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Description of key information

A large number of repeated dose inhalation studies have been performed with sulphuric acid.  Sulphur trioxide reacts rapidly with moisture in the atmosphere and respiratory tract to form sulphuric acid, therefore these studies are relevant to sulphur trioxide.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEC
0.3 mg/m³

Additional information

Sulphur trioxide reacts rapidly with moisture in the atmosphere and respiratory tract to form sulphuric acid, therefore these studies are relevant to sulphur trioxide.

A large number of repeated dose toxicity studies have been performed with sulphuric acid, all of which used inhalation exposure to sulphuric acid aerosol/mist, in several animal species.

In the study by Kilgour et al (2002), groups of female rats were exposed to aerosols of sulphuric acid (mists) at target concentrations of 0, 0.2, 1.0 or 5.0 mg/m3 for 6 hours a day, 5 days a week for 5 or 28 days. Additional groups exposed to 0 or 5.0 mg/m3 (nominal concentration) for 28 days were investigated following recovery periods of 4 or 8 weeks Effects of exposure were limited to the larynx.  Squamous metaplasia and significant cell proliferation was seen following exposure to 1.38 and 5.52 mg/m3 for 5 and 28 days; findings had decreased in severity following the recovery periods. Findings following exposure to 0.3 mg/m3 for 28 days were limited to minimal metaplasia (with no proliferation); no effects were apparent following exposure to 0.3 mg/m3 for 5 days. The absence of systemic toxicity is consistent with a local irritant effect of the substance, attributable to its low pH.

In the study by Last & Pinkerton (1997), groups of male Sprague-Dawley rats were exposed (whole body) to aerosols of sulphuric acid at levels of 0, 20, 100 or 150 ppm for 30 or 90 days. Bodyweights and lung weights were measured. The lungs were investigated histopathologically, morphometrically and biochemically for markers of fibrosis. No effects of treatment were observed in any group.

Schwartz et al (1973), investigated the morphological effects of sulphuric acid droplets on the respiratory tract in various laboratory animal species.  Male Sprague-Dawley rats, male Swiss-Webster mice, male Hartley guinea-pigs and female rhesus monkeys were exposed to different concentrations of sulphuric acid droplets of mass median aerodynamic diameter of 0.3 to 0.6 micrometer.  Animals were killed at various times. Lungs were fixed and tissues (including nasal septum, trachea, major bronchi, and terminal respiratory units) were selected for light microscopy and scanning electron microscopy. No effects were seen in exposed monkeys or rats.  Severe effects were seen in guinea pigs; less marked findings were apparent in mice. The authors conclude that guinea-pigs and mice are sensitive to sulphuric acid and that non human primates do not show irreversible structural changes after short term sulphuric acid exposure.  Rats and guinea pigs were exposed (6 hours/day, 5 days/week for 6 months) to sulphuric acid aerosols (10 mg/m3 ~1 um particle size).  Bodyweights were measured; lung weights were measures at termination. Blood samples were taken for the assessment of haematological and clinical chemistry data. The lungs were investigated histopathologically. No effects of treatment were limited to slight histopathological change (minimal proliferation of alveolar macrophages and a slight loss of tracheal cilia).

Alarie et al (1973) showed that chronic (18 month, continuous) inhalation exposure of monkeys to sulphuric acid resulted in structural and functional changes of the respiratory tract at the highest concentrations of 2.43 mg/m3 (MMAD 3.60 um) and 4.79 mg/m3 (0.73 um). No effects were seen in guinea pigs exposed to 0.1 mg/m3 (MMAD 2.78 um) or 0.08 mg/m3 (MMAD 0.84 um) for 12 months.

In the study of Gearhart & Schlesinger (1989) male New Zealand White rabbits were exposed (nose only) to aerosols of sulphuric acid (250 ug/m3; MMAD 0.3 um) for 1 hours a day, 5 days a week for 4, 8, or 12 months.  Exposure was found to induce airway hyperresponsiveness, a shift towards smaller airway size, increases in the proportions of secretory cells and reduced tracheobronchial mucociliary clearance.  The same authors (Gearhart & Schlesinger, 1988) exposed groups of male New Zealand white rabbits to submicron particles of sulphuric acid aerosols (250 ug/m3; MMAD 0.3 um) for 1 hour/day; 5 days/week for up to 1 year.  Changes were seen on the structure and function of the respiratory tract; early changes included the reduced mucociliary clearance of inhaled particles.  In a further study (Schlesinger et al, 1983), the authors concluded that intermittent daily 1-hr exposures of rabbits to sulphuric acid mist at 250-500 ug/m3 produced changes in the rate of mucociliary clearance from the bronchial tree and produced histological alterations indicative of increased secretory activity.  This study shows that choice of exposure route is an important consideration when performing aerosol inhalation since efficient filtration in the nasal passage may significantly reduce the amount of the test material delivered to the bronchial tree.

Lewkowski et al (1979), exposed male rats and guinea pigs to submicron particles of sulphuric acid for periods of time of 6 -14 weeks. Pulmonary function was found to be affected in rats (but not in guinea pigs). Effects on blood gas parameters are likely were not seen consistently but may be secondary to exposure; inconsistent effects on spontaneous locomotor activity are of unclear toxicological significance.

In the study of Cavender et al (1977) male rats and female guinea pigs were exposed to sulphuric acid aerosols (5 or 10 mg/m3) and ozone (1 -2 ppm) , alone and in combination, for periods of 2 -7 days. In an additional study, animals were exposed to sulphuric acid alone (10, 30 or 100 mg/m3) for five days. In a final study, animals were exposed to sulphuric acid alone at 20 ug/m3 with varying particle sizes. No effects of exposure to sulphuric acid were seen in rats of any group. Mortality and alveolitis was seen in guinea pigs exposed to concentrations of greater than 20 mg/m3 sulphuric acid.The same authors (Cavender et al, 1978) rats and guinea pigs were exposed (6 hours/day, 5 days/week for 6 months) to sulphuric acid aerosols (10 mg/m3 ~1 um particle size).  Bodyweights were measured; lung weights were measures at termination. Blood samples were taken for the assessment of haematological and clinical chemistry data. The lungs were investigated histopathologically. No effects of treatment were limited to slight histopathological change (minimal proliferation of alveolar macrophages and a slight loss of tracheal cilia).  In a further study by this group (Cockrell et al, 1978)  guinea pigs were exposure to sulphuric acid (25 mg/m3, ~1um particle size) for 2 days (6 hours/day). Lung effects were investigated by light microscopy and electron microscopy (SEM, TEM). Exposure to sulphuric acid produced microscopic changes characterised by segmental alveolar haemorrhage, alveolar oedema, and the proliferation of alveolar macrophages and Type II pneumocytes

Alarie et al (1973) exposed groups of male and female monkeys (Macaca irus; 9 animals/group) continuously to either filtered air (control group) to sulphur dioxide alone (5.12 ppm) or to mixtures of sulphur dioxide (0.1-5 ppm) with fly ash (~0.5 mg/m3, MMAD ~5 um) and/or sulphuric acid (0.1-1 mg/m3; MMAD 0.5-3.35 um) for 18 months.   Groups of 50 female and 50 male guinea pigs were also continuously exposed to either filtered air, to 0.9 mg/m3 sulphuric acid (MMAD 0.49 um) or to fly ash (~0.46 mg/m3, MMAD 3.50-5.31 um) and sulphuric acid mist (0.08 mg/m3, MMAD 0.54 or 2.23 um) for 12 months.

In a study by Laskin & Sellakumar (1978), forty male Syrian Golden hamsters were exposed via inhalation for 6 h/day, 5 days/week to 100 mg/m3 sulphuric acid mist (MMAD 2.6 um), for a period of 30 days.  Treatment-related effects were limited to transient signs of respiratory irritation and histopathological effects on the larynx and trachea.

Lewis et al (1973) exposed thirty two female Beagle dogs (whole-body) to filtered air (controls) or to 0.9 mg/m3 sulphuric acid, 13.4 mg/m3 sulphur dioxide or a combination, for 21 h/day for 620 days.  Sixteen of the dogs had prior exposure to 48.9 mg/m3 nitrogen dioxide for 191 days to induce emphysema. Exposure to sulphuric acid significantly reduced carbon monoxide diffusion capacity, residual volume, total lung volume and weight, heart weight, and increased total expiratory resistance.  Furthermore, exposure to sulphuric acid tended to decrease the average response of all pulmonary function measurements except for the ratio of residual volume/total lung capacity and total expiratory resistance.

In the study of Schlesinger et al (1992) groups of 5 male New Zealand White rabbits were exposed via the nose to filtered air with water vapour (controls), 125 ug/m3 sulphuric acid (MMAD: 0.3 um), ozone (0.1 ppm), or their combination for 2h/day, 5d/week, for periods of 4, 8 or 12 months, with an additional group allowed a 6-month recovery period after a 12 month exposure period. Findings related to sulphuric acid exposure were limited to reduced mucociliary clearance of inhaled ferric oxide particles and increased numbers of secretory cells in the small airways after 12 months exposure.  In an additional study by the same group (Schlesinger, 1990), groups of 5 male New Zealand White rabbits were exposed via nasal mask to temperature- and humidity-conditioned air (controls), or to submicron (MMAD 0.3 um) sulphuric acid aerosols of 0.05 mg/m3 (for 1, 2 or 4 hours/day), or 0.1 mg/m3 (for 0.5, 1 or 2 hours/day) on 14 consecutive days. Exposure to 0.05 mg/m3 sulphuric acid for 4h/day or to 0.1 mg/m3 for 2h/day resulted in enhanced clearance of particles

Summary of studies from OECD SIDS

One study was performed according to a relevant guideline (OECD 412) and to GLP, although only the respiratory tract was investigated pathologically.  In this study, nose-only exposure of rats for 6h/d, 5d/wk for a period of 28 days to sulphuric acid aerosols resulted in pathological changes (squamous metaplasia) and increased cell proliferation in the larynx only.  Changes of this type are commonly seen in rats exposed to irritant chemicals.  Minimal squamous metaplasia was observed in the laryngeal epithelium following exposure to the lowest concentration used (0.3 mg/m3); this effect was fully reversible.  Exposure to 1.38 mg/m3 caused more severe metaplasia, accompanied by cell proliferation.

Whereas the other studies have deficiencies and were performed using different experimental conditions, collectively, they show consistent effects in the different animal species studied.  Among the different end points measured, few or no alterations were observed after repeated exposure to sulphuric acid aerosol at concentration up to 10 and 20 mg/m3 in rats and guinea pigs respectively.  The main alterations observed were microscopic changes in the respiratory tract (minimal proliferation of alveolar macrophages and loss of tracheal cilia).  Sulphuric acid aerosols had no effect on haematology or clinical chemistry parameters, bodyweight and/or lung weight.  The results support the hypothesis that sulphuric acid aerosols had a local effect, but had no systemic effect following inhalation exposure in these studies.  Studies performed in rabbits have largely investigated the effects of sulphuric acid on the respiratory tract clearance of labelled particles and histopathological changes.  Sulphuric acid aerosols at concentrations ranging from 50-500 µg/m3 induced alterations of both tracheobronchial and respiratory region clearance as well as microscopic changes (mainly reversible increases in epithelial secretory cell numbers in the absence of any evidence of inflammation.  It is notable that both tracheobronchial and respiratory region clearances were reported to be accelerated or retarded, depending on the individual study.  In monkeys, only the highest concentrations of sulphuric acid mist (2.43 and 4.79 mg/m3) resulted in deleterious effects on pulmonary structure and function; however no effects on bodyweight, survival, haematological and clinical chemistry parameters were observed.  In hamsters exposed to high concentration of sulphuric acid mist (100 mg/m3) with large particle size (2.6 µm), microscopic alterations were seen in the larynx and trachea.  Exposure of dogs to 0.9 mg/m3 sulphuric acid mist induced alterations in pulmonary functions and in organ weight (lung and heart).  Overall, the results indicate a high variability in the response to repeated inhalation, depending on the species and endpoint(s) studied.

Taken together, the studies show that toxicity is confined to changes in the structure and function of the respiratory tract; the observed changes are related to the irritant properties of sulphuric acid and are attributable to the hydrogen ion.  No data are available on repeated dose toxicity following oral or dermal routes of exposure.


Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: larynx

Justification for classification or non-classification

Classification for severe effects after repeated or prolonged exposure (R48) is not proposed. While the studies performed with sulphuric acid clearly show the potential for toxicity following repeated/prolonged exposure to low concentrations, there is clearly no potential for systemic toxicity and the effects seen in these studies are essentially a consequence of the local corrosivity/irritancy. Given the R35 and proposed R23 classification, additional classification with R48 is not considered to be necessary or appropriate.

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