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Carcinogenicity

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Description of key information

Animal data: Taken together the results from the three studies on sodium and potassium metabisulphite (Tanaka et al., 1979; Til et al., 1972; Feron and Wensfoort, 1972) there was no indication that metabisulphite had any carcinogenic effect. The drinking water study by Tanaka et al. (1979) on potassium metabisulphite in mice is considered as most suitable for the assessment of carcinogenicity (read-across info, see `discussion`). 
Human data: 4 reliable studies on pulp and paper mill workers were available ((Milham and Demers, 1984; Robinson, et al. 1986; Anderson, et al. 1998; Rix, et al. 1997), see section 7.10.2.

Key value for chemical safety assessment

Justification for classification or non-classification

The available data on long-term oral exposure of experimental animals to sodium and potassium metabisulfite allow an evaluation of the carcinogenic risks of sulfite substances for humans exposed via the oral route. There was no indication that metabisulfite had any carcinogenic effect itself.

Taking into account the applicability of the read-across approach for the different sulfites, the carcinogenity assessment of the sulfites and hydrogensulfites (group 1), sodium dithionite (group 3), and thiosulfates (group 4) can be based on the negative findings of the above mentioned study on potassium metabisulfite (read-across group 2) in mice.

No classification of the substance as CMR substance is required.

Additional information

Read-across concept for sulfites, hydrogensulfites, metabisulfites, dithionites and thiosulfates:

The basis for the read-across concept for this project is the equilibrium between sulfites, hydrogensulfites, and metabisulfites in aqueous solutions depending on pHvalue which is clearly described in published literature and summarised in the following equations:[1],[2]

           SO2+ H2O <->`H2SO3´         H2SO3<->H++ HSO3-<->2H++SO32-    2HSO3-<->H2O +S2O52-

Since the nature of the cation (i. e., sodium, potassium, ammonium…) is not assumed to contribute substantially to differences in toxicity and solubility (all substances are very soluble in water), only the chemical and biological properties of the anion are considered as relevant determinants. Based on the described equilibrium correlations, unrestricted read-across between the groups of sulfites, hydrogensulfites and metabisulfites is considered justified.

Additionally, it is known that sodium dithionite disproportionates in water to form sodium hydrogen sulfite and sodium thiosulfate (equation II) so that this substance can also be added to the read-across concept.2,[1]It is expected for this case that the substance is not stable enough under physiological conditions to fulfil the requirements of study guidelines and so the products of decomposition have to be considered.

       2 S2O42-+ H2O 2HSO3-+ S2O32-

 

Not completely included in this read-across concept is the substance class of thiosulfates. Although thiosulfates may also disproportionate in aqueous solution to form polythionic acids and SO2(HSO3-), the required conditions are somewhat different (more acidic) and are therefore not strictly comparable with physiological conditions2, except for the case of oral application where read-across should be considered unrestricted due to the strongly acidic conditions in the stomach:

       HS2O3-+ H2S2O3 HS3O3- + SO2+ H2O

Nevertheless, read-across for all other routes (dermal, inhalation) should also be considered.

The proposed read-across concept only applies to toxicological and ecotoxicological/environmental fate endpoints.

[1]Hollemann Wiberg, Lehrbuch der Anorganischen Chemie, 101. Auflage

[2]Handbook of Chemistry and Physics, Ed. Lide, DR, 88thedition, CRC Press

Oral route:

Animal data:

Taken together the results from the three studies on sodium and potassium metabisulphite (Tanaka et al., 1979; Til et al., 1972; Feron and Wensfoort, 1972), there was no evidence that metabisulphite had any carcinogenic effect. The drinking water study by Tanaka et al. (1979) on potassium metabisulphite in mice is considered as most suitable for the assessment of carcinogenicity, because the size of the experimental groups (50 animals of each sex) corresponded to that recommended in the OECD Guidelines for Carcinogenicity studies (451, 453).The highest concentration of 2% potassium metabisulphite, corresponding to an estimated dose of 2500 mg/kg bw/d K2S2O5, did not indicate a carcinogenic potential. However, there is evidence for a tumour-promoting potential of metabisulphite in glandular stomach carcinogenesis (Furihata et al., 1989; Takahashi et al., 1986).

 

Human data:

Only a few detailed studies of pulp and paper mill workers (Milham and Demers, 1984; Robinson, et al. 1986; Anderson, et al. 1998; Rix, et al. 1997) were available which analysed whether the workers might be at an increased risk for several site-specific malignancies. However, analyses of exposure-response relationships were not possible, because no exposure levels were available in any of the studies.

The retrospective cohort study in Danish sulfite pulp mill workers had a 2-fold increased risk for stomach cancer and pancreatic cancer (Rix et al., 1997). Other cancers with elevated risks were leukaemia (SIR 1.84) and soft-tissue sarcomas (SIR 2.37). The increased risk for stomach cancer found in this study was in accordance with that of other studies from sulfite pulp mills. The stomach cancer risk was increased in a retrospective cohort mortality study among workers in American sulfite mills (Robinson et al., 1986). They found 11 cases out of 523 observed deaths (SMR 149) with an increasing risk by time since the first employment. When process-specific analyses were conducted, the risk of lymphosarcoma and reticulosarcoma was increased only for men who had worked in sulfate mills. A proportionate mortality study among pulp and paper workers in the United States and Canada indicated a statistically significant excess risk of stomach cancer (Milham and Demers, 1984). Higher proportionate mortality ratios (PMRs) for lymphosarcoma (statistically significant) and kidney, pancreatic and rectal cancers were associated with jobs in the sulfite process. Hodgkin´s disease deaths occurred primarily in sulfate (Kraft) process workers.

 

IARC:

The International Agency for Research on Cancer (IARC, 1992) has evaluated the evidence for carcinogenicity and concluded: There is limited evidence for sulphur dioxide carcinogenicity in experimental animals. There is inadequate evidence of sulfites, bisulfites and metabisulfites

for carcinogenicity in experimental animals.

 

Inhalation and dermal route:

There are no reliable studies regarding cancer in experimental animals after inhalation or dermal exposure to any of the sulfite substances under consideration. Taking into account the negative oral carcinogenicity data it can be predicted that chronic inhalation or dermal exposure to the various sulfite substances would not result in remote site carcinogenicity. A certain uncertainty may exist with respect to the possibility of the formation of local tumours in the respiratory tract following long-term inhalation. However, SO2 inhalation for 21 weeks did not result in tumour formation in the lung as shown in a study on the potential co-carcinogenic role of SO2 in the induction of lung carcinoma by benzo(a)pyrene.

 

Summary:

The available data on long-term oral exposure of experimental animals to sodium and potassium metabisulfite allow an evaluation of the carcinogenic risks of sulfite substances for humans exposed via the oral route. There was no indication that metabisulfite had any carcinogenic effect itself. However, there is evidence of a tumour-promoting potential in glandular stomach carcinogenesis in animals and stomach cancer in pulp mill and paper workers.

 

Taking into account the applicability of the read-across approach for the different sulfites, the carcinogenity assessment of the sulfites and hydrogensulfites (group 1), sodium dithionite (group 3), and thiosulfates (group 4) can be based on the negative findings of the above mentioned study on potassium metabisulfite (read-across group 2) in mice.