Registration Dossier

Administrative data

Description of key information

Aluminium hydroxide is unlikely to lead to skin, eye or respiratory irritative effects.

Skin irritation

-LAB Research Ltd., Study 09/164-006N (OECD TG# 404) [Al(OH)3 powder, Klimisch=1], test substance is not a skin irritant

-Lansdown (1973), [Al(OH)3 suspension, Klimisch=2] no guideline study, test substance is not a skin irritant

Eye irritation

-LAB Research Ltd., Study 09/164-006N (OECD TG# 405) [Al(OH)3 powder, Klimisch=2], test substance is not a eye irritant

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

Skin irritation:

No human studies were located that examined acute dermal irritation/corrosion effects in workers exposed occupationally to aluminium hydroxide particulates. An animal study of aluminium hydroxide conducted in accordance with OECD TG #404 (Lab Research Ltd., 2009) provides key evidence for the absence of acute dermal irritation effects on exposure to this substance. Supporting evidence is available from an earlier animal study of aluminium hydroxide powder conducted in accordance with OECD TG 404 “Acute Dermal Irritation/Corrosion” (1989) aluminium hydroxide (Aluminium hydroxide, IUCLID, 2000). A full report of this study is not available for review. A negative result from a non-guideline animal study that applied aluminium hydroxide solution (10%) (Lansdown, 1973) daily for five consecutive days also contributes to the weight of evidence for a lack of irritative or corrosive effects according to Regulation (EC) No. 1272/2008.

 

A study investigated dermal irritation effects of aluminium oxide in New Zealand White albino rabbits equivalent to OECD 404 is available (Degussa, 1979a). 0.5 g of the test substance was placed on the intact or abraded skin of the rabbits under a surgical patch measuring 2.5 Χ 2.5 cm. Six rabbits had intact skin and six rabbits abraded skin. The exposure continued for 24 hours (a 4 hour exposure is recommended by OECD 404), and skin lesions were scored immediately after patch removal and 48 hours later (24 and 72 hours after the application of the test material). Two sets of scoring criteria were used: Draize (1944) - 24 hours after the material application and CIVO - 72 hours after the application. 

Slight erythema was observed on the intact skin of 2 animals (one 24 hours after the substance application and the other 72 hours after application). No signs of skin irritation were observed on the abraded skin at any time. The overall primary irritation score from the study (0.2) would not lead to classification.

 

Another study conducted for Degussa corporation investigated dermal irritation effects of aluminium oxide in New ZealandWhite albino rabbits (Degussa, 1979b). 0.5 g of the test substance was placed on the intact or abraded skin of the rabbits under a surgical patch measuring 2.5Χ2.5 cm.Six rabbits had intact skin and six rabbits had abraded skin. The exposure continued for 24 hours (4 hour exposure is recommended by OECD 404), and skin lesions were scored immediately after patch removal and 48 later (24 and 72 hours after the application of the test material). Two sets of scoring criteria were used: Draize (1944) - 24 hours after the material application and CIVO - 72 hours after the application.

Slight erythema was observed on the intact skin of 2 animals 24 hours after the substance application. No signs of skin irritation were seen at 72 hours.No signs of skin irritation were observed on the abraded skin at any time. The overall primary irritation score from the study (0.3 at 24 hours) would not lead to classification.

 

A study conducted at Hazleton Laboratories Inc. for the Cabot Corporation investigated dermal irritation effects of a high purity fumed alumina produced by the chemical hydrolysis of aluminium chloride in New Zealand White rabbits (Cabot, 1969a). 0.5 g of the substance in 1.0 mL of distilled water was applied to pre-moistened skin on the backs of 6 rabbits under gauze patches. Three of the rabbits had abraded skin and three intact skins. The patches remained place for 24 hours. Lesions were scored at 24 hours and at 72 hours using the scoring criteria of Draize (1959). The report lacks detail on animal husbandry and signs of toxicity. Further details of the test substance characteristics were obtained from the study sponsor. The results showed slight erythema in all three rabbits with abraded skin at 24 hours. The erythema had resolved by 72 hours. No erythema was observed in the animals with intact skin. No animal exhibited edema. The overall primary irritation score from the study (0.25) would not lead to classification.

Aluminium hydroxide (SH-20 Muster) was tested in a primary dermal irritation study in New Zealand White rabbits (Lab Research Ltd., 2009). Parameters monitored during this study included mortality, body weight measurements and clinical observations. The irritancy of the test item was evaluated according to the Draize method OECD No.: 404, 2002).

The test item was administered as supplied, at a single dose of 0.5 g. Gauze was placed onto the hairless skin of the rabbit, test item was applied to the gauze, additional gauze was placed over the test item and an adhesive clear plastic patch applied. The trunk was wrapped in clear plastic with medical tubing used to hold the patch in place. The untreated skin of each animal served as control.

After 4 hours, the remaining test item was removed with water at body temperature. To assess skin irritation, animals were examined at 1, 24, 48 and 72 hours after the patch removal. Additional general examinations were performed daily. There was no mortality or systemic clinical changes related to Aluminium Hydroxide administration. There was no effect of treatment on body weight. At observation one hour after patch removal, very slight erythema (score 1) was observed in two animals. At 24, 48 and 72 hours after patch removal, there were no observed clinical signs noted on the skin of the treated animals. As no clinical signs were observed up to 72 hours after patch removal, the study was terminated after the 72 hour observation.

The animals’ individual means scores (considering readings at 24, 48 and 72 hours after patch removal) for erythema and oedema were 0.00, 0.00 and 0.00 respectively.

 

Results from Lansdown (1973), a non-guideline study, indicate that repeated exposure (5 daily administrations) of a 10% aluminium hydroxide suspension did not lead to dermal irritation under the experimental conditions. Lansdown (1973) studied the irritation effects and epidermal damage on mammalian skin (mice, rabbits and pigs) from contact exposure to six aluminium salts at concentrations ranging from 2.5% to 25%. Macroscopic (erythema, thickening and scaling), microscopic pathological (stained thin-sections) and histochemical examinations were carried out. Effects were described in relation to pH and the deposition of aluminium in the stratum corneum. Aluminium hydroxide, chloride (anhydrous), sulphate, nitrate, and basic acetate with minimum purity of 97% were applied to 2 cm² areas of shaved skin on the back of mice (TF strain, n=5) and New Zealand white Norfolk rabbits (n=3), and to 4 cm² areas of shaved skin on the back of pigs (large white strain, n=2) for 5 days. Distilled water was used as a negative control. Aluminium hydroxide (pH 7.2) was applied as a 10% suspension in 0.2% Tween-80. The author reported that previous studies had shown that Tween-80 was not an irritant to mouse skin when applied repeatedly at a concentration of 2.5% (Lansdown & Grasso, 1972). 

Positive results were observed for aluminium chloride and aluminium nitrate. Aluminium hydroxide, and the other salts used, did not cause any visual or microscopic irritation effects or lead to inflammatory effects on the skin of mice, rabbits or pigs. No accumulation of aluminium was observed in the epidermis after application of aluminium hydroxide. Irritation effects on application of aluminium chloride (administered at concentrations of 25%, 10%, 5% and 2.5%) were concentration-dependent and related to the amount of metal ion bound to the skin and the resulting denaturation of epidermal keratin. The pathological changes in the skin of mice treated with 25% aluminium chloride include pronounced epidermal hyperkeratosis, acanthosis with marked inter- and intra-cellular oedema and microabscess formation in the epidermis. Positive irritative effects were observed for aluminium chloride and aluminium nitrate, the two solutions that had the lowest pH values, 2.3 and 2.4, respectively. Results from solutions of hydrochloric acid and Universal buffer showed that the low pH was not the cause of irritative effects. The low pH may however have led to increased deposition of aluminium in the epidermal keratin. The histochemical results suggest that aluminium may cause denaturation of epidermal keratin. For local effects, the possible toxicity of the counter-ions, chloride and nitrate, also require consideration. The study contributes to the weight of evidence for a dermal irritative potential for aluminium if deposited in the keratin. Aluminium hydroxide, due to its insolubility, did not lead to irritative effects.

 

 

Additional information:

 

Verbeken et al.(2011) discussed the results of the evaluation of the potential migration of Al and other metals (arsenic (As), cadmium (Cd), chromium (Cr), lead (Pb)) from food-grade Al foil used for human skin allograft cryo preservation at the Queen Astrid Military Hospital, Belgium. The hospital skin bank has employed food-grade Al foil in preservation of donor skin beginning in 1924 and since then it has been used in treatment of burns and ulcers. The non-toxic properties reported by Johns (1949) and Hambury (1957) and the absence of sensitivity reactions in humans (Hambury, 1957) are among the advantages of the Al foil dressings described. Poole et al. (1979) found no significant increase in serum or plasma Al levels in patients in whom sterilized food-grade Al foil was used as a temporary wound dressing. Those data indicate low transcutaneous Al bioavailability through burned, damaged or otherwise injured skin. It should be noted here that, at present, these publications are not available but have been requested through Interlibrary loan, University of Ottawa.  

Measurements of Al in the pooled cryo preservation medium of seven donor skin samples that had been stored for 10 years detected 1.4 mg Al/L using inductively coupled plasma atomic emission spectrometry (ICP-AES).The method detection limit was 100 µg Al/L. Aluminium, arsenic and lead were not detected in 10 donor skin samples using graphite furnace atomic absorption spectrometry (GFAAS), whereas Cd was detected in 4/10 skin samples (0.001 to 0.045 mg/L) and total Cr was detected in 8/10 skin samples (0.0016 to 0.0242 mg/L). It should be noted that Cr was also detected in the analytical blank at 0.0042 mg/L. Retrospective analyses revealed no adverse reactions (e.g., irritation, hypersensitive reactions or other clinical signs of intoxication) among graft recipients that could be related to the possible presence of Al or other metals in the grafts. Histological analysis revealed no differences between the cryo preserved donor skin samples and fresh skin following blind comparisons of the structural integrity of fresh and preserved skin conducted by an experienced dermato-pathologist. The parameters included evaluation of pigmentation, presence and integrity of hair follicles and their associated muscles, sweat and sebaceous glands and integrity of the dermal-epidermal junction. The presence of apoptotic and/or necrotic cells, sentinels of local tissue stress and signs of inflammation, were also included. It should be noted that this evaluation was conducted on cryo preserved skin (30% (v/v) glycerol in physiological water) that was stored in vapor phase liquid nitrogen (≤ 135 °C).

Overall, Verbeken et al. (2011) provide indirect evidence based on historical experience that aluminium metal/aluminium oxide (present in Al foil) did not cause adverse reactions (e.g., irritation, hypersensitivity) on injured human skin. A Klimisch Score of 4 (not assignable) was considered appropriate for this study.

Mayeux et al. (2012) inspected deposition patterns of aluminium chloride in the stratum corneum (SC) harvested by cyanoacrylate skin surface strippings (CSSS) following one or seven days application of aqueous 5% AlCl3 on the forearms of volunteers. While the study did not give direct information on local irritation, it did indicate low irritancy from the investigations on the CSSS. The study was performed in accordance with the Declaration of Helsinki. A total of 37 volunteers of both genders (aged 21–59 years) participated in the study (no other details available). The AlCl3solution was applied on the normal skin of the volar aspect of the forearm (no other details were available). After air drying, biometrological measurements were performed at rest and after a moderate 10-min physical exercise on a cycloergometer. The AlCl3-treated skin was observed using two ultraviolet light-emitting cameras to record subtle variations or changes related to AlCl3deposition and /or local effects. After a single application of AlCl3, Al deposits on skin were observed predominantly inside the microrelief lines and at their crossings. After daily applications of AlCl3 for 1 week, Al deposits were evident within the plateaus delimited by the microrelief lines. No information regarding local irritation following single or repeated applications of AlCl3or after physical exercise compared with the rest condition was provided.

 

In addition, the corneoxenometry bioassay to predict local AlCl3 irritation was conducted (Goffin et al., 2000; Pie´rard-Franchimont et al., 2010). Briefly, CSSS were dipped into AlCl3solutions at 5, 20 and 40% for 2 h and these samples were then dried and stained with toluidine blue and basic fuchsin for 3 min. After rinsing, the color of the samples was measured and the staining intensity of the SC was calculated. No significant differences in the median or range of staining intensity were detected at any concentration compared to the concurrent water control. The authors suggested these data were indicative of low irritancy potential for AlCl3 under the conditions of their study. 

Among the limitations of this study are: little information was available on the study participants, test compound (chemical characteristics and purity), no information regarding pH of the administered AlCl3 solutions or the pH of the skin after exposure and the report provided no details on the application technique (e.g. duration of contact, occlusion condition, etc.) A Klimisch Score of 3 (not reliable) has been assigned to this study (mechanism of action study).

 

The Mayeux et al. (2012) results are in accord with results by Flarend et al. (2001) who studied the systemic uptake of Al in humans under a “worst case scenario” with occlusive conditions and possibly irritated skin from an aluminium chlorhydrate-containing antiperspirant using 26Al as a tracer. The study was carried out with two volunteers, one male and one female. The female subject developed local irritation to the adhesive bandages used for occlusion. Based on urine and blood measurements, dermal absorption of aluminium chlorhydrate was low - only 0.01% of the applied Al dose was absorbed. Lansdown (1973) observed local irritation and epidermal damage in mice, rabbits and pigs after 5 days exposure to AlCl3. The irritation seen after repeated topical application of AlCl3 at 2.5, 5, 10 or 25% was concentration-dependent and it was related to the amount of Al ion bound to the skin and resulting denaturation of epidermal keratin. The variations in the results between human and animal studies might be attributed in part to different types of test material, differences between animal and human skin, the concentrations and pH of the test materials and overall designs of these studies.

 

Yanagishita et al. (2011) investigated histological localization of Al after topical AlCl3 treatment for palmar hyperhidrosis. The mechanism of the antiperspirant action of AlCl3 was evaluated in 127 patients with palmar hyperhidrosis (no other details available) who received a topical 20% solution without occlusion daily (once a day) for 1 month. No mention was made whether any of the participants complained of local irritation or other clinical signs following prolonged treatment with AlCl3. Wooley-Lloyd and Valins (2009) (as described in Yanagishita et al., 2011) investigated topical exposure to aluminium chloride hexahydrate in a salicylic acid gel as a novel agent for treatment of hyperhidrosis. These authors indicated that treatment-relevant adverse effects were associated with local irritation with transient itching. However, it should be noted that the action of topical antiperspirants depends primarily on the specific active ingredients (aluminium salts, non-ionic agents and ionic agents) (Quatrale, 1985). The findings reported by Yanagishita et al. (2011) are inadequate to evaluate the irritant potential on skin of the aluminium compounds under review. 

 

Overall, the weight of evidence suggests that aluminium hydroxide is unlikely to lead to irritative effects on acute dermal exposure.

 

Eye irritation:

The negative results from the LAB Research Ltd. Study (2009) on aluminium hydroxide support a lack of irritative properties of aluminium hydroxide on acute eye exposure. This study is a key in the weight of evidence assessment. The negative results of the key study are supported by an animal study conducted according to OECD TG 405 “Acute Eye Irritation/Corrosion” (1989) (Aluminium hydroxide, IUCLID, 2000). The studies showing negative results for skin irritation also contribute to the weight of evidence. Overall, the weight of evidence suggests a lack of chemical irritative properties for aluminium hydroxide dust on acute eye exposure.

 

An acute eye irritation study of the test item aluminium hydroxide was performed in New Zealand White rabbits (LAB Research Ltd. Study; 2009). The irritation effects of the test item were evaluated according to the Draize method (OECD No.: 405, 2002). The test item was placed into the conjunctival sac of the left eye of each animal.The untreated right eye served as control. An amount of the test item was administered as a single dose. The eyes of the test animals were washed out at one hour after the application of the test item. The eyes were examined at 1, 24, 48, 72 hours after the application. Initial Pain Reaction (IPR) (score 1) was observed in two animals, IPR (score 2) in one animal. One hour after the application, conjunctival redness (score 2) was observed in all animals, conjunctival discharge (score 2) in one and conjunctival discharge (score 1) was found in two animals. At 24 hours after treatment: two animals showed slight redness (score 1). At 48 hours after treatment: full recovery was observed. At 72 hours after treatment: there were no clinical signs observed.

 

An eye irritation study of the test item Aluminium oxide (coded AK 43/79) was performed in White albino rabbits (Degussa, 1979). Six animals were used in this experiment. The irritation effects of the test item were evaluated according to the FDA criteria. 100 mg of the test item was administered as a single dose. The test item was placed into the conjunctival sac of the eye. The untreated eye served as control. The eyes of the test animals were not washed after the application of the test item. The eyes were examined 24, 48, 72 hours and 7 days after the application. No examination was conducted 1 hour after the application. Initial Pain Reaction was not reported. At 24 hours after instillation a conjunctival redness (score 1) and chemosis (score 1) was observed in all animals. No cornea or iris lesions in any animal. At 48 hours after instillation, conjunctival redness (score 1) was observed in all animals and chemosis (score 1) in 4 animals. No animals showed signs of cornea or iris lesions. At 72 hours after instillation, conjunctival redness (score 1) was observed in all animals. No animal showed signs of chemosis, cornea or iris lesions. At 7 days after instillation, conjunctival redness (score 1) was observed in one animal, and there were no signs of chemosis, cornea or iris lesions in any animal.

No information was provided on symptoms in the control eye. No information was provided on animal behaviour, clinical signs of toxicity, or body weight changes during the study period. The observed changes of grade 1 were not considered positive according to the FDA standards applied in this study.

 

ALON, a high surface area fumed alumina, was tested for acute eye irritation in 9white rabbits (weights 2.2-2.6 kg) (Cabot, 1969). A single application of 100mg of the powdered substance was applied to the conjunctival sac of the left eye of each animal. In three animals, tap water was used to wash the eye after 2 seconds, in three animals washing occurred after 4 seconds, and in the remaining 3 animals, the test substances was not washed from the eyes. This deviates from OECD TG#405 which recommends washing of a solid substance from the eye if it has not been removed by physiological mechanisms 1 hour after administration. Observations were made at 24 hours, 28 hours, 72 hours, 4 days and 7 days post-application. The untreated eyes of the animals served as controls. The animals’ corneas were also examined using fluorescein stain prior to application and at 7 days to assess corneal damage. Eye irritative effects were scored and graded according to Draize (1959). The only effects reported were at 24 hours post-application: slight erythema (score=1) in all unwashed eyes and two eyes washed after 2 seconds.  The erythema had resolved by the 48 hour observation time. Examination of the cornea using the fluorescein stain produced no evidence of damage. The results from this study are negative and a Klimisch Score of 2 is considered appropriate.

 

An eye irritation study of the test item aluminium oxide was performed in White albino rabbits. Six animals were used in this experiment (Degussa, 1979). The irritation effects of the test item were evaluated according to the FDA criteria. 100 mg of the test item was administered as a single dose into the conjunctival sac of the eye. The untreated eye served as control. The eyes of the test animals were not washed after the application of the test item. The eyes were examined 24, 48, 72 hours and 7 days after the application. No examination was conducted 1 hour after the application. The Initial Pain Reaction was not reported. At 24 hours after instillation a conjunctival redness score 1 was observed in 5 animals, conjunctival redness score 2 in 1 animal, and chemosis (score 1) in 3 animals. No cornea or iris lesions were observed in any animal. At 48 hours after instillation, conjunctival redness (score 1) was observed in all animals and chemosis (score 1) in 2 animals. No animals showed signs of cornea or iris lesions. At 72 hours after instillation,conjunctival redness (score 1) was observed in all animals. No animal showed signs of chemosis, cornea or iris lesions. At 7 days after instillation, conjunctival redness (score 1) was observed in 2 animals; there were no signs of chemosis, cornea or iris lesions in any animal. No information was provided on symptoms in the control eye. No information was provided on animal behaviour, clinical signs of toxicity, or body weight changes during the study period. The changes of observed in this study were not considered positive according to the FDA standards applied.

 

Overall, the weight of evidence suggests a lack of chemical irritative properties for aluminium hydroxide dust on acute eye exposure.

 

Respiratory irritation:

Human Studies

Results from two studies that examined cross-shift lung effects among aluminium reduction workers (Chan-Yeung et al., 1983; Kilburn and Warshaw, 1989) provide insufficient evidence for an acute, irritative, substance-specific effect from inhalation of aluminium oxide particulates in this occupational setting. 

Airborne exposures in the potroom are multiple – several of which may contribute to a pulmonary response. The evidence suggests a role for aluminium fluoride (AlF3), cryolite

(Na4AlF6), or hydrogen fluoride (HF) in the causation of observed lung effects (ATSDR, 2008; Krewski et al., 2007; Sorgdrager et al., 1995; Soyseth and Kongerud, 1992; Kongerud, 1992). Co-exposure to nickel and the extremely high, accidental exposure levels cannot be excluded as contributory to the toxic pneumonia and fibrosis found in a thermal sprayer (20% aluminium and 80% nickel metal content; Schaller et al., 2007). Results from three studies that examined cross-shift lung effects among aluminium-exposed welders (Kilburn et al., 1989; Fishwick et al., 2004; Gube et al., 2009) provide insufficient evidence for an acute, irritative, substance-specific effect from inhalation of aluminium oxide fume.

No studies were located that reported acute lung effects in workers from short-term inhalation exposure to aluminium hydroxide dust. Results from cross-sectional studies among bauxite-exposed workers are inconclusive concerning a respiratory irritative effect associated with the cumulative exposure levels encountered in the workplace (Beach et al., 2001; Fritschi et al. 2001/2003; Townsend et al., 1985, 1988). Threats to the validity of the available studies include possible selection biases due to cross-sectional designs, residual confounding by smoking, possibly irritative co-exposures, and the lack of measurements of the respirable fraction.

 

Animal Studies

Pauluhn (2009a) observed an inflammatory response in BALF cytology and biochemistry that was mild and to some degree reversible in a subacute study in rats exposed by inhalation to agglomerated nano-sized aluminium oxyhydroxide particulates. The inflammatory response after 10 days of exposure was significant at the highest dose of 28 mg/m³ but was not detectable at 0.4 and 3 mg/m³. Lindenschmidt et al. (1990) administered single doses of 10 and 50 mg/kg bw Al2O3 to Fischer 344 rats by intratracheal instillation (ITI). Responses to crystalline silica and TiO2 were also examined and compared with a saline control. At 50 mg/kg bw, both Al2O3 and TiO2 exhibited early changes in BAL biochemistry and cells consistent with a mild inflammatory response. All values returned to baseline by 9 weeks post-treatment. For the 10 mg/kg bw level, values had returned to normal 2 weeks post-treatment. Tornling et al. (1993) compared BAL biochemistry in Sprague-Dawley rats on single intratracheal instillation of primary or secondary alumina. Only the fluoride-containing secondary alumina exhibited a reversible, short-term inflammatory response. Fibronectin was elevated in both the primary and secondary alumina-treated groups at the end of the study suggesting a role of the alumina component in the development oflonger-term effects. White et al. (1987) compared BAL biochemistry, BAL cell counts, and lung tissue biochemistry in male Fischer 344 rats exposed to virginal alumina or potroom dust in a short-term, single ITI dose study. The effects of the alumina were typical of a nuisance dust with no evidence of an acute inflammatory response. 

 

Thomson et al. (1986) conducted a study in male Fischer 344 rats (10-12 weeks old) to investigate and compare the acute inhalation toxicity of aluminium flake and brass flake dusts. Both were irregularly shaped flake dusts coated with < 2% palmitic and stearic acids to facilitate the milling process in manufacture. Two experiments were conducted: one with observations at 24 hours and 14 days post-exposure, the other with additional groups observed at 3 and 6 months post-exposure, in order to examine longer term effects of the acute exposure. The animals were exposed to the dust for 4 hours. During the exposure period, the animals were placed in compartmentalized wire cages without food, water or bedding in temperature - (22 °C ± 2 ºC) and humidity - (30 to 70%) controlled chambers. The test atmospheres were produced using a Metronics Model #3 aerosol generator. Nominal concentrations for the aluminium powder were 10, 50, 100, 200 and 1000 mg/m³. The corresponding concentrations determined gravimetrically were 9.16, 47.3, 111, 206 and 888 mg/m³. The MMAD for the aluminium powder was 1.58µm (geometric mean diameter from microscopic analysis = 2.82 ± 0.26 µm). All animals were examined for toxic signs before and after exposure and daily during the post-exposure period. The animals were weighed at weekly intervals during the experimental and post-exposure periods. Pulmonary function measurements were conducted at 24 hours, 14 days, 3 months and 6 months post-exposure. Bronchopulmonary lavage was conducted and the BALF analysed for total cell counts, differential cell counts, and biochemical parameters (total protein and levels of glucose-6-phosphate dehydrogenase (G-6-PD), lactate dehydrogenase (LDH), and alkaline phosphatase (ALKP)). Blood samples were also collected by cardiac puncture at each timepoint post-exposure for the analysis of copper, zinc, and aluminium.  After blood collection, rats were necropsied and the following examinations performed: total body weight, organ weight (heart, lung, kidneys, gonads), gross and microscopic pathology of nasal air passages, trachea, lungs and hilar lymph nodes. No mortality was observed even at the highest aluminium flake concentration. No toxic signs were observed and there were no changes in measurements of lung function even at the highest dose (1000 mg/m³).  At concentrations greater than 10 mg/m³, an increase in polymorphonuclear neutrophils in the bronchoalveolar lavage was observed at 24 hours, typical of a mild acute inflammatory response. Increases in lactate dehydrogenase, alkaline phosphatase and total protein that persisted to 3 months provide evidence for a chronic irritant response in the presence of insoluble aluminium flakes retained in the lungs. These changes were not observed at the lowest dose level, 10 mg/m³. Multifocal microgranulomas were observed in terminal airways and alveolar septae in the 200 and 1000 mg/m³ dose groups at 14 days, 3 months and 6 months. Black particulate material was observed in the hilar lymph nodes at 14 days and also later timepoints suggesting clearance by alveolar macrophages. The acute inflammatory response to aluminium flakes was less dramatic than those for more soluble brass dust. The brass dust, however, did not exhibit evidence of a chronic irritant response, effects were resolved by 14 days post-exposure with the exception of larger numbers of alveolar macrophages around terminal airways which had resolved by 3 months. Brass particulate matter was not found in the lavage fluid or in histopathological examinations. 

This study provided evidence for a mild, acute inflammatory response in rats on inhalation of stearin-coated aluminium flakes and also for the retention of the insoluble flakes in the lungs resulting in a persistent irritation response at doses greater than 10 mg/m³. Aluminium metal is highly reactive and readily undergoes oxidation to form an inert oxide coat in air. When the aluminium dust or powder comes into contact with air prior to inhalation, exposure does not occur to reactive zero valence aluminium metal but to aluminium oxide. Where a coating such as stearine is present that acts to prevent the oxidation of the metal short-term exposure will be to the aluminium-stearate coating, and not to the aluminium metal. It is technically a challenge to conduct studies to assess the acute exposure to “aluminium metal”. In addition, given the physical hazard associated with fine aluminium powders, to conduct such studies would not be technically feasible.

 

Based on an assessment of the available data, acute exposure to uncoated “aluminium metal” powder by inhalation will be exposure to aluminium oxide. The study by Thomson et al. (1986) suggests that acute exposure to stearin-coated aluminium flakes does not lead to a persistent response at dose levels of 10 mg/m³ (NOAEC). 

Overall, the weight of evidence from human and animal studies does not support a substance-specific acute, respiratory irritative hazard for aluminium dust or powder.

 

 

Summary

Overall, the current evidence for an acute irritative effect on inhalation exposure to aluminium oxide or bauxite from human studies does not support a chemical-specific irritative effect. The evidence from animal studies and in-vitro studies also does not support a chemical-specific irritative effect. Based on the available data, aluminium oxide and aluminium hydroxide dust are low cytotoxicity “nuisance dusts” with mild, respiratory irritant effects on acute exposure.

Justification for classification or non-classification

Acute Skin Irritation

Available data are adequate to conclude that there is no need to recommend Classification and Labelling (2008) requirements for skin irritation from acute exposures to aluminium metal, aluminium oxide and aluminium hydroxide dust and powder.

 

 

Acute Eye Irritation

Available data are adequate to conclude that there is no need to recommend Classification and Labelling (2008) requirements for eye irritation from acute exposures to aluminium oxide and aluminium hydroxide dust or powder.

 

For aluminium metal dust or powder that undergoes immediate oxidation to form the oxide on contact with air, the data are adequate to conclude that there is not need to recommend Classification and Labelling (2008) requirements for eye irritation from acute exposures. 

 

Acute respiratory irritation:

The current evidence for an acute irritative effect on inhalation exposure to aluminium hydroxide does not support a chemical-specific irritative effect.

Overall, according toDSD (67/548/EEC) or CLP (1272/2008/EC) classification criteria for irritation/corrosion, no classification is required.