Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10.76 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):
9
Modified dose descriptor starting point:
LOAEC
DNEL value:
33.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

LOAECcorr = LOAEC * (6.7 m³ (8h)/10 m³ (8h)) = 50 * 0.67 = 33.5 mg/m³

AF for dose response relationship:
3
Justification:
Based on a LOAEC
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:
10.76 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
9
Dose descriptor:
LOAEC
AF for dose response relationship:
3
Justification:
based on LOAEC
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) and Pauluhn (2009a) were chosen as the most relevant and adequate studies to consider as possibly key for derivation of a DNEL for aluminium metal dust and powder under repeated exposure (inhalation, local effect). Both studies, however, have limitations. The Gross et al. (1973) study only assessed histopathology and did not measure more sensitive endpoints such as inflammatory markers in BALF. Pauluhn (2009a) exposed rats to manufactured nanoparticulate materials which, although agglomerated (MMAD=0.6 and 1.7 µm) may exhibit different retention kinetics in the lung than the larger particle sizes more typical of worker exposures. Gross et al. (1973), which employed test materials particularly relevant to the exposure scenarios specified by the client, has been chosen as the key study.

The LOAEC from Gross et al. (1973), a chronic study, is 50 mg/m³ for a critical effect of granulomatous inflammation, lipid pneumonitis and collagenous scars. These effects represent a cholesterol granuloma, a rare occurrence in humans (Green et al., 2007), but a progression in the overload-associated alveolar lipoproteinosis response typical of rats.

Additional support comes from the study by Thomson et al. (1986). Although this study used an acute exposure (4 hours) and stearine-coated Al flake-powder, the authors observed no effects on BALF fluid cell counts or biochemistry during 6 months follow-up of rats exposed to 10 mg Al/m³. At the 10 mg Al/m³ level, the average of three separate samples had an average geometric particle size of 3.28±2.25 μm. At 50 mg Al/m³, a persistent increase in polymorphonuclear neutrophils was observed.No adverse pulmonary physiological responses (compliance, resistance or tidal volume) were observed at 1000 mg Al/m³. 10 mg Al/m³ is an acute exposure NOAEC from this study based on a sensititve endpoint (BALF cell counts and cytology).

Key Study: Gross et al. (1973)

Dose Descriptor: 50 mg/m³, LOAEC

Test Animal: Rat

Test substance: aluminium powders - mean particle size diameters: 2.49, 2.22 and 4.85 μm

Doses used: 0, 15, 30, 50, 100 mg/m³

Duration of exposure in the experiment: 6 months (for 50 and 100 mg/m³) and 12 months; 6 hours per day, 5 days per week; follow-up to 30 months.

Effects observed: lipid pneumonitis, granulomatous inflammation; collagenous scars but fibrosis was not evident.

Mode of Action: 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 –

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

= 50 * 6.7/10

= 33.5 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 o f

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: 3 (Based on a LOAEC)

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 = 9

Calculated DNEL long-term, worker = 33.5/9 = 3.72 mg Al/m³, respirable, 8 hour TWA.

Calculated DNEL long-term, worker = 10.76 mg Al(OH)3/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
Explanation for the modification of the dose descriptor starting point:

This is not a relevant exposure route for the general population.

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:
4.74 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:
94.8 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

NOAELcorr = NOAEL * 3.16 = 30 * 3.16 = 94.80 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 (<0.025%).)

AF for dose response relationship:
1
Justification:
Based on 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):
4
Justification:
4 for allometric scaling (rats to humans)[ECHA default, 2008].
AF for other interspecies differences:
1
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. Conservative assumption on the NOAEL as the effects may well be secondary to general toxicity based on crystallization of Al-citrate in the kidneys and not related to Al-exposure
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

Key Study for Dose Descriptor

The long-term consumer DNEL for systemic effects is based on a chronic 1-year oral study with the read-across substance aluminium citrate (ToxTest, TEH-113, 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/kg bw/day. However, this was already a conservative assumption as the effects observed could have been secondary to kidney toxicity based on a crystallization of Al-citrate in the kidneys after chronic exposure and/or reduced body weight and not 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 Al-citrate from GD6 to GD21 and from PND 1 to PND 21. Pups were exposed to Al-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.

Ratio of bioavailability between test and target substance: Priest (2010): Ratios of the whole body fractional uptake for Al-citrate (0.079%) to the whole body fractional uptakes of Al metal (<0.025%).

 

 

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

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 (<0.025%).

NOAEL (corrected) = NOAEL * 3.16

= 94.80 mg Al/kg bw/day; corrected starting point

Assessment factors:

Interspecies: 4

4 for allometric scaling (rats to humans) [ECHA default, 2008]. Due to the fact that inorganic metal compounds are not metabolized by liver enzymes a toxicokinetic factor is not adequate for the extrapolation. In addition the NOAEL was already conservative because it is possible that the effects observed are not related to the Aluminium ion, but secondary to kidney effects in the rats due to crystallistion of Al critrate and/or lower body weight. The allometric factor is therefore already conservative and no additional factor is needed.

Intraspecies: 5

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.

 

Duration of exposure: 1 (The study exposed the animals until they were 1 year of age.) Dose response extrapolation: 1 (Based on a NOAEL (ECHA, 2008))

Adequacy of database: 1

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. Conservative assumption on the NOAEL as the effects may well be secondary to general toxicity based on crystallization of Al-citrate in the kidneys and not related to Al-exposure

 

Total assessment factor = 20

Calculated DNELlong-term, systemic, general population= 94.80/20 = 4.74 mg Al/kg bw/day.