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Description of key information

The references contained in the sub sectionare merely considered as supplementary information as (i) only observations on isolated organs of the test animals have been reported (ii) mechanistic inverstigations focussed on the biochemical effects of sulfur dioxide exposure, e.g. cytokine levels.

Additional information



Studies in Animals

In lung, heart, liver, kidneys, spleen, brain, retina and lens tissue, testis, stomach and intestinal tissues increased lipid peroxidation, changes in lipid profiles, decreased GSH levels and changed activities of antioxidative enzymes were detected, indicating that sulfite or metabolites are readily distributed in the body (Agar et al., 2000a; Haider et al., 1981, 1982, 1985; Kilic, 2003; Langley-Evans et al., 1996; Meng, 2003; Meng and Bai, 2004; Meng and Zhang, 2003; Meng et al., 2003b, c; Wu and Meng, 2003; Yargicoglu et al., 1999).


Due to the high reactivity of bisulfite for disulfide structures, especially in proteins or in oxidized glutathione GSSG, disulfide bonds are cleaved and S-sulfonates are formed (e. g. Langley-Evans et al., 1996). Decreased glutathione levels, found in the lungs and other tissues of rats after exposure to sulfur dioxide, suggest that GSH may be involved in the detoxification process (Langley-Evans et al., 1996).


Studies in Animals

Skin & Mucous membranes

Signs of eye irritation were reported when rats or guinea pigs were subacutely exposed to 10 ppm sulfur dioxide for 1 hour daily (Haider et al., 1981, 1982, 1985).

In pigs exposed to 35 ppm sulfur dioxide signs of ocular and nasal irritation appeared initially that declined within 1-2 days (Martin and Willoughby, 1971).

Respiratory tract

In pigs reversible enhancement of signs of irritation, as severe discomfort and laboured inspiration, was observed only when relative humidity neared 100 % or when sulfur dioxide increased accidentally to 100 ppm (Martin and Willoughby, 1971).

Repeated dose toxicity

Studies in Animals


Exposure of Sprague Dawleyratsfor up to 8 months to 1 ppm sulfur dioxide resulted in bronchiolar epithelial hyperplasia at 4 months which was absent at 8 months. A slight impairment of respiratory function was demonstrated at 4 months of exposure as the only examined time point. No significant pathological changes were observed in the nasal cavities. Furthermore no changes were found in parameters associated with immune competence and in spleen weight. Overall the effects were judged as minimal by the authors of the study (Smith et al., 1989). A further study, which specifically examined nose tissue did not reveal any changes after nose-only exposure of F344 rats exposed to 5 ppm (4 weeks, 2 hours/day, 5 days/week: Wolff et al., 1989).

Numerous further studies have investigated effects on the upper and lower respiratory tract. After subacute or subchronic exposure of different animal species to concentrations of 10 ppm and above changes in the nose region included decreased ciliar activity, disappearance of cilia and changes of goblet cell numbers in the respiratory epithelium, squamous metaplasia and basal cell hyperplasia in the nasal epithelium, sloughing of cells, viscous secretion, oedematous swelling (Fowlie et al., 1990; Giddens and Fairchild, 1972; Johnson et al., 1972; Majima et al., 1986; Martin and Willoughby, 1971; Sugiura et al., 1997).

Histological and inflammatory changes as described above have also been found in several species in the trachea and the lower respiratory tract (Asmundsson et al., 1973; Kasé et al., 1982; Krasnowska et al., 1998; Martin and Willoughby, 1971; Miyata et al., 1990; Okuyama et al., 1979; Scanlon et al., 1987; Seltzer et al., 1984; Sueyoshi et al., 2004; Xu et al., 2000; Yamamoto et al., 1970). Lesions characteristic of those seen in human chronic bronchitis were observedin rats, dogs, rabbitsand ferrets after subacute to chronic inhalation of sulfur dioxide at concentrations of 50 ppm and above (Chakrin and Saunders, 1974; Clark et al., 1980; Greene et al., 1984, 1987; Islam et al., 1977; Knauss et al., 1976; Lamb and Reid, 1968; Miller et al., 1985; Morgenroth, 1980; Spicer et al., 1974; Vai et al., 1980; White et al., 1986; Yamamoto, 1970).

Lesions proceeded from the nasal cavity to the trachea and changes increased in severity as exposure time increased (Asmundsson et al., 1973; Greene et al., 1984, 1987; Knauss et al., 1976; Lamb and Reid, 1968; Long et al., 1999; Martin and Willoughby, 1971; Shore et al., 1987; Yamamoto, 1970). During exposure-free recovery periods reversibility was observed for histological changes, cough and mucous hypersecretion (Clark et al., 1980; Giddens and Fairchild, 1972; Johnson et al., 1972; Lamb and Reid, 1968; Scanlon et al., 1987; Seltzer et al., 1984; Vai et al., 1980). In addition, despite continued exposure, in some experiments partial or full reversibility of specific histological changes such as erosion, hyperplasia of epithelium or goblet cells, and increase of mucus cells and mucus production was found (Smith et al., 1989; White et al., 1986; Yamamoto, 1970). Conflicting results were obtained on the effect of sulfur dioxide on particle clearance, but the studies are difficult to compare due to different species, exposure protocols and parameters analysed (Fraser et al., 1968; Greene et al., 1984; 1987; Hirsch et al., 1975; Holma, 1967; Rylander et al., 1971; Wakabayashi et al., 1977; Wolff et al., 1989).In one study phagocytosis of bacteria was not impaired in guinea pigs after subacute exposure to 10 ppm sulfur dioxide (Rylander et al., 1971).

Some more recent studies have investigated oxidative stress after subacute or subchronic exposure(1 or 6 hours daily exposure) to sulfur dioxide(concentration range 5-100 ppmin rats and guinea pigs. In erythrocytes formation of methaemoglobin and sulfhaemoglobin, lipid peroxidation and changes of the antioxidative defense was found (Agar et al., 2000a, b; Baskurt et al. 1994; Dikmenoglu et al., 1991; Etlik et al., 1995, 1997; Gümüslü et al., 1998, 2000, 2001; Kilic, 2003; Kücükatay et al., 2003; Yargicoglu et al., 1999, 2001; Yücel et al., 1998). Furthermore in lung, heart, liver, kidneys, spleen, brain, retina and lens tissue, testis, stomach and intestinal tissues increased lipid peroxidation, decreased GSH levels and changed activities of antioxidative enzymes were detected (Agar et al., 2000; Kilic, 2003; Langley-Evans et al., 1996; Meng, 2003; Meng and Bai, 2004; Meng and Zhang, 2003; Meng et al., 2003; Wu and Meng, 2003; Yargicoglu et al., 1999). Lipid profiles were changed in different regions of the brain, in lung, heart, liver and kidney (Haider et al., 1981, 1982, 1985). Impairment of visual function was indicated by changes in peak latencies and peak amplitudes of visual-evoked potentials which were found in addition to the oxidative changes (Agar et al., 2000a; Kilic, 2003; Yargicoglu et al., 1999, 2001).  

Blood pressure of rats was lowered significantly both in a dose- and time-dependent manner (LOAEL 20 ppm) which was interpreted as a functional damage to the cardiovascular system. The NOAEL was 10 ppm (Meng et al., 2003).

An inflammatory response in lung tissue of mice was demonstrated at exposure levels of 5 and 10 ppm by a derangement of the balance between pro-inflammatory cytokines (increased levels of IL-6 and TNF-α1) and anti-inflammatory cytokines (decrease of TGF-β1) (Meng et al., 2005).

In summary many endpoints were affected at 10 ppm in studies where this concentration was the lowest tested. A few studies demonstrated specific changes at 5 or 8 ppm. Only minimal effects were detected at 1 ppm. Based on all these studies the overall LOAEL is 5 ppm.

Acute toxicity

Studies on respiratory effects

Lesions in nasal tissue were induced in mice after 24 hours of exposure to 10ppm (Giddens and Fairchild, 1972).

Studies on lethality

Syrian hamsters (N=6) tolerated 4 to 5-hour-exposures to 40 and 200 ppm sulfur dioxide without mortality (LC0200 ppm), whereas 400 ppm sulfur dioxide were lethal within 45 minutes to 1 day following immediate development of respiratory distress. At autopsy greatest mucosal changes were always seen in the trachea and the larger bronchi but the bronchioles were invariably spared (Asmundsson et al., 1973).

Sensitive populations

The predominant response produced by inhalation of sulfur dioxide is bronchoconstriction by a non-allergic mechanism. It is due to contraction of airway smooth muscle via a parasympathetic reflex as well as release of humoral mediators (e. g. Haji et al., 1996). Mediation by receptors in the nose or larynx is suggested as bronchoconstriction is also induced by nose breathing or after isolated exposure of the upper airways, in a condition when virtually all sulfur dioxide is absorbed in the nose (Hahn et al., 1983; Wang et al., 1996).

Entry adopted from the OECD SIAR on sulfur dioxide without modification.