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Neurotoxicity

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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”. The substance is an UVCB substance with aluminium oxide (Al2O3), calcium oxide (CaO) and magnesium oxide (MgO) as main constituents.

Since there are no reliable reports on CaO neurotoxic effect in animals and magnesium oxide (MgO) is exempted from registration according to EC 1907/2006 Annex V Section 10., data from aluminium compounds were taken into account by read across following a structural analogue approach.

Read-across from aluminium compounds:

There were no studies available in which the neurotoxic properties of aluminium oxide were investigated.

Information available on aluminium compounds were therefore considered for this endpoint, 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; ATSDR, 2008).

A GLP-compliant long-term study (similar to OECD guidelines 426 and 452) was available, in which the potential functional and morphological hazards to the nervous system that may arise from pre-and post-natal exposure to aluminium citrate were investigated (ToxTest. Alberta Research Council Inc., 2009). The results of these investigations are presented in more detail in the respective section (Toxicity to reproduction).

Shortly, pregnant Sprague-Dawley rats were exposed during gestation (starting on gestational day 6) through weaning to 30, 100 and 300 mg Al/kg bw/day as aluminium citrate via drinking water; the offspring was exposed to the same dose levels during post-weaning and continuing up to post-natal day 364. The study showed no evidence of an effect of Al-citrate on memory or learning but a more consistent effect was observed in endpoints in the neuromuscular domain. The critical effect was a deficit in fore- and hind-limb grip strength. However the effects on fore and hindlimb grip strength were only observed in adult animals of the F1 generation not in newborn and adolescent animals suggesting a repeated dose effect at relatively high dose levels, but no developmental neurotoxicity.Based on the study results, a LOAEL for neurotoxicity of 100 mg Al/kg bw/day for aluminium toxicity was assigned, the NOAEL being 30 mg Al/kg bw/day.

The majority of the further available intermediate-duration studies has focused on the potential neurological and neurodevelopmental effects induced by aluminium exposure. A variety of behavioural tests have been conducted in rats and mice, in which the most consistently affected behaviours involve motor function (ATSDR, 2008).

In a study by Golub and Germann (2001), groups of pregnant mice were exposed to ca. <1, 10, 50, 100 mg Al/kg bw/day as aluminium lactate in diet on gestational days 0-21 and during lactation until day 21. On postnatal day (PND) 21, one male and one female pup from each litter were placed on the same diet as the dam. The offspring were exposed until PND 35. The females were tested for neurotoxicity using the Morris water maze at 3 months of age. Males were tested for motor activity and function using rotarod, grip strength, wire suspension, mesh pole descent, and beam traversal tests at 5 months of age.

No alterations in pregnancy weight gain or pup birth weights were observed. Significant decreases in pup body weights were observed on PND 21 at 50 and 100 mg Al/kg bw/day. No information on maternal weight gain during lactation was reported; however, the authors stated that the decrease in pup weight was not associated with reduced maternal food intake. The decrease in body weight was statistically significant at 100 mg Al/kg bw/day on PND 35. Female mice in the 100 mg Al/kg bw/day group weighed 15% less than controls on PND 90. Decreases in heart and kidney weights were observed at 100 mg Al/kg bw/day in the females. Increases in absolute brain weight were observed in females at 10 mg Al/kg bw/day and relative brain weights were observed at 10 or 100 mg Al/kg bw/day, but not at 50 mg Al/kg bw/day.

At 5 months, Significant decreases in body weight of the males were observed at 50 (10%) and 100 (18%) mg Al/kg bw/day; at these doses, an increase in food intake was also observed. In the Morris maze, fewer animals in the 100 mg Al/kg bw/day group had escape latencies of <60 seconds during sessions 1-3 (learning phase) and a relocation of the visible cues resulted in increased latencies at 50 and 100 mg Al/kg bw/day. There was no correlation of body weight with latency to find the platform or with the distribution of quadrant times. The authors concluded that controls used salient and/or nonsalient cues, 10 and 50 mg Al/kg bw/day animals used both cues, but had difficulty using only one cue, and 100 mg Al/kg bw/day animals only used the salient cues. A significant decrease in hindlimb grip strength and an increase in the number of rotations on the rotorod were observed at 100 mg Al/kg bw/day, and a shorter latency to fall in the wire suspension test was observed at 50 and 100 mg Al/kg bw/day. The authors stated that there were significant correlations between body weight and grip strength and number of rotations. After adjusting hindlimb grip strength statistically for body weight, the aluminium-exposed mice were no longer significantly different from the controls; the number of rotations was still significantly different from control after adjustment for body weight.

A maternal NOAEL could not be identified. Based on impaired performance on the water maze test in females and shorter latency to fall in wire suspension test in males, the offspring NOAEL was considered to be 10 mg Al/kg bw/day as aluminium lactate.

In another study, groups of female rats were exposed to 0, 50, or 100 mg Al/kg bw/day as aluminium nitrate nonahydrate in drinking water (Colomina et al., 2005). In order to increase aluminium absorption, citric acid (710, 355, and 710 mg/kg bw/day in the control, 50, and 100 mg/kg bw/day groups, respectively) was added to the drinking water. The adult rats were exposed to aluminium for 15 days prior to mating and during gestation and lactation periods. After weaning, the pups were exposed to the same doses as the mothers from PND 21 through 68.Besides aluminium exposure, some animals in each group underwent restraint stress, which consisted in placing the rats for 2 hours/day in cylindrical holders on gestation days 6-20. A battery of neurobehavioral tests was conducted on the offspring: righting reflex (PNDs 4, 5, 6), negative geotaxis (PNDs 7, 8, 9), forelimb grip strength (PNDs 10-13), open field activity (PND 30), passive avoidance (PND 35), and water maze (only tested at 53 mg/kg/day on PND 60). The rats were sacrificed on PND 68.

In the dams exposed to aluminium, no significant alterations in body weight, food consumption, or water consumption were observed during gestation. The authors stated that decreases in water and food consumption were observed during the lactation period in the rats exposed to 100 mg Al/kg bw/day, but these data were not shown and maternal body weight during lactation was not mentioned. No significant effects in the number of litters, number of foetuses per litter, viability index, or lactation index were observed. In addition, no differences in days at pinna detachment or eye opening were observed. Age at incisor eruption was significantly higher in males exposed to 50 mg/kg/day, but not in males exposed to 100 mg/kg/day or in females. A significant delay in age at testes descent was observed at 100 mg/kg/day and vagina opening was delayed at 50 and 100 mg/kg/day. A decrease in forelimb grip strength was observed at 100 mg/kg/day. No effects in other neuromotor tests were observed. Additionally, no alterations in open field behaviour or passive avoidance test were observed. In the water maze test, latency to find the hidden platform was decreased in the 50 mg/kg/day group on test day 2, but not on days 1 or 3; no significant alteration in time in the target quadrant was found.

The overall effects indicated a maternal NOAEL of 100 mg Al/kg bw/day as aluminium nitrate nonahydrate. An offspring NOAEL could not be identified. Based on decreased forelimb grip strength and delay in vagina opening the offspring LOAEL was considered to be 50 mg Al/kg bw/day as aluminium nitrate nonahydrate.

In general, oral exposure to aluminium is not associated with marked signs of neurotoxicity in animals. Studies involving exposure to high aluminium doses have not noted significant increases in the incidence of overt signs of neurotoxicity (Donald et al. 1989; Golub et al. 1992). In another study, an overt sign of toxicity reported was an increase in cage mate aggression in male mice exposed to 200 mg Al/kg bw/day from gestation day 1 through postnatal day 170 (Golub et al. 1995).

Decreases in forelimb and/or hindlimb grip strength have been observed in mice exposed to 100 mg Al/kg bw/day for over 2 years (Golub et al. 2000). However the effects on fore and hindlimb grip strength were only observed in adult animals of the F1 generation not in newborn and adolescent animals suggesting a repeated dose effect at relatively high dose levels, but no developmental neurotoxicity.In contrast, no alterations in grip strength were observed in mouse dams exposed to 330 mg Al/kg bw/day (Donald et al. 1989) as aluminium lactate in the diet on gestation day 1 through lactation day 21 or in mice exposed to 200 mg Al/kg bw/day on gestation day 1 through postnatal day 170 (Golub et al. 1995). No significant alterations have been observed for negative geotaxis in mouse dams exposed to 330 mg Al/kg bw/day as aluminium lactate in diet on gestation day 1 through lactation day 21 (Donald et al. 1989). A decrease in total spontaneous activity, vertical activity (rearing), and horizontal activity were observed in mice exposed to 130 mg Al/kg bw/day for 6 weeks (Golub et al. 1989). Exposure to lower doses of aluminium lactate or aluminium nitrate (with added citric acid) has not been associated with decreases in motor activity. No alterations in motor activity (as assessed in open field tests) were found in rats exposed to 100 mg Al/kg bw/day for 1 or 2 years (Roig et al. 2006). Similarly, no alterations in total activity or horizontal activity were observed in mice exposed to 100 mg Al/kg bw/day as aluminium lactate in the diet during gestation, lactation, and postnatally until 2 years of age (Golub et al. 2000). However, the investigators noted that the automated activity monitor used in this study did not detect vertical movement of the older rats and that their previous study (Golub et al. 1989) found that vertical movement was more sensitive than horizontal movement. Another chronic-duration study (Roig et al. 2006) found no significant alterations in the total distance travelled or the total number of rearings in rats exposed to 100 mg Al/kg bw/day as aluminium nitrate in drinking water (citric acid added) from gestation day 1 through 2 years of age.

Changes in thermal sensitivity was not observed in mouse dams exposed 330 mg Al/kg bw/day as aluminium lactate in the diet on gestation day 1 through lactation day 21 (Donald et al. 1989). No changes in startle responsiveness were observed in mice exposed to 250 or 330 mg Al/kg bw/day as aluminium lactate in the diet on gestation day 1 through lactation day 21 (Donald et al. 1989; Golub et al. 1992a).

In a low quality study, no significant alterations in performance on the water maze test were found in rats exposed to 100 mg Al/kg bw/day as aluminium nitrate in the drinking water for a chronic duration (Roig et al. 2006).

 

Justification for classification or non-classification

Overall, based on the read-across from aluminium compounds forthe neurotoxicity 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”, no classification is required according to DSD or CLP classification criteria.

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