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Carcinogenicity

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Description of key information

No studies are available for sulphur trioxide.  A number of studies of the carcinogenicity of sulphuric acid have been performed using oral gavage, intratracheal instillation and inhalation exposure.  A pubished review of the available animal data is also available.

Key value for chemical safety assessment

Justification for classification or non-classification

The available animal data do not support the classification of sulphuric acid, and therefore sulphur trioxide by extrapolation, for carcinogenicity. Weak evidence of a local carcinogenic effect on the forestomach/oesophagus was seen following lifetime oral gavage of rats with sulphuric acid at the MTD. Similarly, some evidence of a local carcinogenic effect on the respiratory tract was seen in rats treated with sulphuric acid by intratracheal instillation over a lifetime. A synergistic effect was seen in animals instilled with sulphuric acid and benzo(a)pyrene. A weak local carcinogenic effect was also seen in mice gavaged with sulphuric acid at the MTD over a lifetime. In all cases, findings were associated with chronic irritation at the site of contact. Although a number of epidemiological studies report a link between exposure to sulphuric acid mists and laryngeal cancer, the individual studies are imprecise and often do not take sufficient account of confounding factors such as smoking and occupational exposure to other chemicals,

A number of studies (using various animal species) have not demonstrated any carcinogenic effect of inhalation exposure to sulphuric acid mists.

Additional information

No carcinogenicity studies have been performed with sulphur trioxide, however a number of studies are available for sulphuric acid. Sulphur trioxide will rapidly react with water in the atmosphere or at the site of contact (skin, respiratory tract) to produce sulphuric acid, therefore read-across from these studies is appropriate. The suphuric acid carcinogenicity studies and the available epidemiology data are summarised below:

Animal data

Studies in the rat and mouse were performed by Uleckiene & Griciute (1997). In the rat study, weekly lifetime gavage treatment with sulphuric acid (at the MTD) was associated with chronic irritation of the forestomach and oesophagus and slightly increased incidences of forestomach tumours. Administration of sulphuric acid by intratracheal instillation (twice monthly at the MTD) was associated with a slightly increased incidence of respiratory tract tumours; instillation of sulphuric acid also increased the incidence of respiratory tract tumours induced by benzo(a)pyrene. In the mouse study, gavage administration with sulphuric acid (weekly at the MTD) resulted in chronic local irritation of the forestomach and a slight increase in the incidence of benign forestomach tumours. The authors conclude that sulphuric acid is a weak, local carcinogen that may act synergistically with other locally acting carcinogens.

In a study in hamsters (Laskin & Sellakumar, 1978), the effect of exposure to the known carcinogen benzo(a)pyrene (administered by intratracheal instillation) and sulphuric acid (by inhalation) was investigated. No evidence of respiratory tract carcinogenicity was seen in animals exposed for a lifetime to sulphuric acid mist (100 mg/m/3; 6 hours/day, 5 days/week). Clear evidence of respiratory tract carcinogenicity was seen in animals exposed to benzo(a)pyrene, alone and in combination with sulphuric acid; however there was no evidence for co-carcinogenicity in animals exposed to the two compounds.

No effects of exposure to sulphuric acid mists (10 mg/m3) or ozone (0.5 ppm) alone or in combination was seen in rats or guinea pigs exposed for two years (Experimental Pathology Laboratories, 1979).

The OECD SIDS (2001) also reviews these studies and concludes that all present several important deficiencies. It is noted that no carcinogenic effects were observed in studies performed with sulphuric acid mist, although these studies were also considered to have been compromised by deficiencies.

A review of the available animal data by Swenberg and Beauchamp (1997) concludes that there is no evidence for the respiratory tract carcinogenicity following inhalation exposure to sulphuric acid mists.

The available data therefore indicate that sulphuric acid has the potential to act as a local, weak carcinogen following chronic exposure to relatively high levels. Findings are associated with chronic irritation at the site of contact, presumably as a consequence of the low pH of the substance. There is also some evidence that chronic local irritation induced by repeated exposures to sulphuric acid over a prolonged period of time may increase the potency of known genotoxic carcinogens, presumably due to increased cell turnover at the site of contact.

There are a relatively large number of studies investigating the link between occupational (inhalation) exposure to sulphuric acid and the incidence of tumours of the respiratory tract, and specifically the upper respiratory tract.  The epidemiological data have been reviewed in the literature and also by various international bodies.

The IARC (1992) concluded, based on the available human epidemiological data, that there was sufficient evidence to support their conclusion that exposure to ‘strong inorganic acid mists containing sulphuric acid’ is carcinogenic to humans.  It is notable that the IARC have not stated that sulphuric acid per se is carcinogenic.  The IARC’s position was agreed by the Health Council of the Netherlands (2003), who considered the epidemiological, animal carcinogenicity and genotoxicity data, stated that sulphuric acid is likely to be a ‘non-stochastic genotoxic agent’, which is likely to exert its effect through local reduction of pH.  This hypothesis was based on positive results obtained with sulphuric acid in genotoxicity assays in vitro.  In contrast, the OECD SIDS for sulphuric acid (2001) cautions that the available animal data on the carcinogenicity of sulphuric acid following inhalation are negative and that confounding factors (including correction for smoking and exposure to other chemicals) complicate the interpretation of the epidemiological data.  The US ATSDR (1998) concluded base on the available animal and epidemiological data, that there was no evidence to suggest that sulphuric acid by itself is carcinogenic.

Epidemiological data

Soskolne et al (1984) investigated occupational chemical exposure to various chemicals in fifty confirmed cases of upper respiratory tract cancer.  A positive association was reported between exposure to sulphuric acid and all upper respiratory tract cancers, but the association was strongest for cancer of the larynx.  The same authors (Soskolne et al, 1992) report an association between prolonged exposure to high levels of sulphuric acid mists and laryngeal cancer.

A number of the studies identifying a link between sulphuric acid exposure and cancer of the upper respiratory tract were performed in workers involved in the production of ethanol and/or isopropranol.  Wright (1979) cautions that these workers are likely to have been exposed to the alkylating agent and animal carcinogen di-isopropyl sulphate and that this exposure may be an important confounding factor in these studies.

Beaumont et al(1978) investigated the mortality due to lung cancer in workers exposed to sulphuric acid (and other acid) mists in workers involved in steel pickling.  The authors identified a slightly (SMR 1.39) elevated risk of lung cancer in workers exposed to sulphuric acid mist only.  The risk was slightly higher (SMR 1.58) among those with daily exposure, however this was not significant when compared to a cohort of steel workers.  A greater and significantly elevated risk was seen in workers exposed to acids other than sulphuric acid.  teenland (1997) followed a cohort of 1031 men exposed to acid mists in the US steel industry.  Following correction for smoking incidence and alcohol consumption, a rate ratio of 2.2 was observed for laryngeal cancer.  The same author (Steenland et al, 1987) reports an incidence rat ratio of 2.30 for laryngeal cancer in 879 male steelworkers; (Steenland & Beaumont, 1989) report an SMR of 1.56 for lung cancer in 1165 steel workers after correction for smoking incidence.

Sathiakumar et al(1997) reviewed the available epidemiological data and concluded that, in aggregate, there was a moderate association between high or moderate exposure to sulphuric acid and laryngeal cancer.  They caution, however, that individual studies are imprecise and do not adequately take into account confounding factors such as smoking and exposure to other occupational chemicals.

Petrauskaite et al (2002) did not identify any increased risk of lung cancer in the general population in the vicinity of a Lithuanian sulphuric acid plant.

Parent et al (2000), reviewed 99 confirmed cases of oesophageal cancer and analysed for an association with occupational chemical exposure.  The authors conclude that the data provide some support for an association with exposure to sulphuric acid.

Englander et al (1988) did not identify any increased risk of respiratory tract tumours in workers in a sulphuric acid plant.  An increased incidence of bladder cancer (SMR 1.17) was identified in this study, however the authors consider this result to be spurious.

Coggon et al (1996) identified a moderately increased risk (OR 2.0) of upper aerodigestive tract cancers in men occupationally exposed to high levels of sulphuric acid or hydrochloric acid or at least five years.

Teta et al (1992) identified a slight increase in the incidence of upper respiratory tract cancer and the production of alcohol using the strong acid process but not the weak acid process.

Forastiere et al (1987) identified an increased risk of laryngeal cancer in soap production workers and suggested a link with sulphuric acid.

Alderson & Rattan (1980) performed a study of isopropranol workers in the UK and identified an increased incidence of nasal cancer.  The observed increase was, however, due to a single case in the exposed cohort.

Pesatori et al (2002) investigated cancer incidence in a cohort study of Italian sulphuric acid production workers did not reveal any increased mortality from laryngeal cancer (SMR 130) or lung cancer SMR (82). An increased mortality from myeloid leukaemia (SMR 523) seen in this study is not attributable to sulphuric acid exposure.

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