Registration Dossier

Administrative data

Endpoint:
chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1978-1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: A collection of scientific publications that meet high standards for documentation, however, no guideline was followed and no GLP status is available (pre GLP).

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1978
Reference Type:
publication
Title:
Unnamed
Year:
1979

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Studies were 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.
GLP compliance:
no
Remarks:
pre-GLP

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): Aluminum Chlorhydrate
- Source: Reheis Chem. Co., Berkely Heights, New Jersey.

Test animals

Species:
other: rat (Fisher 344) and guinea pig (Hartley)
Strain:
other: F344 and Hartley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Inc.
- food and water ad libitum except during exposures.

ENVIRONMENTAL CONDITIONS
- Photoperiod: 12 / 12 h dark / 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
- Device: 1.3.m^3 stainless steel and glass chambers
- negative H2O Pressure differential with an airflow of 300 L/min
- Aluminum Chlorhydrate was generated as a dry powder using a Wright dust feed mechanism.
- Temperature in air chamber: 22-27 °C
- Humidity: 67 - 72 %

TEST ATMOSPHERE
- Test item concentrations: 0.25, 2.5, and 25 mg/m3 air
- verification: hourly.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Collection of samples:
Gelman spectrograde fiberglass filters

Analysis:
Perkin-Elmer Model 305 atomic absorption spectrophotometer (AA) equipped with a graphite furnace and by means of a fluoride selective electrode (FSE).

Results ware in the same range comparing both methods. The aluminum was sonicated from the filter with dilute HNO3.

- Particle sizing: was performed performed 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 aluminum.
Duration of treatment / exposure:
up to 24 months
Frequency of treatment:
6 h/d, 5 d/w
Doses / concentrations
Remarks:
Doses / Concentrations:
0.25, 2.5, 25 mg/m3
Basis:
nominal conc.
No. of animals per sex per dose:
10
Control animals:
other: vehicle: clean air

Examinations

Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: 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 collection from the abdominal aorta for serum aluminum determinations.
- At #necropsy, peripheral blood was collected from the tail of a rat or the toe of a guinea pig.
- Hematological determinations: Model ZB Coulter Counter (Coulter Electronics, Hileah, Fla.).
- Parameters: total red cells, total white cells, hematocrit, mean corpuscular volume, total hemoglobin, blood smears 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: Yes
Statistics:
Pairwise treatment vs control comparisons: Mann-Whitney U tests (significance level: 0.05)
Significance of dose response trends: Jonckheere-Terpstra test (Hollander & Wolfe, 1973)

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 per bronchial 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:
LOAEC
Effect level:
2.5 mg/L air (nominal)
Based on:
other: body and organ weights, histopathology lung
Sex:
male/female
Dose descriptor:
NOAEC
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable
Remarks:
no NOAEC identified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Aluminum content of lungs of animals exposed to test item in ppm

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 ± 1.6*

10

58.5 ± 4.2**

9

45.9 ± 5.5

2.5

4

45.8 ± 1.1*

10

82.3 ± 7.1**

13

159.8 ± 34.8**

25

4

198.1 ± 54.2*

10

442.6 ± 20.2**

9

582.9 ± 63.0**

Rats (M/F)

Control

4

10.1 ± 0.4

8

49.8 ± 5.5

18

52.2 ± 9.6

0.25

4

22.3 ± 0.2*

8

85.0 ± 12.5*

15

71.9 ± 9.1

2.5

4

201.2 ± 14.4*

8

600.9 ± 59.5**

14

218.5 ± 38.0**

25

4

442.2 ± 71.0*

8

759.5 ± 43.6**

15

337.5 ± 29.3**

Treatment: rats (21 month), guinea pigs (24 month)

*: p < 0.05 vs control

**: p < 0.01 vs control

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:
Under the conditions of this study, effects were observed at all three dose levels. Therefore, no No Observed (Adverse) Effect could be established. But from the data a Lowest Observed Adverse Effect Concentration (LOAEC) of 0.25 mg/m3 could be established.
Executive summary:

Groups of rats and guinea pigs were exposed, by inhalation, to 0.25, 2.5, and 25 mg/m3 of aluminum chlorhydrate (ACH) for six months to study the effects of a common component of antiperspirants. Similar groups of animals of both species exposed to clean air served as controls. The ACH was generated as a particulate dust using a Wright dust feed mechanism. After six months of exposure, animals were sacrificed. Decreases in body weight were seen in rats exposed to 25 mg/m3 of ACH. Marked increases in lung weights and significant increases in lung to body weight ratios were seen in rats and guinea pigs exposed to 25 mg/m3 of ACH. The lungs of all rats and guinea pigs showed significant dose-related increases in aluminum accumulation when exposed to either 0.25, 2.5, or 25 mg/m3 of ACH. 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.

Under the conditions of this study, effects were observed at all three dose levels. Therefore, no No Observed (Adverse) Effect could be established. But from the data a Lowest Observed Adverse Effect Concentration (LOAEC) of 2.5 mg/m3 could be established.

Reference:

Steinhagen, W. H., F. L. Cavender, und B. Y. Cockrell. „Six Month Inhalation Exposures of Rats and Guinea Pigs to Aluminum Chlorhydrate.“Journal of Environmental Pathology and Toxicology1, Nr. 3 (Februar 1978): 267–77.