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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Basic data given Al3+is the predominant aluminium form at low pH (less than 5.5). As pH increases above 5.5, aluminium-hydroxide complexes formed by hydrolysis become increasingly important and dominate aqueous aluminium speciation . Al3+, depending on the composition of the medium and pH, may form Al(OH)3 or Al2O3 or AlCl or AlNO3 or AlSO4 According to the solubility studies, the major elements found at the maximum solubility are 1054 mg/l Al and 856 mg/l Ca, for 100 g of the tested substance, ie approximatively 1%. A read-across was made with all the aluminium salts and oxides.

Data source

Reference
Reference Type:
publication
Title:
Clearance and translocation of aluminum oxide (alumina) from the lungs.
Author:
Schlesinger et al.
Year:
2000
Bibliographic source:
Inhal Toxicol. 2000 Oct; 12(10):927-939.

Materials and methods

Objective of study:
other: The goals of the study were to evaluate the pattern of alumina retention in the lungs of rats during and following repeated exposures and to determine if there was any translocation to other organs during the time period.
Test guideline
Qualifier:
no guideline followed
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name: Alumina
Supplier: ALCOA, Pittsburgh, PA
Purity: a mix of delta, kappa and theta forms – 77.7%, alpha-form – 15.2%, gibbsite – 5.9%, trace amounts of SiO2, Fe2O3, Na2O and TiO2.
Particle size: The obtained raw material had a mass median aerodynamic diameter (MMAD) of 13 µm, but was size classified (Tomen America, Buffalo Grove, IL), and the MMAD of the material used for exposure was 1.2 µm (σg=1.7)
Batch Number: No information
Storage: No information
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Raleigh, NC
- Age at study initiation: 10 weeks
- Housing: The rats were housed in stainless-steel wire-mesh cages.
- Individual metabolism cages: yes/no
- Diet (e.g. ad libitum): The animals had free access to food. The diet was Purina Rodent Laboratory Chow 5001 that contained 290 ppm aluminium
- Water: ad libitum
- Acclimation period: 2 weeks

Administration / exposure

Route of administration:
intratracheal
Vehicle:
other: suspended in 0.9% sodium chloride
Details on exposure:
Details on exposure:
Instillation was performed under halothane anesthesia. The glottis was visualized with a fiber-optic light. A 1-cm³ syringe with an angled 3-in 18-gauge needle was used to deliver the material to the lung.
:
Duration and frequency of treatment / exposure:
Weekly instillations for 20 weeks.
Doses / concentrations
Remarks:
Doses / Concentrations:
1 mg alumina/kg body weight
No. of animals per sex per dose / concentration:
Two rats were sacrificed at each time point.
Control animals:
yes, concurrent vehicle
Positive control reference chemical:
No.
Details on study design:
The rats received weekly instillations for 20 weeks (weeks 0-19), and were followed for 19 weeks post-exposure (weeks 20-38). Two rats were sacrificed by pentobarbital overdose and tissue samples were taken 1 week following 1, 5, 10 and 15 instillations and then weekly beginning 1 week after the last instillation.
Tissue samples were also taken “throughout the course of the study” from the control rats. Based on data from figure 1, it can be inferred that sampling times were the same for exposed and control animals during the exposure period, but in the post-exposure period samples from the control animals were taken only on weeks 20, 30 and 38. These samples were used to determine baseline tissue aluminium levels that included any contribution from aluminium in the diet.
Details on dosing and sampling:
Sampling:
At each time point, the lungs, brain, bone (left tibia and fibula), liver, spleen and kidney were removed for evaluation of aluminium “as the quantifiable endpoint for evaluating alumina exposure.”
Blood and urine samples were not collected.

Chemical Analyses:
Aluminium was assessed in tissue samples and reagent blanks following wet ashing digestion. Standard flame atomic absorption spectroscopy (AAS; Thermo-Jarrel ash model video 12) was used for Al determination in lung tissue and a more sensitive graphite furnace AAS technique (Thermo-Jarrel ash model 655) – for Al determination in other tissues.
Methods used to reduce the possibility of contamination: acid-washing of beakers and centrifuge tubes.
Validation of the analytical procedure: two NIST [National Institute of Standards and Technology] standards were used, oyster tissue SRM 1566a and mussel tissue SRM 2976.
Statistics:
The values for aluminium content of reagent blanks were subtracted from values of aluminium content in the tissue samples of control and exposed animals. Statistical analyses were based on the means of the net values of aluminium burdens for two rats sacrificed at each time point. The individual values of the 2 rats at each time point varied by less than 10%.
The following four groups of tissue Al burden data were defined:
- Control group, exposure period (cntexp)
- Control group, post-exposure period (cntpost)
- Al-exposed group, exposure period (expexp)
- Al-exposed group, post-exposure period (exppost)
Analysis of covariance (ANCOVA) was used to test for time trends in the accumulation or clearance of Al and for differences between the exposed and the control rats.

Results and discussion

Preliminary studies:
In a separate experiment, no evidence of inflammatory response or other pathology was found at microscopic examination of the lungs of two rats after 3 weekly instillations of alumina at the dose used in this study (1 mg alumina/kg body weight).
Main ADME results
Type:
other: accumulation
Results:
lung

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Since there was no evidence of translocation of Al to, or its accumulation in extrapulmonary tissues (see below), it can be suggested any alumina that was transferred from the lungs to the systemic circulation was likely small in amount and effectively removed from the blood by renal clearance. However, as Al levels in blood and urine were not measured, the actual amount of systemic absorption cannot be estimated.
Details on distribution in tissues:
Lung
There was a significant difference between the exposed and the control animals in time trends of lung Al burden (p<0.01). Al burden in the lungs of the control animals remained virtually unchanged during the experiment. Al burden in the lungs of the exposed animals increased during the exposure period. The values read from figure 1 are as follows: ~30 µg Al/g wet tissue on week 1; ~170 µg Al/g on week 5, ~ 390 µg Al/g on week 10 and ~500 µg Al/g on week 15. During the post-exposure period the values of lung Al burden in the exposed animals (read from figure 1) were relatively stable at about the level observed on week 15.

Extrapulmonary tissues
There was no evidence of Al translocation to extra-pulmonary tissues.
Transfer into organs
Transfer type:
other: lung
Observation:
other: There were no significant time trends in Al burdens in extrapulmonary tissues in either the exposed group or the control group, and there was no significant difference between the groups. Transfer in brain, kidney, bone, liver, and spleen (details in any
Details on excretion:
Not assessed.
Toxicokinetic parameters
Toxicokinetic parameters:
other: Details in any other informations and results incl. tables.

Metabolite characterisation studies

Metabolites identified:
not specified
Details on metabolites:
Not applicable.

Any other information on results incl. tables

Transfer into organs:

There were no significant time trends in Al burdens in extrapulmonary tissues in either the exposed group or the control group, and there was no significant difference between the groups. Therefore, the values of Al burden were pooled over time. For the control group, one value pooled over weeks 0-38 is reported and for the exposed group – 2 values are reported, one pooled over the exposure period (weeks 0-19) and the other - pooled over the post-exposure period (weeks 20-38).

 

Tissue burdens of aluminium in µg Al/g tissue wet weight (mean±SE) were reported in the article. The highest levels in both the unexposed and exposed animals were in bone with 2.63±0.36 µg Al/g, 2.41±0.19 µg Al/g, and 2.07±0.16 µg Al/g in the unexposed, the exposed during the exposure period, and the exposed at weeks 20 to 38 (post-exposure period), respectively. Levels in brain were 1.36±0.10 µg Al/g, 1.55±0.40 µg Al/g, and 1.30±0.17 µg Al/g in the unexposed, the exposed during the exposure period, and the exposed at weeks 20 to 38 (post-exposure period), respectively. Levels in the kidneys were 0.39±0.03 µg Al/g, 0.71±0.07 µg Al/g, and 0.66±0.05 µg Al/g in the unexposed, the exposed during the exposure period, and the exposed at weeks 20 to 38 (post-exposure period), respectively. Aluminium levels in the liver of the unexposed rats was 0.17±0.05 µg Al/g, with no significant increase observed in the exposed rats during the exposure (0.27±0.08 µg Al/g) or post-exposure periods (0.18±0.04 µg Al/g). Levels in the spleen were 0.66±0.26 µg Al/g in the unexposed rats.

Toxicokinetic parameters:

Regression parameters of Al accumulation and retention in the lung were provided in the article. The results indicate a statistically significant increase in the lung Al burden during the exposure period (estimated rate of increase 32.855 µg Al/g lung per week, significantly greater than zero) and the absence of statistically significant clearance of Al from the lung of the exposed animals after exposure termination. The (non-significant) negative slope for weeks 20-38 suggests that Al is removed from the lung at a rate of 2.6 µg per gram lung tissue per week. The value predicted from the regression model for Al burden at week 20 was 521 µg/g lung tissue and at week 38 it was 474 µg/g lung tissue; the estimated removal from the lung during the post-exposure period was 47 µg/g lung tissue, i.e ~9% of the lung burden at the end of exposure.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): high bioaccumulation potential based on study results in the lung
Repeated weekly intratracheal instillations of alumina (MMAD=1.2 µm) to Sprague-Dawley rats for 20 weeks at a dose of 1 mg alumina/kg body weight led to significant accumulation of Al in the lung. No significant clearance of Al from the lung occurred during the 19-week post-exposure period. Since no changes in Al levels in extrapulmonary organs of exposed animals were observed over the course of the study, under the experimental conditions the systemic uptake of Al from the lungs does not exceed the clearance capacity of the kidneys. Since Al levels in blood and urine were not measured, the systemic absorption cannot be estimated although the results of the study suggest that uptake was likely to have been low.
Executive summary:

This study examined the pattern of alumina accumulation and retention in the lungs, and its translocation to other organs in Sprague-Dawley rats that received weekly intratracheal instillation of alumina (MMAD=1.2 µm) at a dose of 1 mg alumina/kg body weight for 20 weeks and were followed for 19 weeks post-exposure. Control animals received concurrent intratracheal instillation of vehicle (0.9% sodium chloride). No information is provided on environmental conditions and animal health monitoring. The rats’ diet contained 290 ppm aluminium. Contribution from Al in the diet was taken into account by means of determining baseline Al levels in the tissues of control rats. Tissue samples (lung, brain, bone, kidney, liver spleen) were taken 1 week following 1, 5, 10 and 15 instillations and weekly beginning 1 week after the last instillation. Two exposed and two control rats were sacrificed at each time point. Blood and urine were not collected. Standard flame atomic absorption spectroscopy (AAS) was used for Al determination in lung tissue and a more sensitive graphite furnace AAS technique – for Al determination in other tissues. The possibility of external Al contamination was reduced by acid-washing of beakers and centrifuge tubes. The analytical procedure was validated using two National Institute of Standards and Technology (NIST) standards. Analysis of covariance was used to test for time trends in the accumulation or clearance of Al and for differences between the exposed and the control rats.

There was a significant difference between the exposed and the control animals in time trends of lung Al burden (p<0.01). Al burden in the lung of the control animals remained virtually unchanged during the experiment. Al burden in the lung of the exposed animals significantly increased during the exposure period (the estimated increase was 32.855 µg Al/g lung per week, significantly greater than zero). There was no statistically significant clearance of Al from the lung of the exposed animals after exposure termination. The (non-significant) negative slope for the post-exposure period suggests that Al was removed from the lung at a rate of 2.6 µg per gram lung tissue per week. The estimated removal of Al from the lung during the entire post-exposure period was 47 µg/g lung tissue, i.e ~9% of the lung burden at the end of exposure). There was no evidence of translocation of alumina from the lung to extrapulmonary tissues: no significant time trends in Al burdens in any examined organ of the exposed animals, and no significant difference between the groups. This suggests that any alumina that was transferred from the lungs to the systemic circulation was likely small in amount and effectively removed from the blood by renal clearance avoiding any build up in extrapulmonary tissues. However, as Al levels in blood and urine were not measured, the actual amount of systemic absorption cannot be estimated.