Registration Dossier

Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because (i) the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), (ii) it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and (iii) there is no or no significant human exposure
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING

Regulation (EC) No. 1907/2006, Annex X, 8.7.3 Column 1, states that an extended one-generation reproduction toxicity study (EOGRTS, OECD 443, standard configuration) is required to fulfil the standard requirements for reproductive toxicity, using the most appropriate route of administration, and having regard to the likely route of human exposure.
According to Regulation (EC) No 1907/2006, Annex X, 8.7. Column 2, an extended one-generation toxicity study for assessment of reproductive toxicity is not required if (i) the substance is of low toxicological activity, (ii) it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure and (iii) there is no or no significant human exposure.
Therefore, in accordance with Annex X, 8.7.3. Column 2, the registrant has considered the need to perform an extended one-generation reproduction toxicity study. The summary below explains the rationale for the registrant’s conclusion, that additional testing is not scientifically justified. In fact, additional testing is scientifically not justified based on (i) negligible systemic absorption via inhalation and also via the oral and dermal route of exposure, (ii) low toxicological hazard (including available data on reproduction and developmental toxicity) and (iii) the use of protective gear and adequate dust control measures are implemented to prevent significant human exposure.

Toxikokinetics
Ashes (residues), coal are a complex and heterogeneous mixture of metal and metalloid oxides in variable proportions. Ashes (residues), coal mainly consist of water insoluble compounds such as silicon dioxide (SiO2), aluminium oxide (Al2O3) and iron oxide (Fe2O3). The available information on the toxicokinetic behaviour of Ashes (residues), coal and the main components (SiO2, Al2O3, Fe2O3) indicate no relevant systemic absorption by any route of exposure.
Silicon dioxide and aluminium oxide are slightly soluble in body fluids (e. g. in the stomach) leading to the formation of silicic acid and aluminium chloride, respectively, which show low levels of absorption and rapid clearance via the kidneys (IARC, 1997; McEvoy, 1990). Therefore, a low level of absorption of Ashes (residues), coal via ingestion or after dermal contact is possible, but no relevant systemic bioavailability is expected due to the rapid clearance. This is supported by studies on Ashes (residues), coal, available for acute oral and dermal toxicity. In all of these studies no mortalities occurred and no signs of systemic toxicity were observed (please refer to the study summaries in the respective chapters for more details). Furthermore, in a 3-year feeding study in cattle, the chemical analyses of milk, blood, urine and faeces indicated that no systemic absorption occurred after oral administration of 1850 mg/kg bw/day of fly ash (Herrmann, 1955).
The most relevant route of exposure for Ashes (residues), coal, taken into account the physicochemical properties of the substance and its uses, is by inhalation. About 3 mg fly ashes were inhaled by hamsters nose-only exposed to an aerosol with a concentration of 470 µg/L (Wehner et al, 1980). Approximately 2% of the particles were retained in the respiratory tract. After 99 days, about 90% of the fly ashes retained had been cleared from the lungs. Most of the fly ashes were recovered in the gastrointestinal tract and faeces (together ca. 85%). Some of the test material was recovered in the head (5.25%, combined external and internal deposition), pelt (4.43%) and carcass (2.25%). The latter value is probably due to external deposition on the extremities not removed on skinning of the animals. Little amounts (ca. 3% - which means 0.09 mg) were recovered in internal organs (liver, kidney) indicating a very low level of absorption.
In a further study, the pulmonary deposition and clearance of a coal fly ash were assessed in male Wistar rats exposed to coal fly ash aerosols at average exposure concentration of 10.4 mg/m3 for 7 h/day, 5 days/week during 1 month (Matsuno et al., 1985). The burden of fly ash was estimated by the measurement of aluminium contents in rat organs. The aluminium concentrations in the lungs of the exposed rats for each run were much higher than those of the controls, but they decreased with the increase of the clearance time. There is no statistical significance regarding the amount of fly ash deposited in lungs among the exposure groups. In the other organs (liver, kidney, spleen and blood), there were no significant differences in aluminium concentration between exposed groups and controls, indicating a low absorption of the aluminium from coal fly ash.
Results of a 28-day inhalation study with fly ash derived from electrostatic precipitators of a thermal power station in male Wistar rats suggested that heavy metals derived from inhalation exposure to fly ash may be systemically absorbed and bioaccumulated in lung, liver and kidneys of rats (Mani et al., 2007). However, the metals investigated are all present in Ashes (residues), coal at concentrations < 0.1% (according to the substanc information profile (SIP)). Therefore, no concern and relevance for man can be expected due to the indirect exposure with heavy metals via the ashes. The information available on the main constituents SiO2, Al2O3 and Fe2O3 indicate that inhaled particles of these compounds deposit along the respiratory tract according to their aerodynamic diameter. Thus, small particles (< 5 µm) can reach the alveolar region. Following deposition on the surface of the lung, there is either a rapid mucociliary clearance if deposition is in the upper airways, or phagocytosis by alveolar macrophages and slower clearance if deposition is in the alveolar region. Clearance by mucociliary mechanisms is generally considered to be efficient; clearance from the alveolar region is slow and incomplete and some of the particles may be carried by macrophages into the pulmonary interstitium and lymphoid tissues (ECHA, 2017; Friberg et al., 1986; IARC, 1972, 1997).
Mineralogical investigations showed that the constituent quartz in Ashes (residues), coal is embedded in glass (Borm, 1997; Nathan et al., 2009; Meij et al., 2000). Thus, based on the available information, it can be concluded that silicon dioxide in form of quartz is not freely available in the toxicologically relevant respirable fraction of Ashes (residues), coal, due to the fact that it is embedded in an amorphous glass matrix.
Taken together, Ashes (residues), coal as a whole and its main components are unlikely to be absorbed and systemically distributed to a relevant extent in humans. Moreover, none of these compounds is prone to undergo metabolic transformation. Therefore, Ashes (residues), coal will mainly be excreted within the faeces after oral exposure. Particles deposited in the respiratory bronchioles and proximal alveoli are cleared more slowly. Inhaled particles cleared from the lung as a result of mucociliary mechanisms will likely be swallowed and excreted via the gastrointestinal tract as well. Soluble material leaching from the primary particles and eventually being absorbed will most likely be excreted in the urine, as described for SiO2 and Al2O3 (Friberg et al., 1986; IARC 1997).

Animal studies covering reproductive and fertility parameters
Information on reproduction toxicity of Ashes (residues), coal is available from an oral (gavage) Reproduction / Developmental Toxicity Screening Test performed according to OECD guideline 421 and under GLP with Wistar rats (ČEZ Energetické produkty, 2008, key). The NOAEL was established at 1000 mg/kg bw/day for the parental animals and the pups, which was the highest dose tested.
In an earlier study where fly ash derived from coal combustion was fed to cows over a period of 3 years, pregnancy rates, conception, parturition and body weight development were not disturbed by the oral administration (Herrmann, 1955). Because treated animals showed a slightly higher milk production rate than control animals, the general condition of treated animals was even considered to be better than that of the controls. Necropsy results did not reveal major pathological changes due to fly ash administration.
In addition, there are no indications that the main components of Ashes (residues), coal, i.e. silicon dioxide (SiO2), aluminium oxide (Al2O3) and iron oxide (Fe2O3), induce toxic effects to reproduction / development in animals or humans (according to ECHA dissemination portal).

Additional toxicological data
The whole body of available data on the toxicological properties of Ashes (residues), coal points out the respiratory tract is the only target for potential toxic effects. No hazard, besides local effects in the lung, was observed in all available studies. The local effects in the lungs, observed in acute and repeated inhalation toxicity studies, are a direct result of deposition of fly ash within the lungs and thus, these are considered a natural response to inhaled particle deposition and not being specific for coal fly ash.
Human exposure
The use of protective gear and adequate dust control measures are implemented for all exposure scenarios related to Ashes (residues), coal to comply with the occupational exposure limits for respirable dusts of the different EU countries and thus, to prevent significant human exposure.

Conclusion
In conclusion, information with respect to reproduction and fertility is available from a Reproduction / Developmental Toxicity Screening Test performed according to OECD guideline 421 and a 2-year feeding study with cows over a period of 3 years. The results of these 2 studies did not show any potential for reproduction toxicity in the examined animals. Based on the general toxicological profile, there is no hazard attributed to systemic availability of Ashes (residues), coal. Observed local effects in the lungs are a direct result of deposition of the test substance within the lungs and are considered an important natural response to inhaled particles, not being specific to Ashes (residues), coal. In addition and with respect to man, the use of protective gear and adequate dust control measures are implemented to prevent significant human exposure.
Based on the available information, there is no evidence for reproduction toxicity to be expected from Ashes (residues), coal. Therefore, referring to Regulation (EC) No. 1907/2006, Annex X, 8.7. Column 2, and for animal welfare reasons, performing an extended one-generation reproduction toxicity study (standard configuration or with additional modules) is not scientifically necessary and, considering concerns regarding the use of vertebrate animals for experimental purposes, unjustified.

References:
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.
ECHA (2017). Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance.
Friberg, L., Nordberg, G. F., Kessler, E. and Vouk, V. B. (eds.) (1986). Handbook of the Toxicology of Metals. 2nd ed. Vols I, II. Elsevier Science Publishers B. V.
IARC (1972). Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 1. Some Inorganic Substances, Chlorinated Hydrocarbons, Aromatic Amines, N-Nitroso Compounds and Natural Products. World Health Organization, International Agency for Research on Cancer.
IARC (1997). Monographs on the Evaluation of the Carcinogenic Risks to Humans. Volume 68. Silica, Some Silicates, Coal Dust and para-Aramid Fibrils. World Health Organization, International Agency for Research on Cancer.
McEvoy, G. K. (ed.) (1990). AHFS Drug Information 90. American Society of Hospital Pharmacists, Inc.
Meij, R., Nagengast, S. and te Winkel, H. (2000). The Occurrence of Quartz in Coal Fly Ash Particles. Inhalation Toxicology, 12 (suppl. 3), 109-116.
Nathan, Y., Metzger, A., Dvoracheck, M. and Pardo A. (2009). Occupational Health Aspects of Quartz in Bituminous Coal Fly Ash in Israel.
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reproductive effects observed:
not specified
Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and there is no or no significant human exposure
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
Regulation (EC) No. 1907/2006, Annex IX, 8.7.2. Column 1, states that a pre-natal developmental toxicity study (OECD 414), one species is required to fulfil the standard requirements for developmental toxicity, using the most appropriate route of administration, and having regard to the likely route of human exposure.
According to Regulation (EC) No 1907/2006, Annex X, 8.7. Column 2, a developmental toxicity study is not required if (i) the substance is of low toxicological activity, (ii) it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure and (iii) there is no or no significant human exposure.
Therefore, in accordance with Annex X, 8.7.2. Column 2, the registrant has considered the need to perform a developmental toxicity study. The summary below explains the rationale for the registrant’s conclusion that additional testing is not scientifically justified. In fact, additional testing is scientifically not justified based on (i) negligible systemic absorption via inhalation and also via the oral and dermal route of exposure, (ii) low toxicological hazard (including available data on reproduction and developmental toxicity) and (iii) the use of protective gear and adequate dust control measures are implemented to prevent significant human exposure.

Toxikokinetics
Ashes (residues), coal are a complex and heterogeneous mixture of metal and metalloid oxides in variable proportions. Ashes (residues), coal mainly consist of water insoluble compounds such as silicon dioxide (SiO2), aluminium oxide (Al2O3) and iron oxide (Fe2O3). The available information on the toxicokinetic behaviour of Ashes (residues), coal and the main components (SiO2, Al2O3, Fe2O3) indicate no relevant systemic absorption by any route of exposure.
Silicon dioxide and aluminium oxide are slightly soluble in body fluids (e. g. in the stomach) leading to the formation of silicic acid and aluminium chloride, respectively, which show low levels of absorption and rapid clearance via the kidneys (IARC, 1997; McEvoy, 1990). Therefore, a low level of absorption of Ashes (residues), coal via ingestion or after dermal contact is possible, but no relevant systemic bioavailability is expected. This is supported by studies on Ashes (residues), coal, available for acute oral and dermal toxicity. In all of these studies no mortalities occurred and no signs of systemic toxicity were observed (please refer to the study summaries in the respective chapters for more details). Furthermore, in a 3-year feeding study in cattle, the chemical analyses of milk, blood, urine and faeces indicated that no systemic absorption occurred after oral administration of 1850 mg/kg/day of fly ash (Herrmann, 1955).
The most relevant route of exposure for Ashes (residues), coal, taken into account the physicochemical properties of the substance and its uses, is by inhalation. About 3 mg fly ashes were inhaled by hamsters nose-only exposed to an aerosol with a concentration of 470 µg/L (Wehner et al, 1980). Approximately 2% of the particles were retained in the respiratory tract. After 99 days, about 90% of the fly ashes retained had been cleared from the lungs. Most of the fly ashes were recovered in the gastrointestinal tract and faeces (together ca. 85%). Some of the test material was recovered in the head (5.25%, combined external and internal deposition), pelt (4.43%) and carcass (2.25%). The latter value is probably due to external deposition on the extremities not removed on skinning of the animals. Little amounts (ca. 3% - which means 0.09 mg) were recovered in internal organs (liver, kidney) indicating a very low level of absorption.
In a further study, the pulmonary deposition and clearance of a coal fly ash were assessed in male Wistar rats exposed to coal fly ash aerosols at average exposure concentration of 10.4 mg/m3 for 7 h/day, 5 days/week during 1 month (Matsuno et al., 1985). The burden of fly ash was estimated by the measurement of aluminium contents in rat organs. The aluminium concentrations in the lungs of the exposed rats for each run were much higher than those of the controls, but they decreased with the increase of the clearance time. There is no statistical significance regarding the amount of fly ash deposited in lungs among the exposure groups. In the other organs (liver, kidney, spleen and blood), there were no significant differences of aluminium concentration between exposure groups and controls, indicating a low absorption of aluminium from coal fly ash.
Results of a 28-day inhalation study with fly ash derived from electrostatic precipitators of a thermal power station in male Wistar rats suggested that heavy metals derived from inhalation exposure to fly ash may be systemically absorbed and bioaccumulated in lung, liver and kidneys of rats (Mani et al., 2007). However, the metals investigated are all present in Ashes (residues), coal at concentrations < 0.1% (according to the substanc information profile (SIP)). Therefore, no concern and relevance for man can be expected due to the indirect exposure with heavy metals via the ashes. The information available on the main constituents SiO2, Al2O3 and Fe2O3 indicate that inhaled particles of these compounds deposit along the respiratory tract according to their aerodynamic diameter. Thus, small particles (< 5 µm) can reach the alveolar region. Following deposition on the surface of the lung, there is either a rapid mucociliary clearance if deposition is in the upper airways or phagocytosis by alveolar macrophages and slower clearance if deposition is in the alveolar region. Clearance by mucociliary mechanisms is generally considered to be efficient; clearance from the alveolar region is slow and incomplete and some of the particles may be carried by macrophages into the pulmonary interstitium and lymphoid tissues (ECHA, 2017; Friberg et al., 1986; IARC, 1972, 1997).
Mineralogical investigations showed that the constituent quartz in Ashes (residues), coal is embedded in glass (Borm, 1997; Nathan et al., 2009; Meij et al., 2000). Thus, based on the available information, it can be concluded that silicon dioxide in form of quartz is not freely available in the toxicologically relevant respirable fraction of Ashes (residues), coal, due to the fact that it is embedded in an amorphous glass matrix.
Taken together, Ashes (residues), coal as a whole and its main components are unlikely to be absorbed and systemically distributed to a relevant extent in humans. Moreover, none of these compounds is prone to undergo metabolic transformation. Therefore, Ashes (residues), coal will mainly be excreted within the faeces after oral exposure. Particles deposited in the respiratory bronchioles and proximal alveoli are cleared more slowly. Inhaled particles cleared from the lung as a result of mucociliary mechanisms will likely be swallowed and excreted via the gastrointestinal tract as well. Soluble material leaching from the primary particles and eventually being absorbed will most likely be excreted in the urine, as described for SiO2 and Al2O3 (Friberg et al., 1986; IARC 1997).

Animal studies covering developmental parameters
Information on developmental toxicity of Ashes (residues), coal is available from an oral (gavage) Reproduction / Developmental Toxicity Screening Test performed according to OECD guideline 421 and under GLP with Wistar rats (ČEZ Energetické produkty, 2008, key). The NOAEL was established at 1000 mg/kg bw/day for the parental animals and the pups, which was the highest dose tested.
In addition, there are no indications that the main components of Ashes (residues), coal, i.e. silicon dioxide (SiO2), aluminium oxide (Al2O3) and iron oxide (Fe2O3), induce toxic effects to reproduction / development in animals or humans (according to ECHA dissemination portal).

Additional toxicological data
The whole body of available data on the toxicological properties of Ashes (residues), coal points out the respiratory tract is the only target for potential toxic effects. No hazard, besides local effects in the lung, was observed in all available studies. The local effects in the lungs, observed in acute and repeated inhalation toxicity studies, are a direct result of deposition of fly ash within the lungs and thus, these are considered a natural response to inhaled particle deposition and not being specific to coal fly ash.
Human exposure
The use of protective gear and adequate dust control measures are implemented for all exposure scenarios related to Ashes (residues), coal to comply with the occupational exposure limits for respirable dusts of the different EU countries and thus, to prevent significant human exposure.

Conclusion
In conclusion, information with respect to developmental toxicity is limited to a Reproduction / Developmental Toxicity Screening Test performed according to OECD guideline 421. The results of this study did not show any potential for developmental toxicity in the examined animals. Based on the general toxicological profile, there is no hazard attributed to systemic availability of Ashes (residues), coal. Observed local effects in the lungs are a direct result of deposition of the test substance within the lungs and are considered an important natural response to inhaled particles, not being specific to Ashes (residues), coal. In addition and with respect to man, the use of protective gear and adequate dust control measures are implemented to prevent significant human exposure.
Based on the available information, there is no evidence for developmental toxicity to be expected from Ashes (residues), coal. Therefore, referring to Regulation (EC) No. 1907/2006, Annex X, 8.7. Column 2, and for animal welfare reasons, performing a developmental toxicity study is not scientifically necessary and, considering concerns regarding the use of vertebrate animals for experimental purposes, unjustified.

References:
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.
ECHA (2017). Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance.
Friberg, L., Nordberg, G. F., Kessler, E. and Vouk, V. B. (eds.) (1986). Handbook of the Toxicology of Metals. 2nd ed. Vols I, II. Elsevier Science Publishers B. V.
IARC (1972). Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 1. Some Inorganic Substances, Chlorinated Hydrocarbons, Aromatic Amines, N-Nitroso Compounds and Natural Products. World Health Organization, International Agency for Research on Cancer.
IARC (1997). Monographs on the Evaluation of the Carcinogenic Risks to Humans. Volume 68. Silica, Some Silicates, Coal Dust and para-Aramid Fibrils. World Health Organization, International Agency for Research on Cancer.
McEvoy, G. K. (ed.) (1990). AHFS Drug Information 90. American Society of Hospital Pharmacists, Inc.
Meij, R., Nagengast, S. and te Winkel, H. (2000). The Occurrence of Quartz in Coal Fly Ash Particles. Inhalation Toxicology, 12 (suppl. 3), 109-116.
Nathan, Y., Metzger, A., Dvoracheck, M. and Pardo A. (2009). Occupational Health Aspects of Quartz in Bituminous Coal Fly Ash in Israel.
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Species:
rat
Abnormalities:
not specified
Developmental effects observed:
not specified
Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
developmental toxicity
Remarks:
non-rodent species
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and there is no or no significant human exposure
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
Regulation (EC) No. 1907/2006, Annex IX, 8.7.2. Column 2, states that a pre-natal developmental toxicity study (OECD 414) shall be initially performed on one species. A decision on the need to perform a study at this tonnage level or the next on a second species should be based on the outcome of the first test and all other relevant available data.
According to Regulation (EC) No 1907/2006, Annex X, 8.7. Column 2, a developmental toxicity study is not required if (i) the substance is of low toxicological activity, (ii) it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure and (iii) there is no or no significant human exposure.
Therefore, in accordance with Annex X, 8.7.2. Column 2, the registrant has generally considered the need to perform a developmental toxicity study (both for rodent and non-rodent species). The summary below explains the rationale for the registrant’s conclusion that additional testing is not scientifically justified. In fact, additional testing is scientifically not justified based on (i) negligible systemic absorption via inhalation and also via the oral and dermal route of exposure, (ii) low toxicological hazard (including available data on reproduction and developmental toxicity) and (iii) the use of protective gear and adequate dust control measures are implemented to prevent significant human exposure.

Toxikokinetics
Ashes (residues), coal are a complex and heterogeneous mixture of metal and metalloid oxides in variable proportions. Ashes (residues), coal mainly consist of water insoluble compounds such as silicon dioxide (SiO2), aluminium oxide (Al2O3) and iron oxide (Fe2O3). The available information on the toxicokinetic behaviour of Ashes (residues), coal and the main components (SiO2, Al2O3, Fe2O3) indicate no relevant systemic absorption by any route of exposure.
Silicon dioxide and aluminium oxide are slightly soluble in body fluids (e. g. in the stomach) leading to the formation of silicic acid and aluminium chloride, respectively, which show low levels of absorption and rapid clearance via the kidneys (IARC, 1997; McEvoy, 1990). Therefore, a low level of absorption of Ashes (residues), coal via ingestion or after dermal contact is possible, but no relevant systemic bioavailability is expected. This is supported by studies on Ashes (residues), coal , available for acute oral and dermal toxicity. In all of these studies no mortalities occurred and no signs of systemic toxicity were observed (please refer to the study summaries in the respective chapters for more details). Furthermore, in a 3-year feeding study in cattle, the chemical analyses of milk, blood, urine and faeces indicated that no systemic absorption occurred after oral administration of 1850 mg/kg/day of fly ash (Herrmann, 1955).
The most relevant route of exposure for Ashes (residues), coal, taken into account the physicochemical properties of the substance and its uses, is by inhalation. About 3 mg fly ashes were inhaled by hamsters nose-only exposed to an aerosol with a concentration of 470 µg/L (Wehner et al, 1980). Approximately 2% of the particles were retained in the respiratory tract. After 99 days, about 90% of the fly ashes retained had been cleared from the lungs. Most of the fly ashes were recovered in the gastrointestinal tract and faeces (together ca. 85%). Some of the test material was recovered in the head (5.25%, combined external and internal deposition), pelt (4.43%) and carcass (2.25%). The latter value is probably due to external deposition on the extremities not removed on skinning of the animals. Little amounts (ca. 3% - which means 0.09 mg) were recovered in internal organs (liver, kidney) indicating a very low level of absorption.
In a further study, the pulmonary deposition and clearance of a coal fly ash were assessed in male Wistar rats exposed to coal fly ash aerosols at average exposure concentration of 10.4 mg/m3 for 7 h/day, 5 days/week during 1 month (Matsuno et al., 1985). The burden of fly ash was estimated by the measurement of aluminium contents in rat organs. The aluminium concentrations in the lungs of the exposed rats for each run were much higher than those of the controls, but they decreased with the increase of the clearance time. There is no statistical significance regarding the amount of fly ash deposited in lungs among the exposure groups. In the other organs (liver, kidney, spleen and blood), there were no significant differences of aluminium concentration between exposed groups and controls, indicating a low absorption of aluminium from coal fly ash.
Results of a 28-day inhalation study with fly ash derived from electrostatic precipitators of a thermal power station in male Wistar rats suggested that heavy metals derived from inhalation exposure to fly ash may be systemically absorbed and bioaccumulated in lung, liver and kidneys of rats (Mani et al., 2007). However, the metals investigated are all present in Ashes (residues), coal at concentrations < 0.1% (according to the substanc information profile (SIP)). Therefore, no concern and relevance for man can be expected due to the indirect exposure with heavy metals via the ashes. The information available on the main constituents SiO2, Al2O3 and Fe2O3 indicate that inhaled particles of these compounds deposit along the respiratory tract according to their aerodynamic diameter. Thus, small particles (< 5 µm) can reach the alveolar region. Following deposition on the surface of the lung, there is either a rapid mucociliary clearance if deposition is in the upper airways or phagocytosis by alveolar macrophages and slower clearance if deposition is in the alveolar region. Clearance by mucociliary mechanisms is generally considered to be efficient; clearance from the alveolar region is slow and incomplete and some of the particles may be carried by macrophages into the pulmonary interstitium and lymphoid tissues (ECHA, 2017; Friberg et al., 1986; IARC, 1972, 1997).
Mineralogical investigations showed that the constituent quartz in Ashes (residues), coal is embedded in glass (Borm, 1997; Nathan et al., 2009; Meij et al., 2000). Thus, based on the available information, it can be concluded that silicon dioxide in form of quartz is not freely available in the toxicologically relevant respirable fraction of Ashes (residues), coal, due to the fact that it is embedded in an amorphous glass matrix.
Taken together, Ashes (residues), coal as a whole and its main components are unlikely to be absorbed and systemically distributed to a relevant extent in humans. Moreover, none of these compounds is prone to undergo metabolic transformation. Therefore, Ashes (residues), coal will mainly be excreted within the faeces after oral exposure. Particles deposited in the respiratory bronchioles and proximal alveoli are cleared more slowly. Inhaled particles cleared from the lung as a result of mucociliary mechanisms will likely be swallowed and excreted via the gastrointestinal tract as well. Soluble material leaching from the primary particles and eventually being absorbed will most likely be excreted in the urine, as described for SiO2and Al2O3 (Friberg et al., 1986; IARC 1997).

Animal studies covering developmental parameters
Information on developmental toxicity of Ashes (residues), coal is available from an oral (gavage) Reproduction / Developmental Toxicity Screening Test performed according to OECD guideline 421 and under GLP with Wistar rats (ČEZ Energetické produkty, 2008, key). The NOAEL was established at 1000 mg/kg bw/day for the parental animals and the pups, which was the highest dose tested.
In addition, there are no indications that the main components of Ashes (residues), coal, i.e. silicon dioxide (SiO2), aluminium oxide (Al2O3) and iron oxide (Fe2O3), induce toxic effects to reproduction / development in animals or humans (according to ECHA dissemination portal).

Additional toxicological data
The whole body of available data on the toxicological properties of Ashes (residues), coal points out the respiratory tract is the only target for potential toxic effects. No hazard, besides local effects in the lung, was observed in all available studies. The local effects in the lungs, observed in acute and repeated inhalation toxicity studies, are a direct result of deposition of fly ash within the lungs and thus, these are considered a natural response to inhaled particle deposition and not being specific for coal fly ash.

Human exposure
The use of protective gear and adequate dust control measures are implemented for all exposure scenarios related to Ashes (residues), coal to comply with the occupational exposure limits for respirable dusts of the different EU countries and thus, to prevent significant human exposure.

Conclusion
In conclusion, information with respect to developmental toxicity is limited to a Reproduction / Developmental Toxicity Screening Test performed according to OECD guideline 421. The results of this study did not show any potential for developmental toxicity in the examined animals. Based on the general toxicological profile, there is no hazard attributed to systemic availability of Ashes (residues), coal. Observed local effects in the lungs are a direct result of deposition of the test substance within the lungs and are considered an important natural response to inhaled particles, not being specific to Ashes (residues), coal. In addition and with respect to man, the use of protective gear and adequate dust control measures are implemented to prevent significant human exposure.
Based on the available information, there is no evidence for developmental toxicity to be expected from that Ashes (residues), coal. Therefore, referring to Regulation (EC) No. 1907/2006, Annex X, 8.7. Column 2, and for animal welfare reasons, performing a developmental toxicity study (both with rodent and with non-rodent species) is not scientifically necessary and, considering concerns regarding the use of vertebrate animals for experimental purposes, unjustified.

References:
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.
ECHA (2017). Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance.
Friberg, L., Nordberg, G. F., Kessler, E. and Vouk, V. B. (eds.) (1986). Handbook of the Toxicology of Metals. 2nd ed. Vols I, II. Elsevier Science Publishers B. V.
IARC (1972). Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 1. Some Inorganic Substances, Chlorinated Hydrocarbons, Aromatic Amines, N-Nitroso Compounds and Natural Products. World Health Organization, International Agency for Research on Cancer.
IARC (1997). Monographs on the Evaluation of the Carcinogenic Risks to Humans. Volume 68 Silica, Some Silicates, Coal Dust and para-Aramid Fibrils. World Health Organization, International Agency for Research on Cancer.
McEvoy, G. K. (ed.) (1990). AHFS Drug Information 90. American Society of Hospital Pharmacists, Inc.
Meij, R., Nagengast, S. and te Winkel, H. (2000). The Occurrence of Quartz in Coal Fly Ash Particles. Inhalation Toxicology, 12 (suppl. 3), 109-116.
Nathan, Y., Metzger, A., Dvoracheck, M. and Pardo A. (2009). Occupational Health Aspects of Quartz in Bituminous Coal Fly Ash in Israel.
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Species:
rabbit

Data source

Reference
Reference Type:
publication
Title:
Fate of inhaled fly ash in hamsters.
Author:
Wehner, A.P. et al.
Year:
1980
Bibliographic source:
Environ Res. 1980 Aug;22(2):485-98.

Materials and methods

Objective of study:
absorption
distribution
excretion
Principles of method if other than guideline:
The pulmonary deposition, translocation and clearance of inhaled fly ash was determined in hamsters nose-only exposed to neutron-activated fly ash for 95 min and sacrificed and assessed at intervals over a period of 99 days post-exposure.
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
Ashes (residues), coal
EC Number:
931-322-8
Cas Number:
68131-74-8
Molecular formula:
Not applicable (UVCB substance)
IUPAC Name:
Ashes (residues), coal
Details on test material:
- Name of test material (as cited in study report): coal fly ash (neutron-activated)
- Physical state: solid
- Analytical purity: no data
- Impurities (identity and concentrations): Co, 0.0039%; Sc, 0.00185%; Fe, 20%
- Energy: 60Co, 1.173 MeV; 46Sc, 1.121 MeV; 59Fe, 1.292 MeV
Radiolabelling:
yes
Remarks:
Coal fly ash was prepared for neutron activation in a Hanford's N-reactor. Radionuclides were induced by (n, gamma) reactions on the major and minor elements in the fly ash. The radionuclides 60Co, 46Sc and 59Fe were selected as fly ash tracers.

Test animals

Species:
hamster, Syrian
Strain:
other: outbred LAK:LVG, CRL
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Lakeview Laboratories
- Weight at study initiation: 120-130 g

Administration / exposure

Route of administration:
inhalation: aerosol
Vehicle:
unchanged (no vehicle)
Details on exposure:
TYPE OF INHALATION EXPOSURE: nose only


GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: 20-L aerosol exposure chamber (Wehner et al., 1977. Food Cosmet Toxicol 15:213-224) constructed of Lucite with exposure ports for nose only exposures arranged in 7 tiers, each containing 10 exposure ports.
- Method of holding animals in test chamber: animals were placed in soft-drink bottles from which the bottom and part of the top had been removed in such a way that the noses of the animals were close to the open tops of the bottles. The bottles were inserted through neoprene stoppers into the ports of the exposure chambers. The animals were mantained in this position by wadding pushed against their posteriors, and by neoprene stoppers taped to the bottoms of, and sealing, the bottles.
- System of generating particulates/aerosols: The fly ash aerosol was generated by a Wright Dust Feed Mechanism (Wright, 1950. J Sci Instr 27:12-15) and then passed through a cyclone elutriator for removal of particles larger than 10 µm aerodynamic equivalent diameter (AED).
- Method of particle size determination: An Andersen cascade impactor (Andersen, 1966. Amer Ind Hyg Assoc J 27:160-165) positioned on tier 3 of the exposure chamber.


TEST ATMOSPHERE (if not tabulated)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 3.53 +/- 0.33 µm; 2.77 +/- 0.05 µm
Duration and frequency of treatment / exposure:
95 min, single exposure
Doses / concentrations
Dose / conc.:
470 other: µg/L air
Remarks:
+/- 39 µg/L air
No. of animals per sex per dose / concentration:
58 treated males
10 control animals, 5 of which were killed 2 days, the other five 102 days, after exposure
Control animals:
yes, concurrent no treatment
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, lungs (including mediastinal tissue), liver, kidney, skinned and decapitated carcass, pelt, head, gastrointestinal tract.
- Time and frequency of sampling: 15 min, 1, 3, 7, 14, 24, 51 and 99 days post-exposure.

Statistics:
The deposition in the liver samples from the exposed animals was compared to control animals at both sacrifice times by a two-tailed Mann-Whitney U test.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Based on the data reported, approximately 3 mg fly ash were inhaled in the 95-min exposure. Thereof, ca. 2% was retained in the lungs. After 99 days, 0.2% was still found in the lungs.
Details on distribution in tissues:
The overall amount of fly ashes found in tissue samples after the indicated time and expressed as percentage of the ca. 3 mg fly ashes initially inhaled was:
Liver: 0.39% (99 days)
Kidneys: 0.13% (99 days)
Carcass: 2.25% (99 days)
Gastrointestinal tract: 36.7% (14 days)
Head: 5.25% (7 days)
Pelt: 4.43% (7 days)

Details on excretion:
The overall amount of fly ashes found in excreta samples after the indicated time and expressed as percentage of the ca. 3 mg fly ashes initially inhaled was:
Faeces: 48.41% (3 days)
Urine: 0.58% (3 days)

Any other information on results incl. tables

Fly ash burdens in tissues and excreta as a function of time after exposure (expressed as mean values in µg)

 

Lung

Liver

Kidney

 

Sc

Fe

Co

Sc

Fe

Co

Sc

Fe

Co

15 min

65.8

63.2

40.1

0.52

1.2

3.4

0.12

0.4

0.94

1 day

48.8

48.4

23

0.41

2.7

1.9

0.18

0.51

0.49

3 days

55.7

55.4

25.6

0.62

3.1

1.6

0.25

0.43

0.43

7 days

27.9

29

11.5

0.35

2.5

1

0.13

0.65

0.38

14 days

34.1

37.3

14.1

0.53

4.1

0.86

0.19

0.85

0.28

24 days

20.7

24.2

8.3

0.48

2.9

0.79

0.08

1.2

0.18

51 days

12.2

14.5

5.2

0.59

2.2

0.48

0.09

1.3

0.2

99 days

6.4

7.65

2.4

0.36

2.6

0.21

0.21

2.3

0.17

 

 

Carcass

GI tract

Head

 

Sc

Fe

Co

Sc

Fe

Co

Sc

Fe

Co

15 min

26.9

28

66.9

814

792

767

102

103

120

1 day

10

11.4

14.9

259

228

270

20.3

21.8

46.5

3 days

6

0

8.8

57.6

59.6

67.6

6.1

9.2

25.7

7 days

1.7

4

2.4

4.3

5.3

11.3

2

4.7

22

14 days

1.5

5.7

2.2

4.7

5.7

5.8

 

 

 

24 days

0.82

4.5

1.3

 

 

 

 

 

 

51 days

0.61

3.6

0.67

 

 

 

 

 

 

99 days

0.7

4.3

0.54

 

 

 

 

 

 

 

 

Pelt

Faeces

Urine

 

Sc

Fe

Co

Sc

Fe

Co

Sc

Fe

Co

15 min

80.6

75.8

91.6

873

831

903

1

3.2

21.3

1 day

23.5

21.5

34.1

483

471

464

0.88

3.2

16.8

3 days

8.8

9.2

37.9

127

130

142

0.9

3.5

3.8

7 days

2.9

4.4

18

 

 

 

 

 

 

14 days

 

 

 

 

 

 

 

 

 

24 days

 

 

 

 

 

 

 

 

 

51 days

 

 

 

 

 

 

 

 

 

99 days

 

 

 

 

 

 

 

 

 

Fly ash burden estimates as determined by the radionuclides 46Sc and 59Fe were in good agreement for the majority of the samples analysed. Such close agreement indicated fly ash particulate levels in the lungs, carcass, head pelt, GI tract and faeces rather than leached radionuclides. Fly ash deposition estimates obtained with 60Co were lower for the lungs and higher at one or more sacrifice times for carcass, liver, head, pelt and urine samples. Thus, this indicates selective leaching of Co from fly ash deposited in the deep lung, translocation to other sites and excretion in the urine. Most of the 60Co urinary excretion took place within the first few days after exposure.

Approximately 63 µg fly ash (2% of the inhaled fly ash) was initially retained in the respiratory tract. The estimated biological half-times of the fly ash were 2.6 and 34.5 days, probably for the upper airways and for the deep lung, respectively. After 99 days, the mean lung burden had decreased to about 10% of the initial value. Extrapolating from the clearance data, it can be estimated that near-complete clearance of fly ash from the lung would have been achieved approximately 200 days post exposure.

Applicant's summary and conclusion

Conclusions:
Low bioaccumulation potential based on study results.
The results of this study indicate that about 3 mg fly ash were inhaled by hamsters nose-only exposed to an aerosol with a concentration of 470 µg/L air. Approximately 2% of the particles were retained in the respiratory tract. After 99 days, about 90% of the fly ash retained had been cleared from the lungs. Most of the fly ash was found in the gastrointestinal tract and faeces (together ca. 85%). Some of the test material was found in the head (5.25%, combined external and internal deposition), pelt (4.43%) and carcass (2.25%). The latter value is probably due to external deposition on the extremities not removed on skinning of the animals. Little amounts were found in internal organs indicating a very low level of absorption.