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Description of key information

Combined repeated dose with reproduction/developmental toxicity screening test (OECD 422) performed on Aluminium chloride basic didn't show any systemic effects in male and female rats up to the highest dose of 1000 mg/kg bw/d (90 mg Al3+/kg bw/day). Local effects (stomach irritation) were observed in males at 200 mg/kg bw/d (18 mg Al3+/kg bw/d) while no stomach irritation was not observed in females up to the highest dose.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

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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:
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 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 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:
= 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): 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 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
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 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 (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 controls.

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

(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/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 bw/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 bw/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 bw/d,

From two weeks prior to mating to at least 3 days of lactation (females) or 28 days (males) showed 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 bw/d Al3+).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 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. In a read-across approach, 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 of offspring (see Section of toxicity to reproduction).

Repeated dose toxicity: inhalation - systemic effects

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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

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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

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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

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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

ORAL exposure:

Several oral repeated dose toxicity studies in animals were available for aluminium chloride but they have many deficiencies.The information given in the reports is generally very limited, the studies were not in compliance with guidelines and the parameters assessed were limited. Aluminium content of the diet/drinking water was not checked. A comprehensive assessment of mortality, clinical signs, water/food consumption, pathology etc. was not always conducted. Finally, these studies are assigned a reliability rating of 3 and they are consequently disregarded to evaluate specific target organ toxicity upon repeated exposure to aluminium chloride and therefore to aluminium chloride basic in a read-across approach.

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 systemic toxicity was observed up to the highest dose (1000 mg/kg bw/d).

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

However, the NOAEL for systemic toxicity in males and in females are 1000 mg/kg bw/d (equivalent to 90 mg/kg bw/d Al3+) The NOAEL for localtoxicityis 1000 mg/kg bw/d (equivalent to 90 mg/kg bw/d Al3+) and 200 mg/kg bw/d (equivalent to 18 mg Al3+/kg bw/d) in females and males , respectively.

INHALATION exposure:

Several repeated dose toxicity studies in animals exposed to aluminium chlorhydrate by inhalation may be considered in a weight of evidence. The study of Steinhagen (1978), Cavender (1978) and Stone (1979) showed that the lung is the target organ in rats and guinea-pig following inhaled exposure to particles aerosol of Aluminium chlorhydrate at 0.25, 2.5 or 25 mg/m3 for 6 h/day, 5 days/week up to 24 months. This study indicated that after 24 months of exposure of rats and guinea pigs to aluminum chlorhydrate, Aluminium is primarily contained in the lungs with significant accumulation of aluminium in the lungs of both species at all tested concentrations.

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 ACH.

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 included infiltration of inflammatory cells and granuloma formation. Indeed, these include alterations in aerodynamic patterns within the lung, dissolution of particles, bactericidal and phagocytique activitation, and clearance via lymphatics and the mucociliary escalator.

However, it must be noted that the clearance mechanisms differ between man and rat and therefore, it is questionnable if these effects are relevant to human in the absence of other related effects. Hence, a question could be raised if the local effects observed in the lungs were more linked to the physical state of the substance tested in the study (as fine powder) together with the lack of clearance leading to Aluminium accumulation in the lungs rather than specific effects from Aluminium chloride basic.

Finally, it should be noted that Aluminium chloride basic is registered as solution at highest concentration of 40%.Therefore, effects observed following powder inhaled exposure may not be relevant for the registered substance.

DERMAL exposure:

This intrinsic property / toxicity potential can be extrapolated to repeated dermal route administration. Indeed, Aluminium chloride basic is neither irritating to skin nor skin sensitising inducing local effects. In addition, it is assumed that dermal absorption is not higher than oral absorption, i.e. 1% (see section Toxicokinetics). Therefore it can be concluded that conducting any further study would not lead to new information regarding possible systemic effects of this substance.

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 for Aluminium chloride basic

Self classification:

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