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Toxicological information

Acute Toxicity: inhalation

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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:
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

Reference
Name:
Unnamed
Type:
Constituent
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 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:
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.