Aluminium tributanolate

Endpoint summary

Description of key information

Upon contact with water or moisture (e.g. within mucous membranes) aluminium tributanolate hydrolyses immediately to butan-1ol and aluminium 3+ cations (as hydroxide and oxyhydroxide). Hence, toxicity is determined by the toxicity of these two species.

The skin and eye irritation of butan-1-ol was investigated in an interlaboratory study in 22 different laboratories (Weil 1971). The average outcomes were that butan-1 -ol is not irritating to the skin, but a severe eye irritant. In a test according to OECD 405, irritant effects of butan-1-ol on opacity, iris and conjunctivae appeared to be reversible within 21 days in 4 rabbits tested. Therefore the substance is considered irritating to the eye (ECETOC 1998).

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 in mice, rabbits and pigs. Macroscopic (erythema, thickening and scaling), microscopic pathological (stained thin-sections) and histochemical examinations were carried out. No accumulation of aluminium was observed in the epidermis after application of aluminium hydroxide.

Application of 0.5 mg Aluminium nitrate to the rabbit skin during 24 hours under occlusion showed some slight irritation, not sufficient for classification as irritant (Guillot 1982). Aluminium nitrate was, however shown to be a severe eye irritant in rabbits (Guillot 1982).

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

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:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

under occlusion

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Rouché SA, Couhé, France
- Weight at study initiation: 2.5 kg
- Housing: no data
- Diet/ water: no data

ENVIRONMENTAL CONDITIONS: no data

Type of coverage:

occlusive

Preparation of test site:

clipped

Vehicle:

not specified

Amount / concentration applied:

0.5 g

Duration of treatment / exposure:

4 hour (test includes a protocol with 24 hour exposure, but this is not taken into consideration)

Observation period:

upto 14 days (on day 1, 2, 3, 4, 7 and 14)

Number of animals:

6 males/treatment

Details on study design:

TEST SITE
- Area of exposure: 4-6 cm2 (gauge pad moistened with water was applied to the test site)
- Type of wrap if used: occlusive

REMOVAL OF TEST SUBSTANCE
- Washing (if done): none

OBSERVATION TIME POINTS
(indicate if minutes, hours or days) : after 1, 24, 48 and 72 hours and on day 7 and 14

SCORING SYSTEM:
- Method of calculation: PCI (not further specified)
- Protocols were based on OECD, AFNOR and Cosmetic regulations, which all have slightly different scoring systems

Irritation parameter:

overall irritation score

Basis:

mean

Remarks on result:

no indication of irritation

Remarks:

based on OECD and AFNOR protocols

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Remarks:

Irritation is assessed an primary cutaneous irritation index.

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Remarks:

Irritation is assessed in form of a overall irritation score.

Irritant / corrosive response data:

The PCI was 0.36 and 0.35 for AFNOR and OECD protocols. No details provided.
For the cosmetic protocol with an exposure time of 24 hours under occlusion the substance was found slightly irritating (PCI 0.54)

Interpretation of results:

GHS criteria not met

Conclusions:

The substance is not irritating to the skin

Reference 2

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

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

Specific details on test material used for the study:

Purity > 97%

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)

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.

Irritation parameter:

overall irritation score

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Remarks:

Irritation is assessed in form of a overall irritation score.

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Remarks:

Irritation is assessed in form of a overall irritation score.

Irritant / corrosive response data:

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

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).

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.

Reference 3

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:

test procedure in accordance with national standard methods with acceptable restrictions

Remarks:

method based on US-EPA requirements

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPP 81-5 (Acute Dermal Irritation)

Principles of method if other than guideline:

8 animals were tested each receiving 4 test substances, no test on abraded skin was included

GLP compliance:

no

Species:

rabbit

Strain:

not specified

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Amount / concentration applied:

0.5 mL

Duration of treatment / exposure:

24 hours

Observation period:

evaluated one hour after removal of the dressing and 48 hours thereafter (24 and 72 h)

Number of animals:

8 males (> 2.0 kg)

Details on study design:

TEST SITE
- Area of exposure: 1 x 1 inch
- Type of wrap if used: gauze patch held in place with elastic tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): none

OBSERVATION TIME POINTS
(indicate if minutes, hours or days); 24 and 72 hours

SCORING SYSTEM:
- Method of calculation: Draize (calculation of PSI by dividing sum of scores by 8)

Irritation parameter:

other: PSI

Basis:

other: mean of 22 laboratories

Time point:

other: 24 and 72 h

Score:

>= 0.2 - <= 6.9

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Remarks:

Erythema, Edema and Necrosis are covered using a primary irritation score. No of samples with necrosis are given in the publication.

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Remarks:

Erythema, Edema and Necrosis are covered using a primary irritation score. No of samples with necrosis are given in the publication.

Irritant / corrosive response data:

The conclusion in 3 labs would be severe irritant in 6 labs moderate irritant and in 7 labs mild irritant. No data on other laboratory results

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

Based on the overall evaluation of the results in 22 laboratories the substance needs to be considered as irritating to the skin

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Rouché SA, Couhé, France
- Weight at study initiation: 2.5 kg
- Housing: no data
- Diet/ water: no data

ENVIRONMENTAL CONDITIONS: no data

Vehicle:

unchanged (no vehicle)

Amount / concentration applied:

100 mg

Observation period (in vivo):

at 1, 24, 48, 72, 96 h and 7 days after instillation

Number of animals or in vitro replicates:

6 males

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): additional test with washing after 4 and 30 seconds

SCORING SYSTEM: occular irritation index (Kay & Calandra)

TOOL USED TO ASSESS SCORE: no data

Irritation parameter:

overall irritation score

Basis:

mean

Score:

>= 58.7 - <= 60.5

Remarks on result:

positive indication of irritation

Remarks:

extreme irritant

Irritation parameter:

overall irritation score

Basis:

mean

Score:

16.8

Remarks on result:

positive indication of irritation

Remarks:

severely irritant (rinse after 30 sec)

Irritation parameter:

overall irritation score

Basis:

mean

Score:

1.8

Remarks on result:

positive indication of irritation

Remarks:

irritatnt (rinse after 4 sec)

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Remarks:

Irritation is assessed in form of an overall irritation score.

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Remarks:

Irritation is assessed in form of an overall irritation score.

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Remarks:

Irritation is assessed in form of an overall irritation score.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Remarks:

Irritation is assessed in form of an overall irritation score.

Irritant / corrosive response data:

The pH of a saturated solution of the substance was 0.8

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

The substance is a severe eye irritant

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Remarks:

method based on US-EPA

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPP 81-4 (Acute Eye Irritation)

GLP compliance:

no

Species:

rabbit

Strain:

not specified

Vehicle:

unchanged (no vehicle)

Amount / concentration applied:

0.1 mL

Duration of treatment / exposure:

NA

Observation period (in vivo):

after 1 hour, 24, 72 hours and after 7 days

Number of animals or in vitro replicates:

6 males (> 2.0 kg)

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): none

SCORING SYSTEM: Draize

TOOL USED TO ASSESS SCORE: fluorescein staining at 24 and 72 hours and after 7 days

Irritation parameter:

overall irritation score

Basis:

other: mean of 22 laboratories

Time point:

other: 24 h, 72 h and 7 days

Score:

>= 0.2 - <= 7.3

Max. score:

11.2

Remarks on result:

positive indication of irritation

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Remarks:

Cornea Opacity Score, Iritis Score and Conjunctivitis Score are covered using an overall irritation score.

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Remarks:

Cornea Opacity Score, Iritis Score and Conjunctivitis Score are covered using an overall irritation score.

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Remarks:

Cornea Opacity Score, Iritis Score and Conjunctivitis Score are covered using an overall irritation score.

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Remarks:

Cornea Opacity Score, Iritis Score and Conjunctivitis Score are covered using an overall irritation score.

Irritant / corrosive response data:

Mean irritation score after 24 h: 30.2
Mean irritation score after 72 h: 19.0
Mean irritation score after 7 days: 1.5

The substance was concluded an eye irritant in 20 tests and non-irritant in 2 labs (2 questionable)

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

Based on the overall mean, it can be concluded that the substance can cause severe eye damage

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

It cannot be excluded that the results for the irritant properties as derived from the studies on aluminium nitrate are not representative for the aluminium species formed due to hydrolysis of aluminium tributanolate. As the studies with the other hydrolysis product butan-1-ol lead to classification as severe eye irritant (H318) and the harmonised classification for butan-1 -ol includes classification as skin irritant (H315), these outcomes can be considered a worst case for the classification of aluminium tributanolate,

Justification for classification or non-classification

Upon contact with water or moisture (e.g. within mucous membranes) aluminium tributanolate hydrolyses immediately to butan-1-ol and aluminium 3+ cations (as hydroxide and oxyhydroxide). Hence, toxicity is determined by the toxicity of these two species.

Butan-1-ol and Aluminium 3+ species are considered not irritant to the skin, but butan-1-ol is a severe eye irritant. Therefore aluminium tributanolate needs to be classified as severe eye irritant according to

Regulation EC 1272/2008 (H318). As butan-1-ol is also classified as H315, this classification will also be applied to aluminium tributanolate in a worst case approach.