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1,4-Dioxane
(CAS-N R.: 123-91-1)

Ausgabe: März 2001
Stand: November 2000

Classification for Carcinogenicity:

1,4-Dioxane was shown to be carcinogenic in several drinking water studies in rats, mice and guinea pigs. The target organs were mainly liver and nasal cavities, occassionally also tumors in other tissues were recorded. The studies are comprehensively reported in widespread documents, such as the German MAK documentation (1996), the German BUa report (BUA, 1991) and the EU risk assessment report (1999). Tumor data of drinking water studies are compiled in table 1.

The carcinogenicity of 1,4-dioxane in drinking water was recently reconfirmed in drinking water studies in rats exposed to 200; 1,000 and 5,000 ppm and in mice exposed to 500; 2,000 and 8,000 ppm (50 animals per sex and dose; Yamazaki et al., 1994). Male rats at 5,000 ppm showed nasal cavity metaplasia, proliferation and malignant tumors and increases in hepatocellular adenoma and carcinoma, peritoneal mesothelioma, fibroma of the subcutis and fibroma of the mammary glands. In female rats, at 5,000 ppm similar effects in the nasal cavities including malignant tumors were observed, furthermore increases in hepatocellular adenoma and carcinoma and adenoma of the mammary gland. At 1,000 ppm no nasal effects at all were observed in male and female rats and no hepatocellular carcinoma. Hyperplasia of liver and hepatocellular adenoma, however, were still increased in both sexes. At 200 ppm no effects were noted for the females; for males a slight increase in spongiosis hepatis and two hepatocellular adenomas appeared to be of borderline significance in this group.

Mice responded in the top dose (8,000 ppm) with one adenocarcinoma in the nasal cavity in the female group and one esthesioneuroepithelioma in the male animals. Furthermore, a high number of hepatocellular carcinoma was obtained in both sexes, whereas the number of adenoma was in the control range. At 500 and 2,000 ppm an increase in hepatocellular adenoma and a doserelated increase of hepatocellular carcinoma was noted. Throughout all dose levels, there was an increasing trend to malignancy in liver with the dose. Thus, 500 ppm (0.05 %; 66 mg/kg bw/day) were a LOAEL in this study. It should be noted, that this corresponds to a dose that was previously shown as exceeding the NOEL (10 mg/kg/day) in terms of organ toxicity, cell proliferation and metabolic saturation in rats (see below).

The overall pattern of tumorigenicity and organ toxicity is quite the same as detected in earlier drinking water studies. Toxic tissue damage and cell proliferation appear to precede the tumor formation. As was shown in an earlier report (NCI, 1978) , mice appeared to be on a ppm basis somewhat more sensitive than rats. The only inhalation study that had been carried out so far employed 111 ppm to rats over two years (400 mg/m3; roughly equivalent to a dose of 72 mg/kg/day in case of a 100 %

pulmonary resorption rate). An increased tumor rate was not identified in this study. (a numerical increase of reticuloses was not regarded as treatmentrelated by the authors; Torkelson et al., 1974). The validity of this study is somewhat limited since the MTD was not achieved and also cytotoxic effects on liver and kidney, which are a typical pattern of repeated 1,4-dioxane administration, were not observed. Furthermore, it is not certain that the authors thoroughly examined a sufficient range of sections within the nasal cavity.

Genotoxicity:

a large number of genotoxicity studies has been carried out with 1,4-dioxane (overview: MAK-Dokumentation and BUa report). According to the overall pattern the material is not genotoxic.

In a recent study a positive liver micronucleus assay was observed at 3,000 mg/kg (Moriata and Hayashi, 1998). This result appears to be compatible with earlier findings from Kitchin and Brown (1990), who have found DNa fragmentation at similar (cytotoxic) dose levels.

As a conclusion, it does not appear unlikely that under conditions of severe cytotoxicity 1,4-dioxane may exert some level of clastogenicity. However, as is shown below, these are dose levels exceeding the organisms capacity to adequately oxidize 1,4-dioxane. Under these extreme conditions 1,4-dioxane accumulates in the blood and all tissues and may produce cytotoxicity via a second metabolic pathway in those tissues with a propensity for enzyme induction.

Metabolism / Biotransformation:

Metabolism studies in rats showed that between dose levels of 10 and 100 mg/kg a saturation of the oxidative metabolism from 1,4-dioxane to ß-Hydroxyethoxyacetic acid is achieved which is described by a shift from a first- to zeroorder kinetics. This saturation phenomenon is equivalent to a steep and disproportional increase of the internal dose of 1,4-dioxane which is rather slowly metabolized and accumulates in the plasma (and tissues), whereas the formation and elimination of the main urinary metabolite, ßhydroxyethoxyacidic acid follows only a linear dose relation. Under these conditions a second metabolite, namely 1,4-dioxane-2-ol in equilibrium with ßhydroxyethoxyacetic aldehyde, is formed as suggested by Hecht and Young (1981); the latter being strongly proteinreactive and cytotoxic.

Time course appears to be important: Young et al. (1978a and b) demonstrated that after 17 repeated administrations of 1,000 mg/kg/day, the relative percentage of reexhaled 1,4-dioxane decreased about 3-fold when compared to single administration, whereas the rate of exhaled CO₂increased to the same extent. The authors therefore postulated an enzyme induction, possibly aniline hydroxylase, which may produce an additional metabolite. Enzyme induction may be conceived as a thresholdrelated phenomenon. a similar time course was also observed in cell proliferation studies showing a retarded onset of replicative DNa synthesis (RDS; see below).

In rodents, the nasal tissues contain significant amounts of cytochrome P450's and are therefore metabolically quite active. They may be capable of enzyme induction after repeated exposure and also prone to be target tissues for cytotoxic metabolites arising from P450-mediated oxidation. This is reflected by carcinogenic effects to nasal tissues of many chemicals after oral administration.

Cell proliferation studies:

Several studies have investigated cell proliferating effects of 1,4-dioxane in target organs. Since 1,4-dioxane (and moreover 1,4-dioxane-2-ol) has a proteindenaturing effect, one would expect cytostatic as well as proliferating effects, the latter being due to replacement of necrotic cells.

Heil and Refferscheid (1992) found inhibition of replicative DNa synthesis (RDS) in HeLa cells at 400 mM.