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Chloroacetic Acids

Chloroacetic Acids

Chloroacetic

GU¨ NTER KOENIG, Hoechst Aktiengesellschaft, Augsburg, Germany

ELMAR LOHMAR, Hoechst Aktiengesellschaft, Koln,€ Germany

NORBERT RUPPRICH, Bundesanstalt fur€ Arbeitsschutz, Dortmund, Germany

MARTIN LISON, CABB GmbH, Sulzbach, Germany

ALEXANDER GNASS, CABB GmbH, Gersthofen, Germany

1. Introduction...... 473 3.6. Derivatives...... 481 2. Chloroacetic ...... 473 3.6.1. Dichloroacetyl ...... 481 2.1. Physical Properties ...... 473 3.6.2. ...... 481 2.2. Chemical Properties ...... 474 4. ...... 482 2.3. Production ...... 475 4.1. Physical Properties ...... 482 2.3.1. of ...... 476 4.2. Chemical Properties ...... 482 2.3.2. Chlorination of ...... 476 4.3. Production ...... 482 2.4. Quality Specifications...... 478 4.4. Quality Specifications...... 482 2.5. Uses ...... 478 4.5. Uses ...... 482 2.6. Derivatives...... 478 4.6. Derivatives...... 483 2.6.1. Chloroacetate ...... 478 4.6.1. Trichloroacetyl Chloride ...... 483 2.6.2. ...... 479 4.6.2. Trichloroacetic Acid Esters ...... 483 2.6.3. Esters ...... 479 4.6.3. Trichloroacetic Acid Salts ...... 484 2.6.4. Chloroacetamide ...... 480 5. Environmental Protection ...... 484 3. Dichloroacetic Acid ...... 480 6. Chemical Analysis ...... 485 3.1. Physical Properties ...... 480 7. Containment Materials, Storage, and 3.2. Chemical Properties ...... 480 Transportation...... 485 3.3. Production ...... 480 8. Economic Aspects ...... 486 3.4. Quality Specifications...... 481 9. Toxicology and Occupational ..... 486 3.5. Uses ...... 481 References ...... 488

1. Introduction acid [79-11-8] (ClCH2COOH, Mr 94.50, mono- chloroacetic acid, chloroethanoic acid) is the Chloroacetic acid and its sodium are the most most industrially significant [1]. It does not occur industrially and economically important of the in nature and was first discovered as a chlorina- three chlorination products of acetic acid. The tion product of acetic acid by N. LEBLANC in 1841. sections on physical and chemical properties, It was synthesized in 1857 by R. HOFFMANN, who production, quality specifications, uses, and de- chlorinated acetic acid by using sunlight to initi- rivatives are reported separately for each of these ate the reaction. Discovery of other reaction three acids, whereas those on environmental accelerators, such as phosphorus, , , protection, chemical analysis, containment ma- or , followed rapidly. Develop- terials, storage, transportation, and economic ment of commercial processes, based mainly on aspects are considered together. acetic acid chlorination and later on acid hydro- lysis of trichloroethylene, followed.

2. Chloroacetic Acid 2.1. Physical Properties Chlorinated acetic acids have become important intermediates in organic synthesis because of the Pure chloroacetic acid is a colorless, hygro- ease of substitution of the Cl . Chloroacetic scopic, crystalline solid, which occurs in

Ullmann’s Fine Chemicals 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany ISBN: 978-3-527-33477-3 / DOI: 10.1002/14356007.a06_537.pub3 474 Vol. 2

Table 1. Common physical data of chloroacetic acid

Parameter Form

abgd fp 62–63 C 55–56 C 50–51 C 43.8 C

Latent heat of fusion, DHf 19.38 kJ/mol 18.63 kJ/mol 15.87 kJ/mol – 65 Density d4 1:3703 (liquid) 20 d20 1:58 (solid) 20 nD 1:4297 Surface tension, s (100 C) 35.17 mN/m Viscosity, h 70 C 2.16 mPa s 100 C 1.32 mPa s 130 C 1.30 mPa s Degree of dissociation in water (potentiometric) (25 C) 1.52 103 Dielectric constant (100 C) 16.8 Electrical conductivity, lowest value measured (70 C) 3.1 mS/cm*

Specific heat capacity, cp Solid, 15–45 C 144.02 J mol1 K1 Liquid, 70 C 180.45 J mol1 K1 Liquid, 130 C 187.11 J mol1 K1

Heat of combustion, DHc 715.9 kJ/mol Heat of evaporation, DHv 50.09 kJ/mol Heat of formation, DHf (100 C): 490.1 kJ/mol Heat of sublimation, DHsubl (25 C): 88.1 kJ/mol Heat of solution in H2O, DHsolv (16 C) Solid 14.0 kJ/mol Liquid 1.12 kJ/mol Flash point (DIN 51 758) 126 C Ignition temperature (DIN 51 794) 460 C Lower explosion limit in air (101.3 kPa) 8 vol% * Rises steeply if traces of water present.

monoclinically prismatic structures existing in Chloroacetic acid has excellent the a-, b-, g-, and also possibly the d-form. The in water and good solubility in , a-form is the most stable and the most impor- , diethyl , and , but is only tant industrially. sparingly soluble in hydrocarbons and chlori- Published physical data vary widely [1]. Some nated hydrocarbons. Chloroacetic acid forms of the most common values appear in Tables 1 azeotropes with a number of organic com- and 2. pounds [2]. The freezing points of various binary mixtures of chloroacetic acids are shown in Figure 1. Table 2. Vapor pressure and solubility in water of the a-form of chloroacetic acid

Vapor pressure Solubility in water 2.2. Chemical Properties

Temperature, Pressure, Temperature, g/100 g g/100 g The high reactivity of the C kPa C solution H2O group and the ease of substitution of the a-Cl 189 101.3 0 71 245 are directly related. As a result, chloro- 160 40 10 76 317 acetic acid is a common synthetic organic 150 28 20 80.8 421 intermediate, either as the acid itself or as an 140 19 30 85.8 604 130 13 40 90.8 987 acid derivative (e.g., salt, , anhydride, acyl 100 4.3 50 95 1900 chloride, amide, hydrazide, etc.). Some impor- 90 2.6 60 99 – tant reactions that are used for industrial 80 1.1 applications are as follows. Vol. 2 Chloroacetic Acids 475

[79-14-1] (hydroxyacetic acid) and [110-99-6] (2,20-oxydiacetic acid). Heating the salts gives glycolide, 1,4-diox- ine-2,5-dione [502-97-6]. Reaction with sodi- um or potassium hydrogensulfide forms thio- [68-11-1] and thiodiglycolic acid [123-93-3]. Reaction with ammonia gives either aminoa- cetic acid [56-40-6] () as the main product or, depending on reaction conditions, nitrilotria- cetic acid [139-13-9]. If methyl chloroacetate reacts with ammonia at low temperature, chlor- oacetamide [79-07-2] is obtained. By reaction with tertiary in alkaline solution various commercially important betaines are formed (e.g., N-lauryl betaine [683-10-3]). Aromatic compounds, such as naphthalene, undergo electrophilic substitution with chloroa- cetic acid over suitable catalysts to form aryla- Figure 1. Freezing points of binary mixtures cetic acids. a) Acetic acid (AA), chloroacetic acid (CAA), dichloroacetic Reaction with potassium cyanide in a neutral acid (DCA), trichloroacetic acid (TCA); b) Crystalline phase solution gives the commercially important cya- CAA; c) Crystalline phase AA noacetic acid [372-09-8], which is used as an intermediate in the production of synthetic caf- Reaction with inorganic bases, oxides, and feine [58-08-2]. Reaction with potassium carbonates or with organic bases gives salts; forms [64-69-7]. some salts form adducts with chloroacetic acid. The corresponding phenoxyacetic acids, Sodium chloroacetate [3926-62-3] is an impor- some of which are of industrial importance, are tant commercial product. made by phenol etherification in the presence of Chloroacetic acid esters are obtained by reac- sodium hydroxide. Another industrially signifi- tion with or olefins; methyl chloroace- cant ether formation process gives carboxy- tate [96-34-4], ethyl chloroacetate [105-39-5], methyl derivatives with a relatively high degree and tert-butyl chloroacetate [107-59-5] are also of etherification by reacting polysaccharides, important industrially. such as , starch, guar, etc., in a strongly Chloroacetyl chloride [79-04-9] is produced alkaline sodium hydroxide medium. from the acid by reaction with POCl3, PCl3, PCl5, (SOCl2), (COCl2), etc. (see Section 2.6.2). 2.3. Production Chloroacetic acid reacts with chloroacetyl chloride to form bis(chloroacetic)anhydride A multitude of methods have been proposed and [541-88-8], which can also be obtained by dehy- patented for the production of chloroacetic acid [1, 3–15]. Historically both the hydrolysis of dration of chloroacetic acid with P2O5 or by reaction of chloroacetic acid with acetic anhy- 1,1,2-trichloroethylene [79-01-6] catalyzed with dride. Chloroacetyl chloride forms mixed anhy- (Eq. 1), and the catalyzed chlorina- drides with other carboxylic acids, e.g., acetic tion of acetic acid with (Eq. 2) were used chloroacetic anhydride [4015-58-1]. to produce chloroacetic acid on an industrial Nucleophilic substitution of the chlorine atom scale, however, only the latter (and older) process is an important reaction when the product is used is now used. as an intermediate in organic syntheses. For example, heating neutral or basic aqueous solu- tions hydrolyzes the chlorine atom. This is an industrial method of producing glycolic acid 476 Chloroacetic Acids Vol. 2

2.3.1. Hydrolysis of Trichloroethylene reduces the purification process for technical [13–15] grades [34–38].

Equal amounts of trichloroethylene and 75 % Purification. Thehighdegreeofpurity sulfuric acid are reacted at 130–140 Cina required for many products can only be ob- continuous process so that with complete tri- tained by separating the di- and trichloroacetic chloroethylene conversion, the resultant reac- acids. Fractional distillation is unsuitable be- tion mixture contains about 50 % chloroacetic cause the boiling points of the three chlorinated acid and 1–2 % water. This blend is vacuum acetic acids are so close. Azeotropic distillation distilled to give pure chloroacetic acid. During [39] and extractive distillation [40, 41] have this process the vapors are washed with water, been suggested for separating dichloroacetic which is returned to the sulfuric acid as a acid; it is doubtful, however, that these meth- diluent. The resultant chloride is ods are used. washed with the fresh trichloroethylene and An industrially important purification pro- thenpurifiedbyfreezingandabsorbingin cesses is crystallization without use of a solvent. water. Trichloroethylene (1500–1850 kg) and It is based on the higher of the H2SO4 (600 kg, 95 %) gives 1000 kg of fin- a-modification of chloroacetic acid. The di- and ished product and 700–750 kg of HCl gas as trichloroacetic acids are removed in the mother byproduct. liquor. The trichloroethylene method produces Crystallization is carried out either in sta- highly pure chloroacetic acid free of di- or tionary finger crystallizers [42] or in agitated trichloroacetic acid. The purification procedure stirrer crystallizers. With the latter, the mother consists of separation from trichloroethylene, liquor is separated from the crystal slurry after sulfuric acid, and water. Despite the purity of crystallization by using a centrifuge [43, 44]. the chloroacetic acid formed, this method has The product is washed with water or acetic acid fallen into disuse because of the high cost of and discharged. The chloroacetic acid is usually trichloroethylene and the large amount of HCl melted and converted into flakes. In stationary produced. machines, crystallization is carried out by using cold fingers. When all the chloroacetic acid has crystallized, the mother liquor is drained; the 2.3.2. Chlorination of Acetic Acid pure crystalline product is then melted and flaked. Synthesis. This method converts acetic acid Another purification method that has been into chloroacetic acid with high selectivity [1]. described is a thin-layer crystallization process This is achieved by using suitable catalysts with the raw material [45]. Use of a water content [13, 16–33]. When acetic anhydride is the catalyst, of 5–25 % without organic solvent is also possi- the reaction mechanism is as follows (Eq. 3) [22]: ble [46]. Solvents have also been used for crystalli- zation. Solvents, such as tetrachloride [44, 47], [48], or hydrocar- bons with three chlorine atoms (e.g., trichloro- ethylene), give crystals that are easy to filter [49]. Common to all of these crystallization meth- ods is obtaining a mother liquor consisting of ð3Þ acetic acid, chloroacetic acid, and di- and tri- chloroacetic acids. In the most favorable cases, this mixture is further chlorinated to form the Various inhibitors have also been proposed industrially useful trichloroacetic acid (see to suppress formation of dichloroacetic acid, Section 4.3). which results from chlorination of chloroacetic Meanwhile, a more important purification acid in the crude mixture. This eliminates or method is the catalytic hydrodechlorination of Vol. 2 Chloroacetic Acids 477 the undesired byproducts dichloro- and trichlor- with chlorine [62, 63]. Pd catalysts on optimized oacetic acid. Di- and trichloroacetic acids in the active charcoal carriers give lower amounts of chlorinated crude acid can be dechlorinated by over-reduction byproducts (, etc.) [64]. catalytic hydrogenation at elevated temperature For the hydrogenation step a loop reactor can be to form chloroacetic acid or acetic acid. Palladi- used [65]. um on a carrier, such as carbon or silica gel, is A reduction of dichloroacetic acid from 2000 normally employed [50]. to 210 ppm can be achieved by treatment of crude When the reaction is carried out in the vapor chloroacetic acid with nonnoble metal catalysts phase, dichloroacetic acid is dechlorinated pri- without hydrogen at temperatures between 100 marily to acetic acid [51]. However, when Pd is and 140 C [66]. used on a finely dispersed, inert carrier in the An industrial-scale chlorination process is liquid phase at 130–150 C, dichloroacetic acid is shown in Figure 2. The mixture of acetic acid, dechlorinated selectively to form chloroacetic acetic anhydride, and recycled is acid [52]. Modifications of this procedure, such chlorinated at 90–140 C in reactor (a) or in as spraying the crude acid with hydrogen gas several cascade reactors. Only traces of chlorine under vacuum [53] or trickling the acid over the are still present in the HCl gas formed. Chlor- catalyst in the fixed bed [54, 55] have also been oacetic acid, acetic acid, and acetic anhydride are described. condensed by using water-cooled condensers (b) Selectivity is increased if HCl is mixed with and then returned to the reactor. Acetyl chloride the crude acid before it and the circulating hy- entrained in the HCl gas is condensed (c) in a drogen contact the catalyst in the fixed bed [56]. subsequent low-temperature process and re- Acid and anhydrides are saponified cycled. The HCl gas is further purified and before dechlorination [57]. A particularly active usually converted into concentrated aqueous hy- and selective catalyst is Pd on silica gel (particle drochloric acid. size 40–200 mm) [58]. Especially good results The crude acetic acids can be vacuum dis- are obtained by employing a cocatalytically ef- tilled (d) before the hydrogenation step but this fective additive, such as sodium [59]. The purification step is not obligatory. Di- and catalyst can be made more effective by enrich- trichloroacetic acids in the crude distilled ma- ment of the noble metal on its surface [60, 61]. terial are dechlorinated (f) to chloroacetic acid Spent catalyst can be reactivated by treatment at 120–150 C, using a palladium catalyst and a

Figure 2. Chloroacetic acid obtained by the chlorination–hydrogenation process a) Chlorinating reactor; b) Condenser for acetic acid, acetic anhydride, chloroacetic acid; c) Condenser for acetyl chloride; d) Evaporator; e) Condenser for chloroacetic acid; f) Hydrogenation reactor; g) Hydrogen compressor; h) Condenser; i) Distillation column; j) Condenser for acetic acid 478 Chloroacetic Acids Vol. 2

large excess of hydrogen. Acetic acid is taken A third important outlet for chloroacetic acid overhead from the vacuum fractionation is the manufacture of (mercap- column (i); the bottom product is pure chlor- toacetic acid [68-11-1]), obtained from reaction oacetic acid. Optionally, the chloroacetic acid of chloroacetic acid with sodium or potassium can be further purified by distillation to remove hydrogen sulfide or other sulfur compounds (! high-boiling impurities like condensation Mercaptoacetic Acid). It is used as its salt, ester, products of aldehydes formed in the hydro- or another derivative. The largest amount is genation step. employed to produce stabilizers for poly(vinyl A total of 660–780 kg of acetic acid and chloride). Moreover, thioglycolic acid and its 780–1020 kg of chlorine are required per esters are used in hair cosmetics (! Hair 1000 kg of pure acid, depending on the method Preparations). used (in crystallization processes, the mother Another important industrial application is the liquors are regarded as lost). The process also production of long-chain betaines like N-lauryl gives 400–420 kg of HCl. betaine [683-10-3] that are used as for cleaners or personal care products. A minor use of chloroacetic acid is in the 2.4. Quality Specifications production of glycolic acid by saponification with an alkali hydroxide. Glycolic acid is used Chloroacetic acid is usually marketed to the as an auxiliary in textile printing, leather treating, following specifications: furs finishing, as a component for cleaners and as a peeling agent for skin surface treatment . Chloroacetic acid: min. 99.0 wt %, (‘‘alpha-hydroxy acids’’ [67]); the butyl ester is . Dichloroacetic acid: max. 0.2 wt %, employed as a paint additive (Polysolvan O), . Acetic acid: max. 0.2 wt %, and glycolic acid esters acylated with o-phthalic . Water: max. 0.2 wt %, acid half-esters are used as plasticizers . Iron: max. 5 mg/kg, (! Plasticizers). . Lead: max. 1 mg/kg. Apart from the major fields of application mentioned above, chloroacetic acid and its deri- Specially purified grades of chloroacetic acid vatives are used in a multitude of other organic are marketed with max. 0.05 % or even max. synthetic reactions. For example, and 0.03 % dichloroacetic acid. Technical grades , which are important hypnotics, can contain up to 2 % dichloroacetic acid. be made from or its esters. Chloroacetic acid condenses with aromatic hy- drocarbons to form arylacetic acids. Reaction 2.5. Uses with naphthalene gives 1-naphthylacetic acid as the main product and 2-naphthylacetic acid as the Most of the chloroacetic acid produced is used to byproduct. Both substances promote plant manufacture several hundred thousand tons an- growth. Chloroacetic acid also is important in nually of [9004-32-4], the syntheses of and B6 CMC (! Cellulose ). Starch can be re- (! ). acted with chloroacetic acid to give carboxy- methyl starch, which is as widely used as CMC (! Starch). Other polysaccharides modified 2.6. Derivatives with chloroacetic acid are less important. Another major application is the production of 2.6.1. Sodium Chloroacetate herbicides based on arylhydroxyacetic acids (! Chlorophenoxyalkanoic Acids). These herbi- Physical, Chemical Properties. The sodium cides are some of the most widely used. Chlor- salt ClCH2COONa [3926-62-3], Mr 116.5, is of oacetic acid and methyl chloroacetate are also particular importance. It is colorless and slightly employed for making the insecticide hygroscopic, and has good storage stability. It and the herbicides benazoline and methyl dissolves readily in water (44 wt % at 20 C), b-naphthyloxyacetate. giving a neutral solution. It has limited solubility Vol. 2 Chloroacetic Acids 479 in other polar solvents and is insoluble in nonpo- chloride also has been obtained in 97.1 % yield lar solvents. It hydrolyzes in water, depending on and with a purity of 99.8 % by reacting chlor- temperature and time, forming glycolic acid and oacetic acid with phosgene in the presence of sodium chloride. palladium chloride at 110 C [74]. Chlorination of , which must be present in an excess of Production. This salt is manufactured by at least 50 %, at 100–200 C gives chloroacetyl reacting sodium carbonate with chloroacetic chloride with less than 7 % dichloroacetyl chlo- acid in batches or in a continuous process ride [75]. Chloroacetyl chloride can also be made [68, 69]. from 1,2-dichloroethylene and by using In exceptional cases, localized superheating catalysts, such as bromine. (about 150 C) may occur during the reaction. If it does, slow thermal decomposition can take Uses. Chloroacetyl chloride is used for place, producing sodium chloride and polygly- many syntheses, e.g., to make , chlor- colide as the main products with pronounced oacetic acid esters, and the anhydride. evolution of gas. Another method of manufacturing sodium chloroacetate is spraying molten chloroacetic 2.6.3. Chloroacetic Acid Esters acid together with 50 % caustic soda solution into a spray drier [70]. Physical Properties. The methyl ester The production of salts of chloroacetic acids [96-34-4], ClCH2COOCH3, Mr 108.53, is of in fluidized beds has been described [71]. particular importance. It is a colorless liquid with a pungent odor, bp 128.5–131.5 C (101.3 kPa), Uses. The uses for sodium chloroacetate are fp 32.7 C, d20 1.236, soluble in and virtually the same as those for its free acid. The ether, and only sparingly soluble in water. amount of salt required is less and depends on Also important is the ethyl ester [105-39-5], whether the free chloroacetic acid is used as an ClCH2COOCH2CH3, Mr 122.55, bp 142–144 C 80 % aqueous solution or as a melt. (101.3 kPa), fp 26.0 C, d20 1.159, nearly in- soluble in water, and readily soluble in alcohol and ether. 2.6.2. Chloroacetyl Chloride Of minor industrial importance is the tert- butyl ester [107-59-5], ClCH2COOC(CH3)3, Mr Physical Properties. Chloroacetyl chloride 150.60, bp 157.5 C (101.3 kPa), d20 1.4259. [79-04-9], ClCH2COCl, Mr 112.95, is a colorless, highly corrosive liquid that has a pungent odor Production. The methyl and ethyl ester can and fumes when exposed to moist air; bp 105 C be manufactured from chloroacetic acid and 20 20 (101.3 kPa), d4 1:42; nD 1:454. either methanol or ethanol. In another method, trichloroethylene is converted into ethyl 1,2- Production. Chloroacetyl chloride is usually dichlorovinyl ether, which can be readily hydro- manufactured from chloroacetic acid by reaction lyzed to form chloroacetic acid ethyl ester. with phosphorus trichloride, thionyl chloride, The tert-butyl ester can be manufactured from sulfuryl chloride, or phosgene. It is also obtained chloroacetic acid and isobutylene under pressure by chlorination of acetyl chloride in the presence (3–12 bar) and elevated temperature (80–110 C) of stronger aliphatic acids, preferably chloroace- [76]. tic acids, or from sodium chloroacetate and the usual chlorinating agents. Uses. The reactivity of the ester, which is One patent describes the manufacture of greater than that of the free acid, makes it chloroacetyl chloride by chlorination of a mix- suitable for many syntheses, e.g., , ture of 5–50 wt % acetyl chloride in acetic anhy- chloroacetamide, thioglycolic acid ester [77] dride at 70–100 C [72]. Another claims reaction for pharmaceuticals (vitamin A), and crop pro- of chloroacetic acid and trichloroethylene in the tection agents (dimethoate). Condensation presence of iron(III) chloride and hydrochloric with aldehydes and gives glycide es- acid at 150 C and 2 MPa [72]. Chloroacetyl ters [78]. Other uses are the synthesis of 480 Chloroacetic Acids Vol. 2

heterocyclic compounds, e.g., 2-phenylimino- in the usual organic solvents, such as alcohols, 4-oxooxazolidine from the ester and phenyl ketones, hydrocarbons, and chlorinated urea [79], and the well-known condensation of hydrocarbons. chloroacetic acid and its esters with thioureas to form pseudothiohydantoins. 3.2. Chemical Properties

2.6.4. Chloroacetamide The two chlorine atoms of dichloroacetic acid are susceptible to displacement. For instance, with Physical Properties. Chloroacetamide [79- aromatic compounds, diaryl acetic acids are 07-2], ClCH2CONH2, Mr 93.52, colorless crys- formed, and with phenol, diphenoxy acetic acids talline needles, bp 224 C (101.3 kPa), fp 121 C, are the products. However, dichloroacetic acid is is soluble in water and alcohol, and sparingly less prone to hydrolysis than chloroacetic acid. In soluble in all nonpolar solvents. the manufacture of CMCs and starches, the di- chloroacetic acid impurity in the chloroacetic Production. Chloroacetamide is obtained acid gives rise to cross-linking, which is either on an industrial scale by reaction of methyl- desirable or undesirable, depending on the use of chloroacetate with ammonia at low temperature the end product. [80]. Manufacture from chloroacetic acid and at 150–200 C also has been de- scribed [81]. 3.3. Production

Uses. Chloroacetamide is a versatile inter- The most cost-effective production method is mediate. In addition, it has biocidal properties the hydrolysis of (see and, therefore, is used as an industrial preserva- Section 3.6.1). Moreover, 98 % dichloroacetic tive. Because of its good solubility in water, acid can be obtained in 90 % yield by hydroly- chloroacetamide is a particularly suitable biocide sis of with 88–99 % sulfuric for protection of the aqueous phase, e.g., in acid [88] or by oxidation of 1,1-dichloroace- drilling fluids [82], in water-containing paints tone with nitric acid and air [89]. Extremely [83], and as a wood preservative [84]. Its insec- pure dichloroacetic acid can be produced by ticidal action on aphids [85] and its use as a hydrolysis of the methyl ester [90], which is hardener for urea and melamine resins [86] have readily available by esterification of crude di- also been described. chloroacetic acid. Furthermore, dichloroacetic Various derivatives have the same biocidal acid and ethyl dichloroacetate can be obtained effect as chloroacetamide. For instance, N-octa- by catalytic dechlorination of trichloroacetic decylchloroacetamide is used as an antimicrobial acid or ethyl trichloroacetate with hydrogen plasticizer [87]. over a palladium catalyst [91]. Separation of pure dichloroacetic acid from the other chloroacetic acids cannot be carried out 3. Dichloroacetic Acid by physical methods, especially fractional distil- lation, because the differences in boiling points, 3.1. Physical Properties particularly between di- and trichloroacetic acid, are too small. The ester mixtures, on the other Dichloroacetic acid [79-43-6], 2,2-dichloroetha- hand, can be satisfactorily fractionated in effi- noic acid, Cl2CHCOOH, Mr 128.95, bp 192 C cient distillation columns. In addition, mixtures (101.3 kPa), 102 C (2.7 kPa), fp 13.5 C, of the salts of the three chloroacetic acids can be 20 20 d4 1:564; nD 1:466, vapor pressure 0.19 kPa (at washed with water, alcohol, or water–alcohol 20 C), dissociation constant 5102 mol/L (at solutions. The dichloroacetate can be dissolved 18 C), is a colorless, highly corrosive liquid that preferentially and acidified to give pure dichlor- gives off acidic vapors, which irritate the mucous oacetic acid. membranes. It is miscible with water in any Dichloroacetic acid can be produced in the proportion. Dichloroacetic acid is readily soluble laboratory by reacting and potas- Vol. 2 Chloroacetic Acids 481

Table 3. Technical data of dichloroacetic acid marketed by CABB Chemical Properties. Dichloroacetyl chlo- ride undergoes not only reactions typical of acid Content Technical grade Pharma grade chlorides, but also displacement reactions of the Dichloroacetic acid min. 98.0% min. 99.0% chlorine atoms in the 2-position. The chemistry Chloroacetic acid max. 0.2% max. 0.2% of dichloroacetyl chloride and its derivatives is Trichloroacetic acid max. 0.9% max. 0.9% Water max. 0.3% max. 0.05% analogous in certain respects to that of glyoxylic fp min. 12C min. 12C acid. Thus, dichloroacetyl chloride reacts with Chloral hydrate 100 ppm ammonia and amines to form amino acids, with Platinum-cobalt scale max. 50 alcohols to form ester acetals and acetals, with (Hazen, APHA number) to form diarylacetic acids, and with phenols to form diphenoxyacetic acids. sium or (Eq. 4). Production. Dichloroacetyl chloride is pro- duced by the oxidation of trichloroethylene. Ox- Cl3CCHOþH2OþKCN!HCNþKClþCl2CHCOOH ð4Þ idation with oxygen to form a mixture of dichlor- oacetyl chloride and chloral has been known since the early 1900s [94]. Patents published in 3.4. Quality Specifications the 1960s describe methods to manufacture di- chloroacetyl chloride of > 98 % purity, e.g., at Dichloroacetic acid is a colorless liquid that is 65–200 C and 0.2–2 MPa in the presence of marketed, for instance, by CABB. Table 3 gives free-radical initiators [95], using catalytic quan- the technical data. tities of azo compounds and amines [96], and initiating oxidation with UV light and only add- ing organic nitrogen bases in quantities of 0.005– 3.5. Uses 0.05 % once oxidation has begun [97]. Corre- spondingly, chloroacetyl chloride and trichlor- Dichloroacetic acid is used as a test reagent for oacetyl chloride can be produced from 1,2-di- analytical measurements during fiber manufac- and , but these methods are of ture [poly(ethylene terephthalate)] and as a me- little industrial significance because the products dicinal disinfectant (substitute for formalin). can be obtained more easily by other processes. Dichloroacetic acid is also used as a deblock- Furthermore, dichloroacetyl chloride is man- ing agent in the solid-phase synthesis of oligo- ufactured from pentachloroethane and fuming nucleotides. For this application a dichloroacetic sulfuric acid or from and carbon acid is required that is substantially free of chlo- dioxide in the presence of aluminum chloride at ral (trichloroacetaldehyde) [92, 93]. high pressure [98]. It has also been produced Dichloroacetic acid, particularly in the form from ketene and chlorine in the presence of sulfur of its esters, is an important intermediate in dioxide [99]. organic synthesis. It is a reactive starting material for the production of glyoxylic acid, dialkoxy and Uses. Dichloroacetyl chloride is used to diaroxy acids, and sulfonamides. manufacture dichloroacetic acid (see Section 3.3). In addition, it can be employed for the production of esters and anhydrides. It is used 3.6. Derivatives as the starting material to manufacture pharma- ceuticals, such as sulfonamides and 3.6.1. Dichloroacetyl Chloride (), and to produce crop protec- tion agents (e.g., benoxacor). Physical Properties. Dichloroacetyl chlo- ride [79-36-7], Cl2CHCOCl, Mr 147.40, is a colorless liquid, which has an unpleasant odor 3.6.2. Dichloroacetic Acid Esters and fumes when exposed to moist air; bp 106– 16 16 108 C (101.3 kPa), d4 1:5315; nD 1:4638, Physical Properties. Methyl dichloroace- vapor pressure 3.06 kPa (at 20 C). tate [116-54-1], Cl2CHCOOCH3, Mr 142.98, 482 Chloroacetic Acids Vol. 2

20 20 bp 143.3 C (101.3 kPa), d4 1:3808; nD in the presence of organic or inorganic bases. 1:4428. When water is absent, aniline, resorcinol, and Ethyl dichloroacetate [535-15-9], can catalyze the decomposi- Cl2CHCOOCH2CH3, Mr 157.00, bp 158.5 C tion. Purely thermal decomposition takes place 20 20 (101.3 kPa), d4 1:2821; nD 1:4386. only when the has been exceeded, resulting in the formation of chlorinated hydro- Chemical Properties. These esters are high- , and dioxide, and ly reactive and, for example, condense with phosgene. Trichloroacetic acid salts with inor- aldehydes and ketones in the presence of dilute ganic and many organic bases are known. They metal amalgams to form a-chloro-b-oxyacid decompose when heated in the presence of esters, which can be converted into the corre- water to form chloroform. sponding aldehydes via glycide esters [100]. Dichloroacetic acid esters are readily saponified by boiling water. 4.3. Production

Production. These esters are obtained by the Trichloroacetic acid is produced on an industrial usual esterification methods. The methyl and scale by chlorination of acetic acid, chloroacetic ethyl esters are best produced by alcoholysis of acid, or chloroacetic acid mother liquors at 140– dichloroacetyl chloride. 160 C [101]. If necessary, calcium hypochlorite is added as a chlorination accelerator [102]. Uses. These esters are employed as inter- There are conflicting views concerning adding mediates in the manufacture of chloramphenicol heavy metal salts as chlorination catalysts. Ex- (! Antibiotics), dichloroacetamide, and crop amples of catalysts that have been used are iron protection agents, and are employed as paint and copper compounds, which are precipitated resin solvents. The glyceryl and ethylene glycol with sulfuric acid or phosphoric acid if decom- esters also serve as plasticizers for cellulose position of the reaction mixture occurs [103]; 2 % derivatives. phosphoric acid [104]; and catalysts and UV light [105]. Trichloroacetic acid has also been pro- duced without catalysts [106, 107]. 4. Trichloroacetic Acid The crude product, containing about 95 % trichloroacetic acid, is best isolated by crystal- 4.1. Physical Properties lizing the melt, removing the mother liquor with most of its impurities, and increasing the purity Pure trichloroacetic acid [76-03-9] forms hygro- by centrifugation or recrystallization. scopic, rhombohedral crystals that are extremely If sulfuric acid is used as catalyst at reaction soluble in water and soluble in many organic temperatures of up to 180 C no further purifica- solvents; Cl3CCOOH, Mr 163.40, bp 197.6 C tion is needed. (101.3 kPa), bp ca. 107 C (2.8 kPa), fp 59.2 C, 60 65 d4 1:630; nD 1:459. 4.4. Quality Specifications

4.2. Chemical Properties Trichloroacetic acid is marketed in various de- grees of purity. The specifications in Table 4 are The complete substitution of the hydrogen typical. atoms on the methyl radical by chlorine makes trichloroacetic acid a strong acid (K ¼ 2101 mol/L); it also makes the chlorine atoms less 4.5. Uses prone to substitution than those of chloroacetic acid and dichloroacetic acid. Trichloroacetic Until the 1990s the main application for tri- acid decomposes to chloroform and carbon chloroacetic acid was the production of its dioxide when its aqueous solution is exposed sodium salt, which can be used as a selective to heat. The decomposition is particularly fast herbicide and in formulations with 2,4-D and Vol. 2 Chloroacetic Acids 483

Table 4. Typical quality specifications of trichloroacetic acid free acid and hydrolyzed with ammonium hy- droxide or concentrated sodium carbonate solu- Property Grade tion to form the salts. Industriala Ph. Eur.b ACSc

Freezing point, min., C56– – Production. The acetyl chloride is pre- Trichloroacetic acid, % min. 98.0 98.0 99.0 pared from trichloroacetic acid and various Dichloroacetic acid, % max. 1.2 – – inorganic acid chlorides (e.g., SOCl ,PCl)or Sulfuric acid, % max. 0.3 – 0.02 2 3 Sulfated ash, % max. – 0.1 with P2O5 and HCl. More useful methods are Water, % max. 0.5 – – the oxidation of tetrachloroethylene with Heavy metals in the form of: fuming sulfuric acid, oxygen, or fuming nitric Lead, ppm max. – 20 acid and sulfuric acid at 18–20 C [113], or Iron, ppm max. 10 – 10 Phosphate, ppm max. – – 5 from the reaction of pentachloroethane and dry Chloride, ppm max. – 100 20 oxygen under UV light [114]. Trichloroacetyl Nitrate, ppm max. – – 20 chloride has been obtained in 37 % yield from Insoluble matter, % max. 0.01 carbon tetrachloride and carbon monoxide in Residue after ignition, % max. 0.03 the presence of aluminum chloride at 200 C a Specifications of CABB. and high pressure [115]. Trichloroacetyl b European Pharmacopeia [108]. c Specifications of ACS [109]. chloride can be produced by chlorination of dichloroacetyl chloride in the presence of pyri- dine [116]. 2,4,5-T preparations as a total herbicide. This The most common production method is the application is of minor importance now due to the gas-phase, photochemical oxidation of tetra- ecotoxicological properties of sodium trichlor- chloroethylene with oxygen. The reaction is oacetate (see Section 4.6.3). initiated with UV light, with radioactive irradia- Trichloroacetic acid also is employed as an tion, or it is sensitized with chlorine or iodine etching or pickling agent in the surface treatment [117]. of metals, as a swelling agent and solvent in the plastics industry, as an albumin precipitating agent in , as an auxiliary in textile Uses. Trichloroacetyl chloride can be used finishing, and as an additive to improve high- for the manufacture of the esters and the anhy- pressure properties in mineral lubricating oils. drides of trichloroacetic acid. It is an important Because it is strongly corrosive, trichloroacetic intermediate in the production of pesticides acid is used to remove and hard skin and to (Chlorpyrifos). It can also be used as a starting treat various skin afflictions [110, 111]. Trichlor- material in the production of trifluoroacetic acid oacetic acid and particularly its esters are impor- [118]. tant starting materials in organic syntheses. The acid undergoes numerous color reactions that can serve to identify a wide range of organic com- 4.6.2. Trichloroacetic Acid Esters pounds [112]. Only the methyl and ethyl esters are of industrial interest. They can be used as solvents, if neces- 4.6. Derivatives sary, and for the production of the amide and polyalcohol esters, which have been suggested 4.6.1. Trichloroacetyl Chloride for use as plasticizers. Ethyl trichloroacetate is widely used as a co-catalyst in Ziegler-type Physical Properties. Trichloroacetyl chlo- polymerizations [119]. ride [76-02-8], Cl3CCOCl, Mr 197.9, bp 118 C Methyl trichloroacetate [598-99-2], 20 20 (101.3 kPa), d4 1:620; nD 1:4695, is similar to Cl3CCOOCH3, Mr 177.43, bp 153 C 20 20 dichloroacetyl chloride. (101.3 kPa), d4 1:4864; nD 1:4572. Ethyl trichloroacetate [515-84-4], Chemical Properties. The acid chloride can Cl3CCOOCH2CH3, Mr 191.45, bp 167.5 C 20 20 be hydrolyzed at 75–85 C with water to form the (101.3 kPa), d4 1:3823; nD 1:4505. 484 Chloroacetic Acids Vol. 2

4.6.3. Trichloroacetic Acid Salts Production. is pro- duced industrially by neutralizing trichloroacetic The sodium salt is the only one of industrial acid with sodium hydroxide solution or sodium importance. carbonate [123, 124].

Physical Properties. Sodium trichloroace- Uses. Sodium trichloroacetate, together tate [650-51-1] (TCA, sodium TCA, STCA, with reducing agents and traces of heavy-metal NaTA, Cl3CCOONa, Mr 185.40), is a colorless salts, is recommended as a polymerization salt that decomposes at temperatures below the catalyst for vinyl compounds [125]. It is useful melting point. The salt is very soluble in water as a dyeing auxiliary because of the formation and methanol and soluble in polar solvents. The of NaHCO3 during hydrolysis [126]. It also solubility in water at 5 Cis50wt%,at20C improves absorption of disperse dye systems 60 wt %, and at 40 C70wt%. on polyester (! Fibers, 5. Polyester Fibers) and cellulosic fibers [127]. Moreover, in diazo Chemical Properties. The salt is stable in papers developed by heat, sodium trichloroa- the dry state and at normal storage temperature. cetate is used to liberate base at 100–200 C Hydrolytic cleavage takes place in aqueous so- [128]. lution (Eq. 5). Until the 1990s the most important applica- tion was the use as a selective herbicide to control Cl3CCOONaþH2O!Cl3CHþNaHCO3 ð5Þ monocotyledonous annual or perennial weeds At the boiling point, this reaction takes place [129–131]. As a soil-applied herbicide its half- quantitatively within an hour and is used for life is 1–2 months [132]. For use as a crop quantitative analysis of sodium trichloroacetate protection agent, a minimum content of 95 % [120]. At 20–25 C the aqueous solution is rela- sodium trichloroacetate is required. Because the tively stable; with a 50 % solution only ca. 1 % is salt in powder form causes severe irritation, the hydrolyzed in 4–6 weeks. product is usually marketed as granules [133]. In aprotic solvents, such as 1,2-dimethox- Because of its ecotoxicological properties the use yethane, the reactive intermediate dichlorocar- of sodium trichloroacetate as a herbicide is mean- bene is formed as the primary product at elevated while prohibited in most regions (USA, Canada, temperature (ca. 80 C) (Eq. 6) [121]. European Community, South America except Argentina) but it is still used in less regulated Cl3CCOONa!NaClþCO2þ : CCl2 ð6Þ regions like Asia. When phase-transfer is used, the can add, for example, across 5. Environmental Protection olefinic double bonds to give dichlorocyclopro- pane derivatives [121]. If dichlorocarbene is The waste formed during chlorination of formed in the absence of other acceptors, it reacts acetic acid depend on the degree of chlorination. with additional sodium trichloroacetate (Eq. 7). When purification is done by fractional crystal- lization, less than 1 % of unreacted acetic acid is Cl3CCOONaþ : CCl2!Cl3CCOClþCO2þNaCl ð7Þ necessary in the crude acid. In this case chlorine Consequently, the main products formed dur- occurs in these waste gases; recovery of the ing the thermal decomposition of sodium tri- chlorine has been described [134]. chloroacetate (combination of Eqs. 6 and 7) were Formation of chlorinated hydrocarbon impu- sodium chloride, trichloroacetyl chloride, carbon rities also depends on the production method monoxide, and carbon dioxide; also observed used. They form as a result of decarboxylation were chloroform, carbon tetrachloride, and and occur particularly in the manufacture of traces of phosgene [122]. trichloroacetic acid. Thermal decomposition is exothermic (42 kJ/ In modern chloroacetic and trichloroacetic mol) and starts between 125 and 170 C. This acid production plants the waste gases from decomposition reaction is quenched by adding chlorination steps containing hydrogen chlo- water; hydrolysis then takes place. ride, excess chlorine, and organic impurities Vol. 2 Chloroacetic Acids 485 are incinerated to produce pure hydrochloric Quantitative analysis of chloroacetic acid acid. should include total acidity and a separate deter- In the manufacture of dichloroacetic acid by mination of dichloroacetic acid, sulfuric acid, catalytic oxidation of trichloroethylene, residues , water, and heavy metals, as of the starting materials are always present in the well as total chlorine content by approved meth- waste gases. Such waste gases are purified by ods. From these determinations acetic acid and adsorption onto activated charcoal or are chloroacetic acid content can be calculated. incinerated. Dichloroacetic acid can be determined with a Whereas chloroacetic acid and dichloroacetic high degree of accuracy by saponification with acid are readily biodegradable by activated strong base and subsequent manganometric titra- sludge floc, only slow biodegradation is observed tion. Dichloroacetic acid values are exaggerated in the case of trichloroacetic acid even with in the presence of trichloroacetic acid. If trichlor- activated sludge from industrial wastewater oacetic acid is present, preliminary saponifica- treatment plants that is adapted to chlorinated tion with dilute base is advisable. compounds. Chlorinated acetic acids can cause Acetic acid and dichloroacetic acid can be serious interference particularly in community directly separated and quantitatively determined wastewater treatment plants that have not been by gas chromatography. In addition to these two bioprepared, Preventing effluent contaminated acids, trichloroacetic acid can also be detected in with products of acetic acid chlorination from the form of its methyl ester by gas chromatogra- draining into public sewer systems is therefore phy. Dichloroacetic acid and acetic acid in the essential. presence of chloroacetic acid can also be deter- Among the aquatic organisms, algae are the mined accurately by HPLC [136]. This method is most sensitive species, the half maximal effec- not recommended for chloroacetic acid itself tive concentration (EC50) value of chloroacetic because to determine total chlorine con- acid is < 1 mg/L [135] towards Desmodesmus tent is more accurate. subspicatus. Trichloroacetic acid is determined by hydro- Spills of chlorinated acetic acids and their lysis in acid solution to chloroform and quantita- derivatives, resulting, for instance, from transport tive determination of the hydrogen needed accidents, should be contained with inert materi- for saponification. Formation of a deep-red com- als (sand or earth) and collected for safe disposal, plex from and chloroform can be used or neutralized with agents, such as Na2CO3 or for a colorimetric method [137]. Nitron [1,4- NaHCO3. Any contaminated soil must be re- diphenyl-3-(phenylamino)-1H-1,2,4-triazolium moved (the chlorinated acetic acids are strong hydroxide] produces a salt with trichloroacetic pollutants to groundwater). Waste material acid, which is suitable for detecting the acid should be taken to an approved disposal facility [138]. (incinerator or wastewater treatment plant). Dichloroacetic acid can be determined by Chloroacetic acid is flammable at higher tem- polarography in mixtures with trichloroacetic peratures and forms explosive mixtures with air acid [139]. Large amounts of chloroacetic acid (lower explosion limit 8 vol %). The two other interfere with the determination. acids are nonflammable. If the acids are involved Determination of heavy metals in all chlori- in a fire, the decomposition gases of trichloroa- nated acetic acids and derivatives is carried out cetic acid and dichloroacetic acid may contain by familiar methods, such as atomic absorption phosgene. or colorimetry. For lead, inverse voltammetry is also used. 6. Chemical Analysis 7. Containment Materials, Storage, Rapid analysis of the purity of mono-, di-, and and Transportation trichloroacetic acid is adequately provided by determining the melting and freezing points, Because of the corrosiveness of these chemicals, particularly when the melting depression is most metals are unsuitable for use as container caused by known contamination. materials. Thus, chlorination is carried out in 486 Chloroacetic Acids Vol. 2

ceramic-lined, lead-coated steel containers or 8. Economic Aspects in glass-lined vessels. Pipelines are made of glass-lined steel or steel lined with polytetra- The worldwide consumption of monochloroace- fluoroethylene (PTFE) or perfluoroalkoxy tic acid in 2006 was estimated at 420 000 t/a, (PFA) polymers (e.g., tetrafluoroethylene). Sil- divided as follows: Europe 36.6 %, China ver that has been rendered inert by a silver 43.2 %, India 7.6 %, Japan 6.2 %, and chloride layer can be used for parts of the America ca. 6.4 % equipment (e.g., valves, heat exchangers, dis- Recognized manufacturers are AKZO Nobel, tillation column linings, stirrers). Tantalum and CABB, and Dow. titanium (with certain temperature limits) are Accurate figures are not available on the other suitable metallic materials. Carbon (Dia- amounts of chloroacetic acid and its derivatives bon) and glass are effective materials for heat used for different applications. However, by far exchangers. In addition to PTFE and PFA/TFA, the largest amount goes into the production of fluorinated ethylene–propylene copolymers CMC, starch, and polysaccharides derivatives. (FEP), poly(vinyl chloride) (PVC), polyethylene, This is followed by herbicides based on phenox- and polypropylene can be used at relatively low yacetic acids (2,4-D, MCPA, 2,4,5-T), surfac- temperature and for aqueous solutions. tants, and thioglycolic acid (used in stabilizers for The aqueous solution can be handled in spe- PVC and in hair preparations). All other applica- cial stainless steel or rubber-lined steel contain- tions account for about 17 % of annual ers at temperatures below 40 C. Iron with a production. baked phenolic resin coating can be used below Dichloroacetic acid is of little economic im- 100 C. portance. More significant are its acid chloride During storage and transportation, high cor- and methyl ester, which are used as intermediates rosivity and, with chloroacetic acid, toxicity in the manufacture of agrochemicals (benoxacor) must also be considered. Chlorinated acetic and chloramphenicol. acids and their derivatives are classified as In the case of trichloroacetic acid, the sodium dangerous substances. They are subject to near- salt was very important until the 1990s. About ly all national and international handling reg- 21 000–23 000 t/a were used worldwide as a ulations. Containers must be labeled in the selective herbicide. Meanwhile, only some stipulated manner. In the case of chloroacetic 100 t/a are consumed in South America whereas acid, the most important forms that are shipped the market in India, China and other Asian are the melt (in glass-lined railroad cars or countries is not known. titanium-lined tank trucks) and the 80 % aque- ous solution (in stainless steel or rubber-lined tank trucks and containers). 9. Toxicology and Occupational Crystallized, flaked chloroacetic acid and tri- Health chloroacetic acid are obtained by utilizing chilled rolling flakers and, more recently, with chilled Chloroacetic Acid and Chloroacetate. conveyor-type flakers; the coarser flakes manu- Chloroacetic acid is a corrosive solid material. factured in this manner tend to agglomerate less The lowest published median lethal dose and, therefore, are preferred. Flakes are packed in (LD50) is 76 mg/kg for oral administration to multilayer paper sacks or in polyethylene bags rats [140]. Single oral administration of lethal contained in fiberboard or iron drums. Small doses resulted in apathy and loss of body mass. quantities are supplied in polyethylene contain- Death occurred several days after administra- ers or in glass bottles. Dichloroacetic acid and tion [141]. most of its liquid derivatives usually are shipped Acute inhalational exposure of rats led to in iron drums with polyethylene inner containers. eye and pulmonary irritation. The irritation 3 If stored in a cool, dry place, the chlorinated threshold is 23.7 mg/m .TheLC50 is acetic acids and their derivatives are stable 180 mg/m3 [142]. almost indefinitely, although the crystallized Prolonged inhalation of chloroacetic acid products have a marked tendency to resulted in reduced body mass, reduced oxygen agglomerate. consumption, hemoglobinemia, and inflamma- Vol. 2 Chloroacetic Acids 487 tion of the respiratory tract. A threshold Dichloroacetate demonstrated low-grade mu- limit value for chloroacetic acid of 1 mg/m3 tagenicity in the Ames Salmonella/mammalian is recommended if these experimental animal microsome mutagenicity test [148]. findings are taken as a basis [142]. Until now, the American Conference of Governmental Trichloroacetic Acid and Trichloroace- Industrial Hygienists (ACGIH) has not estab- tate. Trichloroacetic acid is a strong lished a threshold limit value (TLV) but some precipitant and is corrosive to the skin and eye. countries in Europe, e.g., Germany, the TLV The solid material is not readily absorbed (short-term and long-term) ¼ 1 ppm (4 mg/m3) through the skin [148]. The lowest reported oral [143]. LD50 in rats for trichloroacetic acid was Repeated intake of 0.1 % chloroacetate in 3320 mg/kg and 5060 mg/kg for trichloroace- the diet led to depressed growth curves and an tate. The lowest lethal dose of trichloroacetate for increased level of liver glycogen [144]. A female dogs was 1590 mg/kg with toxic effects, major metabolic pathway for chloroacetic acid such as salivation, emesis, sedation, ataxia, and is reaction with glutathion, finally yielding coma [149, 150]. A 4-h exposure to 4800 mg/kg thiodiacetic acid [145]. One report has shown trichloroacetate in ambient air did not result in that chloroacetic acid elevates mutant rates in any clinical symptoms or macroscopically de- the mouse lymphoma forward mutation assay tectable pathologic lesions in rats, guinea pigs, [146]. rabbits, and cats [150]. Medical reports of acute exposure effects of Dichloroacetic Acid and Dichloroacetate. trichloroacetic acid showed mild to moderate Dichloroacetic acid, a clear colorless liquid, is skin and eye burns [151]. In humans, trichlor- corrosive to the skin and mucous membranes. oacetate was an irritant to skin and mucous Its oral LD50 is 2820 mg/kg for rats, which is of membranes. Opaqueness of the cornea may oc- the same order of magnitude as that for tri- cur. Oral ingestion led to intestinal colics, sali- chloroacetic acid. Dichloroacetic acid is able to vation, emesis, diarrhea, muscular weakness, penetrate rabbit skin with a dermal LD50 of anorexia, and apathy [150]. 797 mg/kg [140]. The lowest oral LD50 re- Little relevant chronic toxicity data exists ported for dichloroacetate is 4480 mg/kg for for trichloroacetic acid. The toxicological pro- fasted rats [141]. file of airborne trichloroacetic acid is assumed Sodium dichloroacetate was examined in a to be dominated by lesions of mucous mem- three-month oral toxicity study in rat and dogs. branes of the upper respiratory tract. A TLV- Both species manifested toxic effects, such as time weighted average (TWA) of 1 ppm, 7 mg/m3 depressed appetites and increased body mass, is suggested, based largely on analogy to 2,2- degenerative changes of testicular germinal epi- dichloropropionic acid (TLV-TWA 1 ppm, thelium, hind limb muscular weakness or paral- 6mg/m3) [151]. ysis, and lesions. Cessation of administra- Trichloroacetic acid strongly binds to plasma tion brought about an amelioration or recovery . A high concentration in blood is from all effects except brain lesions. Dogs proved capable of displacing from protein-binding to be more sensitive than rats, showing toxic sites. Because of this systemic effect of potential effects at 50 mg kg1 d1. The central nervous displacement from plasma proteins, a TLV system (CNS) observations are extremely rele- of 1–2 ppm may be accepted for trichloroacetic vant in light of a report that described polyneuro- acid [149]. pathy of a 21-year-old man whose severe hyper- For trichloroacetate, a provisionally tolerat- cholesterolemia had been treated orally with ed daily intake of 0.075 mg/kg body mass has dichloroacetate (50 mg/kg) for 16 consecutive been established. This limit value takes into weeks. The polyneuropathy was characterized by account the results of a subchronic dog feeding weakness of facial, finger, and lower extremity study with concentrations in food of 2000 mg/ muscles, by diminished deep tendon reflexes, and kg, resulting in loss of body mass, malaise, ne- by slowing of nerve conduction velocity. The crosis of gingival and buccal mucosae, changes in neuropathy improved when the therapy was white blood cell count, pathologic urine findings, stopped [147]. lesions of the liver and myocardium, atrophy of 488 Chloroacetic Acids Vol. 2 skeletal muscle, and impairment of spermiogen- 28 Dow Chemical, US 2826610, 1955 (E.K. Morris). esis. The nontoxic effect level was 500 mg/kg in 29 Uddeholms, GB 928178, 1960. the diet [150]. 30 Hoechst, DE 1919476, 1969 (W. Opitz, A. Jacobowsky, On the basis of available data, tri- W. Burkhard). 31 Fondazione de Nora, US 4281184, 1978 (P. Spaziante, chloroacetate does not exert mutagenic effects C. Sioli, L. Giuffre). [150]. 32 Daicel, JP 81127329, 1980. 33 GB 1176109, 1968 (A.L. Englin, E.V. Sergeev, E.R. Berlin); Chem. Abstr. 72 (1970) 110 815 p. References 34 Dow Chemical, US 3152174, 1960 (E.K. Morris, W.W. Bakke). 35 Frontier Chemical Co., US 2917542, 1958 (J.I. 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