxide has a strong tendency to covalently bond to protein, DNA, and RNA, and it rearranges to chloroacetaldehyde, a known mutagen. Therefore, vinyl chloride produces two potentially car- cinogenic metabolites. Both of these products can undergo conjugation with glutathione to yield products that are eliminated from the body. It has been suggested that one of the mechanisms by which vinyl chloride causes liver cancer is by the addition of etheno (C 2 H 4 ) adducts to adenine and cytosine, both nitrogenous bases in DNA (see Section 3.7). The addition of an etheno group (shaded below) to adenine produces 1,N6- ethenoadenine: (16.3.2) and its addition to cytosine produces 3,N4-ethenocytosine: 7 (16.3.3) Based on animal studies and its structural similarity to vinyl chloride, 1,1-dichloroethylene is a suspect human carcinogen. Although both 1,2-dichloroethylene isomers have relatively low toxicities, their modes of action are different. The cis isomer is an irritant and narcotic, whereas the trans isomer affects both the central nervous system and the gastrointestinal tract, causing weakness, tremors, cramps, and nausea. Trichloroethylene has caused liver carcinoma in experimental animals and is a suspect human carcinogen, although a recent review of the literature has concluded that “it would be wholly inappropriate to classify trichloroethylene as a human carcinogen.” 8 Numerous body organs are CC H H Cl H CCH HH Cl O Cl C H H C O H + {O} Rearrangement Chloroacetaldehyde NN N N H 2 N H NN NN N H CC H H Cl H Addition of C 2 H 4 Adenine 1,N6-Ethenoadenine NN N O H NN O H NH 2 CC H H Cl H Addition of C 2 H 4 Cytosine 3,N4-Ethenocytosine L1618Ch16Frame Page 334 Tuesday, August 13, 2002 5:41 PM Copyright © 2003 by CRC Press LLC affected by it. As with other organohalide solvents, skin dermatitis can result from dissolution of skin lipids by trichloroethylene. Exposure to it can affect the central nervous and respiratory systems, liver, kidneys, and heart. Symptoms of exposure include disturbed vision, headaches, nausea, cardiac arrhythmias, and burning or tingling sensations in the nerves (paresthesia). Trichlo- roacetate ion, is a metabolite of trichloroethylene and may be toxicologically important. 9 Tetrachloroethylene damages the liver, kidneys, and central nervous system. Because of its hepatotoxicity and experimental evidence of carcinogenicity in mice, it is a suspect human carcin- ogen. The chlorinated propenes are obnoxious compounds. Unlike other compounds discussed so far in this section, their pungent odors and irritating effects lead to an avoidance response in exposed subjects. They are irritants to the eyes, skin, and respiratory tract. Contact with the skin can result in rashes, blisters, and burns. Chronic exposure to allyl chloride is manifested by aching muscles and bones; it damages the liver, lungs, and kidney and causes pulmonary edema. Chloroprene is an eye and respiratory system irritant. It causes dermatitis to the skin and alopecia, a condition characterized by hair loss in the affected skin area. Affected individuals are often nervous and irritable. Ingestion and inhalation of hexachlorobutadiene inhibits cells in the liver and kidney. Animal tests have shown both acute and chronic toxicities. The compound is a suspect human carcinogen. 16.3.3 Hexachlorocyclopentadiene As shown by the structure below, hexachlorocyclopentadiene is a cyclic alkenyl halide with two double bonds: It was once an important industrial chemical used directly as an agricultural fumigant and as an intermediate in the manufacture of insecticides. Hexachlorocyclopentadiene and still bottoms from its manufacture are found in hazardous waste chemical sites, and large quantities were disposed at the Love Canal site. The pure compound is a light yellow liquid (fp, 11°C; bp, 239°C) with a density of 1.7 g/cm 3 and a pungent, somewhat musty odor. With two double bonds, it is a very reactive compound and readily undergoes substitution and addition reactions. Its photolytic degra- dation yields water-soluble products. Hexachlorocyclopentadiene is considered to be very toxic, with a toxicity rating of 4. Its fumes are strongly lacrimating, and it is a skin, eye, and mucuous membrane irritant. In experimental animals it has been found to damage most major organs, including the kidney, heart, brain, adrenal glands, and liver. Cl C Cl Cl CO - O Trichloroacetate ion ClCl ClCl Cl Cl Hexachlorocyclopentadiene L1618Ch16Frame Page 335 Tuesday, August 13, 2002 5:41 PM Copyright © 2003 by CRC Press LLC 16.4 ARYL HALIDES Figure 16.3 gives the structural formulas of some of the more important aryl halides. These compounds are made by the substitution chlorination of aromatic hydrocarbons, as shown, for example, by the reaction below for the synthesis of a polychlorinated biphenyl: (16.4.1) 16.4.1 Properties and Uses of Aryl Halides Aryl halides have many uses, which have resulted in substantial human exposure and environ- mental contamination. Some of their major applications are summarized here. Figure 16.3 Some of the more important aryl halides. Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Br Cl CH 3 Cl Monochlorobenzene 1,3-Dichlorobenzene 1,2-Dichlorobenzene 1,4-Dichlorobenzene 1,2,3,4-Tetrachlorobenzene 1,2,4-Trichlorobenzene Hexachlorobenzene Bromobenzene 1-Chloro-2-methyl- benzene 1-Chloronaphthalene Chlorinated naphthalenes Polychlorinated biphenyls (Cl) 1-10 (Cl) 1-8 Cl Cl Cl Cl Cl + 5Cl 2 Fe FeCl 2 + 5HCl L1618Ch16Frame Page 336 Tuesday, August 13, 2002 5:41 PM Copyright © 2003 by CRC Press LLC [...]... 2003 by CRC Press LLC L1618Ch16Frame Page 341 Tuesday, August 13, 2002 5:41 PM H O O C C OH H Cl H O O C C OH H Cl Cl Cl Cl 2,4-Dichlorophenoxyacetic acid (and esters) O CH3 HO C C O H 2,4,5-Trichlorophenoxyacetic acid (and esters) Cl Cl Cl Cl O O Cl 2,3,7,8-Tetrachloro-p-dioxin Cl Silvex Cl Figure 16. 6 Herbicidal chlorophenoxy compounds and TCDD manufacturing by-product Cl Cl2 8-Octachlorobornane Cl... The 1, 4- isomer (para-dichlorobenzene) is also used in dye manufacture and as a moth repellant and germicide All three isomers have been used as fumigants and insecticides The 1, 2- and 1,3(meta) isomers are liquids under ambient conditions, whereas the 1, 4- isomer is a white sublimable solid Used as a solvent, lubricant, dielectric fluid, chemical intermediate, and formerly as a termiticide, 1,2,4-trichlorobenzene... in rodents and in human liver cells have shown that pentachlorophenol is metabolized by oxidative dechlorination to tetrachlorohydroquinone and tetrachloro-1,4-benzoquinone: OH O Cl Cl Cl Cl Cl Cl Cl Cl OH Tetrachloro-1,4-hydroquinone O Tetrachloro-1,4-benzoquinone Tetrachlorohydroquinone is more toxic to rats and human liver cells than its parent, pentachlorophenol.17 Lipid peroxidation and liver damage... tetrachlorohydroquinone and pentachlorophenol Liver cells exposed to tetrachlorohydroquinone and tetrachloro-1,4-benzoquinone have shown the formation of DNA adducts.18 Copyright © 2003 by CRC Press LLC L1618Ch16Frame Page 344 Tuesday, August 13, 2002 5:41 PM 16. 6.5 Hexachlorophene Hexachlorophene (Figure 16. 7) has been used as an agricultural fungicide and bacteriocide, largely in the production of vegetables and cotton... 13 Mitrou, P.I., Dimitriadis, G., and Raptis, S.A., Toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds, Eur J Intern Med., 12, 406–411, 2001 14 Miniero, R et al., An overview of TCDD half-life in mammals and its correlation to body weight, Chemosphere, 43, 839–844, 2001 15 Pitot, H.C., III and Dragon, Y.P., Chemical carcinogenesis, in Casarett and Doull’s Toxicology: The Basic... McGraw-Hill, New York, 2001, chap 8, pp 241–319 16 Leet, T et al., Cancer incidence among Alachlor manufacturing workers, Am J Ind Med., 30, 300–306, 1996 17 Wang, Y.-J et al., Oxidative stress and liver toxicity in rats and human hepatoma cell line induced by pentachlorophenol and its major metabolite tetrachlorohydroquinone, Toxicol Lett., 122, 157 169 , 2001 18 Lin, P.-H et al., Oxidative damage and. .. Hexachlorobenzene (perchlorobenzene) is a high-melting solid consisting of white needles and used as a seed fungicide, wood preservative, and intermediate for organic synthesis Bromobenzene (fp, –31°C; bp, 156°C) serves as a solvent and motor oil additive, as well as an intermediate for organic synthesis Most 1-chloro-2-methylbenzene is consumed in the manufacture of 1-chlorobenzotrifluoride There are two major...L1618Ch16Frame Page 337 Tuesday, August 13, 2002 5:41 PM Monochlorobenzene is a flammable clear liquid (fp, –45°C; bp, 132°C) used as a solvent, solvent carrier for methylene diisocyanate, pesticide, heat transfer fluid, and in the manufacture of aniline, nitrobenzene, and phenol The 1, 2- isomer of dichlorobenzene (ortho-dichlorobenzene) has been used as a solvent for degreasing hides and wool and. .. compounds, their esters, and their salts have been used as ingredients of a large number of herbicide formulations Formulations of 2,4,5-T have become notorious largely by a manufacturing by-product, 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD), commonly known as dioxin The structural formulas of these compounds are shown in Figure 16. 6 Copyright © 2003 by CRC Press LLC L1618Ch16Frame Page 342 Tuesday,... farmers who had handled 2,4-D extensively showed an occurrence of non-Hodgkins lymphoma six to eight times that of comparable unexposed populations.12 The toxicity of Silvex appears to be somewhat less than that of 2,4-D, and to a large extent, it is excreted unchanged in the urine Although the toxic effects of 2,4,5-T may even be somewhat less than those of 2,4-D, observations of 2,4,5-T toxicity have . quantities as substi- tutes for ozone-depleting chlorofluorocarbons (CFCs). The two most common HCFCs are 1, 1- dichloro-2,2,2-trifluoroethane (HCFC-123) and 1,1-dichloro- 1- uoroethane (HCFC-141b): + O 2 OO CC H . . CC H Lipid radical,. trifluoroacetylchloride: (16. 2.6) 1,1-Dichloro-2,2, 2- trifluoroethane (HCFC-123) HC Cl Cl CF F F FC Cl Cl CH H H 1,1-Dichloro- 1- fluoroethane (HCFC-141b) O C O OH OH HO OH OCCF HCl HCl HO C C F HCl HCl 2,2-Dichloro-2-fluoroethyl glucuronide 2,2-Dichloro-2-fluoroethanol FC F F C Cl Cl Br FC F F C Cl Cl Br. C CH 3 H C O O OCl Cl Cl Cl 2,4-Dichlorophenoxy- acetic acid (and esters) 2,4,5-Trichlorophenoxy- acetic acid (and esters) Silvex 2,3,7,8-Tetrachloro-p-dioxin Cl 2 Cl Cl Cl Cl Cl Cl 8-Octachlorobornane L1618Ch16Frame Page 341