Registration Dossier

Toxicological information

Toxicological Summary

Currently viewing:

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
15.63 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):
3
Dose descriptor starting point:
NOAEC
DNEL value:
70 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
46.9 mg/m³
Explanation for the modification of the dose descriptor starting point:
NOAECcorr = NOAEC *(6.7 m³ (8h)/10 m³ (8h)) = 70 * 0.67 = 46.9 mg/m³
AF for dose response relationship:
1
Justification:
based on NOAEC
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
1
AF for intraspecies differences:
3
Justification:
Substance specific adaptation.The studies indicate that the effects after inhalation are attributable to the particle per se rather than a substance specific toxicity. Therefore the use of the general dust limit value as the DNEL is appropriate (ECHA Guidance Document R.8; Appendix R8-13). This is based on the substance-specific data indicating a species difference between rats, hamsters and guinea pigs that indicate a non-specific inflammatory response to the particles rather that a direct toxic effect but the substance and the ECHA guidance how to select the critical DNEL in case of inert dusts.
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
15.63 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
3
Dose descriptor:
NOAEC
DNEL value:
70 mg/m³
AF for dose response relationship:
1
Justification:
based on NOAEC
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
1
AF for intraspecies differences:
3
Justification:
Substance specific adaptation.The studies indicate that the effects after inhalation are attributable to the particle per se rather than a substance specific toxicity. Therefore the use of the general dust limit value as the DNEL is appropriate (ECHA Guidance Document R.8; Appendix R8-13). This is based on the substance-specific data indicating a species difference between rats, hamsters and guinea pigs that indicate a non-specific inflammatory response to the particles rather that a direct toxic effect but the substance and the ECHA guidance how to select the critical DNEL in case of inert dusts.
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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

Key Studies for Dose Descriptor

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 70 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: 70 mg/m³, NOAEC

Test Animal: Rat

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

Doses used: 0, 30 and 70 mg/m³

Duration of exposure in the experiment: 6 months (for 70 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 threshold and related to volumetric overloading of macrophages. 

Calculation of DNEL long-term,worker according to the ECHA guidance (ECHA guidance, Chapter R8, p27):

Modification of starting point to correct for differences in inhalation volume between the rats and lightly active humans

NOAEC (corrected) = NOAEC * 6.7m³ (8h)/10m³ (8h)

= 70 * 6.7/10

= 46.9 mg/m³; corrected starting point

 

Assessment factors:

Interspecies: 1

Allometric scaling is not necessary as the mode of action is a portal-of-entry effect (overload) and adjustment for inhalatory volume has been carried out to modify the starting point; scientific evidence suggests rats are at greater susceptibility to overload than humans (Oberdorster, 1995; Pauluhn, 2010), therefore a factor of 2.5 for remaining effects was not considered appropriate.

 

Intraspecies: 3

Eurometaux has adopted the ECETOC (2010) approach for intraspecies and interspecies assessment factors. Therefore, the client indicated that this value should be inserted here As inorganic metal compounds ar not metabolized by the usual metabolic systems and furthetmore the effects are related to unspecifc particle effects, the intraspecies factor can be reasonable reduced to 3.

 

Duration of exposure: 1 (The duration of exposure was adequate.)

 

Dose response extrapolation: 1 (Based on a NOAEC)

 

Adequacy of database: 1

No fibrosis was observed in the study by Gross et al. (1973); the study did not assess more sensitive inflammatory endpoints such as biochemical markers in BALF; the relevance of the critical effect to the human lung is unclear, however, as it is consistent with a rat lung overload response. Considering the human, animal and in-vitro data as a whole, an assessment factor of 1 for database adequacy is considered appropriate.

 

Total assessment factor = 3

Calculated DNEL long-term, worker = 46.9/3 = 15.63 mg Al2O3/m³, respirable, 8 hour TWA.

General Population - Hazard via inhalation 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
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:
6.58 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
DNEL value:
131.67 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
OAELcorr = NOAEL * 4.39 = 30 * 4.39 = 131.67 mg Al/kg bw/day (Modification of starting point, to adjust ratios of the whole body fractional uptake for Al-citrate (0.079%) to the whole body fractional uptakes of Al metal (<0.018%).)
AF for dose response relationship:
1
Justification:
Based on a NOAEL (ECHA, 2008)
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):
1
AF for other interspecies differences:
4
Justification:
4 for allometric scaling (rats to humans) [ECHA default, 2008]. Note: Eurometaux has adopted the ECETOC (2010) approach for intraspecies and interspecies assessment factors. Therefore, the client indicated that an additional factor of 2.5 was not necessary here.
AF for intraspecies differences:
5
Justification:
Due to the fact that inorganic metal compounds are not subject to metabolism, differences in enzyme activities between individuals do not need to be considered and the intraspecies factor for the general population can be reduced to 5. Furthermore ECETOC (2010) provided evidence that a factor of 5 is in most cases sufficiently conservative.
AF for the quality of the whole database:
1
Justification:
Evidence for differences in toxicokinetics of Al when complexed with citrate (Jouhanneau et al., 1997); uncertainty as to the critical period of exposure and lack of information on food consumption in the ToxTest-TEH-113 study.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population