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Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
3.6 mg/kg bw/day
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Only limited data are available on effects of magnesium on the reproductive performance of male and female mice and rats. The results of studies examining the effects of magnesium deficiency in rats substantiated the importance of magnesium for proper reproductive function and foetal development or immune competence of pups, and the detrimental effects of magnesium deficiency during gestation and lactation.

In a comprehensive evaluation of possible adverse health effects of individual nutrients at intakes in excess of dietary requirements presented in the scientific opinions of the Scientific Committee on Food (SCF; Anonymous, 2001), the sources, properties and effects of magnesium on animals as well as on different subgroups of the human population have been re-evaluated and a tolerable upper intake level for magnesium has been defined. The SCF decided to base the derivation of an UL for magnesium on the evidence of different interventional studies of long duration in adults, some of which were placebo-controlled and in which total daily magnesium intakes of 250 mg from both the diet and supplements were tolerated without any adverse effects. Based on the findings, a tolerable upper intake level of 250 mg of magnesium per day for magnesium intake from all sources is proposed for adults, corresponding to a dose of about 3.6 mg magnesium/kg bw/d taking into account an average body weight of 70 kg/person. The UL is considered to also cover any potential reproductive effects.

Therefore, the tolerable upper intake level of 3.6 mg Mg/kg bw/d is recommended as a starting point for hazard assessment regarding reproductive toxicity and derivation of a corresponding DNEL as worst case consideration.

 

Effects on developmental toxicity

Description of key information
Magnesium is not teratogenic. The NOAEL for magnesium, derived from the key study on MgCl2*6H20, was determined at 96 mg Mg/kg bw.
Link to relevant study records
Reference
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.
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
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.
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
Remarks:
Doses / Concentrations:
0 mg/kg/day
Basis:
nominal in water
Remarks:
Doses / Concentrations:
200 mg/kg/day
Basis:
nominal in water
Remarks:
Doses / Concentrations:
400 mg/kg/day
Basis:
nominal in water
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.
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
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.
Dose descriptor:
NOAEL
Effect level:
> 800 - < 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
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.
Dose descriptor:
NOAEL
Effect level:
> 800 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: fetotoxicity
Abnormalities:
not specified
Developmental effects observed:
not specified
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.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
96 mg/kg bw/day
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Read across MgCl2 * 6H2O to Mg:

In view of the the limited relevance of the anionic counter-ions discussed here, magnesium chloride can be considered as structurally equivalent, and the results of the study can be used by read-across.

Pre-natal developmental toxicity of magnesium was studied in rats administered magnesium chloride hexahydrate at dose levels of 200, 4000 and 800 mg/kg bw/d orally by gavage (Usami et al., 1996) from day 6 -15 of gestation. No maternal toxicity and no adverse developmental effects, embryo-/foetotoxic or teratogenic effects were observed up to and including the highest dose level of 800 mg/kg bw/d. Thus, the NOAEL was estimated to be higher than 800 mg/kg bw/d magnesium chloride hexahydratefor both the dams and the foetuses. This dose corresponds to a magnesium dose of 96 mg Mg/kg bw/d.

The NOAEL of 96 mg Mg/kg bw/d is established as an NOAEL for risk assessment purposes of compounds containing magnesium.

Justification for selection of Effect on developmental toxicity: via oral route:
Read-across information from a reliable study with magnesium chloride hexahydrate as test item.

Justification for classification or non-classification

Magnesium is essential minaral nutrients for mammals including humans. Based on evaluation of a wealth of human medical and nutritional data Anonymous, 2001 [SCF opinion]), it is concluded that magnesium, does not pose any hazard for reproduction and/or developmental toxicity. Classification for toxicity to reproduction and/or developmental toxicity is not required according to Regulation (EC) 1272/2008 and subsequent adaptations.

Additional information

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