Boehmite (Al(OH)O)

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:

3.59 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

27

Dose descriptor:

LOAEC

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

Additional information - workers

Aluminium hydroxide

Assuming that the aluminium component is the active moiety with respect to any chemical–specific, long-term pulmonary effects on repeated exposure to aluminium hydroxide, read-across of the aluminium powder results from Gross et al. (1973) was used to derive a DNEL for aluminium hydroxide.

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 (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: Threshold (see Aluminium powder)

 

Calculation of DNEL 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 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: 3 (Based on a LOAEC)

Adequacy of database: 3

The histopathological effects assessed are not the most sensitive endpoint. However, the relevance of the critical effect to the human lung is unclear as effects are consistent with an overload response. Evidence suggests a greater susceptibility of rats to overload and the associated increase in lung retention and chronic pulmonary inflammation. Uncertainties remain with respect to particle dosimetry and toxicokinetics. As: (a) read-across has been used (based on the similar physicochemical properties of aluminium oxide (coat) and aluminium hydroxide) and the assumption that the aluminium component is the active moiety with respect to longer-term pulmonary effects when this substance is retained in the lung; (b) the limitations of the key study (lack of more sensitive endpoints); and (c) the limited nature of the existing database relevant for this substance (cross-sectional human studies of exposure to bauxite are available), overall the confidence in the database is moderate and a database adequacy factor of 3 is considered appropriate. 

 

Total assessment factor = 27

 

Calculated DNEL_{long-term, worker}= 33.5/27 = 1.24 mg Al/m³, respirable, 8 hour TWA

      = 3.54 mg Al(OH)₃/m³, respirable, 8 hour TWA.

 

As the calculated value is slightly higher than, but similar to, general dust limits used in setting Occupational Exposure Limits and the weight of evidence supports behavior of aluminium hydroxide dust as a low cytotoxic, poorly soluble particulate,the general dust limits are considered appropriate for exposure scenarios with exposure to aluminium hydroxide dust.

Proposed DNEL_{long-term,worker}for aluminium hydroxide = 3 mg Al(OH)₃/m³

These DNEL values are supported by the NOAECof 3 mg/m³ observed in the 28 day sub-acute study by Pauluhn (2009a) for aluminium oxyhydroxide particulates with a finer particle size distribution that employed a more sensitive set of endpoints.

At present, the available evidence supports a lack of substance specific effects in the lungs on inhalation exposure to the target substances. The ECHA Guidance (Chapter R8, p144) specifies that a registrant can use a health-based national OEL when the scientific basis of the national OEL has been evaluated and the method validated against the REACH DNEL derivation method.

The adoption of a health-based OEL may be considered for the aluminium oxide component of welding fume, given that the existing evidence does not support a chemical-specific effect of this exposure.

Summary DNEL derivation:

Gross (1973)
Effect:		Pulmonary Toxicity (Repeated Dose)
Target Substance:		Aluminium hydroxide
Target Population:		Workers (exposed to the powder or dust)
Exposure Route:		Inhalation
Exposure Duration:		Repeated Dose
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:		Aluminium powder
EXPOSURE ROUTE/MEDIUM/ CONCENTRATION/DURATION		Inhalation/ dust, powder - mean particle size diameters: 2.49, 2.22 and 4.85μm/ 0, 15, 30, 50, 100 mg/m^3/6 hours per day, 5 days a week for either 6(for 50 and100 mg/m^3)or 12 months.
CRITICAL EFFECT:		Lipid pneumonitis, granulomatous inflammation; collagenous scars
MODE OF ACTION:		Threshold (portal of entry - overload)
RELEVANT DOSE-DESCRIPTOR:	50	mg/m^3
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	There is 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:	33.50	mg/m^3(50 x 6.7/10)
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	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	Adequate duration of exposure. No scaling necessary.
Dose-response extrapolation:	3	Based on a LOAEC (ECHA Chapter R8, ECETOC (2010))
Adequacy of database:	3	The histopathological effects assessed are not the most sensitive endpoint. However, the relevance of the critical effect to the human lung is unclear as the effects are consistent with a rat overload response. Evidence suggests a greater susceptibility of rats to overload and the associated increase in lung retention and chronic pulmonary inflammation. Uncertainties exist with respect to particle dosimetry and toxicokinetics. As: (a) read-across has been used (based on the similar physicochemical properties of aluminium oxide (coat) and aluminium hydroxide) and the assumption that the aluminium component is the active moiety with respect to longer-term pulmonary effects when this substance is retained in the lung; (b) the limitations of the key study (lack of more sensitive endpoints); and (c) the limited nature of the existing database relevant for this substance (cross-sectional human studies of exposure to bauxite are available), overall the confidence in the database is moderate and a database adequacy factor of 3 is considered appropriate.
TOTAL ASSESSMENT FACTOR:	27
	1.24	mg/m^3as Al, daily 8 hour TWA (respirable)
DNEL inhalation-workers-long-term:	3.59	mg/m^3as Al(OH)3, daily 8 hour TWA (respirable)

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:

2.37 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:	Al(OH)3
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:	3.16	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:	3.16
Corrected Starting Point:	94.80	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	2.37	mg Al/kg bw/day
	6.85	mg substance/kg bw/day