Aluminum magnesium oxide

Endpoint summary

Description of key information

A repeated dose 28-day oral toxicity study in rats performed according to OECD 407 guideline and GLP principles is available, the NOAEL was determined to be 1000 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

03 April, 1995 - 01 May, 1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study has been performed according to OECD and/or EC guidelines and according to GLP principles.

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Version / remarks:

(1981)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Version / remarks:

(1992)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Wistar Crl:(WI)BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga, Sulzfeld, Germany
- Age at study initiation: Approximately 6 weeks
- Weight at study initiation: males: 182 - 209 g; females: 153 - 170 g
- Fasting period before study: Overnight prior to dosing.
- Housing: Group housing of 5 animals per sex per cage in stainless steel suspended cages with wire mesh floors.
- Diet: Free access to standard pelleted laboratory animal diet (from Carfil Quality BVBA, Oud-Turnhout, Belgium)
- Water: Free access to tap-water
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 50
- Air changes (per hr): Approximately 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 03 April, 1995 To: 30 April, 1995

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: Formulations (w/w) were prepared daily immediately prior to dosing. Adjustment was made for specific gravity of vehicle (1.036).

DOSE VOLUME: 5 mL/kg body weight. Actual dose volumes were calculated weekly according to the latest body weight.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of formulations, prepared after completion of the in-life phase, were analysed to check homogeneity (highest and middle concentration) and accuracy of preparations (all concentrations).

Test substance formulations in propylene glycol formed a homogeneous suspension at the concentrations tested. Analysis of the accuracy of dose preparations revealed values within the range of 90% to 106% of nominal. One analysis resulted in 122% when compared to the nominal concentration based on Mg.
However, this sample revealed 95% based on the analysis of Al. Therefore, the results were considered to represent an acceptable level of accuracy for formulations of this type.
The stability of the test substance in the vehicle was not determined.

Duration of treatment / exposure:

28 days

Frequency of treatment:

Once daily, 7 d/w.

Remarks:

Doses / Concentrations:
0, 50, 200 and 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose levels were selected on the basis of a 5-day dose range finding study. No mortality was observed in the 50, 200 and 1000 mg/kg bw. No clinical signs were noted except for 3 animals at the 200 mg/kg bw dose level which showed alopecia and scabs. Based on the results, dose levels for the main study were selected to be 50, 200 and 1000 mg/kg bw.

Positive control:

No.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once daily from day 1 onwards. The time of onset, degree and duration were recorded.

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly and on the day preceding termination, prior to overnight fasting.

FOOD CONSUMPTION
- Weekly

WATER CONSUMPTION
- Subjective appraisal was maintained during the study, but no quantitative investigation introduced as no effect was suspected.

OPHTHALMOSCOPIC EXAMINATION: Yes / No / No data
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes / No / No data
- Time schedule for collection of blood: immediately prior to scheduled post mortem examination, between 7.30 and 9.30 a.m.
- Anaesthetic used for blood collection: Yes (light ether)
- Animals fasted: Yes, overnight
- How many animals: all rats/sex/group
- Parameters checked: According to test guidelines

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: immediately prior to scheduled post mortem examination, between 7.30 and 9.30 a.m.
- Animals fasted: Yes, overnight
- How many animals: all rats/sex/group
- Parameters checked: According to test guidelines

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
NECROPSY:
All animals surv1v1ng to the end of the observation period (day 29) were deeply anaesthetised using ether vapour and subsequently exsanguinated. All animals assigned to the study were necropsied and descriptions of all macroscopic abnormalities recorded.

ORGAN WEIGHTS
The following organ weights (and terminal body weight) were recorded from the surviving animals on the scheduled day of necropsy:
Adrenal glands, Heart, Kidneys, Liver, Spleen and Testes.

HISTOPATHOLOGY: Yes
HISTOTECHNOLOGY
All organ and tissue samples, as defined under Histopathology (following), were processed, embedded and cut at a thickness of 2-4 micrometers and stained with haematoxylin and eosin.

HISTOPATHOLOGY
Slides of adrenals, heart, kidneys, liver, spleen, stomach and testes, collected at the scheduled sacrifice from all animals of the control and the highest dose group, and all gross lesions of all animals were examined by a pathologist.
Based on the treatment related morphologic changes, kidneys were also examined from all rats of the intermediate dose groups.
All abnormalities were described and included in the report.

Statistics:

Univariate one-way analysis of variance was used to assess the significance of intergroup differences.
If the variables could be assumed to follow a normal distribution, the Dunnetttest (many to one t-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 (many-one rank test) was applied when the data could not be assumed to follow a normal distribution.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY
No mortality occurred during the study period .
There were no clinical signs of toxicity or behavioural changes over the 28-day observation period that were considered to be related to treatment.

BODY WEIGHT AND WEIGHT GAIN
Body weights and body weight gain of treated animals remained in the same range as controls over the 4-week study period.

FOOD CONSUMPTION
There were no differences in food consumption before or after allowance for body weight between treated and control animals.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)

HAEMATOLOGY
Haematological parameters of treated rats were considered not to have been affected by treatment.

CLINICAL CHEMISTRY
There were no differences noted between control and treated rats that were considered to be related to treatment with Aluminium-magnesium-carbonate-hydroxide-perchlorate-hydrate.

ORGAN WEIGHTS
Spleen weights and spleen:body weight ratios were increased in males receiving 1000 mg/kg when compared to control weights. The spleen weights of the control animals, however, were considered to be slightly low when compared to values in other 28-day toxicity studies with similar rats (where control group mean spleen weights varied from 0.585 to 0.689 gram). The group mean value of 1000 mg/kg treated males remained within this range of historical data. In addition, there were no findings noted in the spleen microscopically and no corroborative findings were noted in the opposite sex. Therefore, it is unlikely that this change represents a toxic effect of the test substance.
Other organ weights and organ:body weight ratios of treated animals were considered to be similar to those of control animals.

GROSS PATHOLOGY
Macroscopic observations at necropsy did not reveal any alterations that were considered to have arisen as a result of treatment.

HISTOPATHOLOGY: NON-NEOPLASTIC
The kidneys of some male and female rats receiving 200 and 1000 mg/kg/day showed degenerative changes which were characterised by cystic dilated tubules containing proteinaceous casts. Regenerative changes, characterised as basophilic tubules, were seen in the kidneys of almost all male and female animals receiving 200 and 1000 mg/kg/day. The severity of both findings was very slight to slight.
One male receiving 1000 mg/kg/day showed a slight inflammatory change diagnosed as pyelonephritis. This finding was considered not to be a clear sign of toxicity as it can incidentally be noted in untreated rats of this age and strain. The small number of other findings recorded are within the normal range of background alterations.

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects on kidneys were observed in the OECD421 study, up to and including 1000 mg/kg bw/day, the highest dose tested.

Critical effects observed:

not specified

Conclusions:

In a repeated dose 28-day oral toxicity study in rats performed according to OECD 407 guideline and GLP principles, the NOAEL was determined to be 1000 mg/kg bw/day.

Executive summary:

A repeated dose 28-day oral toxicity study in rats was performed with Aluminium-magnesium-carbonate-hydroxide-perchlorate-hydrate according to OECD 407 guideline and GLP principles. Based on the results of a 5-day dose range finding study, dose levels for the main study were selected to be 50, 200 and 1000 mg/kg bw. No mortality occurred during the study period . There were no clinical signs of toxicity or behavioural changes over the 28-day observation period that were considered to be related to treatment. Body weights and body weight gain of treated animals remained in the same range as controls over the 4-week study period.

Spleen weights and spleen:body weight ratios were increased in males receiving 1000 mg/kg when compared to control weights. The spleen weights of the control animals, however, were considered to be slightly low when compared to values in other 28-day toxicity studies with similar rats (where control group mean spleen weights varied from 0.585 to 0.689 gram). The group mean value of 1000 mg/kg treated males remained within this range of historical data. In addition, there were no findings noted in the spleen microscopically and no corroborative findings were noted in the opposite sex. Therefore, it is unlikely that this change represents a toxic effect of the test substance. Other organ weights and organ:body weight ratios of treated animals were considered to be similar to those of control animals.

The kidneys of some male and female rats receiving 200 and 1000 mg/kg/day showed degenerative changes which were characterised by cystic dilated tubules containing proteinaceous casts. Regenerative changes, characterised as basophilic tubules, were seen in the kidneys of almost all male and female animals receiving 200 and 1000 mg/kg/day. The severity of both findings was very slight to slight.

One male receiving 1000 mg/kg/day showed a slight inflammatory change diagnosed as pyelonephritis. This finding was considered not to be a clear sign of toxicity as it can incidentally be noted in untreated rats of this age and strain. The small number of other findings recorded are within the normal range of background alterations.

In a recently performed OECD 421 study in the same rat strain (Wistar), additional parental parameters were included in order to study the reported minimal effects on the kidney observed in the 28-day repeated dose toxicity study. No effects on kidneys were observed in the study, up to and including 1000 mg/kg bw/day, the highest dose tested. Based on the absence of any effects on the kidneys in the same rat strain in the recently performed study, it is concluded that the previously observed minimal effects on the kidneys should not be considered adverse.

Based on the results of the study, the NOAEL was determined to be 1000 mg/kg bw/day.

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read-across information.

Justification for type of information:

See the attached read-across document in section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects on kidneys were observed in the OECD421 study, up to and including 1000 mg/kg bw/day, the highest dose tested.

Critical effects observed:

not specified

Conclusions:

In a repeated dose 28-day oral toxicity study in rats performed with the source substance Aluminium-magnesium-carbonate-hydroxide-perchlorate-hydrate according to OECD 407 guideline and GLP principles, the NOAEL was determined to be 1000 mg/kg bw/day. The result is used for read-across to the substance.

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:

An OECD 407 study is the required study for Annex VIII for the endpoint repeated dose toxicity.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

A repeated dose 28-day oral toxicity study in rats was performed with Aluminium-magnesium-carbonate-hydroxide-perchlorate-hydrate according to OECD 407 guideline and GLP principles. Based on the results of a 5-day dose range finding study, dose levels for the main study were selected to be 50, 200 and 1000 mg/kg bw. No mortality occurred during the study period . There were no clinical signs of toxicity or behavioural changes over the 28-day observation period that were considered to be related to treatment. Body weights and body weight gain of treated animals remained in the same range as controls over the 4-week study period.

Spleen weights and spleen:body weight ratios were increased in males receiving 1000 mg/kg when compared to control weights. The spleen weights of the control animals, however, were considered to be slightly low when compared to values in other 28-day toxicity studies with similar rats (where control group mean spleen weights varied from 0.585 to 0.689 gram). The group mean value of 1000 mg/kg treated males remained within this range of historical data. In addition, there were no findings noted in the spleen microscopically and no corroborative findings were noted in the opposite sex. Therefore, it is unlikely that this change represents a toxic effect of the test substance. Other organ weights and organ:body weight ratios of treated animals were considered to be similar to those of control animals.

The kidneys of some male and female rats receiving 200 and 1000 mg/kg/day showed degenerative changes which were characterised by cystic dilated tubules containing proteinaceous casts. Regenerative changes, characterised as basophilic tubules, were seen in the kidneys of almost all male and female animals receiving 200 and 1000 mg/kg/day. The severity of both findings was very slight to slight.

One male receiving 1000 mg/kg/day showed a slight inflammatory change diagnosed as pyelonephritis. This finding was considered not to be a clear sign of toxicity as it can incidentally be noted in untreated rats of this age and strain. The small number of other findings recorded are within the normal range of background alterations.

In a recently performed OECD 421 study in the same rat strain (Wistar), additional parental parameters were included in order to study the reported minimal effects on the kidney observed in the 28-day repeated dose toxicity study. No effects on kidneys were observed in the study, up to and including 1000 mg/kg bw/day, the highest dose tested. Based on the absence of any effects on the kidneys in the same rat strain in the recently performed study, it is concluded that the previously observed minimal effects on the kidneys should not be considered adverse.

Based on the results of the study, the NOAEL was determined to be 1000 mg/kg bw/day. The result is used for read-across to the substance.

Justification for classification or non-classification

Based on the available information on the source substance Aluminium-magnesium-carbonate-hydroxide-perchlorate-hydrate, the substance does not have to be classified for oral repeated dose toxicity according to Regulation (EC) no. 1272/2008 and its amendments.