Aluminium oxide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Dose descriptor starting point:

NOAEC

Value:

75 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

37.7 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAECcorr = NOAECinhal * (6 h/d / 8 h/d) * (6.7 m³ (8h)/10 m³ (8h)) = 75 * 0.75 * 0.67 = 37.7 mg/m³

The inhalatory NOAEC was corrected for the difference between respiratory rates under standard conditions and under conditions of light activity. Furthermore the inhalatory NOAEC was corrected for differences in the experimental and human exposure conditions.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEC.

AF for differences in duration of exposure:

1

Justification:

The DNEL is based on a chronic study.

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

5

Justification:

Default value for workers according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The study is comparable to guideline study with acceptable restrictions.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Dose descriptor:

NOAEC

Value:

75 mg/m³

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEC.

AF for differences in duration of exposure:

1

Justification:

The DNEL is based on a chronic study.

AF for interspecies differences (allometric scaling):

1

Justification:

The DNEL is based on a chronic study.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

5

Justification:

Default value for workers according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The study is comparable to guideline study with acceptable restrictions and the results are in line with other inhalation studies.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Please refer to Additional information - general population.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.75 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEC

Value:

75 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

18.75 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAECcorr = NOAECinhal * (6 h/d / 24 h/d) * = 75 * 0.25 = 18.75 mg/m³

The inhalatory NOAEC was corrected for differences in the experimental and human exposure conditions.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEC.

AF for differences in duration of exposure:

1

Justification:

The DNEL is based on a chronic study.

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default value for general population according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The study is comparable to guideline study with acceptable restrictions.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.75 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor:

NOAEC

Value:

75 mg/m³

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEC.

AF for differences in duration of exposure:

1

Justification:

The DNEL is based on a chronic study.

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default value for general population according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The study is comparable to guideline study with acceptable restrictions.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.32 mg/kg bw/day

Most sensitive endpoint:

neurotoxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

131.67 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

NOAELcorr = NOAEL * 4.39 = 30 mg Al/kg bw/day * 4.39 = 131.67 mg Al/kg bw/day

Modification of starting point to adjust ratios of the whole Al body fractional uptake for aluminium citrate (0.079%) to the whole body fractional uptakes of aluminium oxide (0.018%; Atomic Energy of Canada Ltd., 2010).

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

1

Justification:

The study exposed the animals until they were 1 year of age.

AF for interspecies differences (allometric scaling):

4

Justification:

The experimental animal was the rat.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default value for general population according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high-quality study.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

DNELs have been derived due to effects noted in the available toxicity studies. As a result of the hazard assessment it is found, that the substance aluminium oxide does not meet the criteria for classification according to Regulation (EC) No. 1272/2008. An exposure assessment and risk assessment is therefore not required according to REACH Article 14(4) and as outlined in the ECHA Technical Guidance Part B: Hazard Assessment (B.8, Version 2.1, December 2011).

Key Studies for Dose Descriptor Inhalation Long-term:

Gross et al. (1973) is considered the most adequate study from which to obtain a dose descriptor for a DNEL for repeated dose toxicity (inhalation, local effect) for aluminium oxide. The NOAEC from Gross et al. (1973), a chronic study, is 75 mg/m³. No alveolar proteinosis or endogenous lipid pneumonitis was observed. Alveoli were filled with dust-filled but otherwise “well-preserved” macrophages, septal walls were not thickened, there was no evidence of stromal proliferation, and no fibrosis was found in the lungs or lymph nodes.

Key study: Gross et al. (1973)

Dose Descriptor: 75 mg/m³, NOAEC

Test Animal: Rat

Test substance: aluminium oxide - mean particle size diameters: 0.8 μm

Doses used: 0, 30 and 75 mg/m³

Duration of exposure in the experiment: 6 months (for 75 mg/m³) and 12 months (for 30 mg/m³); 6 hours per day, 5 days per week; follow-up to 30 months.

Effects observed: Dust-filled macrophages; no alveolar proteinosis, endogenous lipid pneumonitis or fibrosis.

Based on the weight of evidence, the target substances behave as low cytotoxic, poorly soluble particulates (PSPs). From a risk assessment perspective based on studies in rats, two possible thresholds can be envisioned for pulmonary toxic effects on chronic exposure to ‘nuisance” PSPs:

1)  a dosimetric threshold to avoid overloading macrophages and leading to a persistent inflammatory response;

2) a mechanistic threshold greater than the dosimetric threshold that occurs when anti-inflammatory responses are overwhelmed and effects may progress to fibrosis (Oberdorster, 2002).

For a persistent inflammatory response potentially leading to fibrosis, the mode of action for aluminium oxide (dust), aluminium hydroxide and aluminium powder (uncoated) in the respirable and inhalable size range is based on a dosimetric threshold and related to volumetric overloading of macrophages. 

Key Study for Dose Descriptor Oral Long-term:

The long-term DNEL for systemic effects via the oral routes is based on a chronic 1-year oral study with the read-across substance aluminium citrate (ToxTest. Alberta Research Council Inc., 2010). The GLP study was designed “to develop data on the potential functional and morphological hazards to the nervous system that may arise from pre-and post-natal exposure to aluminium citrate”. In terms of hazard assessment of toxic effects, available data on the toxicity to reproduction/development of other aluminium compounds was taken into account by read-across following a structural analogue approach, 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). The oral NOAEL for female and male rats was found to be 30 mg Al/kg bw/day. However, this was already a conservative assumption as the effects observed could have been secondary to kidney toxicity based on a crystallisation of aluminium citrate in the kidneys after chronic exposure and/or reduced body weight and not directly Al-related.

 

Key Study: Developmental and One-Year Chronic Neurotoxicity Study of Aluminium Citrate in Rats. ToxTest, Alberta Research Council Inc. Project No. TEH-113.

Dose Descriptor: NOAEL - 30 mg Al/kg bw/day

Test Animal: Rat

Test substance: aluminium citrate

Doses used: 30, 100 and 300 mg Al/kg bw/day

Duration of exposure in the experiment: Pregnant females were exposed to aluminium citrate from GD6 to GD21 and from PND 1 to PND 21. Pups were exposed to aluminium citrate in utero and with maternal milk from PND 1 to PND 21, 64, 120 or 364.

Effects observed: A deficit in footsplay- and hind-limb grip strength in the mid-dose group, supported by evidence of dose response for this endpoint after chronic exposure.