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Repeated dose toxicity: other routes

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Administrative data

sub-chronic toxicity: other route
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
No data
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Study was not conducted according to a guideline or under GLP conditions. Alternative route of exposure was used (IP). Methods and results are reported concise, but clear.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Reference Type:
Effects of aluminum sulfate on erythropoiesis in rats.
Farina M, Lara FS, Brandão R, Jacques R and Rocha JBT.
Bibliographic source:
Toxicol Lett. 132(2):131-139.

Materials and methods

Test guideline
no guideline followed
Principles of method if other than guideline:
Rats were administered aluminum sulphate by intraperitoneal injection for 3 months. At the end of the experimental period, enzyme assay, hematological parameters, TBARS reaction, aluminum analysis and protein quantification were studied.
GLP compliance:
Limit test:

Test material

Constituent 1
Reference substance name:
Automatically generated during migration to IUCLID 6, no data available
Automatically generated during migration to IUCLID 6, no data available
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): Aluminum sulfate
- Source: Merck, Darmstadt, Germany.
- Analytical purity: 99.5 %

Test animals

Details on test animals or test system and environmental conditions:
- Age at study initiation: 12 weeks
- Weight at study initiation: 350 g
- Diet: Food, ad libitum
- Water: Deionized water, ad libitum

- Temperature: 22–25 °C

Administration / exposure

Route of administration:
physiological saline
Details on exposure:
Aluminum sulfate was dissolved in physiological saline solution to permit single administrations of volume doses of 1 mL/kg bw.
Analytical verification of doses or concentrations:
Duration of treatment / exposure:
3 months
Frequency of treatment:
Five times a week for 3 months
Doses / concentrations
Doses / Concentrations:
50 µmol/kg bw/day (Aluminum)
No. of animals per sex per dose:
12 males/dose
Control animals:
yes, concurrent vehicle


Observations and examinations performed and frequency:
No data
Sacrifice and pathology:
No data
Other examinations:
At the end of the experimental period (24 h after the last administration) the rats were anesthetized with ether vapor and bled by puncture of the vena cava. Whole blood was collected into tubes containing heparin for hemoglobin and hematocrit determinations. Iron content and TIBC were determined in serum. Aluminum concentrations were analysed in tissues (liver, kidney and brain); δ- ALA-D activity was assayed according to the method of Sassa (1982).
- Determination of hematological parameters: Blood hemoglobin was determined by the cyanmethemoglobin method (Ventura et al., 1967) and hematocrit was determined according to the method (Strumia et al.,1954).
- Thiobarbituric acid reactie substances (TBARS) reaction: Lipid peroxidation products were evaluated as TBARS measured at 532 nm and expressed as malondialdehyde equivalents.
- Aluminum analysis: Al was analyzed by electrothermal atomic absorption spectroscopy (Allen and Yokel, 1992).
- Iron status: Analysis of iron content (serum) was conducted by flame atomic absorption spectroscopy (Arroyo and Diaz-Rubio, 1972). The amount of Fe3+ needed to fully saturate plasma transferrin was determined (Labtest Lab, Brazil).
- Protein quantification: Protein was measured by the method of Bradford (1976) using bovine serum albumin (BSA) as standard.
The results are expressed as mean ± standard deviation. Comparison between groups was carried out by the Student test, with the level of significance set at P≤0.05.

Results and discussion

Results of examinations

Clinical signs:
not specified
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
- Hematological parameters: After treatment (3 months) with i.p. injections of aluminum sulfate, the hemoglobin content of the Al group decreased significantly (32 %, P<0.01) compared with control. In addition, hematocrit was also significantly decreased (24 %, P<0.01) in the Al group.
- δ- ALA-D activity: Al treatment did not change δ- ALA-D activity in liver, kidney or brain of the Al group compared with control.
- Aluminum distribution: Al group showed a significant increase in aluminum concentration in the liver when compared with control. In contrast to the liver, renal and cerebral concentrations of aluminum did not differ between groups.
- Iron status: Serum iron concentration was significantly lower in aluminum-treated rats. However, aluminum treatment did not change TIBC.
- TBARS reaction: The serum TBARS did not vary after the experimental treatment. Furthermore, aluminum exposure did not change TBARS levels in liver, kidney or brain.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 7.5.4/1: Results



Hb (g/L)


δ-ALA-D (nmol porphobilinogen/mg protein per h)

Fe (serum)


Al concentration (µg/g wet weight)

TBARS levels (MDA equivalents)












14.0 ± 2.0

46.7 ± 3.4

6.4 ± 0.6

4.1 ± 0.4

1.7 ± 0.5

276 ± 43

582 ± 57

0.182 ± 0.013

0.230 ± 0.032

0.335 ± 0.020

2.1 ± 1.2

0.81 ± 0.07

0.74 ± 0.06

0.44 ± 0.07

Aluminum sulfate - 50 µmol/kg bw/day (Aluminum)

9.4 ± 2.4*

35.5 ± 7.8*

5.6 ± 0.3

3.9 ± 0.7

1.6 ± 0.3

189 ± 75**

528 ± 33

0.920 ± 0.042*

0.247 ± 0.020

0.365 ± 0.041

1.9 ± 0.6

0.82 ± 0.11

0.69 ± 0.12

0.44 ± 0.08


MDA equivalents: µmol MDA/mg protein for hepatic, renal and cerebral homogenates and µmol MDA/l for serum. Fe concentration and TIBC are expressed as µg/dl.

Results are reported as mean ± S.D. 

*P<0.01 significant compared with control; **P<0.05 significant compared with control.

Applicant's summary and conclusion

Under the test conditions, exposure to aluminum sulfate promotes signs of anemia in rats as a consequence of alterations in iron status.
Executive summary:

In a repeated dose study, groups of Wistar rats (12 males/dose) administered with Aluminum sulfate at the dose of 50 µmol/kg bw/day (Aluminum) in physiological saline by intraperitoneal injection for 3 months. Control group received physiological saline solution (1 mL/kg bw/day). At the end of the experimental period, enzyme assay, hematological parameters, TBARS reaction, aluminum analysis and protein quantification were performed.


The treated (Al) group showed significantly decreased hemoglobin concentration (32 %) and hematocrit (24 %) compared with the control group. Serum iron decreased significantly in the Al group, whereas total iron binding capacity did not change. Treatment did not alter the activity of hepatic, renal or cerebral delta-ALA-D. Biochemical measurements related to 2-thiobarbituric acid-reactive substance (TBARS) levels from serum and hepatic, renal and cerebral homogenates also did not change after treatment. Hepatic concentrations of aluminum were higher in the Al group than in the control group. Renal and cerebral aluminum concentrations did not vary between groups. The results indicate that exposure to aluminum sulfate promotes signs of anemia in rats as a consequence of alterations in iron status.