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Description of key information

Based on read-across following an analogue approach:
Oral:
NOAEL systemic: 1000 mg/kg bw/day for rats (subacute exposure)
Dermal:
No dermal repeated dose toxicity studies available.
Inhalation:
NOAEC systemic: 4.2 mg/m³ for rats (subchronic exposure to 100% respirable particles); 280 mg/m³ based on total ashes (residues), cenospheres containing < 1.5% respirable particles
LOEC/NOAEC local: 4.2 mg/m³ for rats (subchronic exposure to 100% respirable particles); 280 mg/m³ based on total ashes (residues), cenospheres containing < 1.5% respirable particles
NOAEC local: 30 mg/m³ for rats (subacute exposure to 100% respirable particles); 2000 mg/m³ based on total ashes (residues), cenospheres containing < 1.5% respirable particles

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
4.2 mg/m³
Study duration:
subchronic
Species:
rat

Additional information

There are no substance specific data available on the repeated dose toxicity of ashes (residues), cenospheres.

Ashes (residues), cenospheres and ashes (residues), coal share a common production process as substances derived from coal combustion. Ashes (residues), cenospheres represent a fraction of ashes (residues), coal separated by physical means. Both substances exhibit similarities in physicochemical properties and chemical composition. The main differences consist in a much lower content of water soluble matter and the particle size distribution of ashes (residues), cenospheres.

In terms of hazard assessment, studies available for ashes (residues), coal are therefore taken into account by read-across following an analogue approach, the results of these studies being considered a worst case for ashes (residues), cenospheres.

 

Oral

Ashes (residues) were tested for subacute oral toxicity in Wistar rats following OECD guideline 407 (adopted on 27th July, 1995) and in compliance with GLP (Plodíková, 2008). The test material was administered daily by gavage to groups of 5 male and 5 female rats as a suspension in 0.5% methyl cellulose at 0, 250, 500 and 1000 mg/kg bw/day for 28 days. Two additional (satellite) groups, each consisting of 5 male and 5 female rats, was concurrently treated with vehicle or the test material at 1000 mg/kg bw(day). These groups were observed for 14 days following the final exposure.

Clinical observations and health status control were performed daily. Body weight and food consumption were measured weekly and a detailed clinical observation was carried out once before the beginning of the treatment period and weekly thereafter. Water consumption was measured twice a week. Functional observations were performed in the last week of the study. Urinalysis, haematological and biochemical analysis as well as gross necropsy of animals of the main and satellite groups were conducted at the end of the treatment and observation periods, respectively. Selected organs were removed for weighing and histopathological examination.

There were no unscheduled deaths during the test. No clinical signs of toxicity were observed. The health condition of the animals was good during whole study and functional observation showed no effect of the test substance. No adverse effects on body weight gain were detected. No adverse effects on dietary intake or food conversion were noted.

Statistically significant changes in haematological values were observed in treated males compared to vehicle controls. Prothrombin time and fibrinogen values were increased at 500 and 1000 mg/kg bw/day. Platelet count was increased at 250 mg/kg bw/day. Males in the satellite group showed increased prothrombin time and mean corpuscular volume and decreased total erythrocyte count. However, most changes were marginal and all parameters measured were reported to be within physiological limits, thus not considered to be toxicologically relevant. No statistically significant changes were observed in females of the main and satellite groups.

Biochemical examinations showed statistically significant increases in alkaline phosphatase activity and glucose concentration in females of the satellite group at the dose level of 1000 mg/kg bw/day. All parameters measured were, however, reported to be within physiological limits. No effects were observed in males.

A statistically significant decrease in urine volume was seen in male rats of the main group treated with 1000 mg/kg bw/day. No further significant effects in urinary parameters were observed.

Slight but statistically significant changes in absolute and relative weights of some endocrine glands were seen in both males and females. Absolute thymus weight was increased in males at 250 mg/kg bw/day in the main group and at 1000 mg/kg bw/day in the satellite group. Absolute pituitary gland weight was decreased in males at 500 and 1000 mg/kg bw/day and in females at 250 and 1000 mg/kg bw/day. The relative weight of this gland was decreased in males at 500 mg/kg bw/day and in females at 250 and 1000 mg/kg bw/day. Correlations with microscopic changes were detected only in the pituitary gland. A slight increase in the incidence of cyst and pseudocysts was recorded at all treated groups and control groups. These morphological changes are commonly observed in the rat strain used. Differences in the incidence between control and treatment groups were considered to be of no toxicological significance.

Histopathological examination revealed inflammation of the liver both in treated and control animals of both sexes (with protracted effect in males). An increased incidence of oedema in the prostate gland was recorded in treated males of the main group and in both control and treated males of the satellite group. Due to absence of other changes in biochemical parameters showing functional disturbance, this was considered to be of no toxicological importance.

Based on the overall results of the study, the NOAEL (No-Observed-Adverse-Effect-Level) was considered to be 1000 mg/kg bw/day for both male and female rats.

 

Dermal

This information is not available.

Based on the available data on the physicochemical properties of the ashes (residues), cenospheres as well as on toxicological data from the analogue substance ashes (residues), coal, systemic and/or local toxic effects after repeated dermal exposure are unlikely to occur, mainly due to the lack of biological reactivity and bioavailability via this exposure route. Therefore, testing on the repeated dermal toxicity of the substance is not considered necessary and should be avoided for the sake of animal welfare.

 

Inhalation

Young adult male Sprague-Dawley rats were exposed in a whole body exposure chamber to fly ash in two series of experiments. In the first series, animals were exposed to 0.6 mg/m³, 8 h/day for 7, 50 and 90 consecutive days. No relevant morphological effects were observed, and therefore a longer and higher concentration series was conducted. In the second series, animals were exposed to 4.2 mg/m³ of fly ash, 8 h/day for 90 and 180 consecutive days. In both series, negative control animals were exposed to clean air under identical conditions. The fly ash was obtained from the electrostatic precipitator hoppers of a power plant burning western, low-sulphur, high-ash coal, and size-classified to remove most particles larger than 3 µm in aerodynamic diameter. The analyzed MMAD was about 2 µm and the GSD 1.52.

Animals were observed for mortalities and clinical signs, and body weights were recorded prior to and at the end of the corresponding exposure periods. Gross pathology and histopathological examinations were conducted only on lung tissue. Other examinations included measurements of fly ash lung burden as well as lung DNA, RNA and protein contents. Furthermore, tracheal tissue culture techniques were used for determinations of mucus glycoprotein synthesis and secretion rates; pulmonary alveolar macrophages and haematopoietic progenitor cell kinetics were analyzed.

No unscheduled mortalities occurred, no effects on body weight and no clinical signs of toxicity were noted. No pathological effects were found in the lower exposure group. In the high exposure group, light microscope evaluation of large airway and pulmonary parenchyma showed higher concentrations of pulmonary alveolar macrophages in the alveolar lumens and refractile brownish pigment was visible within these cells, which was considered to be fly ash. The pulmonary alveolar macrophages in the lungs of exposed rats were significantly larger compared to the control animals. Alveolar septal walls occasionally were observed to contain small cellular aggregates consisting of some mononuclear leukocytes admixed with brownish particulate material. The observed differences between exposed and control groups appeared to have minimal impact, if any, on the health status of the rats.

Scanning electron microscope evaluation of the lung airways focused on the centriacinar region, since this anatomical site is especially sensitive to damage by a variety of inhaled irritants. Morphological differences were not apparent between lungs of control and exposed rats. Back-scatter electron studies showed clumping and accumulation of particles in pulmonary alveolar macrophages.

Deposition of fly ash increased time-dependently and the maximal lung burden was ca. 4 mg at the end of the 180-days exposure period. No significant changes were observed in the lung DNA contents (RNA and protein contents not reported). In the first series of experiments (low dose), a progressively decreasing rate of glycoprotein secretion by cultured rat trachea was observed. In the second series (high dose), glycoprotein secretion rates of exposed rats were increased above control values for rats exposed for 6 months. Macrophages lavaged from lungs of exposed rats were more numerous and yielded more progenitor cell colonies in culture than from controls.

In summary, using light microscopy and scanning electron microscopy, histological and cellular observations showed large numbers of small fly ash particles in the lung. However, there was no evidence of spontaneous lung disease and the animals were in good health at the end of the 180 days of exposure to 4.2 mg/m³. No major adverse effects were observed. The only effects observed included small changes in some biochemical parameters and increased numbers of macrophages in the lung lumens. Additionally, the observed increase in colony-forming units of alveolar macrophages in culture from exposed animals without increases in activity of haematopoietic progenitor cells was indicative of recruitment of macrophages within the lung and activation of lung reserve progenitors as a direct result of deposition of fly ash. This response was considered an important natural response to inhaled particles and not being unique to coal fly ash. Based on these findings, 4.2 mg/m³ of respirable coal fly ash was considered a NOAEC for systemic effects and a LOEC for local effects (Raabe et al., 1982).

The respirable fraction of Ashes (residues), cenospheres typically accounts for < 1.5% of the total mass (s. Particle size distribution). Accordingly, the systemic NOAEC/local LOEC value mentioned above correspond to a systemic NOAEC/local LOEC of ca. 280 mg/m³ based on total Ashes (residues), cenospheres.

In another study, the effects of coal fly ash on lung pathology and the immune system in rats were examined. Groups of 20 male Wistar rats were exposed in whole body exposure chambers to 0, 10, 30, or 100 mg coal fly ash/m³ for 6 h/day, 5 days/week for 4 weeks. Additionally, 4 groups of 3 animals were exposed to 0 and 100 mg coal fly ash/m³ for 1 week, or for 1 week followed by a 3-week recovery period in clean air. The MMAD (mass median aerodynamic diameter) of the particles ranged between 1.9 and 2.8 µm. Clinical signs and body weight were recorded daily and at weekly intervals, respectively. Histopathology of the lung, urinalysis, haematology, and clinical chemistry were also performed.

No changes in condition, health, or behaviour were observed. Animals exposed to 100 mg/m³ gained slightly, but significantly, less weight than the controls. A concentration-related increase in absolute and relative lung weight was observed in animals exposed for 4 weeks. Both absolute and relative liver weights were lower in the animals of the 10 and 100 mg/m³ exposure group compared to controls, without showing a concentration-response relationship. Animals exposed to 100 mg/m³ for 1 week, and for 1 week with a 3-week recovery period, showed a significantly increased lung weight.

No treatment-related changes were observed in urine volume or density or in haematological parameters. Mean alkaline phosphatase activity was statistically significantly higher and mean total protein value was statistically significantly lower in the 100 mg/m³ group than in controls. No differences in the other groups and no treatment-related changes were observed in the other parameters.

At macroscopical examination of the 4-week-exposed rats, lungs of coal fly ash-exposed animals were diffusely dark red/black. The mediastinal lymph nodes were enlarged in half of the rats of all exposure groups, and were dark red in most of the animals exposed to 30 mg/m³ and in all animals exposed to 100 mg/m³. Lungs of rats exposed for 1 week had a normal pink appearance. No histological changes were detected in control lungs. After 1 week of exposure to 100 mg/m³, free coal fly ash particles in bronchi and bronchioles, alveoli, and alveolar septa were occasionally observed. However, alveolar macrophages diffusely throughout the whole lung were moderately laden with black material. Alveolar septa showed slightly increased cellularity.

After 4 weeks of exposure, the number of free particles as well as alveolar macrophages appeared to be slightly increased. However, all macrophages were laden with black material in a concentration-related way varying from very slight/slight in the 10 mg/m³ group, to slight/moderate in the 30 mg/m³ group, to moderate/severe in the 100 mg/m³ group. The alveolar septa showed slightly to moderately increased cellularity (presumably caused by proliferation of type II cells), a mononuclear cell infiltrate (mainly macrophages and monocytes), and a minimal fibrotic reaction (fibroblasts and collagen) in animals exposed to 100 mg/m³. An increased number of perivascular lymphocytes was also noticed in this group. The severity and incidence of the lung changes showed clearly concentration-related increases, since animals exposed to the lower concentrations showed less and less severe changes. In the mediastinal lymph nodes black deposits were seen similar to the lungs. Lymphocytic hyperplasia was mainly observed in the paracortical area. In addition, prominent germinal centres were regularly observed in exposed rats. These changes were increased in a concentration-related manner.

After a 1-week exposure followed by a 3-week recovery period, the histological picture was identical to that after exposure for 1 wk. Free particles were detected at the surface of trachea, bronchi, bronchioles, and alveoli in all coal fly ash-exposed rats. Coal fly ash mostly appeared as aggregates of particles smaller than 1μm. Alveolar macrophages in coal fly ash-exposed rats appeared to be larger than those from control rats. In the other organs examined, no histological changes were observed.

Taken together, subacute inhalation of respirable coal fly ash in rats resulted in an accumulation of fly ash particles in lungs, slight fibrotic pulmonary reaction, slight to severe lymphocytic hyperplasia in mediastinal lymph node and slightly to moderately increased septal cellularity at 100 mg/m³. The fibrotic reaction and the overall severity grade of the other effects observed were considered adverse effects due to the high particle load, and therefore 100 mg/m³ was the LOAEC (local) in this study. At 10 and 30 mg/m³, no fibrotic reactions were observed. Both incidence and severity of other lung changes was lower and considered a natural adaptive reaction as a result of the (physical) particle insult, and not adverse effects in terms of test substance specific toxicity. Therefore, 30 mg/m³ was considered a NOAEC for local effects in the lung. No toxicologically significant systemic effect was observed at any concentration. The NOAEC for systemic effects was therefore 100 mg/m³ (Dormans et al., 1999).

The respirable fraction of Ashes (residues), cenospheres typically accounts for < 1.5% of the total mass (s. Particle size distribution). Accordingly, the local and systemic NOAEC values mentioned above correspond to a local NOAEC of ca. 2000 mg/m³ and a systemic NOAEC of ca. 6666 mg/m³ based on total Ashes (residues), cenospheres, respectively. Repeated inhalation exposure of humans to such high concentrations is, however, unrealistic under normal working and handling conditions considering the current occupational exposure limits for respirable inert dust in the European Union, which range from 3 to 10 mg/m³ (8 h TWA).

 

Human data

Human data on the pneumoconiotic effects of coal fly ash (pulverised fuel ash, PFA) derived from a number of studies in UK workers of the electricity supply industry throughout 1950 to 1977 has been reviewed by Bonnell et al. (1980). The results of the studies indicate that PFA is unlikely to give rise to pneumoconiosis caused by working in coal-combusted power plants, other than in subjects with previous exposure in underground coal mining.

In a published review by Borm (1997), in vitro, in vivo and human toxicity data on coal fly ash was assessed and compared to information from coal (mine) dust (which contains up to 10% of quartz) and/or crystalline silica. In summary, in vitro studies showed that coal fly ash is generally less cytotoxic than crystalline silica. In vivo exposure (inhalation and intratracheal instillation) of different animal species to coal fly ashes showed only very mild to moderate fibrosis, the observed pathology being similar to other nuisance dusts, and it appears that silica is less fibrogenic in inhaled coal fly ash than in coal mine dust. Epidemiological studies on fly ash exposed workers failed to show any convincing evidence of pneumoconiosis other than in former coal miners or emphysema as described by Bonnell et al. (1980). Other studies showed lung function impairment and respiratory symptoms in workers with long-term, high exposure (> 5 mg/m³) to coal fly ash. However, this effect is also results from exposure to other inorganic dusts at prolonged and high exposure (review: Oxman et al. 1993).

Borm (1997) concluded that "although most studies have not been designed to test fly ash toxicity in relation to its content of crystalline silica, there are no available data that suggest that coal fly ash is merely an addition of (crystalline) silica and other components. There is minimal knowledge on the effect of the mineralogical properties of fly ash on the activity of (crystalline) silica", and suggested a closer investigation of "matrix" effects masking the toxicity of silica in particles with complex composition.

Further considerations on quartz in ashes (residues), cenospheres

For hazard assessment of ashes (residues), cenospheres, the available toxicological information is taken into account along with physicochemical data, particularly on granulometry and mineralogy, since the presence of SiO2 in form of crystalline silica (quartz) in the respirable (alveolar) fraction (MMAD < 5µm) may represent a critical factor triggering potential toxic effects upon inhalation exposure.

Silicon dioxide is contained in ashes (residues), cenospheres at up to 75%. However, ashes (residues), cenospheres are composed mostly of glassy aluminosilicate. Thus, most of the SiO2 is present in this amorphous matrix. The crystalline silica (quartz) content ranges from 0 to 5% of the total mass.

Data on the particle size distribution of ashes (residues), cenospheres indicates that the content of respirable particles (< 5 µm) is less than 1.5% of the total particles. Thus, most of the ashes (residues), cenospheres particles would not be able to reach the alveolar region of the lungs after inhalation exposure.

This means that, if assuming a homogeneous distribution of free quartz, about 0.075% of ashes (residues), cenospheres are respirable quartz particles. Current occupational exposure limits for respirable quartz in the European Union range from 0.05 mg/m³ to 0.3 mg/m³. An ashes (residues), cenospheres concentration of 6.7 to 40 mg/m³ in air would be required to reach this limit values.

In recent studies on ash samples from Israel and The Netherlands addressing the mineralogy and distribution of quartz along among particle fractions, it could be demonstrated that quartz content is higher in the coarse than in the fine and respirable fractions of ashes (Meij et al., 2000; Nathan et al., 2009), and that crystalline silica in the respirable fraction is either present as inclusion in vitrified material or coated by layers of aluminosilicates. Thus, the reactive quartz particle surface is not free exposed, explaining the lower toxicity of fly ash particles containing silica compared to coal (mine) dust and respirable crystalline silica (Borm, 1997).

The quartz concentration in the respirable fraction of the fly ash produced in Israel was determined to be considerably lower than in the whole ash. X-ray diffraction and scanning electron microscopy analysis showed that most of the quartz particles in the respirable fraction were coated by amorphous aluminosilicate layers. Coated particles are not considered to have pneumoconiotic effects (Nathan et al., 2009).

By means of scanning electron microscopic/X-ray microanalysis (SEM/XMA) and X-ray diffraction (XRD) analysis, it was shown that coal gasification ash (CG slag and CG fly ash), as produced in The Netherlands, consisted entirely of glass and did not contain any crystalline silica forms. No cristobalite or tridymite could be demonstrated in any of the ashes studied. In Dutch power plants after combustion of the coal, about 50% of the original quartz remained in the ash, which was mostly present in the coarse fraction as free angular particles. The quartz content of the health-relevant respirable fraction was lower: less than 1% of the original quartz in coal. However, the major part of the quartz in the respirable fraction was embedded in the glass matrix of the fly ash particle. The authors stated that since the effects of quartz are surface related, these findings explain the negative results of quartz related effects of PFA (pulverized fuel ash) in epidemiological, in vitro and in vivo studies. Besides, the amount of the totalα-quartz in the respirable fraction of the ashes studied was less than 0.2%, so in practice the occupational exposure limits for respirable quartz (0.075 mg/m³ in The Netherlands) will not be exceeded. It was concluded that there is no reason to assume that coal ash, as produced in The Netherlands, would induce PMF (progressive massive fibrosis) (Meij et al. 2000).

 

Conclusion

The whole body of information available on the physicochemical, mineralogical and toxicological properties of ashes (residues), cenospheres do not indicate a hazard for systemic effects specifically related to their intrinsic chemical properties. Exposure to high airborne concentrations of ashes (residues), cenospheres is expected to result in local responses in the lung comparable to the effects occurring after exposure to high airborne concentrations of nuisance dust.

References not as IUCLID entry:

Borm, P.J.A. (1997). Toxicity and occupational health hazards of coal fly ash (CFA). A review of data and comparison to coal mine dust. Ann Occup Hyg 41(6):659 -676.

NIOSH (2002). Health Effects of Occupational Exposure to Respirable Crystalline Silica. US Department of Health and Human Services. DHHS (NIOSH) Publication No. 2002-129.

Oxman, A.D., H.S., Stock, S.R.T., Hnizdo, E. and Lanfe, H.J. (1993). Occupational dust exposure and chronic obstructive pulmonary disease. American Review of Respiratory Diseases 148, 38-48.


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

Justification for classification or non-classification

Based on read-across following an analogue approach, the available data on the repeated dose toxicity of Ashes (residues), cenospheres is conclusive but not sufficient for classfication according to the DSD (67/548/EEC) and GHS (CLP, 1272/2008/EC) criteria for classification and labelling.