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EC number: 932-420-3 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: inhalation
Administrative data
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Study period:
- 2009
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- Comparable to guideline study with acceptable restrictions Al3+is the predominant aluminium form at low pH (less than 5.5). As pH increases above 5.5, aluminium-hydroxide complexes formed by hydrolysis become increasingly important and dominate aqueous aluminium speciation . Al3+, depending on the composition of the medium and pH, may form Al(OH)3 or Al2O3 or AlCl or AlNO3 or AlSO4 According to the solubility studies, the major elements found at the maximum solubility are 1054 mg/l Al and 856 mg/l Ca, for 100 g of the tested substance, ie approximatively 1%. A read-across was made with all the aluminium salts and oxides.
Data source
Reference
- Reference Type:
- publication
- Title:
- Pulmonary toxicity and fate of agglomerated 10 and 40 nm aluminium oxyhydroxides following 4-week inhalation exposure of rats: Toxic effects are determined by agglomerated, not primary particle size.
- Author:
- Pauluhn
- Year:
- 2 009
- Bibliographic source:
- Toxicol Sci 2009; 109(1): 152-167.
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
- Deviations:
- yes
- Remarks:
- : no GLP study
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- aluminium oxyhydroxide
- IUPAC Name:
- aluminium oxyhydroxide
- Details on test material:
- Name: Pural 200
Test material identity: 1) γ-AlO(OH)-40nm/MMAD-0.6μm 2) γ-AlO(OH)-10nm/MMAD-1.7μm
Supplier: Sasol (Germany)
Purity: high
Aluminium content -
Expressed as Al: 43.9%
Expressed as Al2O3: 82.7%
Crystal structure: boehmite (orthorhombic)
N2-BET surface area (m2/g, 500ºC/3h): 105
Specific density (g/cm3): 2.85
Loose bulk density (g/cm3): 0.51
Typical impurity levels:
Na2O – 20ppm
Fe2O3 – 100 ppm
SiO2 – 120 ppm
Batch Number: NR (not reported)
Storage: Information available on manufacturer’s website
(http://www.sasoltechdata.com/alumina_group.asp)
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Age at study initiation: 2 months
- Weight at study initiation: In the AlO(OH)-40 treated animals the body weights were 233±10.3g, 232±10.2g, 228±11.6g and 230±10.9g in the 0, 0.4, 3 and 28 mg/m³ groups. In the AlO(OH)-10 treated animals the body weights were 235±9.9g, 234±9.6g, 234±11.2g and 235±10.9g in the 0, 0.4, 3 and 28 mg/m³ groups.
- Fasting period before study:
- Housing: singly housed in polycarbonate cages
- Diet: KLIBA 3883=NAFAG 9441 maintenance diet
- Water: ad libitum
- Acclimation period: 1 week
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22ºC
- Humidity (%):40-60%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12/12 light/dark
Administration / exposure
- Route of administration:
- inhalation: aerosol
- Type of inhalation exposure:
- nose only
- Vehicle:
- other: Not relevant.
- Remarks on MMAD:
- MMAD / GSD: Particle size was measured using a critical orifice cascade impactor (low-pressure critical orifice Berner-Type AERAS stainless steel 11-stage – HAUKE, Gmunden, Austria.) and also a laser velocimeter TSI APS 3321.
AlO(OH)-40
Primary particle size: ca. 40 nm
Average particle size (d50, measured on powder): 40μm
MMAD: 0.6μm (for agglomerated particles)
The cascade impactor particle size measurements were as follows: MMADs were 0.59±0.1μm, 0.57±0.05μm, and 0.63±0.05μm for the 0.4 mg/m3, 3.0 mg/m3, and 28.0 mg/m3 dose levels, respectively. The corresponding GSD values were 2.47±0.3 μm, 2.63±0.14 μm, and 2.56±0.18 μm and the respirable fractions (% mass < 3 μm) 96.6%, 95.7% and 95.2%.
MMAD values from the laser velocimeter were slightly higher. This was attributed by the authors to incomplete detection of particles less than 0.5 μm.
AlO(OH)-10
Primary particle size: ca. 10 nm
Average particle size (d50, measured on powder): 25 μm
MMAD: 1.7μm (for agglomerated particles)
The cascade impactor particle size measurements were as follows: MMADs were 1.75±0.19μm, 1.65±0.12μm, and 1.68±0.16μm for the 0.4 mg/m3, 3.0 mg/m3, and 28.0 mg/m3 dose levels, respectively. The corresponding GSD values were 2.71±0.2 μm, 2.79±0.14 μm, and 2.72±0.23 μm and the respirable fractions (% mass < 3 μm) 70.9%, 72.2% and 72.0%. - Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
A Wright Dust-Feeder (BGI Inc., Waltham, MA) was used to disperse the materials into the inhalation chambers. AlO(OH)-10 was micronized to enhance the dustiness of the material. Pressurized dry, clean air was used to disperse the powders at a rate of 0.75 L/min. The number of air exchanges per hour was >200. Air flow was monitored and controlled using mass-flow meters. A computerized real-time data acquisition system was used for monitoring all inhalation chamber parameters. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Aerosol concentrations were analyzed in real-time using Microdust Pro, a real-time dust monitor. Breathing zone concentrations were also characterized by the analysis of filters (glass fibre; 4L/min sampling rate) through which volumes of ca. 1200, 300 and 80L of breathing zone air had been passed for the 0.4, 3 and 28 mg/m³ dose levels, respectively.
- Duration of treatment / exposure:
- 4 weeks.
- Frequency of treatment:
- 6 hours/day for 5 days/week
Doses / concentrations
- Remarks:
- Doses / Concentrations:
Basis:
other: Dose levels used in the experiment were 0, 0.4, 3 and 28 mg/m³.
- No. of animals per sex per dose:
- 12 males per timepoint (6 for lavage and histopathology, 6 for determination of Al levels in different tissues)
- Control animals:
- yes
- Details on study design:
- Animals were randomly assigned to exposure groups.
Control animals details:
An air-exposed control time-matched group was included in the experiment. The air was described as “dry, conditioned”. - Positive control:
- Not required.
Examinations
- Observations and examinations performed and frequency:
- Observations and examinations performed:
Clinical observations were performed before and after exposure and body weights were recorded twice weekly during exposure and once weekly after.
An interim sacrifice was made on day 10 during exposure and post-exposure (PE) sacrifices were carried out one day after the end of exposure, 12 days, 33 days and 91 days after the end of exposure.
Bronchoalveolar lavage fluid was collected and analysed for cytological and biochemical parameters.
Lungs and hilar lymph nodes were weighed and their pathology examined.
- Sacrifice and pathology:
- Animals for BAL and histopathology analyses were anaesthetized with sodium pentobarbital (intraperitoneal injection, 120 mg/kg bw) and exsanguinated.
- Other examinations:
- Bronchoalveolar lavage fluid was obtained by the lavage (4x) of wet lungs using a tracheal cannula using two 5mL volumes of physiological saline at 37ºC. The pooled fluid was centrifuged and the pellet resuspended in PBS-BSA. Slides were prepared by cytocentrifuge, air-dried and fixed prior to examination by light microscopy. Cell counts were done in triplicate. The supernatant was analyzed for total cells, lactate dehydrogenase (LDH), protein (Folin-Ciocalteu reagent after Layne (1957), Methods Enzymol 3: 447-454.), γ-glutamyltransferase (γ-GT) (IFCC (2002) reference procedure), β-N-acetylglucosaminidase (β-NAG) (colorimetric assay after Maruhn (1976), Clin Chim Acta 73: 453-461) and different cell types.
Excised lungs and hilar lymph nodes were weighed. The lungs were inflated and fixed with formalin (10% neutral buffered). Pathological examinations were undertaken of all 5 lung lobes, bronchi and the lymph nodes using hematoxylin and eosin stains. Lung tissue was also examined using Sirius red to show collagen. The olfactory bulb, ethmoid turbinates, and the olfactory nerve were also examined
Aluminium levels were measured in urine (collected overnight on days 4, 11, 18 and 25 ) and also in the brain, the right lung lobes, BAL cells, hilar lymph nodes, the kidneys, and the liver after acid digestion using graphite furnace atomic absorption spectrometry. - Statistics:
- BALF parameters and organ weights were compared between groups using one-way ANOVA and Tukey-Kramer post-hoc tests for pairwise comparisons. The significance level was set at p<0.05.
Exposure-related accumulation of particles in the lung was modeled assuming dc/dt=a(1-kt) where k was an empirically-derived first-order elimination constant and a was the daily increase in alveolar region particle deposition.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- Other findings:
Inflammation-associated changes in BALF were observed only at the highest dose. (see details below).
Effect levels
open allclose all
- Dose descriptor:
- NOAEC
- Effect level:
- 3 mg/m³ air
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: overall effects cytology and biochemical parameters in lavage fluid
- Dose descriptor:
- LOAEC
- Effect level:
- 28 mg/m³ air
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: overall effects cytology and biochemical parameters in lavage fluid
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Bronchopulmonary lavage
No significant differences in BALF cytology and biochemical parameters were observed at any time point compared with the time-matched control at the 0.4 and 3 mg/m3dose levels.
At 28 mg/m3
Cytology -
Total cell counts
AlO(OH)-40 [MMAD=0.6μm]
Total cell counts were similar to the control at day 10 but showed a marked increased at days 24 and 35 (factor of 2 to 3; p<0.05). Levels decreased to about 1.5 times the control level at days 56 and 113.
AlO(OH)-10 [MMAD=1.7μm]
Similar to the other boehmite, levels were the same as the controls at day 10 during exposure but showed a significant increase (factor of 2.5; p<0.05) by day 24. This increase was sustained until day 56 followed by a decrease.
Polymorphonuclear neutrophilic granulocytes (PMNs; absolute numbers)
AlO(OH)-40 [MMAD=0.6μm]
Significantly elevated (factor of 100-200; p<0.01) numbers of PMNs were observed at all timepoints in the 28 mg/m3treated animals. The highest levels were observed on days 24 and 35 after which there was a decrease. On day 113, the number of PMNs was still significantly greater than in the time-matched control animals. Interestingly, the number of PMNs in all groups, including the control showed a slight increase with time.
AlO(OH)-10 [MMAD=1.7μm]
Significantly elevated (factor of 100-200; p<0.01) numbers of PMNs were observed at all timepoints in the 28 mg/m3treated animals with highest levels at days 24, 35 and 56 with a slight decrease by day 113.
Biochemical analyses -
Total protein:
AlO(OH)-40 [MMAD=0.6μm]
Significantly elevated relative to the control on study day 24 and study day 113.
AlO(OH)-10 [MMAD=1.7μm]
Significantly elevated relative to the control on study days 10 (during exposure; p<0.05), 24 (one day after the end of exposure; p<0.01), 35 (p<0.01) and day 56 (p<0.05). By day 113 there was no significant difference between groups.
LDH:
AlO(OH)-40 [MMAD=0.6μm]
On study day 10 during exposure there was no significant elevation of LDH.
The highest level was on day 24 just after cessation of exposure. LDH levels then showed a clear decrease with time. The LDH level was still significantly elevated on day 35. On days 56 and 113 there was no significant difference between the 28 mg/m3treated group and the control.
AlO(OH)-10 [MMAD=1.7μm]
The pattern was very similar to the other boehmite alumina. There was no significant difference between the treated groups and the control at day 10 during exposure. The highest level was observed on day 24 after which levels decreased with time. On day 113, the LDH level in the 28 mg/m3treated group was still greater than in the control animals.
β-NAG:
AlO(OH)-40 [MMAD=0.6μm]
No significant difference was observed on day 10. The highest level was observed on day 24. At subsequent time points, levels were similar to the control.
AlO(OH)-10 [MMAD=1.7μm]
Significantly elevated levels were observed on days 24 and 35 only.
γ-GT:
AlO(OH)-40 [MMAD=0.6μm]
On day 10 during exposure, levels of γ-GT were a factor of 2 greater than the control (p<0.05). By day 24, levels were greater by a factor of 3 (p<0.01). Levels then decreased, not attaining statistical significant at any of the subsequent time points.
AlO(OH)-10 [MMAD=1.7μm]
The pattern was very similar to the other boehmite. Levels were significantly elevated at day 10 (factor of 2; p<0.05) and by a factor of 3 to 4 (p<0.01) at day 24. A marked reduction occurred by day 35 after which time levels remained similar to control.
Pathology/histology
No abnormal histopathological findings were observed in control rats or rats exposed to the 0.4 or 3 mg/m3dose level. In rats dosed for 4 weeks with 28 mg/m3, particles were evident in alveoli, enlarged and sometimes foamy macrophages were present and a “slight hypercellularity (increased epithelial cells, inflammatory cells, focal septal thickening – graded as slight to minimal)” were seen. Focal septal collagen was revealed by Sirius red. No progression or regression of these changes was observed post-exposure. Findings were similar for both boehmites. The authors reported a “slight lymphoid activation” with increased accumulation of epitheloid cells post-exposure in the lung-associated lymph nodes (LALN).
Lung weights, hilar lymph nodes weights
AlO(OH)-40 [MMAD=0.6μm]
Absolute lung weights were significantly greater than the control in the 28 mg/m3group at day 24, day 56 and day 113. At day 113, lung weights were significantly greater at 3 mg/m3also.
Absolute hilar lymph node weights in the 28 mg/m3group were significantly greater than the time-matched control on days 24, 35, 56 and 113 showing an increase with time. A decrease was observed on day 113 although it remained statistically elevated (p<0.05).
AlO(OH)-10 [MMAD=1.7μm]
Absolute lung weights were significantly greater than the control only on day 24 in the 28 mg/m3treated group.
Absolute hilar lymph node weights were significantly greater than the time-matched control on days 24, 35, 56 and 113 showing an increased with time. In contrast to the smaller agglomerated particle size boehmite, the largest difference between the 28mg/m3treated group and the control was observed on day 113 for this substance.
Aluminium Levels in Urine and Tissues
Aluminium levels in tissues were presented in the article in figures.
Lungs
In the animals dosed with 28 mg/m3:
AlO(OH)-40 [MMAD=0.6μm]
PE day 1:ca. 1800 μg Al/lung
PE day 12:ca. 1700 μg Al/lung
PE day 33:ca. 1600 μg Al/lung
PE day 91:ca. 1150μg Al/lung
AlO(OH)-10 [MMAD=1.7μm]
PE day 1:ca. 1100 μg Al/lung
PE day 12:ca. 1000 μg Al/lung
PE day 33:ca. 1000 μg Al/lung
PE day 91:ca. 900μg Al/lung
A
time dependent decrease in the amount of Al in the lungs was observed
for both boehmites. Levels
were higher in the AlO(OH)-40 [MMAD=0.6μm] treated animals.
Lung –associated Lymph Nodes
The amount of Al in the hilar lymph nodes was elevated from study day 24 in the 28 mg/m3Pural (AlO(OH)-40 [MMAD 0.6μm]) treated animals. The levels increased with time until the last day of the experiment. Levels also increased with time in the Disperal (AlO(OH)-10 [MMAD 01.7μm]) treated animals, but not to the same extent.
No measurable increase was observed for the 0.4 or 3 mg/m3dose levels for either boehmite.
Brain, liver, kidneys
The results showed no time or dose-dependent increases in Al in the brain, liver or kidneys. This was reported qualitatively in the article.
Al in urine
The authors report no evidence of time or dose-dependent changes in Al in urine (reported qualitatively).
Toxicokinetic Calculations
The results showed that inflammatory responses occurred at ca. 2.2 and 1.5 mg Al/g lung for AlO(OH)-40 [MMAD=0.6μm] and AlO(OH)-10 [MMAD=1.7μm], respectively,
equivalent to 3.9 and 2.7 mg/g lung of the test substances themselves.
Based on the results and assuming first order elimination kinetics, the authors calculated the deposited alveolar fraction, and the half-lives of the substances in the lung tissue and in BAL-cells, separately and combined. The Multiple Path Particle Dosimetry Model (MPPD2) was used to apply a dosimetric adjustment with respect to particle size in the calculation of the deposited alveolar fraction.
Extracted from Table 3 of the article:
|
AlO(OH)-40 [MMAD=0.6μm] |
AlO(OH)-10 [MMAD=1.7μm] |
||||
Concentration (mg/m3) |
0.4 |
3 |
28 |
0.4 |
3 |
28 |
Deposited alveolar fraction |
0.105 |
0.108 |
0.103 |
0.063 |
0.067 |
0.065 |
Half-life in lung tissue (days) |
56 |
43 |
144 |
42 |
60 |
295 |
Half-life in lung tissue and BAL cells (days) |
50 |
43 |
94 |
42 |
58 |
177 |
At the higher particle lung burdens, a marked increase in retention occurred.
Applicant's summary and conclusion
- Conclusions:
- In conclusion, an inflammatory pulmonary response was observed only at the end of the 4 week exposure period in the animals receiving the highest dose (28 mg/m³). Even though measurable aluminium was observed in the lungs at the lower dose levels, adverse effects were not seen despite the sensitive endpoints employed. For the dose levels and exposure durations used in the study, significant translocation of the particles from the lung to other body organs was not evident. A marked increase in lung retention was evident at the highest dose level, consistent with an “overload” phenomenon. The NOAEC from this study is 3 mg/m³ and the LOAEC is 28 mg/m³.
- Executive summary:
This study investigated the pulmonary toxicity of two calcined agglomerated aluminium oxyhydroxide (boehmite) nanoparticles in rats exposed by inhalation for 6 hrs/day, 5 days/week for 4 weeks. The principle hypothesis of the study was to “test whether the pulmonary effects (toxicity and fate) following exposure to aluminium oxyhydroxides of differing primary and agglomerated particle size are more dependent on the primary than agglomerated particle size”. The MMAD of one of the boehmite substances was 1.7μm (primary particle size 10 nm) and of the other substance was 0.6μm (primary particle size 40 nm). The duration of the post-exposure observation period was 3 months and the dose levels used were 0, 0.4, 3 and 28 mg/m3. An interim sacrifice was made on day 10 during exposure and post-exposure (PE) sacrifices were carried out one day after the end of exposure, 12 days, 33 days and 91 days after the end of exposure. Clinical observations were performed before and after exposure and body weights were recorded twice weekly during exposure and once weekly after. Twelve animals were exposed per dose level and timepoint; six for lavage and histopathology and six for determination of Al levels in different tissues. Pulmonary toxicity was determined by analysis of bronchoalveolar lavage fluid (BALF) and histopathological examination of all 5 lung lobes, bronchi and lung-associated lymph nodes using hematoxylin and eosin stains. Lung tissue was also examined using Sirius red to show collagen. The olfactory bulb, ethmoid turbinates, and the olfactory nerve were also examined. Aluminium levels were measured by graphite furnace atomic absorption spectrometry in urine (collected overnight on days 4, 11, 18 and 25 ) and also in the brain, the right lung lobes, BAL cells, hilar lymph nodes, the kidneys, and the liver after acid digestion. Lung retention kinetics were also calculated assuming first order elimination rates.
No significant differences in BALF cytology and biochemical parameters were observed in the animals treated with 0.4 or 3 mg/m3at any time-point compared with the time-matched control groups. At 28 mg/m3, however, an inflammatory response was evident. Total cell counts in the BALF in animals exposed to AlO(OH)-40 [MMAD=0.6μm] were similar to the control at day 10 but showed a marked increased at days 24 and 35 (factor of 2 to 3; p<0.05). Levels decreased to about 1.5 times the control level at days 56 and 113. The response to AlO(OH)-10 [MMAD=1.7μm] was similar. Levels of polymorphonuclear neutrophilic granulocytes (PMNs; absolute numbers) were significantly elevated (factor of 100-200; p<0.01) at all time-points in the animals treated with 28 mg/m3of either substance. For AlO(OH)-40 [MMAD=0.6μm], the highest levels were observed on days 24 and 35 after which there was a decrease. On day 113, the number of PMNs was still significantly greater than in the time-matched control animals. Interestingly, the number of PMNs in all groups, including the control showed a slight increase with time. In animals treated with AlO(OH)-10 [MMAD=1.7μm], significantly elevated (factor of 100-200; p<0.01) numbers of PMNs were observed at all time-points in the 28 mg/m3treated animals with highest levels at days 24, 35 and 56 with a slight decrease by day 113. Lactate dehydrogenase (LDH) showed a similar profile for both boehmite substances. On study day 10 during exposure there was no significant elevation of LDH. The highest level (increased by a factor of 2.5 relative to the control; p<0.05) was on day 24 just after cessation of exposure after which LDH levels showed a clear decrease with time. On day 113 there was no significant difference between the 28 mg/m3treated group and the control for the AlO(OH)-40 [MMAD=0.6μm] substance. For AlO(OH)-10 [MMAD=1.7μm], however, the LDH level in the 28 mg/m3treated group was still greater (p<0.05) than in the control animals on day 113. Levels of β-N-acetylglucosaminidase (β –NAG), total protein, and γ-glutamyltransferase (γ-GT) showed evidence of low levels of reversible lung damage. No abnormal histopathological findings were observed in control rats or rats exposed to the 0.4 or 3 mg/m3dose levels. In rats dosed for 4 weeks with 28 mg/m3, however, particles were seen in alveoli, enlarged and sometimes foamy macrophages were present and a “slight hypercellularity (increased epithelial cells, inflammatory cells, focal septal thickening – graded as slight to minimal)” were observed. Focal septal collagen was revealed by Sirius red. No progression or regression of these changes was observed post-exposure. Findings were similar for both boehmites. The authors reported a “slight lymphoid activation” with increased accumulation of epitheloid cells post-exposure exposure in the lung-associated lymph nodes (LALN).
In the animals treated with AlO(OH)-40 [MMAD=0.6μm], absolute lung weights were significantly greater than the control in the 28 mg/m3group at day 24, day 56 and day 113. At day 113, lung weights were significantly greater at 3 mg/m3also. In the AlO(OH)-10 [MMAD=1.7μm] treated animals, absolute lung weights were significantly greater than the control only on day 24 in the 28 mg/m3treated group. Animals treated with either boehmite showed absolute hilar lymph node weights significantly greater than the time-matched control on days 24, 35, 56 and 113 showing an increase with time. In the AlO(OH)-40 [MMAD=0.6μm] treated animals a decrease was observed on day 113 although the weight remained statistically elevated (p<0.05) compared with the time-matched control. In contrast, in the AlO(OH)-10 [MMAD=1.7μm] treated animals, the largest difference between treated and control was observed on day 113.
A time dependent decrease in the amount of Al in the lungs was observed for both boehmites after cessation of exposure. Levels were higher in the AlO(OH)-40 [MMAD=0.6μm] treated animals. The amount of Al in the hilar lymph nodes was elevated from study day 24 in the 28 mg/m3Pural (AlO(OH)-40 [MMAD 0.6μm]) treated animals. The levels increased with time until the last day of the experiment. Levels also increased with time in the AlO(OH)-10 [MMAD 1.7μm]) treated animals, but not to the same extent. No measurable increase was observed in aluminium levels in lung-associated lymph nodes for the 0.4 or 3 mg/m3dose levels for either boehmite. The results showed no time or dose-dependent increases in Al in the brain, liver or kidneys. The authors also reported no evidence of time or dose-dependent changes in Al in urine (reported qualitatively).
In conclusion, an inflammatory pulmonary response was observed at the end of the 4 week exposure period in the animals receiving the highest dose (28 mg/m3) in this study. Indices of lung damage showed that the effect was to some degree reversible. Even though measurable aluminium was observed in the lungs at the lower dose levels (0.4 and 3 mg/m3), adverse effects were not seen despite the sensitive endpoints employed. Histopathological changes were observed only at 28 mg/m3and included focal septal collagen. For the dose levels and exposure durations used in the study, significant translocation of the particles from the lung to other body organs was not evident. The cumulative lung burden was higher for the test substance with the smaller agglomerated particle size (0.6μm), which interestingly had the larger primary particle size. A marked increase in lung retention was evident at the highest dose level, consistent with an “overload” phenomenon. This study was well-reported and appears to have been well-conducted adhering approximately to guidance for a subacute inhalation toxicity study. The results are informative for the risk assessment of alumina particles in the respirable size range when exposure occurs by inhalation. The NOAEC from this study is 3 mg/m3and the LOAEC is 28 mg/m3.
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