Chloroacetic acid methyl ester H, S

Size: px

Start display at page:

Download "Chloroacetic acid methyl ester H, S"

Clifford Rogers
5 years ago
Views:

1 Chloroacetic acid methyl ester H, S Classification/MAK value: MAK value dates from: 1994 Synonyms: Chemical name (CAS): CAS number: Structural formula: 1 ml/m 3 (ppm) 5mg/m 3 peak limitation category I pregnancy risk group D monochloroacetic acid methyl ester methyl chloroacetate methyl monochloroacetate chloroacetic acid methyl ester O ClH C C O CH Molecular formula: C 3 H 5 ClO 2 Molecular weight: Melting point: Boiling point: about 32 C C Density at 20 C: g/cm 3 Vapour pressure at 20 C: hpa 1 ml/m 3 (ppm) = 4.5 mg/m 3 1mg/m 3 = 0.22 ml/m 3 (ppm) Toxic Effects and Modes of Action Chloroacetic acid methyl ester is used as a solvent and an intermediate for organic synthesis. Like other esters, chloroacetic acid methyl ester can be assumed to hydrolyse to chloroacetic acid in aqueous solutions. The methyl ester therefore has a toxic potential similar to that of the acid. After either a single or repeated inhalation exposure, the main effect is local irritation. Undiluted chloroacetic acid methyl ester is strongly corrosive. It can be assumed that the methyl ester has sensitizing effects like those caused by the ethyl

2 2 Chloroacetic acid methyl ester Volume 9 ester. As with chloroacetic acid, there is no evidence of mutagenic properties. Chloroacetic acid does not have teratogenic effects in rats in doses tolerated by the dams. No information is available on the mechanisms of action. 2 Toxicokinetics In aqueous solutions there is an equilibrium between the ester on the one hand and the acid and alcohol on the other. It can therefore be assumed that chloroacetic acid methyl ester is hydrolysed to chloroacetic acid and methanol in aqueous solutions. After oral administration of chloroacetic acid to rats, at first the highest concentrations were found mainly in the liver and kidneys and a few hours later in the central nervous system (Berardi and Snyder 1983; Bhat et al. 1990; Hayes et al. 1973). Within 24 hours approximately 80 % to 90 % of the administered chloroacetic acid (100 mg/kg body weight) was excreted in the urine, mostly as glutathione conjugates. A small amount (about8%)wasexhaledasco 2 (Hayes et al. 1973; Yllner 1971). 3 Effects in Man Chloroacetic acid methyl ester vapour led in exposed workers to delayed eye irritation (no data on concentration; Torkelson et al. 1971). A 23-year old man spilt a solution of 1.5 M chloroacetic acid in ethanol over his right hand and forearm. He was patch tested 28 days after the accident with a 1 % solution of chloroacetic acid in methanol and showed a strong positive reaction. On day 49, patch tests with the ethyl ester of chloroacetic acid in acetone and ethanol also yielded positive results; with chloroacetic acid in aqueous solution, however, the results were negative. The authors conclude that the sensitization probably results from the ethyl ester which is formed in the ethanolic solution of chloroacetic acid (Braun and van der Walle 1987). The positive reaction to the test with chloroacetic acid in methanol on the 28th day after the accident indicates that, in analogy to the ethyl ester, the methyl ester is formed and can produce cross reactions with the ethyl ester. There are no other data available.

3 Volume 9 Chloroacetic acid methyl ester 3 4 Effects on Animals and in vitro Studies 4.1 Acute toxicity Chloroacetic acid methyl ester is toxic after a single application, independent of species and exposure route Inhalation Data on inhalation toxicity are listed in Table 1. For rats exposed once for 4 hours the LC 50 was about 300 ml/m 3 (about 1350 mg/m 3 ). Chloroacetic acid methyl ester affects breathing, produces eye irritation (corneal clouding), cyanosis, and non-specific symptoms of intoxication such as squatting position, abdominal position and balance disorders. Concentrations of 210 ml/m 3 or more led to severe irritation of the respiratory tract (BG Chemie 1988; Torkelson et al. 1971). Table 1. Inhalation toxicity of chloroacetic acid methyl ester in rats Concentration (ml/m 3 ) Exposure time (h) Number of deaths/total animals exposed Sex References /4 Torkelson et al /4 Torkelson et al /5 Torkelson et al /10 + BG Chemie /10 + BG Chemie /4 Torkelson et al /10 + BG Chemie /10 + BG Chemie /5 Torkelson et al /5 Torkelson et al /4 Torkelson et al /5 Torkelson et al The exposure of a group of 5 male and 5 female rats to an atmosphere saturated with chloroacetic acid methyl ester vapour in an inhalation hazard test was lethal for one animal after 3 minutes, for two more animals after 10 minutes and for all the exposed animals within 30 minutes (Hoechst 1987). In another inhalation hazard test with exposure times of 3, 10, 30 and 50 minutes, the exposure was lethal for some of the rats exposed for 10 minutes or more (BASF 1981).

4 4 Chloroacetic acid methyl ester Volume Oral, dermal and intraperitoneal administration In rats the LD 50 after oral administration of chloroacetic acid methyl ester was reported to be 107 and 140 mg/kg body weight (Table 2). Non-specific symptoms of intoxication and laboured breathing were observed (Hoechst 1979a). 4.2 Subacute, subchronic and chronic toxicity Groups of five male and five female Wistar rats were exposed to chloroacetic acid methyl ester vapour concentrations of 0, 10, 33 or 100 ml/m 3 (about 45, 150, 450 mg/m 3 ) for 6 hours daily, 5 days per week for 28 days. In addition to irritation, effects on breathing and coordination, and non-specific symptoms were seen in the animals from the 100 ml/m 3 group. Body weight gain was clearly impaired, male animals being more susceptible than female animals. The relative lung weights were markedly increased. In the animals from the 33 ml/m 3 group, substance-specific irritation of the mucous membranes was observed and, in the males, a slight delay in body weight gain. The concentration of 10 ml/m 3 is given as the no effect level as in this group no irritative effects were apparent except on day one of the experiment (Hoechst 1988a). Table 2. Acute toxicity of chloroacetic acid methyl ester Species Sex Administration route LD 50 (mg/kg body weight) References rat oral 107 Hoechst 1979a rat + oral 140 BASF 1981 rat dermal 137 Hoechst 1979b rat not specified dermal 470 BASF 1981 rabbit dermal 318 Hoechst 1979c mouse + i.p BASF Local effects on skin and mucous membranes Rabbits were exposed to concentrations of chloroacetic acid methyl ester of 50 or 100 ml/m 3 (about 225 or 450 mg/m 3 ) for 4 or 7 hours; irritation of the conjunctiva and cornea developed at the 100 ml/m 3 concentration. The observed irritation was reversible. A concentration of 50 ml/m 3 did not lead to any eye damage (Torkelson et al. 1971). Six rabbits were administered 0.1 ml undiluted chloroacetic acid methyl ester into the conjunctival sac of one eye. Severe irritation and irreversible corneal damage (vascularization, detachment, scarring) and inflammation of the iris were observed (BASF 1981, Hoechst 1979d). After occlusive application of 0.5 ml undiluted chloroacetic acid methyl ester (about 300 mg/kg body weight) to the shaved, intact or scarified flank skin of 6 rabbits, all animals died after 2 to 8 hours. The skin was greatly swollen and corroded. Occlusive

5 Volume 9 Chloroacetic acid methyl ester 5 application of 125 mg/kg body weight to the shaved, intact skin of the flanks for 24 hours led to severe skin damage and corrosion (Hoechst 1979d). In another study with 3 male and 3 female rabbits necrosis was observed after as little as 1 hour exposure (BASF 1981). The substance is therefore considered to be corrosive. 4.4 Allergenic effects The sensitizing effect of an 80 % solution of chloroacetic acid in methanol was investigated in female guinea pigs using the maximization test of Magnusson and Kligman. For induction purposes, the animals received an intradermal injection in the back of the neck of a 0.05 % solution of the substance dissolved in Freund s adjuvant and paraffin and 7 days later occlusive dermal application of a 2 % solution of the substance in paraffin for 48 hours. Topical occlusive application to the flanks of concentrations between 0.01 % and 1 % was carried out 2 weeks later for provocation. With the provocation concentration of 1 %, 13 of the 20 animals showed a positive reaction; concentrations of 0.1 % and 0.01 % produced positive reactions in 5 animals and one animal, respectively. In none of the 10 control animals was a skin reaction observed (AKZO 1987). It can be assumed, as described in the section Effects in Man, that the sensitization was caused by chloroacetic acid methyl ester which is formed in a methanolic solution of chloroacetic acid. Chloroacetic acid methyl ester can produce cross reactions with the ethyl ester of chloroacetic acid. Four of six female guinea pigs which were sensitized to chloroacetic acid ethyl ester also showed a positive reaction when tested with 0.5 % and 5 % solutions of chloroacetic acid methyl ester (Braun and van der Walle 1987; ENKA 1986). 4.5 Reproductive and developmental toxicity There are no studies available on the reproductive toxicity of chloroacetic acid methyl ester. Chloroacetic acid administered orally to pregnant Long-Evans rats in doses of 0, 17, 35, 70 or 140 mg/kg body weight led to a decrease in body weight gain in the high dose group. An increase in the incidence of malformations of the cardiovascular system was observed in the foetuses at this dose. Skeletal malformations did not occur (Smith et al. 1990). 4.6 Genotoxicity Chloroacetic acid methyl ester was shown not to be mutagenic in vitro in several Salmonella mutagenicity tests with strains TA98, TA100, TA1535, TA1537, TA1538 and in a reversion test with Escherichia coli WP2uvrA, both with and without metabolic activation (Hoechst 1983, 1993, Sato et al. 1985).

6 6 Chloroacetic acid methyl ester Volume 9 In vivo after oral administration of 300 mg/kg body weight to male and female NMRI mice no increase in the incidence of micronuclei in bone marrow cells was detected (Hoechst 1988b). 4.7 Carcinogenicity In a short-term carcinogenicity test for lung adenomas, 10 male and 10 female strain A/St mice received chloroacetic acid methyl ester doses of about 9.7, 19.5 or 39 mg/kg body weight by intraperitoneal injection, 3 times a week for 8 weeks. The follow-up period lasted 16 weeks. There was no increased incidence of lung tumours. All animals survived except one from the lowest dose group (Theiss et al. 1979). There are no long-term carcinogenicity studies available. 5 Manifesto (MAK value, classification) Like other esters, chloroacetic acid methyl ester can be assumed to hydrolyse to chloroacetic acid in aqueous solutions. The methyl ester therefore displays a toxic potential similar to that of the acid. As with chloroacetic acid, the main effect of inhalation of chloroacetic acid methyl ester is severe irritation of the skin and mucous membranes. After 28-day exposure a no effect level of 10 ml/m 3 (about 45 mg/m 3 ) was determined for the irritative effects. Apart from delayed body weight gain, no systemic toxicity was observed. There is no evidence of mutagenic properties. Long-term studies on the carcinogenicity of chloroacetic acid methyl ester are not available; a short-term test produced no evidence of formation of lung tumours. In consideration of the predominantly local irritative effects, the MAK value was established at 1 ml/m 3 (5 mg/m 3 ). This value should be regarded as provisional as to date there is only a 28-day study available on systemic toxicity. Peak limitation is according to category I. Skin contact should be avoided because of the severe irritative and corrosive effects. Because there have been lethal intoxications after dermal contact with chloroacetic acid (Christofano et al. 1970; Kusch et al. 1990; Millischer et al. 1988), chloroacetic acid methyl ester has been given the H designation. Because it is suspected of having skin sensitizing effects, chloroacetic acid methyl ester is designated with an S. A foetotoxic effect under workplace conditions is not to be expected as the ester is probably rapidly degraded and the product of hydrolysis, chloroacetic acid, had foetotoxic effects in rats only at the highest, maternally toxic dose of 140 mg/kg body weight. As, however, the ester itself has not been tested for foetotoxic effects and the product of hydrolysis was only tested in one species and only after oral administration, the substance is categorized in pregnancy risk group D.

7 Volume 9 Chloroacetic acid methyl ester 7 6 References AKZO (1987) Assessment of the skin sensitization potential of Azonol in the guinea pig (Magnusson and Kligman Maximization test). NOTOX, Report No. 0603/758, unpublished report by AKZO NV, Arnheim, Niederlande BASF (1981) Chloressigsäuremethylester. Gewerbetoxikologische Grundprüfung. In: Chloressigsäuremethylester. Toxikologische Bewertung der Berufsgenossenschaft der chemischen Industrie No. 76, Heidelberg, 1994 Berardi M, Snyder R (1983) Toxicity and pharmacokinetics of monochloroacetic acid. Pharmacologist 25: 228 BG Chemie (1988) Monochloressigsäuremethylester: Inhalation im strömenden Gemisch an männlichen und weiblichen SPF-Wistar Ratten, 4 Stunden-LC50. Hoechst, Report No , unpublished report by the Berufsgenossenschaft der chemischen Industrie Bhat HK, Ahmed AE, Ansari GAS (1990) Toxicokinetics of monochloroacetic acid: a whole-body autoradiography study. Toxicology 63: Braun CLJ, van der Walle HB (1987) The ethyl ester of monochloroacetic acid. Contact Dermatitis 16: Christofano EE, Frawley JP, Reed HL (1970) Skin exposure to monochloroacetic acid. Am Ind Hyg Assoc J 19: 35 ENKA (1986) Assessment of the skin sensitization potential of monochloro acetic acid ethyl ester and screening for cross-sensitivity to monochloro acetic acid and monochloro acetic acid methyl ester in the guinea-pig (Magnusson and Kligman Maximization test). NOTOX, Report No. 0278/344, unpublished report by the Medizinische Dienst ENKA, Arnheim, Niederlande Hayes FD, Short RD, Gibson JE (1973) Differential toxicity of monochloroacetate, monofluoroacetate and monoiodoacetate in rats. Toxicol Appl Pharmacol 26: Hoechst (1979a) Akute orale Toxizität von Monochloressigsäuremethylester an weiblichen Ratten. Report No , unpublished Hoechst (1979b) Akute dermale Toxizität von Monochloressigsäuremethylester an weiblichen Ratten. Report No , unpublished Hoechst (1979c) Akute dermale Toxizität von Monochloressigsäuremethylester an Kaninchen. Report No , unpublished Hoechst (1979d) Haut- und Schleimhautverträglichkeit von Monochloressigsäuremethylester an Kaninchen. Report No , unpublished Hoechst (1983) Monochloressigsäuremethylester: study of the mutagenic potential in strains of Salmonella typhimurium (Ames Test) and Escherichia coli. Report No , unpublished Hoechst (1987) Monochloressigsäuremethylester: Inhalationstoxizität im Zeitsättigungstest an männlichen und weiblichen SPF-Wistar Ratten. Report No , unpublished Hoechst (1988a) Chloressigsäuremethylester: subakute Inhalation (20 Applikationen in 28 Tagen) an SPF-Wistar Ratten. Report No , unpublished Hoechst (1988b) Monochloressigsäuremethylester: micronucleus test in male and female NMRI mice after oral administration. Report No , unpublished Hoechst (1993) Monochloressigsäuremethylester: study of the mutagenic potential in strains of Salmonella typhimurium (Ames Test). Report No , unpublished Kusch GD, McCarty LP, Lanham JM (1990) Monochloroacetic acid exposure: a case report. Pol J Occup Med 3: Millischer RJ, Jouglard J, Vincenti M, Ruty J, Contassot JC (1988) Monochloroacetic acid: seven worldwide cases of systemic poisoning resulting from accidental skin contact. WHO Occupational Health in the Chemical Industry, 22nd Congress of the International Commission on Occupational Health, Sidney, , WHO, Copenhagen, pp Sato T, Mukaida M, Ose Y, Nagase H, Ishikawa T (1985) Mutagenicity of chlorinated products from soil humic substances. Sci Tot Environ 46: Smith MK, Randall JL, Read EJ, Stober JA (1990) Developmental effects of chloroacetic acid in the Long-Evans rat. Teratology 41: 593

8 8 Chloroacetic acid methyl ester Volume 9 Theiss JC, Shimkin MB, Poirier LA (1979) Induction of pulmonary adenomas in strain A mice by substituted organohalides. Cancer Res 39: Torkelson TR, Kary CD, Chenoweth MB, Larsen ER (1971) Single exposure of rats to the vapors of trace substances in methoxyflurane. Toxicol Appl Pharmacol 19: 1 9 Yllner S (1971) Metabolism of chloroacetate-1-14c in the mouse. Acta Pharmacol Toxicol 30: completed

formic acid ethyl ester

Formic acid ethyl ester MAK value (1961) 100 ml/m 3 (ppm) 3.10 mg/m 3 Peak limitation (2000) Category I, excursion factor 1 Absorption through the skin (1997) H Sensitization Carcinogenicity Prenatal toxicity