Ceramic materials and wares, chemicals

Endpoint summary

Description of key information

Read-across from aluminium compounds:
Oral: NOAEL (chronic, rat) 30 mg Al/kg bw/day as aluminium citrate.
Inhalation: LOAEC (subchronic, rat) 70 mg Al/m³ as aluminium oxide.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

30 mg/kg bw/day

Study duration:

chronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEC

70 mg/m³

Study duration:

subchronic

Species:

rat

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 >80% , in which aluminium oxide and calcium oxide in varying amounts are combined in various proportions into a multiphase crystalline matrix". As the substance is an UVCB substance with aluminium oxide (Al2O3) and calcium oxide (CaO) as main constituents, data from aluminium and/or calcium compounds were taken into account by read across following a structural analogue approach.

In terms of hazard assessment of toxic effects, available data on the repeated dose toxicity of other aluminium compounds was taken into account by read-across following a structural analogue approach, since the pathways leading to toxic outcomes are likely to be dominated by the chemistry and biochemistry of the aluminium ion (Al³⁺) (Krewski et al., 2007). 

In addition CaO in aqueous media dissociates forming calcium cations and hydroxyl anions, which following oral administration are neutralised in the GI tract and are therefore not relevant for consideration of systemic toxicity. Therefore for assessment of any systemic effects of CaO following administration via the oral route, the calcium ion Ca²⁺is the chemical species of interest.

 

Oral

A GLP study was performed in accordance with OECD Test Guideline (TG) 422 (Beekhuijzen 2007). No mortality or clinical signs of intoxication were observed in male and female Wistar rats due to treatment with Al chloride basic at dose levels of 40, 200, and 1000 mg/kg bw/day.

Treatment with Al chloride basic by oral gavage revealed paternal toxicity (irritation effect on glandular stomach mucosa, local effect) at 1000 mg/kg bw/day in both the male and female Wistar rats. Based on findings observed macroscopically (red foci or thickening of the glandular mucosa of the stomach) and supported by microscopic examination, the maternal/parental NOAEL for local toxic effects on stomach was established at 200 mg/kg bw/day and LOAEL – at level 1000 mg/kg bw/day, for both males and females.

Several statistically significant changes in clinical biochemistry parameters were observed at 1000 mg/kg bw/day suggesting a possible impact on the blood system (decreased Hb level in males, MCHC in both Al treated males and females), on the liver (decreased alkaline phosphatase activity, decreased total protein and albumin levels in blood serum) and possibly the kidney functions (increase potassium level) at this dose. Decreased Hb levels were observed in two other doses in males but no dose response relationship was observed. Lack of relevant baseline values for the observed clinical data limits the interpretation of the results. The authors consider clinical biochemistry and haematology changes observed at 1000 mg/kg bw/day to be of slight nature and generally within the range expected for rats of this age and strain. Because any morphological correlates were absent, these changes were considered not indicative of organ dysfunction and not of toxicological significance.

No reproduction, breeding and early post-natal developmental toxicity was observed in rats at 1000 mg/kg bw/day for males and females. Based on the reported results, a NOAEL for reproduction, breeding and early post-natal developmental toxicity was suggested at a level of 1000 mg/kg bw/day.

In another study (Hicks et al., 1987) Male Sprague-Dawley rats were exposed to aluminium-compounds with diet. The animals were randomly assigned to five groups, 25 animals in each. The groups received 1) basal diet (control), 2) aluminium hydroxide (302 mg Al/kg bw/day), 3) KASAL -the basic form of sodium aluminium phosphate containing ≈6% of Al (141 mg Al/kg bw/day), 4) KASAL II - the basic form of sodium aluminium phosphate containing ≈13% of Al (67 mg Al/kg bw/day) and 5) KASAL II (288 mg Al/kg bw/day). Treatment continued for 28 days, during which the animals were observed twice daily for their behaviour, signs of toxicity, and mortality. General physical examinations, body weight and food consumption measurements were performed weekly. After 28 days of treatment, 15 animals from each group were killed. Blood was collected from 5 rats of each group for blood cell counts, haemoglobin concentration, haematocrit and serum chemistry measurements. These rats were subjected to gross necropsy and histopathological examination. Femurs from 10 rats were taken for possible aluminium analysis; femurs from 5 rats were analyzed for Al concentrations. Five rats were allowed to recover for 2 months and five rats for 5 months after termination of the treatment. During these recovery periods, the rats received the basal diet and were observed daily; body weight and food consumption were measured monthly. Femurs were collected at autopsy from these rats for aluminium analysis. During the entire experimental period, no mortality was reported and no treatment-related clinical signs were observed. All clinical observations were characteristic of male Sprague-Dawley rats of relevant age. There were no significant group differences in body weight, food and water consumption and haematological parameters. A mild (2-4%) but significant increase in serum sodium level was observed in all treated. However, all increased sodium levels were within the range of historical control for rats of the same age in the laboratory. A significant 16% increase in absolute kidney weight was reported in the group of rats receiving KASAL II at 67 mg Al/kg bw/day. This increase appeared not to be treatment-related because no such increase was seen in the group of animals treated with this substance at 288 mg Al/kg bw/day. There were no other significant group differences in organ weights. All lesions seen at microscopic examination were those normally expected for young adult male Sprague-Dawley rats. No lesions suggestive of a treatment-related effect were seen. Aluminium concentrations in all femur samples from all groups were <1 ppm and most were below the limit of detection or quantification. The distribution of samples in which Al was not detectable, was detectable but not quantifiable or was quantifiable, was similar in all the groups. It should be noted that this comparison was based on small numbers of samples from each group (5). Al was quantifiable in all 5 samples from animals treated with Al(OH)₃, in 2 samples from the control animals and in none of the samples from animals treated with KASAL or KASAL II. The results of this study provide no evidence for significant deposition of Al in the bone and for toxicity of Al hydroxide or basic food grade sodium aluminium phosphate (KASAL and KASAL II) during 28-day dietary administration at daily doses up to ≈300 mg Al/kg bw/day. 

Sodium aluminium phosphate was administered to beagle dogs with diet at concentrations 0% (control), 0.3%, 1.0% and 3.0% for 6 months (Katz et al., 1984). There were no significant group differences in body weight throughout the experiment. Reductions in mean body weight occurred in all groups during week 27, were attributed by the authors to “pretermination tests and increased handling by technicians”. No treatment-related clinical signs and no ocular changes in any of the animals were observed. In most weeks, treated male and female dogs consumed less food than control dogs. In male animals, none of the differences in mean food consumption values was statistically significant. In females, significant reductions occurred “sporadically”. The authors did not consider these differences in food consumption as “toxicologically significant”, the conclusion that was supported by the absence of corresponding reduction in body weights. The treatment did not have any effect on haematological and blood biochemistry parameters, urinalysis results and results of analysis for occult blood in faeces. There were no significant differences in mean organ weights between the treated groups and the control group. Gross pathology and histopathology findings were in the “normal range of variations for dogs of this strain and age”; no treatment-related lesions were observed. The results of this study provide no evidence for toxicity of acidic form of sodium aluminium phosphate during 6-month administration at concentrations up to 3% in the diet.

Aluminium citrate was administered to ten female Sprague-Dawley rats with drinking water at a concentration of 80 mmol/L for 8 months (Vittori et al. 1999). Plasma iron concentration and total iron-binding capacity were not different in the control and the Al treated rats, indicating that the Al treated animals were not depleted of iron. There were no significant group differences in blood urea concentration, which suggests that kidney function was not altered by Al administration. Significantly lower haematocrit and blood Hb concentration were observed in the Al treated rats than in the control rats. Significantly higher reticulocyte count, abnormal erythrocyte morphology, a significant inhibition of (late colony-forming unit-rethroid, CFU-E) growth and a significant reduction of ⁵⁹Fe uptake in the bone marrow were reported in the Al treated rats. Plasma haptoglobin concentration was significantly lower in the Al treated animals than in the control animals. This and the presence of abnormal erythrocytes in the Al treated rats are indicative of intravascular haemolysis. Scanning electron microscopy combined with EDAX detected Al inside circulating erythrocytes with abnormal shape from animals in the Al treated group. Al concentrations in the bone, spleen, liver, kidney and plasma were significantly higher in the Al treated group than in the control group. No significant group difference in brain Al concentrations was seen. There was no correlation between plasma Al concentrations and Al levels in the organs or any other biochemical data. The results of this study suggest that Al affects erythropoiesis in rats with normal renal function.

Pregnant Sprague-Dawley dams (n=20 per group) were administered aqueous solutions of aluminium citrate 3225 mg/Al-citrate/ kg bw/day (300 mg Al/kg bw/day); 1075 mg/Al-citrate/kg bw/day (100 mg Al/kg bw/day); 322.5 mg/Al citrate/kg bw/day (30 mg Al/kg bw/day) according to OECD TG 426 (ToxTest TEH-113, 2010) .

Two control groups received either a sodium citrate solution (citrate control with 27.2 g/L) or plain water (control group). The Al citrate and Na-citrate were administered to dams ad libitum via drinking water from gestation day 6 until weaning of offspring. Litter sizes were normalized (4 males and 4 females) at postnatal day PND4. Weaned offspring were dosed at the same levels as their dams. Male and female rats sacrificed at PND 23. Endpoints and observations in the dams included water consumption, body weight, a Functional Observational Battery (FOB), morbidity and mortality. Endpoints were assessed in both female and male pups that targeted behavioural ontogeny (motor activity, T-maze, auditory startle, the Functional Observational Battery (FOB) with domains targeting autonomic function, activity, neuromuscular function, sensimotor function, and physiological function), cognitive function (Morris swim maze), brain weight, clinical chemistry, haematology, tissue/blood levels of aluminium and neuropathology at the different dose levels.

There were no significant Al-citrate treatment-related effects on mean body weights observed in the dams during the gestation and postnatal periods. The Na-citrate group, however, was significantly lighter than the control group on PND 15 (7.3%; p=0.0316). Eight dams in the high dose aluminium group were found to have diarrhoea compared with none in the other treatment groups. The low and mid-dose Al-citrate groups consumed more water than the control group but the high dose group did not, suggesting that the effect was not simply due to treatment. There were no significant treatment-related differences in gestational length. There were no consistent treatment-related effects observed for the Functional Observational Battery (FOB) tests in the dams. 

In the female pups, Na-citrate and high dose groups had significantly lower pre-weaning body weights than the control (control versus Na-citrate, p<0.0001; control versus high dose, p=0.0072). In the male pups, the control group mean body weights were significantly greater than the Na-citrate group (p<0.0001) and also significantly greater than the high dose group (p=0.0051). The mid-dose group mean body weight was significantly greater than the Na-citrate group (p=0.0405). In the female pups, the mean number of days to reach vaginal opening was 31.3 (±2.1, SD) in the control group and 39.7 (±5.6, SD) in the high dose Al-citrate group, a significant difference (p<0.0001). In males, the mean number of days to reach preputial separation was 39.6 (±2.1, SD) in the control group and 42.5 (±3.2, SD) in the high dose group, also a significant difference in the pair-wise comparisons (p<0.0001). FOB observations showed no clear treatment-related effect among the neonatal pups that were assessed at PND 5 and 11 or in the juvenile pups assessed ca.PND 22. No consistent treatment-related effects were observed in ambulatory counts (motor activity) and no significant effects were observed for the auditory startle response, T-maze tests (pre-weaning Day 23 cohort). Haematology parameters showed no significant treatment-related effects in the Day 23 cohort. Serum biochemistry changes associated with aluminium toxicity such as elevated alkaline phosphatase were observed at PND 23. The authors state the levels remained within the normal range. Whole body Al levels in neonatal pups from high dose females and males were greater than those in the control groups. There were no significant sex differences. Concentrations of Al in bone showed the strongest association with Al dose and some evidence of accumulation over time in all of the Al-treated groups. Of the central nervous system tissues, Al levels were highest in the brainstem. Although levels of Al were relatively low in the cortex (< 1µg/g), they were positively associated with Al levels in the liver and femur.  

The study used adequate numbers of animals and randomization to reduce bias, assessed endpoints in both female and male offspring, and studied a wide range of neurotoxicity endpoints. Haematology, clinical chemistry, pathology and general toxicity endpoints were also assessed. Three dose levels were used although the highest was close to the MTD. The results from this study are informative for developmental and neurotoxic effects due to prenatal and early postnatal exposure of rats to high doses of aluminium (30 mg Al/kg bw/day, 100 mg Al/kg bw/day and 300 mg Al/kg bw/day). The study showed no treatment related effects of Al-citrate on maternal body weight, neurobehavior and gestational length. No dose and treatment-relevant effects of Al-citrate on neuromotor maturation and neurobehavioral activity, learning and memory, haematological and clinical biochemistry parameters, post-mortem structure of the internal organs following in-utero and lactation exposure were observed. Delayed development of both male and female pups was observed in the high dose Al-citrate group and also in the Na-citrate group. The effect is considered treatment-related but whether the effect is secondary to decreases in body weight is not clear. In addition, as an effect was observed in the Na-citrate group, the role of aluminium in causing this effect can not be concluded (nor excluded). Reported results suggest the possible transfer of Al from dams to pups in-utero, although a contribution from breast milk PND 0 to 4 is also possible.

A long term toxicity/carcinogenicity study of calcium lactate was performed with 50 male and 50 female F344 rats per group, receiving 2.5 or 5 % calcium lactate via drinking water for 104 weeks (2 years). None of the experimental groups showed a significant increase in the incidence of any specific tumours compared with the corresponding control value, and also no positive trend was noted in the occurrence of any tumour. Therefore, the NOAEL for tumour formation in this study is represented by the high dose of 5 %, corresponding to calcium lactate doses of 2150 and 2280 mg/kg bw/day to male and female rats, respectively. This is equivalent to calcium doses of approximately 279.5 and 296.4 mg Ca/kg bw/day for male and female rats. Accordingly, the lower NOAEL value of 279.5 mg Ca/kg bw/day (male rats) is established as a NOAEL for carcinogenicity hazard assessment (Maekawa et al., 1991).

Inhalation

Available information on repeated dose toxicity inhalation of other aluminium compounds, was taken into account as supporting information.

Gross et al. (1973) exposed rats, guinea pigs and hamsters to three different aluminium powders (British pyro powder, a US-flake powder, and a US-source atomized powder with approximately spherical particles) and also aluminium oxide dust, included as a negative “non-fibrogenic control”. The Al2O3 content was 16.6% for the British pyro powder, not stated for the flake powder and 2.9% for the atomized powder. The doses administered by inhalation ranged from 15 to 100 mg/m³, 6 hours per day, 5 days per week for either 6 or 12 months. Thirty rats were exposed to pyro powder at each 15, 30, 50 and 100 mg/m³, 30 rats were exposed to atomized metal powder at each 15, 30, 50 and 100 mg/m³, 30 rats were exposed to flake powder at 15 and 30 mg/m³, and 30 rats were exposed to aluminium oxide dust at 30 and 70 mg/m³. Five rats were sacrificed per time point (6, 8, 12 and 18 months). Thirty hamsters were exposed to pyro powder at 50 and 100 mg/m³, 30 hamsters were exposed to atomized powder at 50 and 100 mg/m³, and 30 hamsters were exposed to aluminium oxide at 70 mg/m³. Between 15 and 25 guinea pigs were exposed to each of the aluminium powders at 15 and 30 mg/m³. Twelve guinea pigs were exposed to aluminium oxide dust at 30 mg/m³. The chambers were approximately 1.2 m³ in volume, moisture was removed using anhydrous calcium chloride and powders were dispersed through the chambers by means of a dust-feed mechanism (Wright). Air flow was limited to10 litres/min to attain high dust concentrations. 

 

The dusts, suspended in tap water, were also administered by intratracheal instillation to different groups of animals. Concentrations were used such that 1mL of the suspension contained the required dose. Injections were performed under anaesthetic (ether) using an illuminated laryngeal speculum to facilitate the introduction of the 18-gauge, blunt needle. A tap water “vehicle” control group was included. For intratracheal instillation, 15 rats and 15 hamsters were allocated to each dose for the pyro, atomized and flaked powders. With the exception of the highest dose level, 1 to 5 animals were sacrificed at 6 months and 7 to 10 animals at 12 months post-exposure. At the 100mg/m³ dose level for the pyro powder, 15 animals were dosed, 4 were sacrificed at 2 months, 4 at 4 months and 7 at 6 months. At the 100mg/m³ dose level for the atomized powder, 15 animals were dosed, 3 animals were sacrificed at 2 months, 3 animals at 4 months and 2 animals at 6 months.

 

Mortality was reported but no data on clinical signs, body weight, or organ weights was provided. Histopathological examinations of the lungs were conducted on sections cut in triplicate from lung tissue stained with either eosin alone to show aluminium particles, hematoxylin-eosin, or PAS/ van Gieson. To show cellular components and stromal support structures, the hematoxylin-eosin stained sections were examined before and after decolourization and impregnation with silver (Gordon and Sweets method).

 

Intratracheal injection of the aluminium powders caused nodular pulmonary fibrosis in the lungs of the rats only at the highest dose administered (100 mg). A fibrotic response was not observed in hamsters indicating inter-species differences in response. 12 mg of dust administered intratracheally did not lead to collagen production in rats or hamsters. The response of hamster and guinea pigs lungs differed from rats. At higher concentrations, hamster and guinea pig lungs developed metaplastic foci of alveolar epithelium that persisted beyond the resolution of alveolar proteinosis and clearance of the dust particles. 

 

Progressive fibrosis was not observed in rats on inhalation exposure to the powders indicating that the intratracheal instillation mode of test compound delivery may lead to artefacts not representative of physiologically relevant exposures. There was no dose response evident or a noticeable difference between responses to the different aluminium powders. All three species developed widespread alveolar proteinosis, rats exhibiting the most severe response. However, alveolar walls appeared thin and normal. The proteinosis resolved progressively after cessation of exposure. Small scattered foci of endogenous lipid pneumonitis (granulomatous inflammation) developed associated with cholesterol crystals that were not surrounded by alveolar proteinaceous material. These effects generally occurred in regions not associated with dust particles and left small collagenous scars. The group of rats exposed for 12 months to 15mg/m³ of aluminium powder showed moderate alveolar proteinosis after 6 months of exposure. Granulomatous inflammation was observed at 50 mg/m³ after about 3 months of exposure.

 

Overall, there was no consistent relationship between dose and severity of response for any of the aluminium powders. The results showed no clear difference in reaction to the different powders. The results from this study do not provide evidence to support a progressive fibrotic response on inhalation exposure to aluminium powder. No alveolar proteinosis or thickening of alveolar walls was observed in rats, hamsters or guinea pigs exposed to Al2O3 dust (66% <1μm) included in the study as a “non-fibrogenic” control. 

 

Pauluhn (2009) investigated the pulmonary toxicity of two calcined agglomerated aluminium oxyhydroxide (boehmite) nanoparticles in rats exposed by inhalation for 6 hrs/day, 5 days/week for 4 weeks. The principle hypothesis of the study was to “test whether the pulmonary effects (toxicity and fate) following exposure to aluminium oxyhydroxides of differing primary and agglomerated particle size are more dependent on the primary than agglomerated particle size”. The MMAD of one of the boehmite substances was 1.7μm (primary particle size 10 nm) and of the other substance was 0.6μm (primary particle size 40 nm). The duration of the post-exposure observation period was 3 months and the dose levels used were 0, 0.4, 3 and 28 mg/m³. An interim sacrifice was made on day 10 during exposure and post-exposure (PE) sacrifices were carried out one day after the end of exposure, 12 days, 33 days and 91 days after the end of exposure. Clinical observations were performed before and after exposure and body weights were recorded twice weekly during exposure and once weekly after. Twelve animals were exposed per dose level and timepoint; six for lavage and histopathology and six for determination of Al levels in different tissues. Pulmonary toxicity was determined by analysis of bronchoalveolar lavage fluid (BALF) and histopathological examination of all 5 lung lobes, bronchi and lung-associated lymph nodes using hematoxylin and eosin stains. Lung tissue was also examined using Sirius red to show collagen. The olfactory bulb, ethmoid turbinates, and the olfactory nerve were also examined. Aluminium levels were measured by graphite furnace atomic absorption spectrometry in urine (collected overnight on days 4, 11, 18 and 25 ) and also in the brain, the right lung lobes, BAL cells, hilar lymph nodes, the kidneys, and the liver after acid digestion. Lung retention kinetics were also calculated assuming first order elimination rates. 

 

No significant differences in BALF cytology and biochemical parameters were observed in the animals treated with 0.4 or 3 mg/m³ at any time-point compared with the time-matched control groups. At 28 mg/m³, however, an inflammatory response was evident. Total cell counts in the BALF in animals exposed to AlO(OH)-40 [MMAD=0.6μm] were similar to the control at day 10 but showed a marked increased at days 24 and 35 (factor of 2 to 3; p<0.05). Levels decreased to about 1.5 times the control level at days 56 and 113. The response to AlO(OH)-10 [MMAD=1.7μm] was similar. Levels of polymorphonuclear neutrophilic granulocytes (PMNs; absolute numbers) were significantly elevated (factor of 100-200; p<0.01) at all time-points in the animals treated with 28 mg/m³ of either substance. For AlO(OH)-40 [MMAD=0.6μm], the highest levels were observed on days 24 and 35 after which there was a decrease. On day 113, the number of PMNs was still significantly greater than in the time-matched control animals. Interestingly, the number of PMNs in all groups, including the control showed a slight increase with time. In animals treated with AlO(OH)-10 [MMAD=1.7μm], significantly elevated (factor of 100-200; p<0.01) numbers of PMNs were observed at all time-points in the 28 mg/m³ treated animals with highest levels at days 24, 35 and 56 with a slight decrease by day 113. Lactate dehydrogenase (LDH) showed a similar profile for both boehmite substances. On study day 10 during exposure there was no significant elevation of LDH. The highest level (increased by a factor of 2.5 relative to the control; p<0.05) was on day 24 just after cessation of exposure after which LDH levels showed a clear decrease with time. On day 113 there was no significant difference between the 28 mg/m³ treated group and the control for the AlO(OH)-40 [MMAD=0.6μm] substance. For AlO(OH)-10 [MMAD=1.7μm], however, the LDH level in the 28 mg/m³ treated group was still greater (p<0.05) than in the control animals on day 113. Levels ofβ-N-acetylglucosaminidase (β–NAG), total protein, and γ-glutamyltransferase (γ-GT) showed evidence of low levels of reversible lung damage. No abnormal histopathological findings were observed in control rats or rats exposed to the 0.4 or 3 mg/m³ dose levels. In rats dosed for 4 weeks with 28 mg/m³, however, particles were seen in alveoli, enlarged and sometimes foamy macrophages were present and a “slight hypercellularity (increased epithelial cells, inflammatory cells, focal septal thickening – graded as slight to minimal)” were observed. Focal septal collagen was revealed by Sirius red. No progression or regression of these changes was observed post-exposure. Findings were similar for both boehmites. The authors reported a “slight lymphoid activation” with increased accumulation of epitheloid cells post-exposure exposure in the lung-associated lymph nodes (LALN).

 

In the animals treated with AlO(OH)-40 [MMAD=0.6μm], absolute lung weights were significantly greater than the control in the 28 mg/m³ group at day 24, day 56 and day 113. At day 113, lung weights were significantly greater at 3 mg/m³ also. In the AlO(OH)-10 [MMAD=1.7μm] treated animals, absolute lung weights were significantly greater than the control only on day 24 in the 28 mg/m³ treated group. Animals treated with either boehmite showed absolute hilar lymph node weights significantly greater than the time-matched control on days 24, 35, 56 and 113 showing an increase with time. In the AlO(OH)-40 [MMAD=0.6μm] treated animals a decrease was observed on day 113 although the weight remained statistically elevated (p<0.05) compared with the time-matched control. In contrast, in the AlO(OH)-10 [MMAD=1.7μm] treated animals, the largest difference between treated and control was observed on day 113. 

 

A time dependent decrease in the amount of Al in the lungs was observed for both boehmites after cessation of exposure. Levels were higher in the AlO(OH)-40 [MMAD=0.6μm] treated animals. The amount of Al in the hilar lymph nodes was elevated from study day 24 in the 28 mg/m³ Pural (AlO(OH)-40 [MMAD 0.6μm]) treated animals. The levels increased with time until the last day of the experiment. Levels also increased with time in the AlO(OH)-10 [MMAD 1.7μm]) treated animals, but not to the same extent. No measurable increase was observed in aluminium levels in lung-associated lymph nodes for the 0.4 or 3 mg/m³ dose levels for either boehmite. The results showed no time or dose-dependent increases in Al in the brain, liver or kidneys. The authors also reported no evidence of time or dose-dependent changes in Al in urine (reported qualitatively).

 

In conclusion, an inflammatory pulmonary response was observed at the end of the 4 week exposure period in the animals receiving the highest dose (28 mg/m³) in this study. Indices of lung damage showed that the effect was to some degree reversible. Even though measurable aluminium was observed in the lungs at the lower dose levels (0.4 and 3 mg/m³), adverse effects were not seen despite the sensitive endpoints employed. Histopathological changes were observed only at 28 mg/m³ and included focal septal collagen. For the dose levels and exposure durations used in the study, significant translocation of the particles from the lung to other body organs was not evident. The cumulative lung burden was higher for the test substance with the smaller agglomerated particle size (0.6μm), which interestingly had the larger primary particle size. A marked increase in lung retention was evident at the highest dose level, consistent with an “overload” phenomenon. This study was well-reported and appears to have been well-conducted adhering approximately to guidance for a subacute inhalation toxicity study. The results are informative for the risk assessment of alumina particles in the respirable size range when exposure occurs by inhalation. The NOAEC from this study is 3 mg/m³ and the LOAEC is 28 mg/m³.

 

Dermal

No animal studies are available in which the repeated exposure toxicity of aluminium and calcium has been investigated

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 >80% , in which aluminium oxide and calcium oxide in varying amounts are combined in various proportions into a multiphase crystalline matrix". 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 comparable to OECD 402 (Kietzmann, 1994) showed no systemic effects of calcium dihydroxide (LD50 > 2000 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 >80%, in which aluminium 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.

 

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

Justification for classification or non-classification

According to DSD or CLP classification criteria for repeated dose toxicity, no classification is required.