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Description of key information

Repeated dose toxicity, oral route: NOAEL = 1000 mg/kg bw/d of Aluminium chloride basic(OECD 422, Key, rel.2), corresponding to a ca. NOAEL of 1890 mg/kg bw/day for Aluminium chloride hydroxide sulphate at 16.01%

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Study was conducted according to OECD guideline 422 and under GLP conditions.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
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 relevant
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 or test system 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
- Concentration in vehicle: ?
- 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:
actual ingested
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Remarks:
actual ingested
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
actual ingested
Dose / conc.:
3.6 mg/kg bw/day (actual dose received)
Remarks:
actual ingested Aluminium
Dose / conc.:
18 mg/kg bw/day (actual dose received)
Remarks:
actual ingested Aluminium
Dose / conc.:
90 mg/kg bw/day (actual dose received)
Remarks:
actual ingested 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): Not 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 of toxicity noted.
Incidental findings that were noted consisted of salivation and alopecia of various body parts. These findings are commonly noted in rats of this age and strain which are housed and treated under the conditions in this study.
No clinical signs were noted in control males, males at 40 mg/kg bw/day and in both sexes at 200 mg/kg bw/day.
Mortality:
no mortality observed
Description (incidence):
One female sacrificed in extremis due to parturition difficulties on day 22 p.c.
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
Description (incidence and severity):
Not performed
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 higher 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 males at 40 & 200 mg/kg/d
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
All parameters (hearing ability, pupillary reflex, static righting reflex and grip strength) were normal in all animals.
The variation in motor activity did not indicate a relation with treatment
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 spleen in the control F sacrificed in extremis.
Incidental findings were considered changes of no toxicological significance.
No macroscopic abnormalities were noted among M at 200 mg/kg bw/d and F at 1000 mg/kg bw/d
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Mild to moderate subacute inflammation of the glandular mucosa and minimal to moderate superficial easinophilic spheroids in all examined animals of both sexes at 1000 mg/kg bw/d
Histopathological findings: neoplastic:
not examined
Dose descriptor:
NOAEL
Remarks:
Local effects
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Local effects (stomach) at 1000 mg/kg bw/day
Dose descriptor:
NOAEL
Remarks:
Local effects
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
Remarks:
Local effects
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 1000 mg /kg bw/day
Dose descriptor:
LOAEL
Remarks:
Local effects
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
Remarks:
Systemic effects
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
clinical biochemistry
gross pathology
haematology
histopathology: non-neoplastic
Dose descriptor:
NOAEL
Remarks:
systemic effects
Effect level:
90 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
Al 3+
Sex:
male
Basis for effect level:
clinical biochemistry
gross pathology
haematology
histopathology: non-neoplastic
Dose descriptor:
NOAEL
Remarks:
Local and systemic effects
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
NOAEL
Remarks:
Local and systemic effects
Effect level:
90 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
Al 3+
Sex:
female
Basis for effect level:
histopathology: non-neoplastic
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 40, 200 or 1000 mg/kg/d (equivalent to 3.6, 18 and 90 mg/kg bw/d Al3+) 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 for Aluminium chloride basic (equivalent to 90 mg/kg bw/d Al3+). For males the NOAEL for local effects was established to be 200 mg/kg bw/day (equivalent to 18 mg/kg bw/d Al3+) and for systemic toxicity 1000 mg/kg bw/day (equivalent to 90 mg/kg bw/d Al3+).
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 40, 200 or 1000 mg /kg/d (equivalent to 3.6, 18 and 90 mg/kg bw/d Al3+). 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 Al3+) 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 controls.

Mean food consumption of females at 1000 mg/kg bw/day (equivalent to 90 mg/kg bw/d Al3+) 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 Al3+) group.

Minor, but statistically significant higher plateled count was observed in males at a dose of 1000 mg/kg bw (equivalent to 90 mg/kg bw/d Al3+).

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/d (equivalent to 3.6 and 18 mg/kg bw/d Al3+).

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 Al3+), 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 Al3+).

 

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 Al3+).

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 Al3+). 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 conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 890 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
No guideline Study was available on Aluminum chloride hydroxide sulphate. Read- across approach using the key study performed on Aluminum chloride basic and conducted according to OECD guideline 422 in compliance with GLP is considered as adequate to assess the repeated dose toxicity.

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:
Endpoint conclusion
Quality of whole database:
No guideline Study was available on Aluminum chloride hydroxide sulphate. Read- across approach using the key study performed on dialuminium chloride pentahydroxide and conducted according to OECD guideline 403 in compliance with GLP is considered as adequate to assess the repeated dose toxicity.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose 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

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose toxicity, Oral

A key study was identified (Beekhuijzen, 2007). In this combined repeated dose / reproductive screening study (OECD 422), the analogue substance Aluminium chloride basic is administered by oral gavage to male and female Wistar rats at dose levels of 20, 200 or 1000 mg /kg bw/d corresponding to 3.6, 18, 90 mg Al3+/kg bw/day. 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 systemic toxicity was observed up to the highest dose (1000 mg/kg bw/d).

NOAEL(oral, combined, systemic effects) = 1000 mg/kg bw/d (equivalent to 90 mg/kg bw/d Al3+)

Based on the read-across approach, NOAEL(Aluminium chloride hydroxide sulphate 16.01%) = ca. 1890 mg/kg bw/day

Repeated dose toxicity, Dermal

No study was available but no systemic effects were observed in acute dermal toxicity, skin irritation or skin sensitisation studies.

Repeated dose toxicity, Inhalation

No relevant study was available but no systemic effects were observed in acute toxicity by inhalation.

Justification for classification or non-classification

Harmonized classification:

The test material has no harmonized classification according to the Regulation (EC) No 1272/2008.

Self-classification:

Based on the available data, no self-classification is proposed regarding the specific target organ toxicity after oral dose-repeated exposure and after inhalation-repeated dose exposure according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.

There were no data regarding the dermal route.