Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Written toxicokinetics assessment
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
A written assessment of toxicokinetic behaviour is considered appropriate for the substance. It is not possible to evaluate the toxicokinetics of trimethylaluminium as the substance converts violently to aluminium oxide and aluminium hydroxide in the presence of air and water. Therefore, the toxicokinetics effects of aluminium oxide and aluminium hydroxide need to be considered when evaluating the effects of exposure to trimethylaluminium.

Data source

Materials and methods

Objective of study:
other: Assessment of toxicokinetic behaviour
Principles of method if other than guideline:
Written assessment based on published data.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Not applicable

Test animals

Species:
other: Not applicable

Administration / exposure

Details on exposure:
Not applicable
Duration and frequency of treatment / exposure:
Not applicable
Doses / concentrations
Remarks:
Doses / Concentrations:
Not applicable
No. of animals per sex per dose:
Not applicable
Positive control:
Not applicable
Details on study design:
Not applicable
Details on dosing and sampling:
Not applicable
Statistics:
Not applicable

Results and discussion

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
Not applicable

Any other information on results incl. tables

It is not possible to evaluate the toxicokinetics of trimethylaluminium as the substance reacts with water to produce aluminium hydroxide and methane or methanol and reacts spontaneously in air to form aluminium oxide, carbon dioxide and water. Therefore, the toxicokinetics effects of aluminium oxide and aluminium hydroxide need to be considered when evaluating the effects of exposure to trimethylaluminium.

Summary and discussion of toxicokinetics of aluminium oxide and aluminium hydroxide

Absorption

Oral

Published studies have evaluated the oral bioavailability of aluminium hydroxide, one of the most recent studies being an oral gavage study (Priest, 2010) in female Sprague-Dawley rats. The whole body fractional uptake calculated for aluminium hydroxide, aluminium oxide and pot electrolyte were 0.025 ±0.041%, 0.018 ±0.038% and 0.042 ±0.0036%, respectively. The use of26Al as a tracer and accelerator mass spectrometry has allowed studies of aluminium toxicokinetics with relevant doses in humans. Oral aluminium bioavailability from water has been reported to be 0.1 to 0.4%. Oral aluminium bioavailability is increased by citrate, acidic pH, and uraemia and may be reduced by silicon-containing compounds. Oral aluminium bioavailability is also inversely related to iron status (Krewski et al, 2007).

Inhalation

The available data indicate a low rate of absorption of aluminium to the systemic circulation following inhalation exposure to aluminium oxide. McAughey et al. (1998) calculated a half-time for pulmonary clearance by dissolution processes i.e. transfer to the systemic circulation from the lungs, of approximately 3000 days (8.25 years).

 

Dermal

Dermal absorption and subsequent binding of aluminium with skin proteins can occur upon dermal exposure to ionic aluminium complexes in solution. Aluminium oxide and aluminium hydroxide are poorly soluble in water and are unlikely to be available for adsorption and penetration. If dissolved in sweat, and in the form of an ionic aluminium complex, the substances will exhibit only shallow penetration due to binding in the upper layers of the stratum corneum.

Systemic Distribution & Metabolism

Following a bolus oral gavage dose, maximum serum concentrations of aluminium occur during the first hour after dosing. After ingestion, aluminium blood concentrations decrease rapidly, however, renal excretion is maintained during this period. The data indicate that a large fraction of available aluminium is initially bound to low molecular weight species that can move out into tissue fluids. Aluminium in this form can move easily between tissue fluids and blood and remains available for excretion allowing maintenance of the early excretion levels. In blood, the majority of aluminium is bound to transferrin which is retained in blood vessels. With time the tissue fluid pool is depleted and renal clearance rates decrease as it becomes more difficult first to excrete aluminium that is bound to higher molecular weight proteins and then aluminium that is bound to red blood cells.

Aluminium levels and accumulation in the brain

A small fraction (10-7 to 10-8) of orally administered Al was found in the rat brain (Fink et al., 1994 and Jouhanneau et al., 1997). After intravenous infusion, Yokel et al. (2001) found that the Al concentration in the brain of rats reached its peak (~0.005% of the administered dose per gram of brain tissue) on day 1, regardless of the form of the Al compound (Al transferrin or Al citrate). Yokel et al. (2001) also showed that Al was retained in the brain for longer than 256 days after administration and that the Al chelator, desferrioxamine, enhanced Al elimination from the brain. The terminal brain half-times were 150 days and 55 days, respectively, for rats that did not receive and rats that received desferrioxamine.

Potential mechanisms of transport of Al [administered as the citrate] across the blood brain barrier have been examined and have shown that Al transport cannot be explained solely by diffusion and that the process is carrier-mediated (Allen et al., 1995; Ackley and Yokel, 1997; Yokel et al., 2002; Nagasawa et al., 2005).

The results of studies with intranasal administration of Al salts to New Zealand rabbits indicate that Al may enter the central nervous system directly via nasal-olfactory pathways. The available evidence does not indicate that this is an important route of exposure for aluminium (Krewski et al., 2007 & Perl and Good, 1987).

Markesbery et al. (1984) analyzed trace element concentrations in various brain regions in 28 neurologically normal adults aged up to 85 years and also in seven infants. Brain Al concentrations increased with increasing age. The mean Al concentration was 0.467±0.033 µg/g wet weight in adults and 0.298±0.05 in infants. Based on information presented on the graph, mean Al concentrations in the brain were ~0.35 µg/g in the age group 20-39 years, around 0.43-0.47 µg/g in the age groups 40-59 and 60-79 years, and ~0.70 µg/g in those older than 80 years. Mean concentrations were highest in the globus pallidus (0.893 µg/g), putamen (0.663 µg/g) and middle temporal lobe (0.654 µg/g), and lowest in the superior parietal lobule (0.282 µg/g). Based on the review of available literature (Priest, 2004), normal human brain Al levels are within the range <1 to ~5 µg/g, with most results being closer to the lower end of this range.

Elevated concentrations of Al were observed in the frontal cortex of 21 uremic patients (McDermott et al., 1978). The concentrations were significantly higher in the 7 patients with dialysis encephalopathy (mean 15.9 ±10.5 µg/g dry weight) than in the 12 patients on dialysis but without encephalopathy (4.4±2.7 µg/g), and than in the 2 uremic patients who were not dialyzed (2.7±1.4 µg/g). In patients with dialysis encephalopathy, the mean Al concentration in the grey matter was about 3 times higher than that in the white matter (20.6±16.4 µg/g and 6.9±5.3 µg/g, respectively). This difference was small in the other two groups of patients.

Aluminium accumulation in other organs and tissues

Priest (2004) reviewed data collected by the International Commission on Radiological Protection on aluminium content in organs and tissues (ICRP publication 23). Excluding the lung and lymph nodes (these tissues can contain undissolved Al that is not part of the systemic Al body burden); only the liver, connective tissues, skin and skeleton concentrate more Al than the body average. Data for the skin might not be valid because of the likelihood of external contamination. Other data on Al tissue distribution in workers occupationally exposed to Al and members of the public (also summarized by Priest, 2004) are generally consistent with those reported by the ICRP. The skeletal system is the primary site of accumulation in humans. Aluminium may also accumulate in the lungs due to inefficient transfer to the systemic circulation.

The injection studies by Guo et al. (2005a, 2005b) and Llobet et al. (1995) show that systemic aluminium can be transferred to the testes when administered at high doses. The study by Ondreicka et al. (1966) shows that Al levels may increase in the testes on chronic oral exposure. Older rats may show increased accumulation relative to adult and young rats (Gomez et al., 1997).

Urinary excretion is the main route by which aluminium is eliminated from the body (Priest, 2004; Talbot et al., 1993, 1995). The filtration of aluminium from the blood into urine occurs in the kidney glomerulus and its efficiency shows a dependency on the chemical species to which the Al is complexed in the blood (Shirley and Lote, 2005).

Talbot et al. (1993, 1995) observed an average of 59 (sd, 10) % of26Al excreted in urine during the first 24 hours after intravenous injection and 72 (sd, 7) % - by day 5 in a study with six healthy, male volunteers. A marked inter-individual variability in the pattern of early urinary excretion of26Al was observed. The cumulative fraction of26Al excreted by day 5 was in the range from 62% to 84%. The mean renal clearance rate was 16 litres of whole blood per day (sd, 10) and the range 5 to 33 indicating a change in the binding of Al with increasing time in the blood. Based on the series of26Al radiotracer experiments conducted in human volunteers at the Harwell Laboratory, UK, Priest (1998) reported that 85 to 90% of aluminium is excreted in urine during the first day after intravenous exposure.

A dose-dependence of efficiency of initial urinary excretion has been observed that may result from the formation of high molecular weight aggregates at high blood aluminium concentrations (Xu et al., 1991; Yokel and McNamara, 1988). Studies that have been conducted on the rate of elimination of aluminium in animals and humans have shown half-times that increase with the duration of follow-up indicating the presence of several compartments. The longer elimination half-times, reflecting slower elimination from compartments other than blood, do not show evidence of dose-dependence.

Greger and Radzanowski (1995) observed differences in the accumulation and kinetics of aluminium administered by oral gavage to Sprague-Dawley rats of different ages in a 44 day experiment. The growing rats accumulated more aluminium in their tibias on day 1 of the experiment and also retained more aluminium over the 44-day experimental period. Half-times in the bone of the ageing rats were several times greater than in the growing and mature rats (173 days versus 38 and 58 days in the growing and mature rats, respectively). Iron status may also affect the distribution and retention of aluminium. Greger et al. (1994) observed more aluminium in the livers but less aluminium in the tibias and spleens of male anaemic rats compared with male normal rats but these differences were not significant at all time-points.

As filtration in the kidneys is the main route by which systemic aluminium is excreted, individuals with renal insufficiency will retain more aluminium. The immature renal systems of neonates, particularly those who are pre-term, places them at increased risk of accumulating higher levels of aluminium (Krewksi et al., 2007).

 

 

 

 

 

 

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
It is not possible to evaluate the toxicokinetics of trimethylaluminium as the substance converts violently to aluminium oxide in the presence of air and water.Therefore, the toxicokinetics effects of aluminium oxide need to be considered when evaluating the effects of exposure to trimethylaluminium. Absorption of aluminium by the oral, inhalation and dermal routes is predicted to be low. Filtration in the kidneys is the main route by which systemic aluminium is excreted.