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Description of key information

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Human studies:

There are currently no adequate human studies available to assess the sensitising potential of aluminium hydroxide on dermal exposure.

Aluminium sensitisation has been observed, although rarely, in studies of children who received subcutaneous and intramuscular injections of aluminium hydroxide as a vaccine adjuvant (Bergfors et al., 2003; Bergfors et al., 2005; Netterlid et al., 2004). A low sensitising potential is supported by the fact that aluminium compounds, especially aluminium hydroxide and aluminium chlorohydrate, have been used for decades in a variety of pharmaceutical and cosmetic products without reports of frequent or strong sensitisation effects.

 

Three new case reports and studies presented at the scientific conferences (available ahead of publication) have reported single cases of sensitization which might be due to Al after exposure to Al-containing deodorants (Garg et al., 2011; Gies et al., 2010 or Watson et al., 2012).

Garg et al. (2011) described in brief the case of a 28-year-old woman who presented at the hospital with eczema in both axillae. The patient complained her condition occurred after the use of deodorants that contained aluminium chlorohydrate. Patch testing was performed to the British Contact Dermatitis Society (BCDS) baseline series (the series includes approximately 30 substances and mixtures which account for around 85% of all contact dermatitis reactions), fragrance series and AlCl3. Allergens were supplied by Trolab®, Reinbeck, Germany and Chemotechnique Diagnostics®, Vellinge, Sweden. The results were scored and evaluated according to the International Contact Dermatitis Research Group (ICDRG) criteria. The patient had the 3+ reaction with 2% AlCl3 (in petrolatum (pet.), but there was no skin reaction after contact with the 8 mm Aluminium Finn Chambers® (Epitest Ltd Oy, Tuusula, Finland). In addition, the patient responded with a 2+ reaction to quaternium-15 (1% in pet.) at day 2 and at day 4 she had a 1+ reaction to benzophenone 4 (10% in pet.), farnesol (2.5% pet.) and citral (1% pet.). After she avoided all Al-containing deodorants, her eczema cleared completely. Limited details provided by the authors regarding the patient’s overall health, dietary habits, possible occupational exposures or other factors precluded rigorous evaluation of the case. It should be noted that together with Al salts these deodorants contained a mixture of other chemicals which might be responsible for or contribute to the patient’s complaints of local irritation and sensitization. In the absence of the positive reaction to the Al in Finn Chambers and the established patch testing for multi-chemical sensitivity, the clinical relevance of the reported Al allergy is unclear. A Reliability Score is 3 (not reliable) for this weight of evidence study.

Watson et al. (2012) carried out a clinical study to evaluate whether the use of Al- based antiperspirants while receiving external beam radiotherapy for stage 0, I, or II breast cancer could exacerbate local irritation to axilla skin. A total of 198 participants were randomized to either the experimental group (antiperspirant) or a control group (standard care-wash only). The skin reactions in both groups were measured weekly and at two weeks after cessation of treatment using the National Cancer Institute Common Toxicity Criteria Adverse Events (version 3) toxicity grading criteria. The skin reaction data were analyzed using the generalized estimating equation. No statistically significant differences were observed in axilla skin reactions between the antiperspirant group and the control group. The authors concluded that using antiperspirant routinely during external beam radiotherapy for Stage 0, I, or II breast cancer had no influence on the intensity of the skin reaction. However, the full report is currently not available for review thereby precluding an assessment of reliability. A Reliability Score is 4 (not assignable) for this weight of evidence study.

 

The available human evidence is limited in amount but supports a low sensitisation potential for aluminium hydroxide.

 

Animal studies:

 

The results on the sensitisation potential of aluminium hydroxide from OECD TG #406 test (LAB Research Ltd, 2010) indicate that aluminium hydroxide is not a strong skin sensitizer. Data presented in IUCLID (Aluminium hydroxide, IUCLID, 2000) provide support for a low sensitising potential. The lack of detail that is available about the study, however, limits its use for hazard identification.Data from a recently conducted guideline-compliant test on the skin irritative properties of aluminium hydroxide (Lab Research, 2009a; Klimisch Score 1) indicate that aluminium hydroxide does not cause irritative effects after a single application to rabbit skin. These results support a low sensitisation potential for this substance. Data published by Lansdown (1973) indicate that repeated dermal application of 10% aluminium hydroxide to three different species of animals using an open epicutaneous method did not cause any skin symptoms which is also suggestive of a low sensitisation potential.Results from animal studies with designs similar to OECD TG #429 and #406 (Basketter et al.,1999; Magnusson and Kligman, 1969) provide evidence that aluminium chloride and/or aluminium chloride hexahydrate have low sensitisation potential after epicutaneous and intradermal administration to laboratory animals. 

Based on the reported test results (OECD TG 406, LAB Research 2010), aluminium hydroxide does not require classification as a skin sensitizer.

 

A study was performed in Guinea pigs (Dunkin Hartley (LAL/HA/BR) using the Magnusson and Kligman method (LAB Research Inc., 2010). The study design was based on OECD TG # 406 (17 July 1992), Commission Regulations (EC) No 440/2008 of 30 May 2008; B.6; and the US EPA OPPTS 870.2600 (EPA 712-C-03-197, March 2003). Methylcellulose (1%), selected based on results from a Preliminary Compatibility Test, was used as the vehicle in this study. Based on the preliminary dose range finding study, 1% (w/v) was used for a first induction stage by intradermal administration. This consisted of three injections to both left and right flanks: an injection with 0.10 mL of Freund's Complete Adjuvant mixed with physiological saline (1:1 v/v); an injection with 0.10 mL of the test item in 1% methylcellulose at the selected concentration; and an injection with 0.10 mL of test item at the appropriate concentration in a 1:1 (v/v) mixture of Freund's Adjuvant and physiological saline. The animals in the control group received three similar injections to each side with the omission of the test item. Again based on the results of a dose range finding study, 100% (w/v) was used for a second induction stage by dermal application. 0.5 mL of the suspension was applied with occlusion for 48 hours. Two weeks after the last induction exposure, two concentrations were used for the occlusive epicutaneous challenge exposure: 0.5 mL of 75% (w/v) suspension was applied to the left flank of the animals and 0.5 mL of 37.5% (w/v) suspension was applied to the right flank. The test item was applied to the flanks of the test and control animals using a 5x5 cm sterile gauze patch saturated with the test item. The patches remained in place, occluded, for 24 hours. After patch removal, residual test item was removed with a swab and observations were made at 24 and 48 hours. No irritation effects (scored according to Draize, 1977) were observed during the dose-range finding study or the induction exposures. In the test group, no positive responses were observed in the treated animal (n=10) with either the 75% (w/v) or 37.5% (w/v) formulations. No positive responses were observed on challenge exposure in the control animals (n = 5). In summary, the Guinea-Pig Maximisation Test was used to determine the skin sensitisation potential of the test item, aluminium hydroxide.Challenge with the test item produced no positive responses in the previously sensitized test animals or in the control animals. The incidence rate was 0% and the net score 0.00. Thus, it was shown that, under the conditions of this test, aluminium hydroxide had no detectable sensitisation potential and does not meet EU criteria for classification for sensitisation.

 

The skin sensitisation potential of two samples aluminium oxide, namely aluminium oxide TBH: AK 43/79 and aluminium oxide TOF: AK 44/79, was assessed in guinea pigs (male albino SPF, 8 animals in each group) using the Landsteiner/Draize method (Degussa, 1979). Both compounds were administered by intra-dermal injections. A 33.3% aqueous suspension was used in both the induction and challenge phases. During the induction phase, the test animals received 10 intra-dermal injections of the test suspension, 3 times per week over a 3 week period. The test suspensions were administered to different shaved spots on the right flank of the animals within an area of 3 x 4 cm. The injected volume was 0.05 mL for the first injection and 1.0 mL for subsequent. The control group received a single injection during this phase. The injection sites were examined 24 hours after the injection and the diameter, colour and thickness of any lesions were used as criteria for the intensity of the reaction. In the induction phase, following 1 to 7 injections of AK 43/79, all animals showed mild reactions. Two animals showed moderate reactions after the 8th injection, an additional 2 animals showed moderate reactions after the 9th injection and all 8 animals showed a moderate reaction after the 10th injection. Data were provided on any skin reactions on the single injection received by the control animals. For AK 44/79, all reactions were mild until after the 6th injection when 5 animals showed a moderate reaction. All animals showed moderate reactions after the 7th to 10th injections. Two weeks after the last injection, guinea pigs from both test groups and the control group received the challenge dose in the amount of 0.05 mL per animal. The reaction sites were examined 24 hours after the injection. After the challenge dose of AK 43/79, all animals exposed during the induction period developed a mild skin reaction. A mild reaction was also found in 7 and a moderate reaction in 1 of the animals in the control group. The challenge dose of AK 44/79 provoked a mild reaction in 6 animals and moderate reaction in 2 animals exposed during the induction period. In the control animals, 7 mild reactions and 1 moderate reaction were observed. No significant differences were observed between the test and control animals with respect to the degree and incidence of erythema and oedema. Under the conditions of this test, aluminium oxide AK 43/79 and aluminium oxide AK 44/79 are not skin sensitizers (Landsteiner/Draize test, guinea pig).

 

Basketter et al. (1999) investigated the allergenic potential of 13 metal salts including aluminium chloride hexahydrate (99% purity) in the Local Lymph Node Assay (LLNA). Groups of 4 CBA/Ca mice (7 to 12 weeks of age) were treated with 25 μL of substance or with an equal volume of the vehicle alone, on the dorsum of both ears. The mice were treated once daily for 3 days. Two days later, the mice were injected with 250 μL of phosphate buffered saline (PBS) with 20 μCi of tritiated thymidine (2 Ci mmol-l). The mice were killed 5 hours later and a single-cell suspension of lymph node cells was prepared by mechanical disaggregation. A substance was considered a skin sensitizer the proliferation in the lymph nodes of treated mice was 3-fold or greater than that in the concurrent vehicle-treated controls. Aluminium chloride hexahydrate administered in petrolatum (vehicle) at test concentrations of 5.0%, 10.0% and 25.0% did not induce a lymph node proliferation response compared to concurrent vehicle-treated controls, and therefore the response was judged as negative. Although this study did not provide sufficient detail in the description of the study and its outcome (Klimisch score 3), the results add to the weight of evidence for a low sensitisation potential of the target substances.

 

Additional information

 

Sun et al. (2011) studied the hyper-susceptibility of guinea pigs in the sensitization assay after intravenous injection of an aluminum hydroxide-containing adjuvant. Forty-two guinea pigs were divided into seven groups (6 animals per group) and sensitized 12 days later with 1.5, 4, 7, 10 or 13 mg/mL Al(OH)3 by i.v. injection. The vehicle control group was injected with an equivalent volume of physiological saline and the positive control group was treated with 1% BSA. Animals were observed for clinical reactions, as well as the time of appearance and resolution of the response. Another 24 guinea pigs were divided into four groups (6 animals per group) and intra-dermally injected with antisera and 48 h later they were given i.v. injections of 1.5 or 4 mg/mL of Al(OH)3, physiological saline and 1% BSA + 1% Evans blue (v/v = 1:1), respectively, for excitation.The sizes of blue spots on inner layers of guinea pig skin were measured 30 min after excitation.The results showed that the i.v. administration of Al(OH)3 at a concentration of less than 4 mg/mL caused no anaphylactic reaction in guinea pigs, while treatment with 7-10 mg/mL caused strong anaphylactic shock and treatment with 13 mg/mL caused extreme reactions. However, in the passive cutaneous anaphylaxis (PCA) test, neither of Al(OH)3 at concentrations of 1.5 or 4 mg/mL caused anaphylaxis. The authors concluded that Al(OH)3at a concentration of less than 4 mg/mL failed to elicit any sign of anaphylactic reactions. The type of test compound used in the study is not clear. Currently, only the abstract is available for review thereby precluding an assessment of reliability. A Reliability Score is 4 (not assignable).

 

Overall, the weight of evidence supports a low sensitisation potential for aluminium hydroxide on dermal exposure.

Migrated from Short description of key information:

On the basis of the  study performed by LAB Research Ltd., OECD TG #406 test, the test substance is not a  a skin sensitizer.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Based on an assessment of the available data, the weight of evidence does not support an important role for alumina in the development of potroom asthma. The weight of evidence supports an irritative effect of the fluoride component of pot emissions (Taiwo et al., 2006; Søyseth et al., 1992, 1994, 1997; Sorgdrager et al., 1998; Kongerud and Samuelsen, 1991). Work-related asthmatic symptoms in potroom workers may result, in part, from non-specific “irritant” and also from “allergic inflammation” reactions (Sariҫ et al., 1986; Mackay et al., 1990; Eklund et al., 1989). The relative contributions of these mechanisms are unclear and individuals with pre-existing bronchial hyper-responsiveness or a history of respiratory allergy may be at increased risk (Barnard et al., 2004; Kongerud and Samuelsen, 1991).

Some studies among aluminium welders have shown decrements in lung function (Fishwick et al., 2004; Abbate et al., 2003; Nielsen et al., 1993) and others have not (Sjogren and Ulfvarson, 1985; Kilburn et al., 1989). Sjogren and Ulfvarson (1985) observed an association between respiratory symptoms and exposures to ozone among welders. The small sample sizes, questionable comparability of referent groups (e.g. Kilburn et al., 1989) and possible (residual) confounding by smoking and irritative co-exposures such as ozone and other fume constituents are limitations of the available studies.

Results from a few case reports, notably Vandenplas et al. (1998) (also Park et al.,1996 and Burge et al., 2000) indicate that respiratory sensitization on exposure to poorly soluble aluminium substances can occur, but results from larger studies (Fritschi et al., 2001; Beach et al., 2001; Taiwo et al., 2006) suggest that it is rare. 

The only animal study identified that employed a guideline assay with results relevant to the respiratory sensitization endpoint and the target substances (the LLNA; Basketter et al., 1999) found that aluminium chloride, a more soluble aluminium substance, did not possess “significant ability to sensitize the skin”. As discussed by ECHA (2008):“In combination with other data it might be possible to conclude in a WoE assessment that chemicals that (at an appropriate test concentration and test conditions, i.e. skin penetration should have occurred) are negative in the LLNA, as well as being considered as not being skin sensitizers, can also be regarded as lacking the potential to cause allergic sensitisation of the respiratory tract.” (ECHA, 2008). The mouse study of Ichinose et al. (2008) supports a weak allergic inflammatory potential for Al2O3. In addition, the guideline compliant study by Lab Research Ltd. (2010) that tested the skin sensitisation potential of Al(OH)3reported negative results, thereby contributing to the weight of evidence supporting a low sensitizing potential for the poorly soluble target substances (See the companion RSI hazard assessment report on skin sensitisation, HAR_skin_sensit_100831_FINAL.doc).

Migrated from Short description of key information:

Based on a weight of evidence argument, aluminium metal does not require classification as a respiratory sensitizer.

Justification for classification or non-classification

The current weight of evidence supports a low respiratory and skin sensitizing potential for the poorly soluble substance aluminium hydroxide.

Therefore, according to DSD (67/548/EEC) or CLP (1272/2008/EC)c lassification criteria for sensitisation, no classification is required.