Registration Dossier

Diss Factsheets

Administrative data

Description of key information

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. No studies with the oral route were available.  However, there is no potential for oral exposure following the normal use of sulphuric acid; the routes of exposure relevant to occupational exposure are inhalation and dermal. Information from acute toxicity studies indicates much greater sensitivity following inhalation exposure and no systemic toxicity following oral exposure. Testing for repeated dose toxicity by the oral route cannot therefore be justified on scientific grounds. Given the corrosive nature of the substance, testing is also not justified for reasons of animal welfare.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study is published, but was performed largely in compliance with a recognised guideline and is GLP compliant.
Qualifier:
according to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
: Exposure for 5 or 28 days; pathology limited to the respiratory tract
Principles of method if other than guideline:
The study was performed to OECD 412 with the addition of a 5-day exposure. Pathology was limited to the respiratory tract.
GLP compliance:
yes
Species:
rat
Strain:
other: ALPK:APfSD (Wistar)
Sex:
female
Details on test animals or test system and environmental conditions:
Rats were housed 5 per cage, in multiple rat racks suitable for animals of this strain and the weight range expected during the course of the study.
The rats were transferred to clean cages and racks as necessary during the studyBoth temperature and relative humidity were measured and recorded daily and the recorded values were within the specified ranges.
Diet (CT1) supplied by Special Diet Services Limited, Witham, Essex, UK and mains water, supplied by an automatic system, were available ad libitum, except during exposure.
Each batch of diet was routinely analysed for composition and for the presence of contaminants. Water was also periodically analysed for the presence of contaminants. No contaminants were found to be present in the diet or water at levels considered to be capable of interfering with the purpose or outcome of the study. The animals were housed under the experimental conditions for 13 days at CTL, prior to the start of the study (animals arrived 12 November 1998; first exposure 25 November 1998). The study was divided into 2 replicates (randomised blocks), each containing 10 cages, one per treatment group. Computer-generated, random number permutations were used to allocate the cages within each replicate to an experimental group.
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: Particle sizes were 0.62, 0.83 and 0.94 um, respectively.
Details on inhalation exposure:
The rats were exposed nose-only to the test atmospheres. Animals were restrained in polycarbonate tubes supplied by Battelle, Geneva, Switzerland. These were inserted into a PERSPEX exposure chamber. The chamber was covered with a stainless steel cone and stood on a stainless steel base. The atmosphere was shown to be acceptably stable over approximately 30 minutes before exposure of the test animals. During this period the holes of the exposure chamber were plugged. The animals were exposed for 6 hours per day, 5 days per week, for a period of 28 days.Test atmospheres were generated using a glass concentric - jet atomiser to generate atmospheres into 2 reservoir chambers (each fitted with a cyclone), one serving the exposure chambers for groups 4&5 and 6&7, and another serving exposure chambers for groups 8, 9 & 10. Clean, dry air (dried and filtered using equipment supplied by Atlas-Copco, Sweden) was passed through the atomiser at nominal flow rates (given below) for each group respectively and carried the atmosphere to each of the exposure chambers (internal volume of 36.8 litres), in order to achieve a minimum of 12 air changes per hour. Air flows were monitored and recorded at approximately 30 minute intervals using variable area flowmeters (KDG Flowmeters, Burgess Hill, Sussex, UK) and were altered as necessary to maintain the target concentrations.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The particulate concentration of each test atmosphere, close to the animals’ breathing zone, was measured gravimetrically at least twice during exposure. This was done by drawing each test atmosphere, at a known flow rate, for a known time, through a 25mm diameter, polyvinyl chloride (PVC) GN-4 filter housed in a Delrin open-faced filter holder (both filters and holders supplied by Gelman Sciences Limited, Northampton, UK). The filter was weighed before and after the sample was taken. The aerodynamic particle size distribution of each test atmosphere was measured at least once during exposure period, using a Marple Cascade Impactor (supplied by Schaeffer Instruments Limited, Wantage, Oxon, UK) which aerodynamically separates airborne particles into pre-determined size ranges. The amount of aerosol, by weight, in each size range, was then used to calculate the aerodynamic particle size distribution of the aerosol. Using a microcomputer, the data were transformed using a log/probit transform and a linear regression derived from the cumulative data.
Using this regression line, the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were calculated.
Duration of treatment / exposure:
Animals were exposed for 6 hours/day; 5 days/week for 5 or 28 days.
Frequency of treatment:
Animals were exposed for 6 hours/day; 5 days/week for 5 or 28 days.
Remarks:
Doses / Concentrations:
0.00, 0.2, 1.0, 5.0 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0.00, 0.30. 1.38, 5.52 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
10 females
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
For examination of effects in the lung, 5 designated rats per group, per time point, were implanted subcutaneously with osmotic minipumps (Alzet 2ML1) for delivery of BrdU 7 days before termination. The minipumps contained BrdU at a concentration of 15mg/ml.
At post mortem, the lungs (tracheas attached but larynx removed) were excised and weighed, prior to inflation with 10% neutral buffered formalin. The lungs were fixed in 10% neutral buffered formalin for 24 hours. The tissue was trimmed and processed to paraffin wax blocks and sections made and stained to reveal BrdU positive nuclei. Labelling indices (LI) were determined for the central acinar region and in the terminal bronchiole regions of the lung. LI were determined by counting the number of BrdU labelled cell nuclei and the total number of cell nuclei (labelled and non labelled). LI were then determined by dividing the number of BrdU labelled cells by the total number of labelled and non labelled cells, the result being expressed as a percentage.Labelling indices were determined for the small intestine. The small intestine has an inherently high rate of cell turnover and as such acts as a positive control for the BrdU immunostaining. Pulse labelling with tritiated thymidine, followed by autoradiography, was used for the assessment of rate of cell proliferation in the nasal passages; thymidine being incorporated into DNA during s-phase.
Five designated rats per group were injected intra-peritoneally with tritiated thymidine at a dose level of 1¿Ci/g bodyweight, approximately one hour prior to scheduled termination. At post mortem, the heads from all designated animals were removed, excess skin and muscle removed, the brain excised and the nasal cavity perfused with 10% formol saline through the nasopharynx. The head was then immersed in formol saline followed by decalcification with 20% formic acid. After processing, six standard sections were produced to include all different epithelial cell types and accessory nasal structures (Appendix I). The six sections were exposed to nuclear emulsion (Ilford K2) for 8-10 weeks. Sections were developed and examined by light microscopy. Labelling indices (LI) were determined for each of the 6 nasal passage levels. LI were determined by counting the number of thymidine labelled cell nuclei and the total number of cell nuclei (labelled and non labelled). LI were then determined by dividing the number of thymidine labelled cells by the total number of labelled and non labelled cells, the result being expressed as a percentage.
Where more than one section was examined from a tissue, results for each level of that tissue are reported separately.
Sacrifice and pathology:
AFrom all animals surviving to scheduled termination (day 29 for main study animals and after 4 or 8 weeks monitoring in recovery animals), the lungs were removed, trimmed free of extraneous tissue and weighed (with trachea attached but larynx removed, each pair of lungs weighed together). t post mortem the larynx was removed from all animals and fixed in 10% neutral buffered formalin for 24 hours. The tissues were trimmed and processed to paraffin wax blocks and three standard sections of larynx produced, taken at the level of the base of the epiglottis, through the ventral pouch and the cricoid cartilage to include all different epithelial cell types of the larynx and underlying seromucinous glands (Appendix I).
Standard sections of larynx from animals receiving BrdU were stained to reveal BrdU positive nuclei, while those from animals receiving thymidine, were exposed to nuclear emulsion (Ilford K2) for 8-10 weeks before being developed. For both the BrdU and thymidine animals, cell replication rates in the larynx were expressed as unit length labelling indices (ULLI).
In ULLI’s, the basement membrane length is substituted for the total cell count in the labelling index equation. ULLI’s were determined by counting the number of BrdU (and thymidine) labelled nuclei and dividing the result by the length of underlying basement membrane; ULLI’s being expressed as the number of BrdU (or thymidine) labelled cells per unit length (mm) of epithelium. The length of the basement membrane was determined using a Kontron Image Analyser attached to a Leitz light microscope.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Dose descriptor:
LOAEC
Effect level:
0.3 mg/m³ air (analytical)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Findings at 0.3 mg/m3 were limited to minimal metaplastic change after 28 days, considered to be an adaptive response to a respiratory irritant.
Critical effects observed:
not specified

There were no deaths, no signs of toxicity, and no adverse effects on bodyweight or lung weight in any treatment group.  There were no macroscopic findings in animals killed at term.  Microscopically, no treatment related changes were seen in either the lung or the nasal cavity.   The major treatment related effect was squamous metaplasia of the ventral epithelium of level 1 of the larynx, the severity of which was concentration-dependant.  In the 5 day satellite study, the NOEL for this effect was 0.30mg/m3.  In the 28 day study, squamous metaplasia of the larynx was seen at all concentrations (including minimal squamous metaplasia in 3/10 animals exposed to 0.30mg/m3); the severity of this finding was directly related to exposure concentration.  After 4 and 8 weeks recovery following exposure to the highest concentration (5.52mg/m3) evidence of metaplasia remained, although it was less severe than that seen immediately following the 28-day exposure period.  No increases in cell proliferation were detected in either the lung or the nasal cavity at either 5 or 28 days; results were in agreement with the pathological assessment.  In the larynx, a treatment related increase in cell turnover was seen in the same region of level 1 as the exposure related pathological finding of squamous metaplasia, with a NOEL for this finding of 0.30 mg/m3 for both 5 and 28 days. 

Conclusions:
Following inhalation exposure to sulphuric acid mists, treatment-related findings were limited to histopathology and cell proliferation of the larynx, consistent with a local irritant effect of the substance
Executive summary:

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 LOAEC for this study is therefore considered to be 0.3 mg/m3.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
0.3 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
Klimisch score = 1. Study compliant with current test guidelines and GLP.

Additional information

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 inhalation 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. Actual measured concentrations were 0.00, 0.30. 1.38, 5.52 mg/m3. 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.

 

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 measured at termination. Blood samples were taken for the assessment of haematological and clinical chemistry data. The lungs were investigated histopathologically. 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 hyper-responsiveness, 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; no data are required given the corrosive nature of the substance.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
A waiver is presented for this endpoint

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Guideline compliant study

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 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 proposed classification as Corrosive Category 1A, further classification based on repeated exposure is not considered to be necessary or appropriate.