Triethylaluminium

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1998 and 2004

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given

Data source

Reference

Reference 1

Reference Type:

publication

Title:

The biological behaviour and bioavailability of aluminium in man, with special reference to studies employing aluminium-26 as a tracer: review and study update.

Author:

Priest, N.D.

Year:

2004

Bibliographic source:

J Environ Monit. 2004 May; 6(5):375-403.

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1998

Materials and methods

Test guideline

Qualifier:

no guideline available

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Aluminium oxide

EC Number:

215-691-6

EC Name:

Aluminium oxide

Cas Number:

1344-28-1

IUPAC Name:

aluminium oxide

Details on test material:

Name: aluminium oxide (26Al labeled transitional)
Supplier: The 26Al was produced at the Joint International Nuclear Research Centre, Dubna, Russia.
Analytical purity: no data
Particle size: mean aerodynamic diameter 1.2 µm
Batch Number: No information
Storage: No information

Production of the test materials:
A monodisperse distribution of droplets was produced by nebulisation of 27-aluminium nitrate solution radiolabelled with 26Al and 67Ga. The aerosol was then dried in a drying tube and calcined in a furnace. The particle size distribution was determined using an on-line API Aerosizer instrument (Amherst Process Industries, Mass, US). The crystalline characteristics of the particles were determined by X-day diffraction. XRD results showed that the particles were predominantly transitional alumina and that alpha-alumina was absent. The aqueous solubility of the particles was measured and found to be <0.2% per day.

Radiolabelling:

yes

Remarks:

26Al

Test animals

Species:

human

Strain:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

Not applicable.

Administration / exposure

Route of administration:

inhalation

Vehicle:

not specified

Details on exposure:

Particles were re-suspended from a 50% v/v ethanol/water mixture into a 100 L chamber. The subjects inhaled from the chamber for 20 minutes using a computer-controlled valve system that allowed separation of inhalation from exhalation and thus collection of exhaled particulate matter.

Duration and frequency of treatment / exposure:

The inhalation period was 20 minutes long. The subjects breathed to a pre-programmed pattern (6 x 1000 mL breaths per minute).

Doses / concentrations

Remarks:

Doses / Concentrations:
The estimated initial whole body deposits of 26Al after inhalation were 16±5 Bq for one subject and 6±5 Bq for the other.

No. of animals per sex per dose / concentration:

2

Control animals:

no

Positive control reference chemical:

No.

Details on study design:

No data.

Details on dosing and sampling:

Sampling & Chemical Analyses:
Whole Body Retention
Estimates of whole body retention of 26Al were made from serial measurements of body 26Al. Measurements were made for the 2 days before inhalation and then on the five days following. The measured 26Al body burden was added to the measured cumulative loss of 26Al by excretion to give daily 26Al body burdens. The mean of these was considered the best estimate of the initial body deposit.

Faecal Excretion of 26Al
The subjects collected faeces for the two days prior and for seven days after inhalation. Additional faecal samples were collected by each subject at the approximate mid-point and the end of the study. Accelerator Mass Spectrometry (AMS) was required to measure the small amounts in the faeces.

Urinary Excretion of 26Al
Subjects collected their total 24-hour urine output for 6 days and then at intervals until day 922 in one subject and day 938 in the other subject. Fourteen daily urine samples were collected by the first subject and 20 by the other. After weighing, evaporation, and dissolution in conc. HNO3 and addition of 305 mg 27Al, the aluminium was precipitated using calcium and phosphate (pH=7.0). After removal of calcium and boron from the precipitate (solvent extraction), the sample was fired at 900ºC in oxygen to produce the oxide. AMS was then used to measure the ratio of 26Al:27Al.

Statistics:

No information is available in the review; not applicable.

Results and discussion

Preliminary studies:

Not applicable.

Main ADME results

Type:

other: Accumulation

Results:

lung

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The estimated fraction of the initial respiratory deposit transferred to blood was 1.9%.

Details on distribution in tissues:

Not applicable.

Details on excretion:

0.02% of the initial lung deposit was excreted each day in the first months post-inhalation. By 900+ days post-inhalation, measurable 26Al excretion ceased. ~98% of the Al transferred to the blood was excreted with urine. 26Al was still measureable in the faeces several hundred days post-inhalation suggesting continued mechanical clearance of alumina particles by mucociliary transport.

Toxicokinetic parameters

Toxicokinetic parameters:

other: Estimated lung retention half-time for loss by dissolution: ~3000 days (8.25 years). Lung retention half-time based on 26Al excreted each day: 87 and 89 days in the two subjects.

Metabolite characterisation studies

Metabolites identified:

not specified

Details on metabolites:

Not applicable.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): high bioaccumulation potential based on study results for the lung. Bioaccumulation potential (for other organs) cannot be judged based on study results.
The results of this study indicate that, because of low solubility, inhaled aluminium oxide does not effectively transfer from the lungs to the systemic circulation.

Executive summary:

The objectives of the study described by Priest (2004) and initially in McAughey et al. (1998) were: the development and validation of a method for the production of transitional alumina aerosol representative of actual worker exposures; determination of the fraction of inhaled aluminium that is transferred directly from the lungs to the blood; and also the fraction that is removed from the lungs, swallowed and excreted in faeces. Two male human subjects were chosen who had no history of cardiac, hepatic, renal, pulmonary, neurological, gastrointestinal, haematological or psychiatric conditions and who were not regularly taking any prescriptions or over-the-counter drugs. The test aerosol was produced using several steps. First, a nebuliser was used to produce a monodisperse distribution of aluminium nitrate solution aerosol containing the²⁶Al tracer. These droplets were then dried and calcined in an “alumina-tube flow-through furnace” and collected on a PTFE filter. The radiotracer-labelled particles were resuspended in 50% v/v ethanol/water mixture and the suspension nebulised into a chamber (100 L volume). The volunteers, following a breathing pattern of 6 x 1000 mL breaths per minute, were exposed through a system with valves attached to the chamber that separated inhaled and exhaled air for 20 minutes. Re-breathing of exhaled air was used until the last two minutes of the exposure period. During the last two minutes, the particulate matter in the exhaled air was collected for estimation of the deposition efficiency. Post exposure, whole body²⁶Al was measured using a shielded whole-body monitor. Faecal excretions from the subjects were collected for the two days prior to, and seven days after, the exposure for determination of²⁶Al. Twenty-four hour faecal samples were also collected at the mid-point of the study and at the end of the study. Venous blood samples were collected at intervals from 1 hour to 82 days after exposure. Daily outputs of urine (bulk 24 hour samples) were collected for six days after the exposure and then at longer intervals until the end of the study (922 days in subject A and 938 days in subject B). The samples were preserved with concentrated nitric acid and, subsequently, the ratio of²⁶Al:²⁷Al was determined by accelerator mass spectrometry (AMS). The aerodynamic size distribution of the particles was determined using an API Aerosizer time-of-flight instrument and the crystalline structure was examined using X-ray diffraction (XRD). The MMAD from these analyses was 1.2 µm and XRD showed that the test substance consisted of transitional aluminium oxides, some amorphous aluminium oxide, and thatα-alumina was absent. McAughey et al. (1998) reported that similar peaks were observed on XRD analysis of a lowα-content industrial alumina. Priest (2004) reported a best estimate for the amount of²⁶Al initially inhaled and deposited anywhere in the respiratory tract of 16 ± 5 Bq for one of the subjects and 9 ± 5 Bq for the other. On average, 36% of the initial respiratory deposit was rapidly cleared from the major airways and pharynx within the first 48 hours. After these short-term mechanical removal processes, 9 ± 5 Bq and 4 ± 5 Bq remained (“the initial lung deposit”) in subject A and subject B, respectively. Levels of²⁶Al in the blood collected from the participants were very close to the detection limit of the AMS technique, limiting their reliability. AMS was also required for the determination of²⁶Al in the faecal samples as the levels were lower than expected. During the first week post-exposure, excretion in faeces, representing the²⁶Al that was mechanically removed from the respiratory tract and swallowed, was 43.3% of the inhaled amount in subject A, and 28.1% of the inhaled amount in subject B. During the same time period, one subject voided 6.9 Bq in urine and the other 1.5 Bq. The amount of²⁶Al in urine decreased at rates consistent with half-times of close to 90 days in both subjects. After the initial period, an average of about 0.015% of the initial deposit (0.023% of the initial lung deposit) was eliminated daily in urine, allowing calculation of a half-time for clearance by dissolution processes i.e. transfer to the systemic circulation from the lungs, on the order of 3000 days (8.25 years). Based on these results, mechanical clearance appears to be the main mechanism of particle removal. Measurements of²⁶Al in urine showed that, by 900 days post-exposure, any excretion of²⁶Al was below the detection limit of the analytical methods. Integrating the transfer of Al dissolved in the lungs to the blood stream from time zero to infinity indicated that 1.9% of the initial²⁶Al₂O₃dose deposited in the lungs was ultimately transferred to the systemic circulation. Assuming that 95% of the aluminium that ends up in blood is eliminated through the kidneys then, for every mg of aluminium inhaled, only 500 ng would be retained in the body.