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Neurotoxicity

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Description of key information

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Effect on neurotoxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Effect on neurotoxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There were no studies available in which the neurotoxic properties of aluminium hydroxide 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 recent combined one-year developmental and chronic neurotoxicity study with Al-citrate (Alberta Research Council Inc, 2010) may be of interest for the evaluation of the neurotoxicity of Aluminium hydroxide, taking into consideration the tenfold lower bioavailability of Al-hydroxide compared to Al-citrate and excluding effects that can likely be related to the salt rather than the cation. The study was conducted according to OECD TG 426 and GLP, and the exposure covered the period from gestation day 6, lactation and up to 1 year of age of the offspring. Pregnant Sprague-Dawley dams (n=20 per group) were administered aqueous solutions  via drinking water of  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). The highest dose was a saturated solution of Al-citrate. Two control groups received either a sodium citrate solution (citrate control with 27.2 g/L, equimolar in citrate to the high dose Al-citrate group) 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 (PND) 4. Weaned offspring were dosed at the same levels as their dams. Dams were sacrificed at PND 23. At PND 4  1 male and 1 female pup of each litter  were allocated to 4 testing groups: D23-sacrifice group for pre-weaning observations and D23 neuropathology, D64, D120 and D365 postweaning groups for post weaning observations and neuropathology at the respective days of sacrifice. Endpoints and observations in the dams included water consumption, body weight, morbidity and mortality and a Functional Observational Battery (FOB) (GD 3 and 10, PND 3 and 10). Pups were examined daily for morbidity and mortality. Additional neurobehavioral tests were performed at specified intervals and included, T-maze, Morris water maze, auditory startle, and motor activity. Female pups were monitored from PND26 for vaginal opening, male pups from day 35 for preputial separation. Clinical chemical and haematological analysis was performed for each group on the day of scheduled sacrifice. Al-concentrations were determined in blood, brain, liver, kidney, bone and spinal cord tissues by inductively coupled plasma mass spectrometric analysis. Further metals such as iron, manganese, copper and zinc were also determined. The pathological investigation includes rain weight and neuropathology. Statistical analyses were performed using the SAS software release 9.1. Data collected on dams and pups were analysed separately. All analysis on pups was performed separately for each sex. Statistical significance was declared from P ≤ 0.05.

Results: Dams: Eight high dose dams developed diarrhoea. In the Na-citrate group one dam stopped nursing and the pups were euthanized. No significant differences between mean body weights of dosed animals compared to controls were observed during gestation and lactation. During gestation and lactation low and mid dose group animals consumed considerably more fluid than controls and high dose group animals. This is not considered treatment related as there was no dose response. In all animals the target dose was exceeded during lactation due to the physiologically increased fluid consumption.

Pups: During the pre-weaning phase weights of mean body weights of male and females in the sodium citrate and high dose group were significantly lower than the untreated controls. This suggests a citrate rather than Al-related effect. No differences between treated and control animals were observed in the FOB. No other clearly treatment related effects were observed pre-weaning.

F1-postweaning: General toxicity

No significant differences in body weights throughout the study were observed between low and mid-dose animals sodium-citrate and untreated controls. High dose males had significant lower body weights than controls by PND 84. These animals also had clinical signs. At necropsy urinary tract lesions were observed in the animals of the high dose group, most pronounced in the males, hydronephrosis, uretal dilatation, obstruction and/or presence of calculi. All high dose males were sacrificed on study day 98. The effect is probably due to Al-citrate calculi precipitating in the urinary tract at this high dose level. This effect is related to the citrate salt and cannot be attributed to the Al-ion. Female high dose animals showed similar urinary tract lesions, but with a lower incidence and severity. Urinary tract lesions were also observed in single mid dose males, but also in a few sodium citrate and control animals. Fluid consumption during the study was increased in the sodium citrate and Al-citrate groups (in particular high and mid dose) compared to controls. This is probably due to the high osmolarity of the dosing solutions. However, the consumed dose levels decreased in all dose groups during the study. In the beginning the target dose was considerably exceeded, while versus the end of the study it was considerably below the target dose.  According to the authors the assigned dose levels still remain valid.

Developmental landmarks:

In sodium citrate controls and high dose males and females the number of days to reach preputial separation or vaginal opening was longer than in untreated control animals. This may be related to the lower body weights in these animals at the respective time-point. As the sodium citrate group showed similar retardation this effect cannot be allocated to the aluminium cation.

Neurobehavioral testing

No consistent treatment related effects that could be related to Al-ion exposure were observed in the FOB. No treatment related effects on autonomic or sensimotoric function were observed in the study. A weak association between Al exposure and reduced home cage activity, a very weak association with excitability, some association with neuromuscular performance were reported but according to the authors this may also be related to group differences in body weight, and an association with physiological function and is thus not considered clearly treatment related. No treatment related effect on general motor behavior was observed. No clearly treatment related effect on auditory startle response was observed. There was no evidence of any treatment related effect on learning and memory in the Morris Water Maze test and no clearly treatment related effects in the T-maze test. Hind limb grip strength and to a lesser extend foot splay were reported to be reduced compared to controls in high and mid dose male and female animals, more pronounced in younger than in older  rats. However, the observed effects can be related to the lower body weights of the individual animals undergoing this test. No details on the individual findings and historical control data are available. It can therefore not be concluded with certainty that the observed neuromuscular effects are primary effects of the treatment and attributable to Al3+. The NOAEL was reported based on this effect as 30 mgAl/kg bw in a conservative approach.

Haematology: No clinically significant differences in hematology were observed at the investigation on day 23. In day 64 and 120 females and day 64 males the high dose group showed slight reduction in hematocrit (males only), mean hemoglobin and mean corpuscular cell volume.No such changes were observed in the 364 day group.

Clinical chemistry: while a number of borderline statistically significant changes were observed, such as globuline levels, alkaline phosphatase and glucose in the high dose group little or no biological significance is associated with them. Elevated creatinine and urea levels in Day 64 males are consistent with the renal toxicity observed in these animals.

Organ weights: Brain weights did not differ among the groups, with two exceptions in the day 64 group males brain weights were significantly lower than controls. In the 120 day female high dose group brain weights were also significantly lower than controls. These findings were not reproduced at the other sacrifice times. Brains to body weight ratios were not significantly different and the lower brain weights can be attributed to the body weight.

Pathology: The main pathology findings were the renal lesions with precipitates in the urinary tract and secondary lesions such as hydronephrosis and uretal dilatation   in particular in the high dose group males and to a lesser extend females. Fluid colonic content was also observed in some high dose animals, in particular males. According to the authors the test item clearly precipitated in the urinary tract causing stone formation and blockage and resulted in fluid colonic content. No other macroscopic effects were observed in other organs.

Histopathology: No treatment related histopahological effects were observed in the nervous system at any time point.

Aluminium concentrations in different organs were dose related. Tissue concentrations were highest in blood, and then in decreasing order brainstem, femur, spinal cord, cerebellum, liver cerebral cortex.

A conservative NOAEL of  322 mg Al-citrate/kg bw  corresponding to 30 mg Al/kg bw for neuromuscular effects was derived from this study (with a bioavailability correction this would correspond to ca. 300 mg Al from Al(OH)3).

The most important effects were however related to a precipitation of the citrate in the kidneys and urinary tract and this effect is not related to the Al3+ ion.  The effects on grip strength and foor splay observed can also not be attributed unequivocally to Al-exposure as they may have been secondary to the general toxicity and body weight differences between treated and control animals undergoing this test. Neurobehavioral effects as reported by e.g. Thorne et al., 1986 could not be confirmed in this study.

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 nitrate nonahydrate 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 nitrate nonahydrate 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 nitrate nonahydrate, 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 Al/kg/day, but not in males exposed to 100 mg Al/kg/day or in females. A significant delay in age at testes descent was observed at 100 mg Al/kg/day and vagina opening was delayed at 50 and 100 mg Al/kg/day. A decrease in forelimb grip strength was observed at 100 mg Al/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 Al/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.

However, due to the lack of body weight data during crucial periods of development , the effects observed cannot unequivocally be attributed to the Al exposure.

In general, weight of evidence would suggest that 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). Only in one 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). 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 for the neurotoxicity of aluminium hydroxide, no classification is required according to DSD (67/548/EEC) or CLP (1272/2008/EC) classification criteria.