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Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: It was not indicated if the study was conducted according to a guideline while it has been conducted before the GLP came into force. However, the study design is proper and the methods and results are described extensively.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Six month inhalation exposures of rats and guinea pigs to Aluminum chlorhydrate.
Author:
Steinhagen WH, Cavender FL and Cockrell BY.
Year:
1978
Bibliographic source:
J Environ Pathol Toxicol. 1(3):267-277.
Reference Type:
publication
Title:
Chronic toxicity of aluminium chlorohydrate
Author:
Cavender, F.L., Steinhagen, W.H., Cockrell, B.Y.
Year:
1978
Bibliographic source:
Clin.Toxicol. 12, 606
Reference Type:
publication
Title:
Tissue deposition patterns after chronic inhalation exposures of rats and guinea pigs to Aluminum chlorhydrate
Author:
Stone CJ, McLaurin DA, Steinhagen WH, Cavender FL and Haseman JK.
Year:
1979
Bibliographic source:
Toxicol Appl Pharmacol. 49(1):71-76.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Study was conducted to determine the tissue deposition pattern of aluminum in rats and guinea pigs exposed by inhalation to varied concentrations of aluminum chlorhydrate and to evaluate the effects of this exposure on normal body weight gains.
GLP compliance:
no
Remarks:
pre-GLP
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Aluminum chlorhydrate

Test animals

Species:
other: rat and guinea pig
Strain:
other: Fischer 344 (rat) and Hartley (guinea pig)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Inc.
- Animals were allowed free access to food and water except during exposures.

ENVIRONMENTAL CONDITIONS
- Photoperiod: 12 h dark / 12 h light

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
clean air
Remarks on MMAD:
MMAD / GSD: MMAD: 50 % EAD - 3.09, 2.45 and 2.93 µm for concentrations 0.25, 2.5, and 25 mg/m3, respectively
MMAD: 84 % EAD - 10.20, 8.49 and 9.30 µm for concentrations 0.25, 2.5, and 25 mg/m3, respectively
GSD: 3.51, 3.51 and 3.25 for concentrations 0.25, 2.5, and 25 mg/m3, respectively
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Exposures were carried out in 1.3.m^3 stainless steel and glass chambers patterned after Hinners et al., (1968). Each chamber was maintained at 0.5 in. of negative H2O Pressure differential with an airflow of 300 L/min.
- System of generating particulates/aerosols: Aluminum Chlorhydrate was generated as a dry powder using a Wright dust feed mechanism.
- Temperature and humidity in air chamber: 73-81 °F (78 °F) and 47-72 % (62 %)

TEST ATMOSPHERE
- Test item chamber concentrations (0.25, 2.5, and 25 mg/m3) were determined hourly.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were collected on Gelman spectrograde fiberglass filters and analyzed using either a Perkin-Elmer Model 305 atomic absorption spectrophotometer (AA) equipped with a graphite furnace or by means of a fluoride selective electrode (FSE). There was no significant difference in the results obtained from these two analytical methods. In both cases, the aluminum was sonicated from the filter with dilute HNO3.
- Particle sizing was accomplished weekly using a Delron DCI-6 cascade impactor with cutoff sizes from 0.5-16 µm. Teflon slides, coated with Dow Anti-foam A to reduce particle bounce upon impaction, were used in place of standard glass slides which contain small amounts of aluminium.
Duration of treatment / exposure:
up to 24 months
Frequency of treatment:
6 h/day, 5 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
0.25 mg/m³ air (nominal)
Dose / conc.:
2.5 mg/m³ air (nominal)
Dose / conc.:
25 mg/m³ air (nominal)
No. of animals per sex per dose:
10
Control animals:
other: clean air
Positive control:
None

Examinations

Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were taken weekly for the first 8 weeks of exposure and biweekly thereafter. A final body weight was recorded for each animal at necropsy.

FOOD AND WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Blood was collected from the abdominal aorta for serum aluminum determinations. At each necropsy, peripheral blood was collected from the tail of a rat or the toe of a guinea pig for hematological determinations performed on a Model ZB Coulter Counter (Coulter Electronics, Hileah, Fla.).
- Parameters checked: Hematological parameters examined were total red cells, total white cells, hematocrit, mean corpuscular volume, and total hemoglobin. In addition blood smears were prepared and used for white cell differential counts.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:
Aluminum analysis: Blood, heart, lung, liver, kidney, spleen and brain aluminum concentrations were determined by atomic absorption spectrometry.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, ten animals from each sex/species/group were randomly selected and sacrificed after 6 months of exposure; an additional eight animals from each sex/species/group were sacrificed after 12 months of exposure; remaining guinea pigs were sacrificed at 21 months and the rats at 24 months.
ORGAN WEIGHTS: Brain, lung heart, liver, spleen, kidney, and adrenals.
HISTOPATHOLOGY: No
Other examinations:
None
Statistics:
Jonckheere's test (Hollander and Wolfe, 1973) was employed to determine the significance of dose response trends. Pairwise treatment vs control comparisons were made by Mann-Whitney U tests and all differences significant at the 0.05 level were noted.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
- The percentage of animals in each group dying spontaneously or sacrificed because of morbidity during the course of the study averaged 18 % among rats and 14 % among guinea pigs.

BODY WEIGHT AND WEIGHT GAIN
- There was a depression of body weight in both sexes of rats with increasing dose/exposure time to test item. At the high dose, 25 mg/m3, this was statistically significant at 12 and 24 months. The weight loss seen in the final months of the study probably reflects the general morbidity seen in the older animals. Guinea pig weights were not affected.

HAEMATOLOGY
- Hematology parameters were not affected by exposure to test item.

ORGAN WEIGHTS
- Ratios were calculated for the weight of each tissue taken in respect to body weight. The only biologically significant finding was in the lung/body weight ratio where the high dose animals (25 mg/m3) of both species and sexes had increased ratios at all sacrifice periods. This reflects an absolute increase in lung weights in these animals as well as a depression in body weight in the rat. For other organs, the number of statistically significant effects was sporadic and did not exceed what would be expected by chance alone.

HISTOPATHOLOGY: NON-NEOPLASTIC
- The Al appeared to be primarily contained in the lung. The lungs of all rats and guinea pigs exposed to either 2.5 or 25 mg/m3 of ACH contained exposure-related granulomatous reactions characterized by giant vacuoled macrophages containing basophilic material in association with eosinophilic cellular debris.

OTHER FINDINGS
- Tissue aluminum content analysis revealed no appreciable accumulation of Al in heart, brain, spleen, kidney, liver, or serum in either species at any sacrifice period. Aluminum concentrations were either not detectable or were very low. The major accumulation was in the lungs and appeared as early as 6 months. Table 7.5.2/1 indicates the amount of Al deposition in the lungs of both sexes for the three sacrifice periods. The only other significant Al concentrations were found in the adrenal glands of rats (Table 7.5.2/2) and the peribronchial lymph nodes of medium and high dose guinea pigs (Table 7.5.2/2) In all cases, data for males and females were pooled since there was no statistically significant difference seen in Al deposition between sexes.

Effect levels

open allclose all
Dose descriptor:
NOAEC
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable
Remarks:
no NOAEC identified
Dose descriptor:
LOAEC
Effect level:
ca. 0.25 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Significant accumulation of aluminium in the lungs of rats and guinea pigs

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 7.5.2/1: Aluminum content of lungs of animals exposed to test itema

Species (sex)

Treatment (mg/m3)

Sacrifice (months)

6

12

21-24 b

N

Mean ± SE

N

Mean ± SE

N

Mean ± SE

Guinea pigs (M/F)

Control

4

1.7 ± 1.0

10

0.0 ± 0.0

13

32.3 ± 7.9

0.25

4

23.5 ± 1.6c

10

58.5 ± 4.2d

9

45.9 ± 5.5

2.5

4

45.8 ± 1.1c

10

82.3 ± 7.1d

13

159.8 ± 34.8d

25

4

198.1 ± 54.2c

10

442.6 ± 20.2d

9

582.9 ± 63.0d

Rats (M/F)

Control

4

10.1 ± 0.4

8

49.8 ± 5.5

18

52.2 ± 9.6

0.25

4

22.3 ± 0.2c

8

85.0 ± 12.5c

15

71.9 ± 9.1

2.5

4

201.2 ± 14.4c

8

600.9 ± 59.5d

14

218.5 ± 38.0d

25

4

442.2 ± 71.0c

8

759.5 ± 43.6d

15

337.5 ± 29.3d

 

a All data given as parts per million of Al.

b 21 months for guinea pigs; 24 months for rats.

c p< 0.05 vs control

d p <0.01 vs control

Table 7.5.2/2: Aluminum content of adrenal glands and peribronchial lymph nodes of animals exposed to test item

Species (sex)

Treatment (mg/m3)

Sacrifice (months)

Adrenal glands

Peribronchial lymph nodes

N

Mean ± SE (ppm Al)

N

Mean ± SE (ppm Al)

Guinea pigs (M/F)

Control

21

8

16.1 ± 2.5

8

3.0 ± 0.5

0.25

4

16.1 ± 3.5

4

8.1 ± 3.7

2.5

8

20.9 ± 3.8

8

12.0 ± 4.2b

25

5

25.9 ± 5.0

5

99.0 ± 9.9a

Rats (M/F)

Control

24

6

15.3 ± 2.4

6

7.6 ± 1.9

0.25

5

23.0 ± 6.0

6

15.6 ± 4.7

2.5

6

63.4 ± 11.9a

6

12.3 ± 2.1

25

9

61.4 ± 14.7a

9

18.9 ± 5.4

 

a p< 0.01 vs control

b p <0.05 vs control

Applicant's summary and conclusion

Conclusions:
This study revealed that after 24 months of exposure of rats and guinea pigs to aluminum chlorhydrate, Aluminium is primarily contained in the lungs. The lungs of all rats and guinea pigs exposed to either 2.5 or 25 mg/m3 of ACH contained exposure-related granulomatous reactions characterized by giant vacuoled macrophages containing basophilic material in association with eosinophilic cellular debris.
No NOAEC was observed as exposure by inhalation to 0.25, 2.5, or 25 mg/m3.
LOAEC was determined at 0.25 mg/m3 based on significant accumulation of Al3+ in the lung.
Executive summary:

In a repeated dose study, groups of rats and guinea pigs were exposed to 0.25, 2.5 or 25 mg/m3 aluminum chlorhydrate (ACH) as particles aerosol by inhalation for 6 h/day, 5 days/week up to 24 months. Similar groups of animals of both species exposed to clean air served as controls. The tissue deposition pattern of aluminum was determined as well as the effect of ACH on body weight gain and organ/body weight ratios.

Decreases in body weight were seen in rats exposed to 2.5 and 25 mg/m3 ACH, this was statistically significant at 12 and 24 months. Guinea pig weights were unaffected.

Increases in lung to body weight ratios were seen in both species. The Aluminium appeared to be primarily contained in the lungs and appeared as early as 6 months. Tissue aluminium content analysis revealed no appreciable accumulation of Aluminium in heart, brain, spleen, kidney, liver or serum in either species at any sacrifice period. Aluminium concentrations were either not detectable or were very low. ACH results in a significant accumulation of aluminium in the lungs of rats and guinea pigs at all tested concentrations.

The only other organs with significant concentration of Al were the peribronchial lymph nodes in the high dose guinea pigs and in the adrenal glands of the medium- and high-dose rats. The authors reported that the Aluminium concentration in adrenals remained unclear.

The only biologically significant finding was in the lung/bw ratio where the high dose animals (25 mg/m3 ACH) of both species and sexes had increased ratios at all sacrifice periods. This reflects an absolute increase in lung weights in these animals as well as a depression in bw in the rat.

The lungs of all rats and guinea pigs exposed to either 2.5 or 25 mg/m3 of ACH contained exposure-related granulomatous reactions characterized by giant vacuoled macrophages containing basophilic material in association with eosinophilic cellular debris.

No NOAEC was observed as exposure by inhalation to 0.25, 2.5, or 25 mg/m3.

LOAEC was determined at 0.25 mg/m3 based on significant accumulation of Al3+ in the lung.

The authors considered that alveolar clearance of inhaled particles results from several pulmonary defense mecanisms. These include alterations in aerodynamic patterns within the lung, dissolution of particles, bactericidal and phagocytique activitation, and clearance via lymphatics and the mucociliary escalator. The results from this study indicate that in rats and guinea pigs, inhaled ACH is primarily contained in the respiratory tract.