Magnesium hexafluorosilicate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1982

Report date:

1982

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

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

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Magnesium hexafluorosilicate hexahydrate

Cas Number:

18972-56-0

Molecular formula:

MgSiF6·6H2O

IUPAC Name:

Magnesium hexafluorosilicate hexahydrate

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: WIGA
- Age at study initiation: 34 days old
- Weight at study initiation: mean 138,5 g (male), 132,3 g (female)
- Diet (e.g. ad libitum): Herilan MRH
- Water: ad libitum
- Housing: V2A-Draht-käfigen, Type 3 (900 cm2)
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 ºC
- Humidity (%): 55 +/- 10 %
- Photoperiod (hrs dark / hrs light): 12 h dark/12 h light

IN-LIFE DATES: From: 01.10.80 To: 06/07.11.80

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): daily
- Mixing appropriate amounts with (Type of food): Herilan MRH

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Before the test, the principal of each dosing substance preparation were sent to Analytical verification.

Duration of treatment / exposure:

28 days

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

Doses / Concentrations:
300, 900, 3000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

10

Control animals:

yes, concurrent no treatment

Details on study design:

ND

Positive control:

ND

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

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
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 28 days after first application
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: All (60 rats)
- Parameters checked in table [Page 18] were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 28 days after first application
- Animals fasted: No data
- How many animals: All (60 rats)
- Parameters checked in table [Page 13, 14] were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: Enzymactivity.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table 016-017-018-019-020-021-022-023-024-025-026)
HISTOPATHOLOGY: Yes (Page 22)

Other examinations:

For each case a lower incisor of all animals from the groups 1 and 3 was x-rayed after fine preparation and then taken through the normal process.

Statistics:

In the statistical evaluation of the test for the variables (food intake, body weight and absolute and relative organ weights) were mean values​​, standard deviation (of the items) and standard errors calculated for the animals of each experimental group .

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Substance in rats for 4 weeks of administration in the diet at a dosage of 3000 ppm to inappetence, decreased body weight gain enlarged abdominal circumference, white color of the teeth and partly led to hair loss, whereas have clinically on administration of 300 ppm and 900 pm substance no changes compared with the untreated controls were observed.

Mortality:

mortality observed, treatment-related

Description (incidence):

Substance in rats for 4 weeks of administration in the diet at a dosage of 3000 ppm to inappetence, decreased body weight gain enlarged abdominal circumference, white color of the teeth and partly led to hair loss, whereas have clinically on administration of 300 ppm and 900 pm substance no changes compared with the untreated controls were observed.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

All animals in the experimental groups 1 and 2 (300 and 900 ppm) showed a normal, corresponding to the rats of the untreated control group growth, whereas in the experimental group 3 (3000 ppm), there was a greatly delayed increase in body weights.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not specified

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):

Parameters determined: hemoglobin, Erythrocyte count, hematocrit, Hemoglobin content of individual erythrocytes, Mean cell volume, Mean corpuscular hemoglobin concentration, Platelet count, WBC

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Parameters determined: Total bilirubin, creatinine, urea, sodium, potassium, total protein, Gluose, inorganic phosphate, calcium, chloride, albumin and magnesium.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Weighed organs: liver, kidneys, testes and adrenal glands.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Observed: Heart, aorta, trachea, lungs, teeth, esophagus, stomach, duodenum, liver, spleen, sternum, kidneys, bladder, testes, adrenals, thyroid, brain, skeletal muscle and skin.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Determined: Alkaline phosphatase and leucine aminopeptidase in the liver (frozen sections); Kidney, in application of Anshan and Movat staining; Teeth and Trahea and Sternum.

Histopathological findings: neoplastic:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY
Substance in rats for 4 weeks of administration in the diet at a dosage of 3000 ppm to inappetence, decreased body weight gain enlarged abdominal circumference, white color of the teeth and partly led to hair loss, whereas have clinically on administration of 300 ppm and 900 pm substance no changes compared with the untreated controls were observed.

BODY WEIGHT AND WEIGHT GAIN
All animals in the experimental groups 1 and 2 (300 and 900 ppm) showed a normal, corresponding to the rats of the untreated control group growth, whereas in the experimental group 3 (3000 ppm), there was a greatly delayed increase in body weights.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
See table 1&2 in next section "Any other information on results incl. tables"

HAEMATOLOGY
Increase in bilirubin concentration and platelet counts and decrease in hemoglobin, erythrocytes and hematocrit. Increase in Segmet neutrophils. (only for 3000 ppm dose groupe).

CLINICAL CHEMISTRY
Increase in urea levels. Waste de total protein, albumin, potassium, glucose, and calcium concentration, and the alkaline phosphatase activity. Increase of the magnesium concentration. (only for 3000 ppm dose group)
Reduction in the total protein level in males (only for 900 ppm dose group)

ORGAN WEIGHTS
See table 2&3 in next section "Any other information on results incl. tables"

GROSS PATHOLOGY
(300 ppm dose group) teeth: striped brown-orange coloration, stripes, zebra
(900 ppm dose group) teeth brightened, zebra stripes, depigmentation, enamel defects, impaired growth
(3000 ppm dose group) kidneys: yellowish, pinhead big herd, uneven surface. Lung: pneumonia lesions (male only). Stomach: wall thickening. Teeth whitened and underdeveloped depigmentation, enamel defects, mineralization disorder, impaired growth

HISTOPATHOLOGY: NON-NEOPLASTIC
Determined: Alkaline phosphatase and leucine aminopeptidase in the liver (frozen sections); Kidney, in application of Anshan and Movat staining; Teeth and Trahea and Sternum

Effect levels

Dose descriptor:

NOAEL

Effect level:

ca. 300 ppm

Based on:

test mat.

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1: Feed consumption (g/animal/day) MALE

Group	Acclimatization (7 days)	1 -7 day	8 - 14 day	15 -21 day	22 -28 day
Group 0 (0 ppm)
M (mean)	22.01	24.21	25.33	24.61	25.47
SD (standard deviation)	0.18	0.14	0.10	0.46	1.07
SE (standard error)	0.13	0.10	0.07	0.33	0.76
Group 1 (300 ppm)
M	21.81	25.29	27.14	26.57	25.49
SD	0.46	1.33	0.36	0.16	0.24
SE	0.33	0.94	0.26	0.11	0.17
Group 2 (900 ppm)
M	22.54	24.03	25.79	25.40	26.80
SD	0.48	0.53	0.50	0.44	0.93
SE	0.34	0.37	0.36	0.31	0.66
Group 3 (3000 ppm)
M	22.81	13.86	16.93	17.81	19.33
SD	0.71	0.12	0.75	0.06	0.34
SE	0.50	0.09	0.53	0.04	0.24

Table 2: Feed consumption (g/animal/day) FEMALE

Group	Acclimatization (7 days)	1 -7 day	8 - 14 day	15 -21 day	22 -28 day
Group 0 (0 ppm)
M (mean)	17.67	18.57	19.16	19.09	21.00
SD (standard deviation)	0.75	0.16	0.26	0.24	0.36
SE (standard error)	0.53	0.11	0.19	0.17	0.26
Group 1 (300 ppm)
M	17.91	18.93	19.47	19.06	22.04
SD	0.20	0.22	0.79	0.12	0.10
SE	0.14	0.16	0.56	0.08	0.07
Group 2 (900 ppm)
M	18.23	19.37	19.83	19.60	21.90
SD	1.25	0.65	0.77	0.36	0.46
SE	0.89	0.46	0.54	0.26	0.33
Group 3 (3000 ppm)
M	18.43	11.19	15.16	15.90	16.66
SD	0.48	0.06	0.10	0.30	0.20
SE	0.34	0.04	0.07	0.21	0.14

Table 3: Organ weight (g) FEMALE

	Group 0	Group 1	Group 2	Group 3
	0 ppm	300 ppm	900 ppm	3000 ppm
Body weight animal (g)	181.90	184.10	180.20	142.60
Liver	5.51	5.61	5.68	5.46
Kidneys	1.64	1.63	1.56	1.93
Testicle	-	-	-	-
Adrenal	75.10	74.50	71.90	59.70

Table 4: Organ weight (g) MALE

	Group 0	Group 1	Group 2	Group 3
	0 ppm	300 ppm	900 ppm	3000 ppm
Body weight animal (g)	268.80	275.50	268.90	178.10
Liver	8.27	8.33	8.50	6.56
Kidneys	2.28	2.29	2.39	2.36
Testicle	3.24	3.37	3.47	3.15
Adrenal	58.20	64.10	56.50	54.50

Applicant's summary and conclusion

Conclusions:

  Magnesium hexafluorosilicate at a dosage of 3.000ppm showed a significant toxic effect on target organs.

Executive summary:

             In an in vivo test, the toxicological effects of Magnesium Hexafluorosilicate Hexahydrate with a purity of ca. 99% in Rats via the diet were studied.The substance was administered during 28 days to 60 Sprague-Dawley rats. For reasons of comparison, a group of animals remained untreated (10 per sex) and were used as a control group. The medium body weight of the male rats was 188,1 g and 157,6 g for the female rats. The doses were 300, 900 and 3.000 ppm. The food consumption was determined daily and the weight weekly, the health of the rats was studied every day. It was conducted a clinical-chemical and hematological examinationat the end of the experiment. All animals were examined pathologically.

 

              Magnesium hexafluorosilicate Hexahydrate at a dosage of 3.000ppm showed a significant toxic effect on target organs; kidney,tooth and bonetissue.The findings and the fast-growing of front teeth and bone tissue of young rats were the typical image of a fluorosis.For all other findings that were observed at the highest dose group, a dependence on the reduced feed intake is likely. Only the slight anemia could be a toxic event basis, because the bilirubin concentration in Plasma was increased at the same time.

 

             At a dosage of 900 ppm the main effects were clearly pronounced impairment of enameland dentinofthe incisors, considered a dose effectbecause of thedecreased plasmaprotein levelsin the male animals.

 

             At 300ppm there were nostrong effects asthe onesat the higher doses.Only in some animals yellowish teeth whitening with banding was observed, while at the same time, the melt-forming epithelium and granulation of the cytoplasm showed isolated vacuoles. At concentration of about 2 ppm Fl^-in drinking water, it was described banding and opacity of the teeth in children. Such findings are not affected by the tooth structure.

 

             The results of extremely fast growing of the incisors teeth in rats cannot be direct apply to humans due to the investigations about the influence of the dental apparatus in the oral intake of Fluor at different concentrations. The action of reducing the dose in order to achieve an absolute “no adverse effect level” is not useful in these results.

 

             In relation to other study corresponding to toxic effects of Magnesium hexafluorosilicate hexahydrate, the dosage of 300 ppm was considered as a dose without effects.