Bis(acetato-O)hydroxyaluminium

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.8 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Dose descriptor starting point:

NOAEL

Value:

180 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

222 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route).

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

The default factor for remaining interspecies differences is used.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

36 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

180 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 800 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. A low dermal absorption value can be expected due to the physico-chemical properties of the substance. Thus, only a 10 % dermal absorption is concluded.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

The default factor for remaining interspecies differences is used.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

medium hazard (no threshold derived)

Additional information - workers

General information

No repeated dose toxicity is available for aluminium acetate. In the WHO/JECFA opinion from 2012 several repeated dose or multi generation studies testing different aluminium compounds were evaluated. Merely all of the available studies had many limitations and were not adequate for defining a dose response relationship. One study performed with aluminium citrate (Poirier et al., 2011) was considered as appropriate by WHO/JECFA and was used for the derivation of the provisional tolerable weekly intake (PTWI).

In the respective developmental neurotoxicity study according to OECD 426 and GLP target substance aluminium citrate was added to drinking water starting on gestational day 6, during gestation, lactation, and to offspring during post-weaning, through to post-natal day (PND) 364. A NOAEL of 30 mg Al/kg bw/d was determined.

The study from Poirier et al 2011 further included a bioavailability study with rats orally gavaged with Al citrate, Al nitrate, Al chloride, Al sulfate, Al hydroxide. Here, bioavailability of Al citrate was higher compared to other Al salts (nitrate, chloride, sulfate) and Al hydroxide; Al concentrations were higher in kidney and bone after treatment (30 mg/kg bw/day elemental Al) with Al citrate for 14 days.

Thus, using the aluminium citrate and the corresponding NOAEL as basis for the DNEL derivation can be regarded as worst case based on the higher bioavailability and can therefore be regarded as justified.

The primary route of industrial exposure to aluminium acetate is skin contact and inhalation. DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2010). In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

Acute, systemic DNEL

Short-term DNELs are not required as the acute toxicity of the test substance is low. The test substance is not classified and labelled for acute systemic toxicity (oral and dermal), according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral toxicity. For acute inhalative toxicity no adequate test data is available to decide on classification and labelling. A low inhalation hazard can be assumed based on the physico-chemical properties of the test substance (vp < 1.7E-05 Pa at 25 °C).

Acute/long-term, local

Respiratory irritation: No study for local respiratory effects of the test material is available. However, the test material showed eye irritation (eye damage cat. 1). This implies that a potential damage to mucosal tissue may occur by inhalative exposure. Additionally a risk of particle inhalation can be assumed regarding the particle size of the test substance. Thus, test substance is allocated to the moderate hazard band according to the ECHA guidance on IR/CSA, Part E (2016) Since no threshold limit values can be defined, a qualitative approach was applied to exposure and risk assessment with relevant RMMs (ECHA CSR R.8, 2012).

Skin irritation/corrosion: The test substance is not irritating to the skin. Therefore no qualitative risk assessment is required.

Eye irritation: The test substance is eye damaging cat, 1 (H318). Thus, the test substance is allocated to the moderate hazard band according to the ECHA guidance on IR/CSA, Part E (2016). Since no threshold limit values can be defined, a qualitative approach was applied to exposure and risk assessment with relevant RMMs (ECHA CSR R.8, 2012).

Skin sensitization potential was not observed in the available guinea pig maximisation test with the test substance. Therefore no qualitative risk assessment is required.

Long-term, systemic DNEL

Occupational exposure to the test substance occurs mainly by dermal route, and may also occur by inhalation exposure. Therefore two long-term DNELs are calculated for workers. In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

Exposure by inhalation

Step 1: Selection of the relevant dose descriptor (starting point):

The NOAEL of 30 mg Al/kg bw/day, assessed in the key repeated dose oral toxicity study (OECD 426, 2012) with the target substance aluminium citrate is identified as the relevant dose descriptor and starting point. The NOAEL for aluminium acetate is 180 mg/kg bw /d after adaption for molecular weight differences.

Step 2: Modification into a correct starting point:

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is derived. This worker DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).

Relevant dose descriptor (NOAEL): 180 mg/kg bw/day

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw/d

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5

Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected inhalatory NOAEC for workers

= 180 mg/kg bw/d × 0.5 × (1 / 0.38 m³/kg bw/d) × (6.7 m³/10 m³) × 1.4

= 222 mg/m³

Step 3: Use of assessment factors: 12.5

Interspecies AF: Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF: 1

In conclusion, the long-term inhalation DNEL, worker = 17.8 mg/m³

 

Dermal exposure

Step 1: Selection of the relevant dose descriptor (starting point):

The NOAEL of 30 mg Al/kg bw/day, assessed in the key repeated dose oral toxicity study (OECD 426, 2012) with the target substance is identified as the relevant dose descriptor and starting point. The NOAEL for aluminium acetate is 180 mg/kg bw /d after adaption for molecular weight differences.

Step 2: Modification into a correct starting point:

Correction for dermal absorption rates of the test substance (based on Guidance on information requirements and chemical safety assessment, R. 7C, 2014, Chapter R 7.12):

Dermal absorption is supposed to be low regarding the molecular weight of 162 g/mol, the low log Pow of -0.6 and the water solubility (13 mg/L at 20 °C). The barrier function of the skin for ionic substances further decreases the penetration of the test substance. Additionally, no effect has been observed in the available skin sensitisation study with guinea pigs.

Krewski et al. (2007) further concluded a poor penetration of aluminium through the skin. In a study different aluminium salts were topically applied to excised human skin. Removal of the stratum corneum (the outer layer of the skin that is 25 to 35 μm thick) by stripping with adhesive tape resulted in no greater aluminium penetration into the dermis.

Therefore, oral NOAEL of 180 mg/kg bw/day was converted to a dermal NOAEL, expecting a low dermal absorption of 10 % through the skin.

In conclusion, dermal NOAEL = oral NOAEL × 100/10 = 1800 mg/kg bw/d.

Step 3: Use of assessment factors: 50

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF (chronic): 1

In conclusion, long term systemic dermal DNEL, workers = 36 mg/kg bw/day

 

References

(not included as endpoint study record)               

- ECHA (2016) Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation. Version 3. ECHA-2016-G-04-EN.

- ECHA (2010). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2. ECHA-2010 -G-19 –EN.

- ECHA (2010). Guidance on information requirements and chemical safety assessment. Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. May 2008.

- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report. ECHA-12-B-49-EN.

- Krewski et al. (2007), HUMAN HEALTH RISK ASSESSMENT FOR ALUMINIUM, ALUMINIUM OXIDE, AND ALUMINIUM HYDROXIDE, J Toxicol Environ Health B Crit Rev. 2007 ; 10(Suppl 1): 1–269

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

Exposure is not intended for the general population. Thus, no risk assessment has been performed.