Aluminium triisopropanolate

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Title:

Production of epidermal damage in mammalian skins by some simple compounds.

Author:

Lansdown ABG

Year:

1973

Bibliographic source:

Br J Dermatol 98: 67-76 1973

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

All animals were treated with 10% aluminium hydroxide in tween 80. Mice and rabbits at a 2 cm2 area, pigs at a 4 cm2 area. 24 hours after application the animals were terminated and skins were examined visually (with a hand lens) for erythema, thickeming and scaling.
For microscopic examination (fluorescence microscopy and ordinary light microscopy), samples of treated skin were fixed in 70% ethanol for at least 18h, embedded in paraffin wax and sectioned at 5-7μm for staining with haematoxylin and eosin. Morin (dye) was used to determine the presence of aluminium (Pearse, 1960); the congo red/thioflavine T technique (Jarrett et al., 1959) was used for epidermal keratins, the DDD technique (Barrnett & Seligman, 1952) for protein-bound sulphydryl groups and Baker’s method (1944) was used for examining epidermal phospholipids.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Aluminium hydroxide

EC Number:

244-492-7

EC Name:

Aluminium hydroxide

Cas Number:

21645-51-2

Molecular formula:

AlH3O3

IUPAC Name:

aluminum trihydroxide

Specific details on test material used for the study:

Purity > 97%

Test animals

Species:

other: rabbit, mouse and pig

Details on test animals or test system and environmental conditions:

mice: 5 female TFI strain from Carworth FatmStock, Raleigh, Essex, UK (8 weeks)
rabbits: 3 New Zealand White from Norfolk Rabbits Ltd., Attleborough, Norfolk UK (6 months)
pigs: 2 large white strain from Benhill, Carlehalton, Surrey UK (6 months)

Test system

Type of coverage:

open

Preparation of test site:

shaved

Vehicle:

other: Tween 80

Amount / concentration applied:

mice and rabbits: 0.5 mL
pigs: 1 mL

Duration of treatment / exposure:

24 h

Observation period:

24 h

Number of animals:

5 mice, 3, rabbits and 2 pigs

Details on study design:

All animals were treated with 10% aluminium hydroxide in tween 80. Mice and rabbits at a 2 cm2 area, pigs at a 4 cm2 area. 24 hours after application the animals were terminated and skins were examined visually (with a hand lens) for erythema, thickeming and scaling.
For microscopic examination (fluorescence microscopy and ordinary light microscopy), samples of treated skin were fixed in 70% ethanol for at least 18h, embedded in paraffin wax and sectioned at 5-7μm for staining with haematoxylin and eosin. Morin (dye) was used to determine the presence of aluminium (Pearse, 1960); the congo red/thioflavine T technique (Jarrett et al., 1959) was used for epidermal keratins, the DDD technique (Barrnett & Seligman, 1952) for protein-bound sulphydryl groups and Baker’s method (1944) was used for examining epidermal phospholipids.

The pH of the test solutions were measured although details of the measurement method were not provided.


Additional informations to the control animals:

A negative control group received applications of distilled water. 
Previous studies were referenced as evidence for the lack of irritative effects of the 0.2% Tween-80 vehicle used for the aluminium hydroxide and the basic aluminium acetate.
A series of “hydrochloric acid” control groups (5 mice per group) received administrations of dilute solutions of hydrochloric acid with pH values of 2.2, 3.0 and 4.0.
 
Another series of control groups (5 mice per group) received administrations of solutions of Universal buffer with pH of 2.5, 3.1, 3.4 or 4.0.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

overall irritation score

Remarks on result:

no indication of irritation

Results 2

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Remarks:

No specific erythema score is reported. An overall irritation score is available.

Results 3

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Remarks:

No specific edema score is reported. An overall irritation score is available.

Irritant / corrosive response data:

Negative for hyperkeratosis, acanthoss. microabsesses and aluminium in keratin inall three species tested
pH of the solution was 7.2

Any other information on results incl. tables

In the same publication other aluminium salts were tested as solutions in water. From these test it was deducted that effects of aluminium were related to the pH of the solution and the interference with keratinocytes (see attachment for a table of the results).

Applicant's summary and conclusion

Interpretation of results:

other: not irritant

Conclusions:

The substance does not show irritating effects to the skin of mice, rabbits and pigs after exposure for 24 hours. This is confirmed by histopathological examination

Executive summary:

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 cm²areas of shaved skin on the back of mice (TF strain, n=5) and New Zealand white Norfolk rabbits (n=3), and to 4 cm²areas of shaved skin on the back of pigs (large white strain, n=2) for 5 days. Distillled 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 did not lead to irritative effects.