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Description of key information

Information on acute toxicity is based on read-across from aluminium and calcium compounds.
Read-across from aluminium compounds:
Oral LD50 (rat) > 2000 mg/kg bw
Inhalation LC50 (rat) > 2.3 mg/L
Read-across from calcium compounds:
Oral LD50 (rat) > 2000 mg/kg bw
Dermal LD50 (rabbit) > 2500 mg/kg bw

Key value for chemical safety assessment

Additional information

There are no studies available for “Reaction product of thermal process between 1000°C and 2000°C of mainly aluminium oxide and calcium oxide based raw materials with at least CaO+Al2O3+MgO >80% , in which aluminium oxide, magnesium oxide and calcium oxide in varying amounts are combined in various proportions into a multiphase crystalline matrix”. As this substance is an UVCB substance with aluminium oxide (Al2O3), calcium oxide (CaO) and magnesium oxide (MgO) as main constituents, and magnesium oxide (MgO) is exempted from registration according to EC 1907/2006 Annex V Section 10, data based on aluminium and calcium compounds were taken into account by read across following a structural analogue approach.

Oral route:

The available data are adequate to meet the REACH information requirements for aluminium oxide with respect to acute toxicity. According to the reported results (acute oral toxicity study, Butter, 1969; Nagy, 1979; Spanjers, 1979, IUCLID, Aluminium Oxide Dataset, 2000; and Balasubramanyam et al., 2009b and Balasubramanyam et al., 2009a, Spanjers, 2009), the oral LD50for aluminium oxide and aluminium hydroxide is above 2000 mg/kg bw in both female and male rats. In an acute oral toxicity GLP study according to OECD 425, one group of 5 female Wistar rats was treated by oral gavage with Precal 30S (Calcium oxide (burnt lime)) at 2000 mg/kg bw (Arcelin, 2007). The test item was applied diluted in Polyethylene glycol 300 (PEG 300) in a volume of 10 mL/kg bw. The observation period was 14 days. All animals survived until the end of the study period. No clinical signs were evident during the course of the study. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were observed at necropsy. The acute oral LD50 was found to be greater than 2000 mg/kg bw.

In addition, an acute oral toxicity GLP study according to OECD 425, one group of 5 female Wistar rats was treated by oral gavage with Precal 50S (Calcium dihydroxide (hydrated lime) at 2000 mg/kg bw (Arcelin, 2007). The test item was applied diluted in Polyethylene glycol 300 (PEG 300) in a volume of 10 mL/kg bw. The observation period was 14 days. All animals survived until the end of the study period. No clinical signs were evident during the course of the study. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were observed at necropsy. The acute oral LD50 was found to be greater than 2000 mg/kg bw

 

Dermal route:

There are no studies available for "Reaction product of thermal process between 1000°C and 2000°C of mainly aluminium oxide and calcium oxide based raw materials with at least CaO+Al2O3+MgO >80% in which aluminium oxide, magnesium oxide and calcium oxide in varying amounts are combined in various proportions into a multiphase crystalline matrix were investigated.

The substance is an UVCB substance with aluminium oxide (Al2O3) and calcium oxide (CaO) as main constituents.Therefore justification based on aluminium and calcium compounds were taken into account. Regarding CaO the focus of toxicokinetics, metabolism and distribution is on calcium since in aqueous media calcium oxide dissociates forming calcium cations and hydroxyl anions. For aluminium and aluminium compounds the pathways leading to toxic outcomes are dominated by chemistry and biochemistry of aluminium ion (Al3+) (Krewski et al., 2007).The HERAG guidance for metals and metal salts proposed default dermal absorption factors for metal cations in the range of maximally 0.1-1%. Dermal absorption in this order of magnitude is not considered to be significant.

In addition the results of an acute dermal toxicity study conducted in rabbit and comparable to OECD 402 (Kietzmann, 1994) showed no systemic effects of calcium dihydroxide (LD50 > 2500 mg/kg bw)

Aluminium hydroxide and aluminium oxide, are insoluble in water. Due to their insolubility it can be assumed that the above mentioned aluminium compounds will not be absorbed via skin. Moreover Flarend et al., 2001 showed a negligible bioavailability of aluminium after dermal application.

Furthermore, the results of acute oral toxicity studies conducted with read-across substances (aluminium compounds and calcium compounds) showed no acute systemic toxicity after oral administration (LD50 > 2000 mg/kg bw).

The above exposed allows the prediction that the dermal LD50 of ""Reaction product of thermal process between 1000°C and 2000°C of mainly aluminium oxide and calcium oxide based raw materials with at least CaO+Al2O3+MgO >80% in which aluminium oxide, magnesium oxide and calcium oxide in varying amounts are combined in various proportions into a multiphase crystalline matrix” will be much greater than 2000 mg/kg bw. This predictability makes acute dermal toxicity testing unnecessary and should be avoided in terms of animal welfare.

 

Inhalative route

Data from structurally related substances (read-across approach) are available.

The study by Cerven (1996) was conducted according to EPA Guidelines for Test Procedures Subdivision F, Series 81-3 and TSCA 40 CFR 798.1150. Five healthy male and five healthy female Wistar Albino rats were exposed to fumed alumina in an inhalation chamber for 4 hours. The number of animals used and the exposure duration were adequate according to the guidelines. The air concentration in the chamber, determined gravimetrically, was 2.3 mg/L. Only one concentration was tested. The average mass median diameter was 2.58 µm with a geometric standard deviation of 3.10 µm (2.31 µm, GSD 2.97 in the first 30 second sampling period and 2.85 µm, GSD 3.22 in a second sampling period). Chamber airflow, temperature (20.7 – 23.3 ºC) and humidity (60 to 61%) were monitored throughout the exposure period. Animals were observed for signs of toxicity at approximately one hour intervals during exposure, at one hour post exposure and then daily during a 14 day exposure period. Body weights were recorded pre-test, weekly and at termination.  No deaths were observed during exposure or during the 14 day post-exposure period. All animals had closed eyes, wet nose/mouth areas and fur coated with the test materials during the exposure. Observations were normal during the 14-day post-exposure period. Weight gain was normal in all the male animals. Weight loss was observed in two females on day 7 of the post-exposure period and in another two females on day 14. Lungs that were darker than normal with red areas were observed in only one female on necropsy. Based on the results of this study, the LC50is greater than 2.3 mg/L. The main limitations of this study were the lack of description of the test materials and the use of only one concentration with no rationale provided for the level chosen. 

The objective of the pre-guideline acute inhalation toxicity study conducted by Hazleton Laboratories (Cabot, 1969) was “to determine the acute inhalation toxicity and calculate the LC50, the confidence limits and slope function of the test material.”  Male rats (age unspecified) were exposed for one hour to concentrations of 0, 5.06, 5.88, 6.28 and 8.22 mg of aluminium oxide (fumed alumina) per litre of air in inhalation chambers. The authors stated that 8.22 mg/L was the highest concentration obtainable under the experimental conditions. The mean weight of each experimental group was reported (201g for the negative control and 203g, 195g, 200 g and 200 g for the treatment groups, ordered with increasing dose). Individual weights were not provided. Limited detail was provided on the production of the test atmosphere. Briefly, the compound was aerosolized and delivered into a 100 litre exposure chamber. The concentrations of test material were analytically verified by drawing known volumes of chamber atmosphere across weighed filters. The filters were then re-weighed and the average concentration of the test compound calculated on the basis of the volume and the gravimetric measurement. After the one hour exposure period, the animals were removed from the chamber and observed for 14 days. After this time, they were killed and necropsy was performed. Mortality and clinical signs appear to have been monitored daily post-exposure. During the one-hour exposure period, observation appears to have been continuous. The trachea, lungs, liver and kidneys were examined for gross pathological changes. Body weights were determined at the start and termination of the experiment. The LC50, 95%CI and slope (S) were estimated from the data using the graphical log-probit method of Litchfield and Wilcoxon (1949) (J Pharmacol Exp Ther 96: 99). Mortality was observed at the highest of three dose levels, reaching 50% in the group exposed to the highest levels (8.22 mg/L). Deaths occurred either during or shortly after exposure. The clinical symptoms observed were consistent with respiratory distress. The surviving animals were described as showing only “slight” toxic effects and good recovery by the end of the 14 day observation period. The authors report only a slight effect on weight gain. The statistical or biological significance of the difference was not mentioned. A greater amount of discolouration was observed on the surface of lungs of treated animals compared with control animals. A “slight” increase in the number of lesions on the lungs of the test animals was also reported – although individual data or further detailed was not provided. Animals that died were found to have a white gel in their trachea and stomachs. Their stomachs were also gas-filled and enlarged. The liver and kidney showed no difference between the treated and control animals on macroscopic examination. The authors of the study suggest that the deaths were likely due to suffocation from blockage of air passages by gel formed from the test substance in the high humidity of the air passages. The LC50 estimated from this study based on one hour of exposure was 7.6 mg/L (95% CI: 6.45 – 8.95 mg/L). This study report lacked some detail on the test substance (information obtained from sponsor), the chamber conditions and animal husbandry, and also the results from the examination of the gross pathology of the trachea, lungs, kidney and liver. The duration of exposure was only one hour. The number of animals and the reporting of the results that were included were adequate. 

Thomson et al. (1986) conducted a study in male Fischer 344 rats (10-12 weeks old) to investigate and compare the acute inhalation toxicity of aluminium flake and brass flake dusts. Both were irregularly shaped flake dusts coated with <2% palmitic and stearic acids to facilitate the milling process in manufacture. Two experiments were conducted: one with observations at 24 hours and 14 days post-exposure, the other with additional groups observed at 3 and 6 months post-exposure, in order to examine longer term effects of the acute exposure. The animals were exposed to the dust for 4 hours. During the exposure period, the animals were placed in compartmentalized wire cages without food, water or bedding in temperature - (22 ºC±2 ºC) and humidity - (30 to 70%) controlled chambers. The test atmospheres were produced using a Metronics Model #3 aerosol generator. Nominal concentrations for the aluminium powder were 10, 50, 100, 200 and 1000 mg/m³. The corresponding concentrations determined gravimetrically were 9.16, 47.3, 111, 206 and 888 mg/m³.  The MMAD for the aluminium powder was 1.58 µm (geometric mean diameter from microscopic analysis=2.82 ±0.26 µm). All animals were examined for toxic signs before and after exposure and daily during the post-exposure period. The animals were weighed at weekly intervals during the experimental and post-exposure periods. Pulmonary function measurements were conducted at 24 hours, 14 days, 3 months and 6 months post-exposure. Bronchopulmonary lavage was conducted and the BALF analysed for total cell counts, differential cell counts, and biochemical parameters (total protein and levels of glucose-6-phosphate dehydrogenase (G-6-PD), lactate dehydrogenase (LDH), and alkaline phosphatase (ALKP)).  Blood samples were also collected by cardiac puncture at each time point post-exposure for the analysis of copper, zinc, and aluminium.  After blood collection, rats were necropsied and the following examinations performed: total body weight, organ weight (heart, lung, kidneys, and gonads), gross and microscopic pathology of nasal air passages, trachea, lungs and hilar lymph nodes. No mortality was observed even at the highest aluminium flake concentration. No toxic signs were observed and there were no changes in measurements of lung function even at the highest dose (1000 mg/m³).  At concentrations greater than 10 mg/m³, an increase in polymorphonuclear neutrophils in the bronchoalveolar lavage was observed at 24 hours, typical of a mild acute inflammatory response. Increases in lactate dehydrogenase, alkaline phosphatase and total protein that persisted to 3 months provide evidence for a chronic irritant response in the presence of insoluble aluminium flakes retained in the lungs. These changes were not observed at the lowest dose level, 10 mg/m³. Multifocal microgranulomas were observed in terminal airways and alveolar septae in the 200 and 1000 mg/m³dose groups at 14 days, 3 months and 6 months. Black particulate material was observed in the hilar lymph nodes at 14 days and also later time-points suggesting clearance by alveolar macrophages. The acute inflammatory response to aluminium flakes was less dramatic than those for more soluble brass dust. The brass dust, however, did not exhibit evidence of a chronic irritant response; effects were resolved by 14 days post-exposure with the exception of larger numbers of alveolar macrophages around terminal airways which had resolved by 3 months. Brass particulate matter was not found in the lavage fluid or in histopathological examinations. The 4 hour exposure period conforms to acute inhalation toxicity guidelines. The use of only one sex of animals and the dose levels were adequately justified. Concentrations were analytically verified and sufficient numbers of animals were used. The results from lung function measurements were not provided in the publication and the highest dose was not intended to allow estimation of the LC50. 

Justification for classification or non-classification

According to DSD or CLP classification criteria for acute toxicity, no classification is warranted.

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