Aluminium triisopropanolate

Endpoint summary

Description of key information

Aluminium triisopropylate hydrolyses upon contact with moisture or water immediately to form aluminium hydroxides and 2-propanol. The same effect would be expected upon contact with skin or eyes and thus the irritation/corrosion effects upon skin and eye contact can be assessed by a weight of evidence approach based on results from 2-propanol, aluminium hydroxide and aluminium nitrate

The skin and eye irritation of isopropanol was investigated with the outcome showing no skin irritation (Nixon 1975) and some eye irritation (ECETOC 1998). The harmonised classification of isopropanol includes Category 2 for eye irritation

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:

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:

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

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

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 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1975

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Published study with limited documentation.

Qualifier:

no guideline followed

Principles of method if other than guideline:

This test followed the revised Federal Hazardous Substances Act (FHSA) procedure that had been proposed by the FDA (Edwards, 1972), with a 4-hour rather than 24-hour exposure.

GLP compliance:

no

Species:

rabbit

Strain:

not specified

Details on test animals or test system and environmental conditions:

No details provided.

Type of coverage:

occlusive

Preparation of test site:

other: intact and abraded skin

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

No details provided.

Duration of treatment / exposure:

4 hours

Observation period:

at 4, 24, and 48 hours

Number of animals:

No details provided.

Details on study design:

TEST SITE
- Area of exposure: 2 intact sites and 2 abraded sites per animal
- % coverage: not reported
- Type of wrap if used: patch (unspecified)


REMOVAL OF TEST SUBSTANCE
- Washing (if done): not reported
- Time after start of exposure: not reported


SCORING SYSTEM: see below

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 4, 24, 48 hr

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: no irritation observed

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

other: 4, 24, 48 hr

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: no irritation observed

Irritation parameter:

other: tissue destruction

Basis:

mean

Time point:

other: 4, 24, 48 hr

Score:

0

Max. score:

6

Reversibility:

other: not applicable

Remarks on result:

other: no corrosion observed in any (0) of the 6 sites tested

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.

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.

Interpretation of results:

GHS criteria not met

Conclusions:

isopropanol was found to be non-irritant under the conditions of this test.

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:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Remarks:

A specific cornea opacity score was not reported but 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:

A specific iris score was not reported but 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:

A specific conjunctivae score was not reported but 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:

A specific chemosis score was not reported but 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

Study period:

1998

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study without detailed documentation

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

not specified

Principles of method if other than guideline:

This report is a compilation of eye irritation studies obtained from the literature. Studies were required to have been conducted according/similar to OECD guideline 405 under GLP to be included in this report.

GLP compliance:

yes

Species:

rabbit

Strain:

other: not reported

Vehicle:

unchanged (no vehicle)

Controls:

not required

Duration of treatment / exposure:

single administration

Observation period (in vivo):

10 days

Number of animals or in vitro replicates:

4

Irritation parameter:

other: Modified maximum average score

Basis:

mean

Time point:

other: 1 day

Score:

ca. 30.5

Max. score:

110

Reversibility:

fully reversible

Remarks:

10 days

Irritation parameter:

cornea opacity score

Basis:

animal: 1-4

Time point:

24/48/72 h

Score:

>= 0 - <= 40

Max. score:

80

Reversibility:

fully reversible

Irritation parameter:

iris score

Basis:

animal: 1-4

Time point:

24/48/72 h

Score:

>= 0 - <= 10

Max. score:

10

Reversibility:

fully reversible

Irritation parameter:

conjunctivae score

Basis:

animal: 1-4

Time point:

24/48/72 h

Score:

>= 4 - <= 16

Max. score:

20

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal: 1-4

Time point:

24/48/72 h

Score:

>= 1 - <= 3

Max. score:

4

Reversibility:

fully reversible

Animal	Effect	24 hrs	48 hrs	72 hrs	24-72hr avg	7 days	10 days
1	Cornea	1	1	0	0.67	0	0
	Iris	1	1	1	1.00	0	0
	Redness	3	3	1	2.33	0	0
	Chemosis	2	1	1	1.33	1	0
2	Cornea	1	0	0	0.33	0	0
	Iris	1	0	0	0.33	0	0
	Redness	3	2	1	2.00	1	0
	Chemosis	2	1	1	1.33	0	0
3	Cornea	0	0	0	0.00	0	0
	Iris	0	0	0	0.00	0	0
	Redness	2	2	1	1.67	1	0
	Chemosis	2	1	1	1.33	0	0
4	Cornea	2	2	2	2.00	0	0
	Iris	1	2	2	1.67	0	0
	Redness	3	3	3	3.00	1	0
	Chemosis	2	3	2	2.33	0	0
4-animal averages:   Cornea Iris Redness Chemosis					0.75	not fully reversed	Fully reversible in 10 days

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

Isopropanol was found to be irritating to eyes in this test.

Executive summary:

Under the conditions of this test isopropanol was found to be irritating to eyes, mainly due to formation of chemosis and redness. All effects were fully reversible and thus the substance is considered irritating to eyes Category 2 according to CLP (Regulation EC No 1272/2008).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Aluminium triisopropylate hydrolyses upon contact with moisture or water immediately to form aluminium hydroxides and 2-propanol. The same effect would be expected upon contact with skin or eyes and thus the irritation/corrosion effects upon skin and eye contact can be assessed by a weight of evidence approach based on results from 2-propanol and aluminium hydroxide.

Justification for classification or non-classification

Aluminium triisopropylate hydrolyses upon contact with moisture or water immediately to form aluminium hydroxides and 2-propanol.

Isopropanol and Aluminium 3+ species are considered not irritant to the skin, but isopropanol is an eye irritant. Therefore aluminium tri-isopropanolate needs to be classified as eye irritant according to Regulation EC 1272/2008 (H319).