Registration Dossier

Toxicological information

Repeated dose toxicity: oral

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Endpoint:
sub-chronic toxicity: oral
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
a short-term toxicity study by the oral route does not need to be conducted because an appropriate inhalation study is available and inhalation is the most appropriate route of administration as based on the provided thorough and rigorous exposure assessment
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING -
Repeated dose toxicity study with GGBS (ground granulated blast furnace slag) has been done for inhalation because this is the likely route of human exposure.
GGBS is considered to cover the worst case of slags, ferrous metal and blast furnace as GGBS has the finest particulates, and the marketed products of other slags only contain far smaller proportions of fine particles. GGBS is produced with the highest production volume and is broadly available in the market, also freely accessible for consumers.
In a key study concerning inhalation (Charles River Laboratories, 2015) data suggests that there is no likely acute inhalation hazard due to repeated exposure of rats to GGBS for 4 weeks up to 24 µg/L. There were no deaths or adverse clinical signs during the study period and no evidence of lung injury was seen. Minimal to mild changes noted in BAL (Bronchoalveolar lavage) fluid indicative of macrophage-mediated particle clearance and unspecific findings in the lung reflect the time-dependent physiological response of the body to inhaled mineral particulates of low solubility. There was a trend towards reversibility following a 13 weeks recovery period. At 24 µg/L the histopathological changes in the lung resembled pulmonary macrophage clearance, suggesting that the inhaled particulate is processed by alveolar macrophages and mononuclear inflammatory cells at high level concentration. Based on the results of this study, the No Adverse Effect Level (NOAEL) was determined to be 24 μg/L (target concentration) or 24.9 μg/L (achieved concentration).
In another acute inhalation toxicity study in rats by GGBS conducted by Bayer Healthcare 2012, concentration- and time-related onset of lung changes were monitored up to 90 days after a single short-term exposure to GGBS. The findings showed no likely acute inhalation hazard due to aerosolized GGBS.
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Reason / purpose:
reference to other study
Reason / purpose:
data waiving: supporting information
Reason / purpose:
assessment report
Reference
Endpoint:
sub-chronic toxicity: inhalation
Remarks:
Expert Toxicological Opninion IASON 2018
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
a sub-chronic toxicity study (90 days) does not need to be conducted because the substance is unreactive, insoluble and not inhalable and there is no evidence of absorption and no evidence of toxicity in a 28-day 'limit test' and human exposure is limited
Justification for type of information:
A sub-chronic toxicity study (90 days) for inhalation does not need to be conducted because the substance (slags) is unreactive, insoluble and not inhalable and there is no evidence of absorption and no evidence of toxicity in a 28 day short-term study and human exposure is limited. See executive summary and conclusion.
Reason / purpose:
reference to other study
Conclusions:
A sub-chronic toxicity study (90 days) for inhalation does not need to be conducted because the substance (slags) is unreactive, insoluble and not inhalable and there is no evidence of absorption and no evidence of toxicity in a 28 day short-term study and human exposure is limited. There is no need to perform additional animal studies because ferrous slags behave toxicologically similar as natural mineral samples; no further action is required.
Executive summary:

Ferrous slags are solid UVCB substances (substances of Unknown or Variable composition, Complex reaction products or Biological materials) that resemble natural rocks found in terrestrial and sediment systems. The physicochemical properties are almost identical among ferrous slags, and their benign toxicological and ecotoxicological profiles are very similar. Similarities comprise also the mineralogical composition of the ferrous slags. Importantly, all mineral components of ferrous slags are present in natural rocks; no new component is introduced during steel processing. Ferrous slags demonstrate low extractability in water as metals in slag were found to be generally resistant to leaching. Ferrous slags are virtually free of hazardous fibres. Overall, ferrous slags can be considered artificial volcanic rocks.

The ‘Ferrous Slag Category’ comprises the following 5 slag types: (1) ABS/GBS i.e., Slag, ferrous metal, blast furnace (air cooled or granulated), (2) BOS i.e., Slag, steelmaking, converter (converter slag), (3) EAF C i.e., Slag, steelmaking, elec. furnace (carbon steel production), (4) EAF S i.e., Slag, steelmaking, elec. furnace (stainless/high alloy steel production), and (5) SMS i.e., Slag, steelmaking. No significant hazard to environmental and ecological receptors has been anticipated for these slags.

The pathways of exposure quantitatively evaluated in this assessment were inhalation of suspended airborne ferrous slag particulates, incidental ingestion of ferrous slag, and dermal contact with ferrous slag.

From single-dose toxicity testing in animals via the oral, dermal and inhalation routes it can be concluded that ferrous slags are not acutely toxic. They do not need to be classified as oral, dermal and inhalation toxicants; neither a signal word nor hazard statement is required. Furthermore, ferrous slags exhibit no relevant irritant or sensitising potential, and does not show any mutagenic potential. Extensive testing in rat inhalation studies revealed that the biological responses to inhaled ferrous slag show no correlation to the course of pulmonary toxicity reported for amorphous silica (quartz); quartz dust served as positive control as it is well known to produce irreversible lung damage. Overall, ferrous slag in vivo data differ markedly from those reported for quartz in rats exposed at similar doses.

Supplemental in vitro testing also shows that ferrous slags, alike natural mineral samples, do not cause significant toxicity in cultured alveolar macrophages, nor does the slags induce major reactive oxygen species (ROS) formation and oxidative stress or trigger any inflammation in a biological system. On the contrary, the positive assay control quartz caused consistently evidence for an inflammation response in vitro associated with a significant secretion of the mature forms of pro-inflammatory cytokines from the cells, strong activation of the inflammasome pathway, and impaired phagocytosis functionality of alveolar macrophages.

Taken together the data generated in vivo and in vitro for ferrous slags it can be summarised that ferrous slags behave like natural rock, representing a rather inert category of UVCB substances. As expected biokinetics investigations in rats following inhalation exposure to high concentrations of ferrous slag particulates showed concentration-dependent lung burdens of persistent metals after inhalation exposure of rats to ferrous slags but there was no translocation to other organs of any metal investigated. The animal data suggest that the rat lung was able to get rid of the inhaled solid aerosol via physiological clearance mechanisms.

The toxicology programme for ferrous slags, as documented in the Chemical Safety Report (CSR) as part of the registration dossier of ferrous slags (CSR 2017), can be considered to fulfil information requirements for REACH (Registration, Evaluation, Authorisation and Restriction of Chemical substances) registration at the European Chemicals Agency (ECHA). There is sufficient, adequate and reliable information on hazardous properties for classification and risk assessment of ferrous slags.

The registrant makes use of Annex XI criteria regarding the scientific necessity of information, the technical possibility for testing, and exposure-based waiving to adapt the standard information requirements under REACH. These non-clinical studies are waived based on physico-chemical properties of ferrous slags that resemble natural rocks, mimicking the natural concentration of an element in the environment, and the low solubility in water, low extractability of components from ferrous slags, and lack of toxicological bioavailable fraction / systemic bioavailability of metals. Slag has been utilised in road construction for more than two centuries and wealth of humane experiences are available. Furthermore, ferrous slags have no PBT (persistent, bioaccumulative and toxic) or vPvB (very persistent and very bioaccumulative) properties. It is also of note that no toxicity effects of particular concern were observed in animal inhalation studies that is the likely route of human exposure, and results obtained from suitable in vitro studies demonstrate no certain dangerous property of ferrous slags. Finally, previous risk assessments of slags provide sufficient supporting evidence that toxicity can reliably be excluded.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion

Conclusions:
A short term-toxicity study by the oral route does not need to be conducted because an appropriate inhalation study is available and inhalation is the most appropriate route of administration as based on the expected uses, exposure assessment and the chemical- and physico properties of the slags.
The inhalation studies are showing no likely toxicity on inhalation; therefore, no oral toxicity is expected. Additional measurements are not recommended for reasons of animal welfare.