Magnesium hydroxide sulfate (Mg6(OH)10(SO4)), hydrate (1:3)

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Not reported.

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Biological effects of inhaled magnesium sulphate whiskers in rats.

Author:

Hori, H., Kasai, T., Haratake, J., Ishimatsu, S., Oyabu, T., Yamato, H., Higashi, T. & Tanaka, I.

Year:

1994

Bibliographic source:

Occupational and Environmental Medicine, Vol. 51, pp. 492-499.

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The study was used to investigate the potential for damage to the lungs and systemic toxicity of the test material. The test methodology was designed to maximise the amount of asbestos like 'whiskers' in the test atmosphere which is inhaled by the test animals. Two test substances were used with different 'whisker' lengths in order to better obtain the potential for damage to the lungs.
There was a large variation in the test concentrations for the short and large 'whisker' substance types. This deficiency in test methodology was considered not to affect the reliability of the study result.

GLP compliance:

no

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

483-390-9

EC Name:

-

Cas Number:

12508-61-1

Molecular formula:

H16Mg6O17S

IUPAC Name:

hexamagnesium(2+) trihydrate decahydroxide sulfate

Details on test material:

Although the test material identity is the same as that specified in section 1, two lengths of 'whisker' were used in this study.

Short whisker:
Count median length: 4.9 µm (2.1)
Count median diameter: 0.31 µm (1.5)
Aspect ratio: 15.8
Surface area: 9.5 m3/g
True density: 2.3 g/cm3
Bulk density: 0.084 g/cm3

Long whisker:
Count median length: 12.0 µm (2.3)
Count median diameter: 0.44 µm (1.6)
Aspect ratio: 27.3
Surface area: 7.98 m3/g
True density: 2.3 g/cm3
Bulk density: 0.086 g/cm3

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Not reported.
- Age at study initiation: 4 weeks old.
- Weight at study initiation: Not reported.
- Housing: Not reported.
- Diet (e.g. ad libitum): Not reported.
- Water (e.g. ad libitum): Not reported.
- Acclimation period: Not reported.

ENVIRONMENTAL CONDITIONS
Not reported.

IN-LIFE DATES: From: Day 1 To: ca. Day 730

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Vehicle:

other: dehumidified compressed air.

Remarks on MMAD:

MMAD / GSD: Short whisker: 1.5 µm (3.0)
Long whisker: 1.8 µm (2.5)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:
See figure 1

- Source and rate of air:
Air passed through a compressor, 150 l/min.

- Method of conditioning air:
Passed through silica gel bed to dehumidify.

- System of generating particulates/aerosols:
See figure 1. The compressed, dehumidified air was passed through a layer of glass beds (25cm thick) to obtain a steady flow and then through a fluidized layer of the test substance and glass beads. The glass beads moved vigorously due to air flow and the whiskers detached from the glass beads. Because of the difference of the sedimentation rate and the air velocity only whiskers were eluted from the top of the bed and transported to the exposure chamber by air.

- Temperature, humidity, pressure in air chamber:
25ºC, 50% humidity, air pressure not reported.

- Air flow rate:
150 l/min

- Air change rate:
Not reported

- Method of particle size determination:
Scanning electron microscope (particle length and diameter)
One point BET method (particle surface area)

- Treatment of exhaust air:
The exhaust air was discharged after passing through an air cleaner.

TEST ATMOSPHERE
The whisker concentration in the chamber was monitored continuously with a digital dust indicator.
To determine the concentration, the whiskers in the chamber were collected on a filter paper with a sampling pump.
The aerodynamic diameter of the whiskers and their size distributions were determined by sampling the whiskers with a cascade impactor.

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

No analytical verification was performed. The test concentrations were determined continuously during the test by digital dust indicator.

Duration of treatment / exposure:

6 hour exposure period repeated for 1 year

Frequency of treatment:

5 days per week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

1.1 mg/m³ air

Remarks:

Basis: dust concentration for short whisker type

Doses / concentrations 2

Dose / conc.:

1.4 mg/m³ air

Remarks:

Basis: dust concentration for large whisker type

No. of animals per sex per dose:

Short whisker: 27
Long whisker: 27

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale: Not reported.

Positive control:

Not applicable to test methodology.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations:
Weekly for the exposure period (4 weeks) then at 2 months, 4 months, 6 months and 12 months during the observation period (12 months).

FOOD CONSUMPTION:
Not applicable to test methodology.

FOOD EFFICIENCY:
Not applicable to test methodology.

WATER CONSUMPTION:
Not applicable to test methodology.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At termination of observation period before necropsy.
- Anaesthetic used for blood collection: Yes (Sodium pentobarbitone: 50mg/kg bw)
- Animals fasted: No data
- How many animals: All surviving animals

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At termination of observation period before necropsy.
- Animals fasted: No data
- How many animals: All surviving animals

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, the presence of tumours in the lungs, liver, kidneys, pancreas, spleen and any other organs were recorded.
HISTOPATHOLOGY: Yes, the lungs, liver, kidneys, pancreas, spleen and any other organs with tumours were sampled at necropsy.

Other examinations:

No other examinations were reported.

Statistics:

Although the results were subject to statistical analysis to determine significance the statistical method was not reported.

Results and discussion

Results of examinations

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:

not examined

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

not examined

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:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

HISTOPATHOLOGY:
In the rats with one year clearance after the one year exposure, several neoplastic lesions were found in both experimental and control groups. Two, two, and one pulmonary adenoma occurred in the short whisker, long whisker, and the control groups, respectively.
One of them showed a pronounced epithelial atypia, but this was not conclusive of carcinoma (fig 4). The number of adenomas in the exposure groups was not significantly greater than that of the control group. Hepatocellular adenoma and carcinoma (fig 5) occurred somewhat more often in the long whisker group than in the control groups.

Effect levels

1

Dose descriptor:

NOAEC

Basis for effect level:

other: Any adverse effects observed in the test groups were also observed in the control groups and were considered not to be statistically significant.

Remarks on result:

not determinable

Remarks:

no NOAEC identified

2

Key result

Dose descriptor:

NOEC

Effect level:

1.1 mg/m³ air (nominal)

Based on:

other: digital dust indicator

Sex:

male

Basis for effect level:

other: No statistically significant effects were noted in the study at the concentration (short whiskers) tested.

3

Key result

Dose descriptor:

NOEC

Effect level:

1.8 mg/m³ air (nominal)

Based on:

other: digital dust indicator

Sex:

male

Basis for effect level:

other: No statistically significant effects were noted in the study at the concentration (long whiskers) tested.

Target system / organ toxicity

Key result

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1. Weights of body and organs.

Time after end of exposure	n	Bodyweight (g(SD))	Lung (g(SD))	Liver (g(SD))	Kidneys (g(SD))	Spleen (g(SD))
1 day
Control	5	663.4 (66.3)	1.77 (0.19)	13.22 (1.24)	2.71 (0.28)	0.98 (0.14)
Short whisker	5	642.8 (49.2)	1.57 (0.16)	12.60 (1.02)	2.60 (0.17)	0.97 (0.09)
Long whisker	5	691.6 (77.1)	1.92 (0.15)	14.12 (1.43)	3.19 (0.40)	1.00 (0.09)
1 year
Control	11	759.3 (115.1)	1.94 (0.22)	16.20 (2.06)	3.65 (0.35)	1.32 (0.26)
Short whisker	13	739.0 (167.7)	1.85 (0.17)	15.66 (3.14)	3.51 (0.44)	1.51 (0.64)
Long whisker	14	715.2 (107.1)	1.85 (0.14)	15.66 (2.88)	3.70 (0.57)	1.19 (0.24)

Table 2. Summary of histopathological features.

	Short whisker	Long whisker	Control
No. of rats	13	14	11
Pulmonary lesions:
Thickening of the pleura	4	6	3
Calcification of pulmonary artery	6	5	2
Squamous metaplasia	0	0	0
Aggregate of form cells	0	2	0
Pulmonary tumour:
Adenoma	2	2	1
Squamous cell carcinoma	0	0	0
Extrapulmonary lesions:
Pancreas:
Acinic cell adenoma	2	1	0
Islet cell adenoma	2	1	1
Kidney:
Pyelonephritis	0	6	0
Infarct	0	1	1
Liver:
Hepatocellular adenoma	0	1	0
Hepatocellular carcinoma	1	0	0
Soft tissue tumour:
Fibroma	0	1	1
Sarcoma (fibrosarcoma)	1	0	0
Salivary gland adenoma	0	0	0
Pituitary adenoma	2	1	0

Applicant's summary and conclusion

Conclusions:

No statistically significant systemic toxicological effects or effects related to the physical form of the test substance were noted in the study.

Executive summary:

Male Wistar rats were exposed to two types of magneisum sulphate whiskers by inhalation for six hours a day, five days a week, for one year to clarify the biological effects of the whiskers.

A histopathological examination indicated a frequent occurence of adenoma and carcinoma in theyear after chronic exposure, but it was not significantly different between exposed and control rats.