Reaction mass of aluminium and aluminium oxide and calcium oxide and magnesium oxide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Acute/short term exposure

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

Overall assessment factor (AF):

3

Dose descriptor:

NOAEC

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

Additional information - workers

This discussion relates to the main component, aluminium oxide, and the assuesment of the reaction mass based upon its main component can be considered as a worst case approach. Generic issues relating to inorganic substances can be considered as appropriate for all other components within the reaction mass.

Aluminium oxide

Key study 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 diameter 0.8 µm

Doses used: 0, 30, 70 mg/m³

Duration of exposure in the experiment: 6 (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.

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 according 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

Duration of exposure: 1

The duration of exposure was adequate.

Dose response extrapolation: 1 (Based on a NOAEC)

Adequacy of database: 1

This study assessed only histopathological effects and did not look at sensitive effects such as inflammatory markers in the BALF. However, the evidence for the lack of fibrogenic effects of Al₂O₃dust is also supported by consistent results from intratracheal instillation studies and the inhalation studies of Christie et al. (1963) and Pigott et al. (1981). An AF of 1 is considered appropriate.

Total assessment factor = 3

 

Calculated DNEL_{long-term,worker}for aluminium oxide = 46.9/3 = 15.63 mg/m³, respirable, 8 hour TWA for Al₂O₃

 

As the weight of evidence supports the low cytotoxic and low fibrogenic nature of aluminium oxide and the calculated DNEL is higher than the general dust limits used in setting Occupational Exposure Limits,the general dust limits are considered appropriate for exposure scenarios for aluminium oxide dust.

 

Proposed DNEL_{long-term,worker}for aluminium oxide = 3 mg/m³, respirable, 8 hour TWA

Summary DNEL derivation:

Gross (1973)
Effect:		Pulmonary Toxicity (Repeated Dose)
Target Substance:		Aluminium oxide (CAS# 1344-28-1)
Target Population:		Workers (exposed to dust)
Exposure Route:		Inhalation
Exposure Duration:		Repeated Dose (6 or 12 months)
Effect type:		Local/Chronic
KEY REFERENCE:		Gross P, Harley R, de Treville RTP. 1973. Pulmonary reaction to metallic aluminium powders. Arch Environ Health.26:227-236.
TEST ANIMAL:		Rats
TEST SUBSTANCE:		Al2O3
EXPOSURE ROUTE/MEDIUM/ CONCENTRATION/DURATION		Inhalation/ dust, powder/ 0, 30, 70 mg/m^3/6 hours per day, 5 days a week for either 6(70 mg/m^3)or 12(30 mg/m^3)months.
EFFECTS:		Dust-filled macrophages; no alveolar proteinosis, endogenous lipid pneumonitis or fibrosis.
MODE OF ACTION:		Threshold (portal of entry - overload)
RELEVANT DOSE-DESCRIPTOR:	70	mg/m^3(NOAEC)
MODIFYING FACTORS:
Adjustment for differences in exposure conditions and respiratory rates
Inhalation volume (experiment)	6.7	Inhalation volume (rat resting): 6.7 m^3(8h).
Inhalation volume (target population)	10	Inhalation volume (human light activity): 10 m^3(8h)
Ratio of bioavailabilities between test and target species:	1	No evidence suggesting that there would be a difference between animal species with respect to actual bioavailability.
Ratio of inhalation bioavailabilities between test and target substances:	1
TOTAL MODIFICATION FACTOR:	0.67
Corrected Starting Point:	46.90	mg/m^3(70*6.7/10)
ASSESSMENT FACTORS
Interspecies:	1	Allometric scaling not necessary as adjustment for inhalation volume has already been done; mode of action is a portal-of-entry effect (overload); scientific evidence suggests a greater susceptibility to overload in rats (Pauluhn, 2010; Jarabek et al., 2005) therefore a factor of 2.5 for remaining uncertainty (the default in the ECHA Guidance) was not considered appropriate.
Intraspecies:	3	ECETOC (2010) gives a value of 3 for the worker population. A value of 5 would be inserted for the general population. Note: Eurometaux has adopted the ECETOC (2010) approach for intraspecies and interspecies assessment factors. Therefore, the client indicated that these values should be inserted here.
Duration of exposure:	1	The duration of exposure was adequate.
Dose-response extrapolation:	1	Based on a NOAEC
Adequacy of database:	1	Based on histopathological effects - a strong but not very sensitive endpoint. However, the evidence for the lack of fibrogenic effects of Al2O3dust in the occupational setting is supported by consistent results from intratracheal instillation studies. Confidence in the database is considered strong.
TOTAL ASSESSMENT FACTOR:	3
DNEL-long-term (worker)	15.63	mg/m^3Al2O3, daily 8 hour TWA (respirable)*
		* not applicable to aluminium fume.

Short-term DNEL

 

According to REACH guidance (ECHA, 2008, Chapter 8, p.106), there is no generally accepted methodology for the establishment of an acute toxicity DNEL for effects occurring after a single exposure of a few minutes up to 24 hours. In most cases it may be unnecessary to derive an acute DNEL, as the long-term DNEL is usually sufficient to ensure that these effects do not occur. In summary, according to ECHA, a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential for high peak exposures, for example, connecting or disconnecting vessels.

 

The weight of evidence suggests that these substances behave as poorly soluble low cytotoxicity particulates. A chemical-specific acute toxicity hazard leading to C&L was not identified for the target substances. The long-term DNEL should ensure that these effects do not occur.

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.29 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - General Population

Summary DNEL derivation:

Oral DNEL Derivation Summary
TEH-113
Effect:		Repeated Dose - neurotoxicity
Target Substance:	Al2O3
Target Population:		Adults
Exposure Route:		Oral exposure
Effect type:		Long-term, systemic
KEY REFERENCE:		Developmental and One-Year Chronic Neurotoxicity Study of Aluminium Citrate in Rats. ToxTest, Alberta Research Council Inc. Project No. TEH-113.
TEST ANIMAL:		Sprague-Dawley male and female rats
TEST SUBSTANCE:		Aluminium citrate (CAS# 31142-56-0)
EXPOSURE ROUTE/MEDIUM/ CONCENTRATION/DURATION		Pregnant females were exposed to Al-citrate at dose levels 30, 100 and 300 mg Al/kg bw/day from GD6 to GD21 and from PND 1 to PND 21. Pups were exposed to Al-citratein uteroand with maternal milk from PND 1 to PND 21, 64, 120 or 364.
EFFECTS:		A deficit in fore- and hind-limb grip strength in the mid-dose group, supported by evidence of dose response for this endpoint
ENDPOINT- CONCENTRATION:		LOAEL - 100 mg Al/kg bw/day; NOAEL - 30 mg Al/kg bw/day
MODE OF ACTION:		Threshold
RELEVANT DOSE-DESCRIPTOR:	30	mg Al/kg bw/day; NOAEL
MODIFYING FACTORS
Route-to-route:	1	Oral to oral extrapolation with the same units (ECHA, 2008)
Bioavailability differences between animal species:	1	Evidence suggests no difference between animal species for oral exposure (Priest, 2010).
Ratio of bioavailability between test and target substance:	4.39	Priest (2010): ratios of the whole body fractional uptake for Al-citrate (0.079%) to the whole body fractional uptakes of Al metal (<0.015%), Al-oxide (0.018%), and Al-hydroxide (0.025%). Note: The whole body fractional uptake (f) of Al metal powder was g
TOTAL MODIFICATION FACTOR:	4.39
Corrected Starting Point:	131.67	mg Al/kg bw/day
ASSESSMENT FACTORS
Interspecies:	4	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
Intraspecies:	5	ECETOC (2010) gives a value of 5 for the general population. A value of 3 would be inserted for the worker population. Note: Eurometaux has adopted the ECETOC (2010) approach for intraspecies and interspecies assessment factors. Therefore, the client ind
Duration of exposure:	1	The study exposed the animals until they were 1 year of age.
Dose-response extrapolation:	1	Based on NOAEL (ECHA, 2008)
Adequacy of database:	2	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-TEH113 study.
TOTAL ASSESSMENT FACTOR:	40
DNEL: general population	3.29	mg Al/kg bw/day
	6.22	mg substance/kg bw/day