Registration Dossier

Administrative data

Description of key information

Combined repeated dose / reproductive screening study (OECD 422): study performed on Aluminium chloride basic relevant for Aluminium sulphate in a read-across approach based on Aluminium  (Al3+)  toxicity (K, Reliability 1).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
11 September 2006 - 03 November 2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study was conducted according to OECD guideline 422 and under GLP conditions.
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Principles of method if other than guideline:
Not applicable.
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
- Stability under test conditions: At least 48 hours
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation:
Males: approx. 9 weeks
Females: approx. 11 weeks
- Weight at study initiation: All animals within +/- 20% of the sex mean
- Fasting period before study:
- Housing:
Pre-mating: groups of 5 animals/sex/cage
Mating: 1 male, 1 female
Post-mating: males in groups of 5 animals/sex/cage, females individually
Lactation: offspring together with dam
- Diet (e.g. ad libitum): Ad libitum, pelleted rodent diet
- Water (e.g. ad libitum): Ad libitum, tap-water
- Acclimation period: 4 days prior to start of treatment

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.9-23.4
- Humidity (%): 37-95
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Formulations (w/w) were prepared within 4 hours prior to dosing and were homogenised to a visually acceptable level. Adjustment was made for specific gravity of the test substance. No adjustment was made for specific gravity of the vehicle and formulation.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Water
- Amount of vehicle (if gavage): 5 ml/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Formulated samples were analysed using ICP-MS
Duration of treatment / exposure:
Males: 28 days
Females: 37 to 53 days (because of developmental purpose of study)
Frequency of treatment:
Once daily, 7 days a week
Dose / conc.:
40 mg/kg bw/day (actual dose received)
Remarks:
= 3.6 mg/kg bw/day Aluminium
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Remarks:
= 18 mg/kg bw/day Aluminium
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
= 90 mg/kg bw/day Aluminium
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Based on the results of a dose range finding study (NOTOX project 473524)
- Rationale for animal assignment (if not random): Random
- Section schedule rationale (if not random): No data
Positive control:
Not relevant
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least twice daily
- Cage side observations checked: Mortality/viability

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once daily

BODY WEIGHT: Yes
- Time schedule for examinations: At start, once weekly and at death (females also at: gestation days 0, 4, 7, 11, 17, 20, lactation day 1, 4)

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, weekly
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: No, not recorded, only subjective appraisal

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Immediately prior to scheduled post mortem examination
- Anaesthetic used for blood collection: Yes (Isoflurane)
- Animals fasted: Yes, max. 20 hours overnight
- How many animals: 5 males and 5 females randomly selected from each group
- Parameters checked: see "Any other information on materials and methods incl. tables"

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Immediately prior to scheduled post mortem examination
- Animals fasted: Yes, max. 20 hours overnight
- How many animals: 5 males and 5 females randomly selected from each group
- Parameters checked: see "Any other information on materials and methods incl. tables"

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Males during week 4, females during lactation
- Dose groups that were examined: 5 males and 5 females, randomly selected from all groups
- Battery of functions tested: hearing ability / pupillary reflex / static righting reflex / grip strength / motor activity test
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, of all organs of all animals
HISTOPATHOLOGY: Yes, examination of following organs from 5 animals/sex/group: see "Any other information on materials and methods incl. tables"
Other examinations:
Not relevant
Statistics:
- Variables with normal distribution: Dunnett-test based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex
- The steel-test was applied if the data was not assumed to follow a normal distribution
- The Fisher Exact-test was applied to frequency data

All tests were two-sided and in all cases p<0.05 was accepted as the lowest level of significance.
No statistical analysis performed on histopathology findings.
Test statistics were calculated on the basis of exact values for means and pooled variances.
Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs noted. Functional observation battery: all parameters normal in all animals None related to test substance One female sacrificed in extremis due to parturition difficulties on day 22 p.c. Cause of death could not be established
Mortality:
no mortality observed
Description (incidence):
No clinical signs noted. Functional observation battery: all parameters normal in all animals None related to test substance One female sacrificed in extremis due to parturition difficulties on day 22 p.c. Cause of death could not be established
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Slightly lower mean bw for females at 1000 mg/kg bw/d at day 8 with slight weight loss for three of these females. BW recovered during the following mating and post-coital period. In the other groups no deviations compared to controls
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Mean food consumption of females at 1000 mg/kg bw/d slightly lower than controls. Otherwise no deviations compared to controls
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Minor, but statistically significant lowering of MCHC in M and F of 1000 mg/kg bw/g group Minor but statistically significant higer plateled count in males at 1000 mg/kg bw
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Males at 1000 mg/kg bw/d: statistically significant - lower ALP activity - lower albumin levels - higher Potassium levels - higher inorganic phospate levels no deviations in females or in M?F at 40 & 200 mg/kg/d
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Minor changes in brain weight of females at 1000 mg/kg and kidney weight of females at 200 mg/kg were not considered to be relevant or substance-related.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Red foci on glandular mucosa of the stomach in 5/10 males at 1000 mg/kg/day, with thickening of glandular mucosa or limiting ridge in two of these five. No other relevant abnormalities were seen except coagulum in the caecum and enlargement of liver and s
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Mild to moderate subacute inflammation of the glandualr mucosa and minimal to moderate superficial easinophilic spheroids in alle xamined animals of both sexes at 1000 mg/kg bw/d
Histopathological findings: neoplastic:
not examined
Details on results:
BODY WEIGHT AND WEIGHT GAIN
Slightly lower mean bw for females at 1000 mg/kg bw/d at day 8 with slight weight loss for three of these females. BW recovered during the following mating and post-coital period. In the other groups no deviations compared to controls

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Mean food consumption of females at 1000 mg/kg bw/d slightly lower than controls. Otherwise no deviations compared to controls

HAEMATOLOGY
Minor, but statistically significant lowering of MCHC in M and F of 1000 mg/kg bw/g group
Minor, but statistically significant higher plateled count in males at 1000 mg/kg bw

CLINICAL CHEMISTRY
Males at 1000 mg/kg bw/d: statistically significant
- lower ALP activity
- lower albumin levels
- higher Potassium levels
- higher inorganic phospate levels
no deviations in females or in M/F at 40 & 200 mg/kg/d

GROSS PATHOLOGY
Red foci on glandular mucosa of the stomach in 5/10 males at 1000 mg/kg/day, with thickening of glandular mucosa or limiting ridge in two of these five. No other relevant abnormalities were seen except coagulum in the caecum and enlargement of liver and spleen in the animal sacrificed in extremis.

HISTOPATHOLOGY: NON-NEOPLASTIC
Mild to moderate subacute inflammation of the glandular mucosa and minimal to moderate superficial easinophilic spheroids in alle examined animals of both sexes at 1000 mg/kg bw/day
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: Local effects (stomach) at 1000 mg/kg bw/day
Dose descriptor:
NOAEL
Effect level:
18 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
Al 3+
Sex:
male
Basis for effect level:
other: Local effects (stomach) at 90 mg Al/kg bw/day
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Local effects (stomach) at 90 mg Al/kg bw/day
Dose descriptor:
LOAEL
Effect level:
90 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
Al 3+
Sex:
male
Basis for effect level:
other: Local effects (stomach) at 90 mg Al/kg bw/day
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
Al chloride basic
Sex:
male
Basis for effect level:
other: Systemic effects: haematology, clinical chemistry, gross pathology, histopathology
Dose descriptor:
NOAEL
Effect level:
90 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
Al 3+
Sex:
male
Basis for effect level:
other: Systemic effects: haematology, clinical chemistry, gross pathology, histopathology
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: Local and systemic (HISTOPATHOLOGY EFFECTS at 1000 mg/kg/day)
Dose descriptor:
NOAEL
Effect level:
90 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
Al 3+
Sex:
female
Basis for effect level:
other: Local and systemic (HISTOPATHOLOGY EFFECTS at 90 mg Al/kg/day)
Critical effects observed:
not specified

Not relevant

Conclusions:
In a combined repeated dose / reproductive screening study (OECD 422), administration of Aluminium chloride basic by oral gavage to male and female rats at dose levels of 20, 200 or 1000 mg /kg/d (equivalent to 3.6, 18 and 90 mg/kg bw/d) was studied. No toxic effects were observed in females at any dose. Therefore, the overall NOAEL for female rats was established to be 1000 mg/kg bw/day(equivalent to 90 mg/kg bw/d). For males the NOAEL for local effects was established to be 200 mg/kg bw/day (equivalent to 18 mg/kg bw/d) and for systemic toxicity 1000 mg/kg bw/day aluminium chloride (equivalent to 90 mg/kg bw/d).
Executive summary:

A combined repeated dose / reproductive screening study (OECD 422), studied the administration of Aluminium chloride basic by oral gavage to male and female Wistar rats at dose levels of 20, 200 or 1000 mg /kg/d (equivalent to 3.6, 18 and 90 mg/kg bw/d). 10 animals/sex/group were used. Males were exposed for 28 days, females between 37 -53 days (because of developmental toxicity purpose of study). Detailed clinical signs, body weight, food consumption, water consumption (subjective appraisal), haematology, clinical chemistry, neurobehaviour and gross and histopathology were studied.

Slightly lower mean bodyweight was observed for females at the 1000 mg/kg bw/day (equivalent to 90 mg/kg bw/d)

group at day 8, with slight weight loss for three of these females. Bodyweight recovered during the following mating and post-coital period. In the other groups no deviations were observed as compared to control.

Mean food consumption of females at 1000 mg/kg bw/day (equivalent to 90 mg/kg bw/d)

was slightly lower than controls. Otherwise no deviations were observed as compared to controls.

Minor, but statistically significant lowering of MCHC was observed in males and females of the 1000 mg/kg bw/day (equivalent to 90 mg/kg bw/d)

group. Minor, but statistically significant higher plateled count was observed in males at a dose of 1000 mg/kg bw/d

(equivalent to 90 mg/kg bw/d).

Males at 1000 mg/kg bw/day had statistically significant lower ALP activity, lower albumin levels, higher Potassium levels, higher inorganic phospate levels. No deviations were observed in females or in males and females at a dose of 40 & 200 mg/kg bw/d (equivalent to 3.6 and 18 mg/kg bw/d).

Red foci on glandular mucosa of the stomach were observed in 5 of 10 males at a dose of 1000 mg/kg/day (equivalent to 90 mg/kg bw/d)

, with thickening of glandular mucosa or limiting ridge in two of these five. No other relevant abnormalities were seen.

Mild to moderate subacute inflammation of the glandular mucosa and minimal to moderate superficial easinophilic spheroids was observed in all examined animals of both sexes at 1000 mg/kg bw/day (equivalent to 90 mg/kg/d Al 3 +).

Based on these results, the overall NOAEL for female rats was established to be 1000 mg/kg bw/day

(equivalent to 90 mg/kg/d Al 3 +).

For males the NOAEL for local effects was established to be 200 mg/kg bw/day and for systemic toxicity 1000 mg/kg bw/day (equivalent to 90 mg/kg/d Al 3 +). In a combined repeated dose / reproductive screening study, administration of Aluminium chloride basic by oral gavage to male and female rats at dose levels of 20, 200 or 1000 mg /kg/d,

From two weeks prior to mating to at least 3 days of lactation (females) or 28 days (males) revealed no toxicity in females at any dose.

The NOAEL for local (stomach) toxicity in males is 200 mg/kg bw/d (equivalent to 18 mg Al3+)

The LOAEL for local (stomach) toxicity in males is 1000 mg/kg bw/d (equivalent to 90 mg Al3+)

The NOAEL for systemic toxicity in males is 1000 mg/kg bw/d (equivalent to 90 mg/kg/d Al3+).

The NOAEL for local and systemic toxicity in females is 1000 mg/kg bw/d (equivalent to 90 mg/kg/d Al3+).

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Common precursor(s)/breakdown product(s): Al3+ is the substance of biological interest and that the toxicological effects of Aluminium sulphate can be attributed exclusively to Al3+.

2. SOURCE AND TARGET CHEMICAL(S)
Source substance: Aluminum chloride, basic (CAS 1327-41-9)
Target substance: Aluminium sulphate hydrated (CAS No 17927-65-0)

3. ANALOGUE APPROACH JUSTIFICATION
Based on the similar behaviour regarding toxicokinetics, data from the different soluble Aluminium salts are used in read-across approach to assess the toxicological properties of Aluminium sulphate. Hence, the data from the other soluble Aluminium salts are considered as a starting point in the hazard assessment of Aluminium sulphate taking into account the differences in bioavailability using available toxicokinetic information.

4. DATA MATRIX
See attached justification
Reason / purpose:
read-across source
Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs noted. Functional observation battery: all parameters normal in all animals None related to test substance One female sacrificed in extremis due to parturition difficulties on day 22 p.c. Cause of death could not be established
Mortality:
no mortality observed
Description (incidence):
No clinical signs noted. Functional observation battery: all parameters normal in all animals None related to test substance One female sacrificed in extremis due to parturition difficulties on day 22 p.c. Cause of death could not be established
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Slightly lower mean bw for females at 1000 mg/kg bw/d at day 8 with slight weight loss for three of these females. BW recovered during the following mating and post-coital period. In the other groups no deviations compared to controls
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Mean food consumption of females at 1000 mg/kg bw/d slightly lower than controls. Otherwise no deviations compared to controls
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Minor, but statistically significant lowering of MCHC in M and F of 1000 mg/kg bw/g group Minor but statistically significant higer plateled count in males at 1000 mg/kg bw
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Males at 1000 mg/kg bw/d: statistically significant - lower ALP activity - lower albumin levels - higher Potassium levels - higher inorganic phospate levels no deviations in females or in M?F at 40 & 200 mg/kg/d
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Minor changes in brain weight of females at 1000 mg/kg and kidney weight of females at 200 mg/kg were not considered to be relevant or substance-related.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Red foci on glandular mucosa of the stomach in 5/10 males at 1000 mg/kg/day, with thickening of glandular mucosa or limiting ridge in two of these five. No other relevant abnormalities were seen except coagulum in the caecum and enlargement of liver and s
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Mild to moderate subacute inflammation of the glandualr mucosa and minimal to moderate superficial easinophilic spheroids in alle xamined animals of both sexes at 1000 mg/kg bw/d
Histopathological findings: neoplastic:
not examined
Details on results:
BODY WEIGHT AND WEIGHT GAIN
Slightly lower mean bw for females at 1000 mg/kg bw/d at day 8 with slight weight loss for three of these females. BW recovered during the following mating and post-coital period. In the other groups no deviations compared to controls

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Mean food consumption of females at 1000 mg/kg bw/d slightly lower than controls. Otherwise no deviations compared to controls

HAEMATOLOGY
Minor, but statistically significant lowering of MCHC in M and F of 1000 mg/kg bw/g group
Minor, but statistically significant higher plateled count in males at 1000 mg/kg bw

CLINICAL CHEMISTRY
Males at 1000 mg/kg bw/d: statistically significant
- lower ALP activity
- lower albumin levels
- higher Potassium levels
- higher inorganic phospate levels
no deviations in females or in M/F at 40 & 200 mg/kg/d

GROSS PATHOLOGY
Red foci on glandular mucosa of the stomach in 5/10 males at 1000 mg/kg/day, with thickening of glandular mucosa or limiting ridge in two of these five. No other relevant abnormalities were seen except coagulum in the caecum and enlargement of liver and spleen in the animal sacrificed in extremis.

HISTOPATHOLOGY: NON-NEOPLASTIC
Mild to moderate subacute inflammation of the glandular mucosa and minimal to moderate superficial easinophilic spheroids in alle examined animals of both sexes at 1000 mg/kg bw/day
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: Local effects (stomach) at 1000 mg/kg bw/day
Dose descriptor:
NOAEL
Effect level:
18 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
Al 3+
Sex:
male
Basis for effect level:
other: Local effects (stomach) at 90 mg Al/kg bw/day
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Local effects (stomach) at 90 mg Al/kg bw/day
Dose descriptor:
LOAEL
Effect level:
90 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
Al 3+
Sex:
male
Basis for effect level:
other: Local effects (stomach) at 90 mg Al/kg bw/day
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
Al chloride basic
Sex:
male
Basis for effect level:
other: Systemic effects: haematology, clinical chemistry, gross pathology, histopathology
Dose descriptor:
NOAEL
Effect level:
90 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
Al 3+
Sex:
male
Basis for effect level:
other: Systemic effects: haematology, clinical chemistry, gross pathology, histopathology
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: Local and systemic (HISTOPATHOLOGY EFFECTS at 1000 mg/kg/day)
Dose descriptor:
NOAEL
Effect level:
90 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
Al 3+
Sex:
female
Basis for effect level:
other: Local and systemic (HISTOPATHOLOGY EFFECTS at 90 mg Al/kg/day)
Key result
Dose descriptor:
NOAEL
Remarks:
systemic effects
Effect level:
1 141 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: systemic effects
Remarks on result:
other: the NOAEL for systemic effects Aluminium sulphate was calculated at 1141 mg/kg bw/day using the molecular mass of aluminium sulphate as anhydrous of 342.1 g/mol
Critical effects observed:
not specified

Not relevant

Conclusions:
In a combined repeated dose / reproductive screening study (OECD 422), administration of Aluminium chloride basic by oral gavage to male and female rats at dose levels of 20, 200 or 1000 mg /kg/d (equivalent to 3.6, 18 and 90 mg/kg bw/d) was studied. No toxic effects were observed in females at any dose. Therefore, the overall NOAEL for female rats was established to be 1000 mg/kg bw/day(equivalent to 90 mg/kg bw/d). For males the NOAEL for local effects was established to be 200 mg/kg bw/day (equivalent to 18 mg/kg bw/d) and for systemic toxicity 1000 mg/kg bw/day aluminium chloride (equivalent to 90 mg/kg bw/d).
Based on these results, it is possible to predict the effect following chronic exposure to Aluminium sulphate by reading across from the repeated dose toxicity result on Aluminium Chloride basic. Consequently, the NOAEL for systemic effects Aluminium sulphate was calculated at 1141 mg/kg bw/day using the molecular mass of aluminium sulphate as anhydrous of 342.1 g/mol.
Executive summary:

A combined repeated dose / reproductive screening study (OECD 422), studied the administration of Aluminium chloride basic by oral gavage to male and female Wistar rats at dose levels of 20, 200 or 1000 mg /kg/d (equivalent to 3.6, 18 and 90 mg/kg bw/d). 10 animals/sex/group were used. Males were exposed for 28 days, females between 37 -53 days (because of developmental toxicity purpose of study). Detailed clinical signs, body weight, food consumption, water consumption (subjective appraisal), haematology, clinical chemistry, neurobehaviour and gross and histopathology were studied.

Slightly lower mean bodyweight was observed for females at the 1000 mg/kg bw/day (equivalent to 90 mg/kg bw/d)

group at day 8, with slight weight loss for three of these females. Bodyweight recovered during the following mating and post-coital period. In the other groups no deviations were observed as compared to control.

Mean food consumption of females at 1000 mg/kg bw/day (equivalent to 90 mg/kg bw/d)

was slightly lower than controls. Otherwise no deviations were observed as compared to controls.

Minor, but statistically significant lowering of MCHC was observed in males and females of the 1000 mg/kg bw/day (equivalent to 90 mg/kg bw/d)

group. Minor, but statistically significant higher plateled count was observed in males at a dose of 1000 mg/kg bw/d

(equivalent to 90 mg/kg bw/d).

Males at 1000 mg/kg bw/day had statistically significant lower ALP activity, lower albumin levels, higher Potassium levels, higher inorganic phospate levels. No deviations were observed in females or in males and females at a dose of 40 & 200 mg/kg bw/d (equivalent to 3.6 and 18 mg/kg bw/d).

Red foci on glandular mucosa of the stomach were observed in 5 of 10 males at a dose of 1000 mg/kg/day (equivalent to 90 mg/kg bw/d)

, with thickening of glandular mucosa or limiting ridge in two of these five. No other relevant abnormalities were seen.

Mild to moderate subacute inflammation of the glandular mucosa and minimal to moderate superficial easinophilic spheroids was observed in all examined animals of both sexes at 1000 mg/kg bw/day (equivalent to 90 mg/kg/d Al 3 +).

Based on these results, the overall NOAEL for female rats was established to be 1000 mg/kg bw/day

(equivalent to 90 mg/kg/d Al 3 +).

For males the NOAEL for local effects was established to be 200 mg/kg bw/day and for systemic toxicity 1000 mg/kg bw/day (equivalent to 90 mg/kg/d Al 3 +). In a combined repeated dose / reproductive screening study, administration of Aluminium chloride basic by oral gavage to male and female rats at dose levels of 20, 200 or 1000 mg /kg/d,

From two weeks prior to mating to at least 3 days of lactation (females) or 28 days (males) revealed no toxicity in females at any dose.

The NOAEL for local (stomach) toxicity in males is 200 mg/kg bw/d (equivalent to 18 mg Al3+)

The LOAEL for local (stomach) toxicity in males is 1000 mg/kg bw/d (equivalent to 90 mg Al3+)

The NOAEL for systemic toxicity in males is 1000 mg/kg bw/d (equivalent to 90 mg/kg/d Al3+).

The NOAEL for local and systemic toxicity in females is 1000 mg/kg bw/d (equivalent to 90 mg/kg/d Al3+).

Based on these results, it is possible to predict the effect following chronic exposure to Aluminium sulphate by reading across from the repeated dose toxicity result on Aluminium Chloride basic. Consequently, the NOAEL for systemic effects Aluminium sulphate was calculated at 1141 mg/kg bw/day using the molecular mass of aluminium sulphate as anhydrous of 342.1 g/mol.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 142 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information as a whole meets the tonnage driven data requirement of REACH. Moreover, reliability and consistency are observed across the different studies. The repeated dose toxicity by oral is also covered in the Developmental and One-Year Chronic Neurotoxicity Study of Aluminium Citrate in Rats as the dams are exposed up to 300 mg/kg bw/d of aluminium citrate from day 6 of gestation until weaning (see section of toxicity to reproduction).

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Studies are available with Aluminium sulphate but they focused on specific endpoints which are not considered appropriate to conclude on the overall chronic study of the substance. In addition, there are no reliable studies available on the repeated dose toxicity of aluminium sulphate by the oral, inhalation and dermal route.

In terms of hazard assessment of toxic effects, available data on the repeated dose toxicity of other aluminium soluble salt was taken into account by read-across following a structural analogue approach, since the pathways leading to toxic outcomes are likely to be dominated by the chemistry and biochemistry of the aluminium ion (Al3+) as describedin the toxicokinetic section.

A combined repeated dose / reproductive screening study (OECD 422), studied the administration of Aluminium chloride basic by oral gavage to male and female Wistar rats at dose levels of 20, 200 or 1000 mg /kg bw/dcorresponding to 3.6, 18, 90 mg Al3+/kg bw/day (Beekhuijzen, 2007). Ten animals/sex/group were used. Males were exposed for 28 days, females between 37 -53 days (because of developmental toxicity purpose of study). Detailed clinical signs, body weight, food consumption, water consumption (subjective appraisal), haematology, clinical chemistry, neurobehaviour and gross and histopathology were studied.

From two weeks prior to mating to at least 3 days of lactation (females) or 28 days (males) revealed no toxicity in females at any dose.

While the NOAEL for local (stomach) toxicity in males is 200 mg/kg bw/d (equivalent to 18 mg Al3+), the LOAEL for local (stomach) toxicity in males is 1000 mg/kg bw/d (equivalent to 90 mg Al3+).

However, the NOAEL for systemic toxicity in males and in females are 1000 mg/kg bw/d (equivalent to 90 mg/kg/d Al3+).

The NOAEL for local and systemic toxicity in females is 1000 mg/kg bw/d (equivalent to 90 mg/kg/d Al3+). Based on these results, it is possible to predict the effect following chronic exposure to Aluminium sulphate by reading across from the repeated dose toxicity result on Aluminium Chloride basic. Consequently, the NOAEL for systemic effects Aluminium sulphate was calculated at 1141 mg/kg bw/day using the molecular mass of aluminium sulphate as anhydrous of 342.1 g/mol.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

No guideline Study was available on Aluminum sulphate. Read- across approach using the key study performed on Aluminum chloride and conducted according to OECD guideline 422 in compliance with GLP is considered as adequate to assess the oral repeated dose toxicity of aluminium sulfate  (see §"Toxicokinetics").

Justification for classification or non-classification

Harmonized classification:

No harmonized classification is available for the repeated dose toxicity by oral and dermal route , by inhalation

Self classification:

Based on available data, Aluminium Sulphate is not classified for the chronic toxicity according to the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.