Magnesium

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study allows the derivation of a NOAEL value for developmental toxicity of Mg. In the current study, magnesium was administered in the form of magnesium chloride, the chloride ion being an ubiquitous component of mammalian mineral supply via the diet, omnipresent in body fluids and involved in osmoregulation, and therefore of limited toxicologically relevance at the tested doses. The objective of the study was the evaluation of effects of magnesium on the development of rat foetuses.

Data source

Reference

Reference Type:

publication

Title:

Teratogenicity study of magnesium chloride hexahydrate in rats

Author:

Usami, M. et al.

Year:

1996

Bibliographic source:

Bull. Natl. Inst. Health Sci., 114: 16-20.

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Teratogenicity test, not performed according to OECD 414, but fulfilling basic scientific principles for evaluating this endpoint.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Magnesium chloride

EC Number:

232-094-6

EC Name:

Magnesium chloride

Cas Number:

7786-30-3

IUPAC Name:

magnesium dichloride

Constituent 2

Reference substance name:

7791-18-6

Cas Number:

7791-18-6

IUPAC Name:

7791-18-6

Constituent 3

Reference substance name:

magnesium chloride hexahydrate

IUPAC Name:

magnesium chloride hexahydrate

Test material form:

solid: crystalline

Details on test material:

- Name of test material (as cited in study report): Magnesium chloride hexahydrate
- Physical state: solid, colourless or white crystals
- Analytical purity: at least 95%
No further details are given.

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: obtained from Nippon Charles River.
- Age at study initiation: 10 to 11 weeks old
- Housing: pregnant animals were kept individually in aluminum cages.
- Diet: ad libitum, solid food (Oriental Yeast, MF)
- Water: ad libitum, tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25 +/- 2
- Humidity (%): 55 +/- 5
- Photoperiod. 12 hours dark/light cycle

No further details are given.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

The dose volume of the test substance solutions was 5 mL/kg/day at each dosage level and the control.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Details on mating procedure:

- Nulliparous females were mated over night with males.
- Females revealing spermatozoa in the vaginal smear in the following morning were considered as being pregnant and, then, used in the experiment.
- The day, when sperms were found in the vaginal smear, was designated as day 0 of gestation.

Duration of treatment / exposure:

10 days ( between gestation day 6 and 15)

Frequency of treatment:

once a day

Duration of test:

until day 20 of gestation

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0 mg/kg/day
Basis:
nominal in water

Doses / concentrations 2

Remarks:

Doses / Concentrations:
200 mg/kg/day
Basis:
nominal in water

Doses / concentrations 3

Remarks:

Doses / Concentrations:
400 mg/kg/day
Basis:
nominal in water

Doses / concentrations 4

Remarks:

Doses / Concentrations:
800 mg/kg/day
Basis:
nominal in water

No. of animals per sex per dose:

4 groups with 22 pregnant animals in each group

Control animals:

yes

Details on study design:

- For setting the dosages, a pretest was conducted with 4 animals per group and 3 different dosage levels of 0 (control), 250, 500 and 1000 mg/kg.
- At dosages of 1000 mg/kg/day sedation, decrease of body temperature, salivation and aqueous feces were observed, in addition, two animals died.
- As for the reproduction of the animals which had survived, no negative affects related to magnesium chloride hexahydrate were found.

Examinations

Maternal examinations:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: general conditions of the animals was observed every day.

BODY WEIGHT: Yes
- Time schedule for examinations: body weight of the pregnant animals were measured on day 0, 1, 3, 6, 9, 12, 15 and 17 of pregnancy.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule for examinations: food intake of the pregnant animals were measured on day 0, 1, 3, 6, 9, 12, 15 and 17 of pregnancy.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on day 20 of gestation.

No further details are given.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes; living young were weighed and inspected externally for anomalies and sex.
- Soft tissue examinations: Yes; internal organs were inspected according to a gross sectioning technique (head and abdominal cavity) and a microdissection technique (thoracic space).
- Skeletal examinations: Yes; about the half of the living young of each pregnant animal were prepared for staining with alizarin red S.

Statistics:

Pregnant animals or one uterus were taken as sample units. For frequency data, Fisher's direct exact probability test was applied to test the significance of differences between the control group and the magnesium chloride hexahydrate groups. As for measuring data, statistical analysis and Scheffé's method were applied when no variance differences between the groups were found according to Bartlett's equal variance test. For measuring data and count data with variance differences between the groups, the H test (Kruskal-Wallis test) and Scheffé's method were used.

Indices:

no data

Historical control data:

no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
- There were no changes between the control and treatment (200, 400, 800 mg/kg bw/d) groups as far as general condition and dead animals are concerned.
- No significant differences between control group and magnesium chloride hexahydrate groups with respect to body weight were observed.
- No significant differences were found for food consumption.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

> 800 - < 1 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- No significant differences between the control and magnesium treated groups (200, 400 or 800 mg/kg bw/d) were observed for the number of corpora lutea, number of implants, number of living fetuses, sex ratio, fetal weight and mortality of implants/fetuses.
- 1 to 4 fetuses with gross malformations were found in each group, however, the incidence rate was not significant different between groups.
- In the 800 mg/kg/day group, 1 fetus had skeletal malformations, however, the incidence rate was not significant different from the control group.
- No significant differences between control group and magnesium treated groups were observed for the incidence rate of skeletal variations.
- There were no significant differences between control and treated groups in the incidence rate of fetuses with lumbar rib and additional rib bones, the number of ossification centers, the metacarpal and metatarsal bones as well as the sacral vertebrae and the tail vertebrae.
- 4 to 6 fetuses in each group showed malformations, however, no significant difference between control and magnesium treated groups was observed.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

> 800 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

It was concluded that magnesium chloride hexahydrate was not teratogenic in rats when given orally by gavage. The no observed adverse effect levels for maternal toxicity and developmental effects were estimated to be over 800 mg/kg bw/day for both pregnant rats and rat foetuses. This dose level corresponds to a Mg dose of 95.7 mg/kg bw/d.