Aluminium hydroxide

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1969, otherwise unclear.

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1969

Report date:

1969

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

yes

Remarks:

: only 1 hour exposure

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Al2O3

IUPAC Name:

Al2O3

Details on test material:

Name: ALON (a.k.a Al2O3)Supplier: Cabot CorporationPurity: Not provided in report but sponsor indicated that it was close to 100%.Batch Number: Not reportedStorage: Not reportedLevels of impurities: Not reportedInformation received from the study sponsor:ALON is Alon-C – a “fumed alumina produced by the hydrolysis of aluminium chloride in a flame process.” (Bailey RR, Wightman JP. Interaction of gaseous hydrogen chloride and water with oxide surfaces. J Colloid Interface Sci 1979 70: 112-123. It is predominantly gamma-alumina, fine particle size, and close to 100% purity.

Test animals

Species:

rat

Strain:

other: Charles River

Sex:

male

Details on test animals or test system and environmental conditions:

Details on test animals and environmental conditions:- Source of animals: Not reported- Age: Not reported.- Weights at start of exposure: The mean weight of each experimental group was reported (201g for the negative control group and 203g, 195g, 200g, and 200g for treatment groups ordered with increasing dose). Individual weights were not provided.- Housing and environment: Not reported- Diet and water: Not reported- Acclimation and monitoring animal health: Not reported

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

other: Not relevant.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTIONLimited detail was provided on the production of the test atmosphere. Briefly, the compound was aerosolized and delivered into a 100 litre exposure chamber.The method of allocation to groups was not specified. Particle size MMAD (mass median aerodynamic diameter)/GSD (geometric standard deviation): Not reported.Further detail on particle characteristics (e.g. shape):Predominantly gamma-alumina formed by hydrolysis of aluminium chloride in a flame process. (Bailey RR, Wightman JP. Interaction of gaseous hydrogen chloride and water with oxide surfaces. J Colloid Interface Sci 1979 70: 112-123.)

Analytical verification of test atmosphere concentrations:

yes

Remarks:

Known volumes of chamber atmosphere were drawn across weighed filters, the filters were re-weighed and the air concentration of the test compound was calculated on the basis of the volume and the gravimetric measurement.

Duration of exposure:

1 h

Concentrations:

The concentrations were 0, 5.06, 5.88, 6.28 and 8.22 mg of product per litre of chamber air. The authors state that 8.22 mg/L was the highest concentration obtainable under the experimental conditions.

No. of animals per sex per dose:

10 animals were in each treated group. The control group consisted of 5 animals.

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days- Frequency of observations and weighing: After the one hour exposure period, the animals were removed from the chamber and observed for 14 days. After this time, they were killed and necropsy was performed. Mortality and clinical signs appear to have been monitored daily post-exposure. During the one-hour exposure period, observation appears to have been continuous.- Other examinations performed: Mortality, clinical sign, and gross pathology were examined. The trachea, lungs, liver and kidneys were examined for pathological changes. Body weights were determined at the start and termination of the experiment.

Statistics:

LC50, 95% CI and slope (S) were estimated from the data using the graphical log-probit method of Litchfield and Wilcoxon (1949) ( J Pharmacol Exp Ther 96: 99)

Results and discussion

Preliminary study:

Not relevant.

Effect levels

Sex:

male

Dose descriptor:

LC50

Effect level:

7.6 mg/L air

95% CL:

6.45 - 8.95

Exp. duration:

1 h

Remarks on result:

other: Slope: 1.30

Mortality:

Mortality was observed at the highest three dose levels, reaching 50% in the group exposed to the highest levels (8.22 mg/L). Deaths occurred either during or shortly after exposure.

Clinical signs:

other: The clinical symptoms observed were consistent with respiratory distress. The surviving animals were described as showing only “slight” toxic effects and good recovery by the end of the 14 day observation period.

Body weight:

The authors report only a slight effect on weight gain. The statistical or biological significance of the difference was not mentioned.

Gross pathology:

A greater amount of discolouration was observed on the surface of lungs of treated animals compared with control animals. A “slight” increase in the number of lesions on the lungs of the test animals was also reported – although individual data or further detailed was not provided. Animals that died were found to have a white gel in their trachea and stomachs. Their stomachs were also gas-filled and enlarged. The liver and kidney showed no difference between the treated and control animals on macroscopic examination.

Any other information on results incl. tables

Mortality

Analytical concn.	Air flow (l.min)	Mortality	Time
0	-	0/5	-
5.06	10	0/10	-
5.88	18	1/10	At 45 minutes of exposure
6.28	18	3/10	3 deaths at 35 mins, 50 mins, 60 mins of exposure.
8.22	15	5/10	3 deaths at 10 minutes into the post-exposure period; 2 deaths at 20 minutes after cessation of exposure

 Mortality was observed at the highest three dose levels, reaching 50% in the group exposed to the highest levels (8.22 mg/L). Deaths occurred either during or shortly after exposure. 

Clinical Signs

Analy-tical concn.	Time (min)	During exposure	Time	Post-exposure
0	-	None	-	None
5.06	5	Preening, mastication type movements.	1-2 days	Loss of hair
	7	Partially closed eyes
	8	Inactive and sneezing
	23	Gasping
	26	Piloerection
	35	Brown discharge around nose
	37	Slow and deep respiration
5.88	1	Preening	2 days	Loss of hair
	4	Slow and deep respiration and partially closed eyes
	6	Mastication-like movements
	8	Gasping
	12	Piloerection
	19	Nasal discharge
	45	Death (n=1)
6.28	1	Preening	1 day	Brown crust around nose
	3	Inactive
	4	Rapid and deep respiration
	11	Slow and deep respiration
	13	Brown nasal discharge
	14	Gasping and piloerection
	35	Death (n=1)
	50	Death (n=1)
	60	Death (n=1)
8.22	1	Active preening	8 min	Convulsive-like movement
	3	Sneezing	10 min	Death (n=3)
	5	Partially closed eyes	14 min	Convulsive-like movements
	7	Gasping	20 min	Death (n=2)
	10	Slow and deep respiration	2 days	Loss of hair
	12	Nasal discharge
	19	Piloerection
	28	Edema of face
	33	ataxia

 

The clinical symptoms observed were consistent with respiratory distress. The surviving animals were described as showing only “slight” toxic effects and good recovery by the end of the 14 day observation period.

Body Weight

Analy-tical concn.	Avg. body wt (t=0)	Avg. body wt (t=end)	Change in body wt
0	201	319	118
5.06	203	287	84
5.88	195	299	104
6.28	200	300	100
8.22	200	292	92

 

The authors report only a slight effect on weight gain. The statistical or biological significance of the difference was not mentioned.

Details on Results:

The authors of the study suggest that the deaths were likely due to suffocation from blockage of air passages by gel formed from the test substance in the high humidity of the air passages.

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated informationCriteria used for interpretation of results: EU

Conclusions:

Mortality occurred either during or shortly after exposure and the clinical symptoms observed were consistent with respiratory distress. A slight (otherwise unspecified) effect on weight gain was reported. The surviving animals were described as showing only “slight” toxic effects and good recovery by the end of the 14 day observation period. A greater amount of discolouration was observed on the surface of lungs of treated animals compared with control animals. A “slight” increase in the number of lesions on the lungs of the test animals was also reported – although individual data or further detailed was not provided. The LC50 estimated from this study based on only one hour of exposure was 7.6 mg/L (95% CI: 6.45 – 8.95 mg/L). This study report lacked detail on the descriptions of the test compound (critically on the particle size, and also the shape and purity), the chamber conditions and animal husbandry, and the results from the examination of the gross pathology of the trachea, lungs, kidney and liver.

Executive summary:

The objective of the pre-guideline acute inhalation toxicity study conducted byLaboratories (Cabot, 1969) was “to determine the acute inhalation toxicity and calculate the LC50, the confidence limits and slope function of the test material.”  Malerats (age unspecified) were exposed for one hour to concentrations of 0, 5.06, 5.88, 6.28 and 8.22mg of aluminium oxide (fumed alumina) per litre of air in inhalation chambers. The authors state that 8.22 mg/L was the highest concentration obtainable under the experimental conditions.The mean weight of each experimental group was reported (201g for the negative control and 203g, 195g, 200g and 200g for the treatment groups, ordered with increasing dose). Individual weights were not provided. Limited detail was provided on the production of the test atmosphere. Briefly, the compound was aerosolized and delivered into a 100 litre exposure chamber. The concentrations of test material were analytically verified by drawing known volumes of chamber atmosphere across weighed filters. The filters were then re-weighed and the average concentration of the test compound calculated on the basis of the volume and the gravimetric measurement. After the one hour exposure period, the animals were removed from the chamber and observed for 14 days. After this time, they were killed and necropsy was performed. Mortality and clinical signs appear to have been monitored daily post-exposure. During the one-hour exposure period, observation appears to have been continuous. The trachea, lungs, liver and kidneys were examined for gross pathological changes. Body weights were determined at the start and termination of the experiment. The LC50, 95%CI and slope (S) were estimated from the data using the graphical log-probit method of Litchfield and Wilcoxon (1949) ( J Pharmacol Exp Ther 96: 99). Mortality was observed at the highest three dose levels, reaching 50% in the group exposed to the highest levels (8.22 mg/L). Deaths occurred either during or shortly after exposure.  The clinical symptoms observed were consistent with respiratory distress. The surviving animals were described as showing only “slight” toxic effects and good recovery by the end of the 14 day observation period. The authors report only a slight effect on weight gain. The statistical or biological significance of the difference was not mentioned. A greater amount of discolouration was observed on the surface of lungs of treated animals compared with control animals. A “slight” increase in the number of lesions on the lungs of the test animals was also reported – although individual data or further detailed was not provided. Animals that died were found to have a white gel in their trachea and stomachs. Their stomachs were also gas-filled and enlarged. The liver and kidney showed no difference between the treated and control animals on macroscopic examination. The authors of the study suggest that the deaths were likely due to suffocation from blockage of air passages by gel formed from the test substance in the high humidity of the air passages.  The LC50 estimated from this study based on one hour of exposure was 7.6 mg/L (95% CI: 6.45 – 8.95 mg/L). This study report lacked some detail on the test substance (information obtained from sponsor), the chamber conditions and animal husbandry, and also the results from the examination of the gross pathology of the trachea, lungs, kidney and liver. The duration of exposure was only one hour. The number of animals and the reporting of the results that were included were adequate.