1,4-Butane sultone Classification/MAK value: Classification/MAK value dates from: 1986 Synonyms: Chemical name (CAS): see Section III B MAK List 1987 butanesultone δ-butane sultone δ-valerosultone butanesulfone 1,4-butylene sulfone CAS number: 1633-83-6 Structural formula: Molecular formula: 1,2-oxathiane 2,2-dioxide C 4 H 8 O 3 S Molecular weight: 136.17 Melting point: 14 C Boiling point: Vapour pressure at 20 C: H 2 C CH 2 CH 2 CH 2 O 2 S O 238 C (extrapolated) 3 10 4 hpa (extrapolated) 2,4-Butane sultone Classification/MAK value: see Section III A2) MAK List 1985 Classification/MAK value dates from: 1986 Synonyms: Chemical name (CAS): CAS number: 1121-03-5 Structural formula: Molecular formula: 1-methyl-1,3-propane sultone 4-hydroxy-2-butane sulfonic acid γ-sultone 3-methyl-1,2-oxathiolane 2,2-dioxide H 2 C CH CH 2 CH 2 O 2 S O C 4 H 8 O 3 S
46 1,4-Butane sultone and 2,4-Butane sultone Volume 4 Molecular weight: 136.17 Melting point: Boiling point: Vapour pressure at 20 C: 1 ml/m 3 (ppm) = 5.55 mg/m 3 1 mg/m 3 = 0.18 ml/m 3 (ppm) 1 Toxic Effects and Modes of Action The toxicology of 2,4-butane sultone and 1,4-butane sultone has not been adequately investigated. Because of their alkylating properties and their close chemical relationship with propane sultone, which has been shown in animal studies to be highly carcinogenic [1,2], the main question in any toxicological assessment of 2,4-butane sultone, 1,4- butane sultone and mixtures containing these compounds must be their carcinogenic potential. Preliminary studies of the mutagenic and carcinogenic effects of these substances suggest that 2,4-butane sultone has marked carcinogenic potential whereas 1,4-butane sultone is only a weak carcinogen. 2 Effects in Man Butane sultone appears to be produced only in small quantities as a technical product (~70 80% 2,4-butane sultone). Effects of this product in man are not known. 3 Effects on Animals Animal studies have been carried out only with 1,4-butane sultone and with a technical mixture containing both 1,4-butane sultone and 2,4-butane sultone. These were preliminary studies of the carcinogenic effects of these substances. Studies with 1,4-butane sultone in the rat [3] LD 50 s.c.: 350 mg/kg (in water) i.v.: 270 mg/kg (in water) p.o.: 500 mg/kg (in water) 12 rats received 30 mg/kg s.c. (3 % aqueous solution) once weekly for 76 weeks (total dose ~2 g/kg) and were then observed for the rest of their lives. 1/12 rats developed a local sarcoma at the injection site. Local necrosis was not observed. 16 rats received 30 mg/kg i.v. once weekly for 84 weeks (total dose 2.1 g/kg) and were then observed for the rest of their lives. Tumours were not induced in any of the rats (0/16).
Volume 4 1,4-Butane sultone and 2,4-Butane sultone 47 Table 1. Administration of Butansulton-T to rats by subcutaneous injection Treatment Number of rats Average survival (in days) Sarcomas at the injection site Other malignant tumours (various sites) Total dose (mg/kg) Butansulton-T 25 223 ± 50 24 275 25 310 ± 118 23 2 275 oil control 25 762 ± 180 1 6 25 787 ± 126 1 6 1,4-Butane sultone is sufficiently stable to be administered in the drinking water. 16 rats received 6 mg/kg p.o. 5 times weekly (30 mg/kg/week). After total doses between 1.3 and 2.8 g/kg, 6/16 rats died with malignant tumours (2 adenocarcinomas of the small intestine, 1 neurofibroma of the nervus acusticus, 1 ovarian carcinoma, 1 uterus carcinoma, 1 mammary carcinoma). On the basis of these preliminary studies the authors classified 1,4-butane sultone as "a very weak carcinogen". Studies in rats with "Butansulton-T", a technical mixture containing ~ 70% 2,4-butane sultone and ~ 30% 1,4-butane sultone (impurities ) [4] LD 50 s.c. 480 mg/kg (in arachis oil, DAB 7) 25 male and 25 female Wistar rats, 100 days old at the beginning of the study, were given Butansulton-T (in arachis oil) by subcutaneous injection, once weekly or at longer intervals, depending on the condition of the animals. The largest tolerated single doses were between 5 and 50 mg/kg. When the first local tumour developed (injection site), the last injection was given; at this time a total dose of 275 mg/kg had been administered in 133 days. The rats were then observed until they died naturally. The control group comprised 25 male and 25 female rats of the same strain. Like the treated animals, they were given subcutaneous injections (each 0.1 ml/100 g body weight) of arachis oil (DAB 7). The last injection was administered after 700 days; at this time a total dose of 60 ml arachis oil/kg body weight had been administered to the controls in 60 injections. The results of this study are shown in Table 1. In almost all treated rats marked necrosis was visible at the injection site as symptom of acute tissue damage. 4 Genotoxicity 1,4-Butane sultone was shown as early as 1962 to be mutagenic in Schizosaccharomyces pombe [5] and this result was later confirmed [6]. 1,4-Butane sultone in the concentration range between 3 and 9 mm was also shown to be clearly mutagenic in barley seedlings [7].
48 1,4-Butane sultone and 2,4-Butane sultone Volume 4 1,4-Butane sultone was mutagenic in the Ames test, increasing the number of revertants to 4 to 9 times the control values in Salmonella typhimurium TA98, TA100, TA1535 and TA1538. The maximum effects were obtained with concentrations between 20 and 500 µg per plate [8]. It could be shown in strain TA1535 that the mutagenicity was markedly reduced by the addition of S9 mix [11]. 1,4-Butane sultone also yielded positive results in the cell transformation test in vitro (Syrian hamster kidney cells, human lung fibroblasts or human liver cells) [8] and in the degranulation of the rough endoplasmic reticulum of isolated rat liver cells [8], in the sebaceous gland test on mouse skin [8] and in the tetrazolium reduction test on mouse skin [8]. (The relevance of these latter three tests is not clear.) In the host-mediated assay (mouse) 1,4-butane sultone (106 mg/kg i.m. or 138 mg/kg p.o.) proved to be clearly mutagenic in the S. typhimurium strains TA1530, TA1535 and TA1538 [9]. No results of mutagenicity studies are available for 2,4-butane sultone. 5 Manifesto (MAK value, classification) Carcinogenic alkylating agents may be expected to have local carcinogenic effects. If a high incidence of local sarcomas develops after a relatively short period in rats injected subcutaneously with relatively small doses of such alkylating agents, this is to be seen as a symptom of local carcinogenic action and not as an unspecific effect [10]. In such a study, a technical mixture containing ~70% 2,4-butane sultone and ~30% 1,4-butane sultone had marked local carcinogenic effects. (The effect was at least as marked as that of dimethyl sulfate which was tested in parallel.) This butane sultone mixture was, without doubt, much more carcinogenic than 1,4-butane sultone which had proved to be a very weak carcinogen when tested in a similar manner in an older study. These findings suggest that the 2,4-butane sultone in the technical mixture of the two butane sultones (~70% 2,4-butane sultone and ~30% 1,4-butane sultone) is a considerably stronger carcinogen than the 1,4-butane sultone. 2,4-Butane sultone is classified in Section III A2) of the MAK List, 1,4-butane sultone in Section III B. A MAK value cannot be established for either substance. The carcinogenic 2,4-butane sultone cannot be classified in any of the pregnancy groups. During pregnancy all contact with the substance should be avoided. 6 References 1. Henschler, D. (Ed.): Gesundheitsschädliche Arbeitsstoffe. Toxikologisch-arbeitsmedizinische Begründung von MAK-Werten, Verlag Chemie, D-6940 Weinheim, 1975 and 1985 2. Doak, S. M. A., B. J. E. Simpson, P. F. Hunt, D. E. Stevenson: Toxicology 6, 139 (1976) 3. Druckrey, H., H. Kruse, R. Preussmann, S. Ivankovic, Ch. Landschütz, J. Gimmy: Z. Krebsforsch. 75, 69 (1970) 4. Bayer AG: Butansulton-T, p-toluolsulfonsäuremethylester, Dimethylsulfat - Vergleichende orientierende Kanzerogenese-Versuche bei subkutaner Gabe an Ratten, unpublished report no. 5222, Bayer AG, D-5600 Wuppertal, 1975 5. Heslot, H.: Abh. dtsch. Akad. Wiss. Berlin, Kl. Med. 193 (1962)
Volume 4 1,4-Butane sultone and 2,4-Butane sultone 49 6. Ostermann-Golkar, S., C. A. Wachtmeister: Chem.-Biol. Interact. 14, 195 (1976) 7. Singh, C., G. Ram, B. L. Kaul: Mutat. Res. 91, 229 (1981) 8. Purchase, I. F. H., E. Longstaff, J. Ashby, J. A. Styles, D. Anderson, P. A. Lefevre, F. R. Westwood: Brit. J. Cancer 37, 873 (1973) 9. Simmon, V. F., H. S. Rosenkranz, E. Zeiger, L. A. Poirier: J. nat. Cancer Inst. 62, 911 (1979) 10. Steinhoff, D.: in Norpoth, K. H., R. C. Garner (Eds.): Short-term Test Systems for Detecting Carcinogens, Springer Verlag Berlin, Heidelberg, New York, 1980 11. Rosenkranz, H. S., L. A. Poirier: J. nat. Cancer Inst. 62,. 873 (1979) completed 1.10.1986