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Key value for chemical safety assessment

Effects on fertility

Description of key information
It is concluded that the substance Magnesium  does not meet the criteria to be classified for human health hazards for Reproductive toxicity
Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
please see 'overall remark' below
GLP compliance:
yes
Remarks:
Testing laboratory:Biotoxtech Co., Ltd.,Report № B09179
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
[TEST ANIMALS]
- Source: ORIENTBIO INC., Korea
- Age at study initiation: Male, 9 weeks old, 311.6–344.1 g ; Female, 8 weeks old, 190.6–232.3 g
- Weight at study initiation: Male, 311.6–344.1 g ; Female, 190.6–232.3 g
- Housing: Stainless wire mesh cages, 260W×350D×210H (mm), Polycarbonate cage 260W×420L×180H (mm)
- Number of animals per cage: One animal (during pre- and post mating periods), One male and one female (during mating period), One female and pups (during lactation period)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: approximately 7 days
[ENVIRONMENTAL CONDITIONS]
- Temperature (°C): 20.8–23.1 °C
- Humidity (%): 38.4–77.8 %
- Air changes (per hr): 10–15 clean, fresh, filtered air changes per hr
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle
Route of administration:
oral: gavage
Vehicle:
other: water for injection
Details on exposure:
Amount of vehicle : 5 mL/kg
Details on mating procedure:
- M/F ratio per cage: 1 to 1
- Length of cohabitation: 14 days
- Proof of pregnancy: a vaginal plug twice a day, AM and PM.
- the mating indices : 100 %
- the mating periods : 2.2 - 2.7 days
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Male in main group and both sexes in recovery group : a total of six weeks (two weeks each prior to, during and post mating).Female in main group : two weeks prior to mating, throughout gestation and five days (six days in twelve females) after delivery
Frequency of treatment:
Once a day
Remarks:
Doses / Concentrations:
0, 50, 150, and 450 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
Control : Male-13 rats(main group)+6 rats(recovery group, not mating), Female-13 rats(main group)+6 rats(recovery group, not mating)
Low dose : Male-13 rats, Female-13 rats
Mid dose : Male-13 rats, Female-13 rats
High dose : Male-13 mice(main group)+6 mice(recovery group), Female-13 mice(main group)+6 mice(recovery group)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: In the preliminary study (Biotoxtech Study No. : B09179P), acute diarrhea was observed in animals dosed with 1000 mg/kg, and soft stool and diarrhea were observed in animals dosed with 500 mg/kg. Based on the results, 450 mg/kg was selected as the high dose level for this study and sequentially divided by a geometric ratio of 3 to produce two additional lower doses of 150 and 50 mg/kg as mid- and low dose levels. The control group received vehicle only (water for injection) at the same dose volume as the dosed groups.
Parental animals: Observations and examinations:
CLINICAL OBSERVATIONS:
- All animals were observed once a day throughout the study on mortality, general condition and gross evidence of clinical signs and symptoms
Detailed physical examinations :
- All animals were once in pretest period, once a week throughout the dosing and recovery periods on central and autonomic nervous system effects, motor activity, and behaviour.
BODY WEIGHT: Body weight were measured just prior to dosing, once a week throughout the dosing period, and the day prior to necropsy
Litter observations:
The following parameters were examined in F1 offspring:
- Number and sex of pups
- Number of corpora lutea and uterine implants
- Mean litter size
- Live births
- Postnatal mortality
- Body weights of pups on postnatal days 0 and 4.
- External examination : All pups on delivery day and on postnatal day 4
Postmortem examinations (parental animals):
Necropsy : Yes (see table [No. 15-1 and 15-2] and appendix [No. 15-1 and 15-2]) Urinalysis : Yes (see table [No. 10-1 and 10-2] and appendix [No. 10-1 and 10-2] )
Blood biochemistry : Yes (see table [No. 11-1 and 11-2] and appendix [No. 11-1 and 11-2] ) Hematology : Yes (see table [No. 12-1 and 12-2] and appendix [No. 12-1 and 12-2] ) Histopathology : Yes (see table [No. 16-1 and 16-2] and appendix [No. 16-1 and 16-2] )
Statistics:
- The SAS program
- Bartlett's test, ANOVA, Dunnett's test, Kruskal-wallis test, Mann-whitney u-test :
the data including body weights, food consumption, mating period, gestation period, pre- and post-implantation loss rate, live birth index, viability index postnatal Day 0 and 4, traction test, rotarod test, spontaneous motor activity test, urine volume, hematology and blood biochemistry parameters and organ weights data.
- Kruskal-wallis test, Mann-whitney u-test : the data of external examinations
- Folded-F test, Aspin-Welch t-test : the data of recovery groups
Reproductive indices:
- The gestation indices : 100 %
- The pre-implantation loss rates : 10.5 % (control), 6.5 % (50 mg/kg), 7.1 % (150 mg/kg), 4.8 % (450 mg/kg)
- The post-implantation loss rates : 7.9 % (control), 6.9 % (50 mg/kg), 8.4 % (150 mg/kg), 5.5 % (450 mg/kg)
Offspring viability indices:
- The live birth indices : 92.1 % (control), 93.1 % (50 mg/kg), 91.6 %(150 mg/kg), 94.5 %(450 mg/kg)
- The viability index postnatal day 0 : 97.6 % (control), 95.6 % (50 mg/kg), 100 %(150 mg/kg), 99.0 %(450 mg/kg)
Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS) - In the main and recovery groups, all animals survived the duration of the study. There were no effects on mortality. In the main group, loss of fur in forelimb was observed in one male dosed with 50 mg/kg from Days 19–41 after dosing, and soft stool was observed in one male dosed with 150 mg/kg from Days 7 and 9 after doing. Soft stool was observed in five males dosed with 450 mg/kg on Day 1, and it was observed sporadically or frequently in totals eleven males during the study. Diarrhea was observed in one male dosed with 450 mg/kg from Day 2 after dosing. Soft stool was observed each one female (total three females) dosed with 150 mg/kg from Days 9 and 14 after dosing and Day 2 of gestation. Also, it was observed in six females dosed with 450 mg/kg on Day 1 and in total ten females until a mating period sporadically. It was observed sparsely in two females during a gestation period and was not observed during a lactation period. No effects were evident in the other dosed groups. In the recovery group, soft stool was observed in one or two animals of both sexes dosed with 450 mg/kg on Day 1 after dosing, and it was observed sporadically or frequently in total five males and in total six females during a dosing period. During a recovery period, it was observed in each one animal of both sexes on the first day of recovery.
BODY WEIGHT AND WEIGHT GAIN - In parental animals, no statistically significant differences in body weights were noted in all animals in main and recovery groups compared to the control group during the study. In pubs, statistically significant decrease in body weight was noted in male pubs in 450 mg/kg dosed group compared to the control group on postnatal Day 4. No dose-related effects were noted.
FOOD CONSUMPTION (PARENTAL ANIMALS) - Statistically significant decrease in food consumption was noted in males dosed with 150 mg/kg in main group compared to the control group on Day 7 after dosing. Statistically significant increase was noted in males dosed with 450 mg/kg in recovery group compared to the control group on the day prior to dosing (Day 0). No statistically significant differences were evident in the other dosed groups.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS) - In 0, 50, 150, and 450 mg/kg dosed groups, the mating periods were 2.3, 2.2, 2.9 and 2.7 days, the mating indices were 100 %, the gestation periods were 22.1, 21.9, 22.1 and
22.2 days, the fertility indices of both sexes were 92.3, 84.6, 100 and 92.3 %, respectively. There were no statistically significant differences in any dose group.
ORGAN WEIGHTS (PARENTAL ANIMALS) - In the main group, absolute organ weights of kidneys in males dosed with 50 and 150 mg/kg were statistically significantly decreased (p<0.05) compared to the control group. Relative organ weights of testes in males dosed with 150 mg/kg were statistically significantly increased (p<0.05) compared to the control group. No statistically significant differences on absolute and related organ weights were noted in females. In the recovery group, absolute and relative organ weights of males were not statistically significantly different from control, but relative organ weights of ovaries in females dosed with 450 mg/kg were statistically significantly increased (p<0.05) compared to the control group.GROSS PATHOLOGY (PARENTAL ANIMALS) - Results of the gross postmortem examinations performed on all animals in the study did not reveal any evidence of grossly visible morphologic abnormalities in all groups.
HISTOPATHOLOGY (PARENTAL ANIMALS): NON-NEOPLASTIC - The squamous cell hyperplasia of forestomach, edema of submucosa, inflammation of submucosa, focal erosion of mucosa, focal ulcer of mucosa into forestomach and hyperplasia of mucosa into cecum were evident in one female dosed with 450 mg/kg in main group. Stomach and cecum were conducted for histopathology in animals dosed with 50 and 150 mg/kg in main group and in all recovery groups. There were no abnormal findings. In addition, in the control and 450 mg/kg main groups of both sexes, focal basophilic tubules of kidneys, mineralization of corticomedullary junction, mononuclear pyelitis, bilateral lymphocytic, focal lymphocytic cell infiltration of liver, focal mononuclear cell infiltration of liver, interstital lymphocytic cell infiltration of prostate and lymphocytic depletion of cortical into thymus were spontaneously or sporadically observed. In the recovery group of both sexes, no abnormal findings were observed.
Other findings : Normal deliveries were observed in all animals.
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
BODY WEIGHT -The body weight of male pups on postnatal Day 4 was 10.9±1.1 g (control), 9.7±1.0 g (50 mg/kg),
10.5±1.2 g (150 mg/kg) and 9.5±1.6 g (450 mg/kg). The decrease in body weight in male pups treated with 450 mg/kg group was statistically significant (p<0.05), but no dose-related effects were noted. So, we concluded no effect on body weight of offspring. See appendix [No. 3-3].

External findings : Edema of left in hind limb was observed in one pup (0.55%) in 50 mg/kg group on postnatal Day 0, and brachyury was observed in one pup (0.62%) in 150 mg/kg group on Days 0 and 4. No effects were evident in the other dosed groups. Detailed data was suggested below.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 450 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Reproductive effects observed:
not specified

 

Group

 

Implantation

loss rate (%)

Live birth

index (%)

 

Viability index

(%)

 

Sex ratio

(male/Female)

 

Pre-

 

Post-

 

PND 0

 

PND 4

 

PND 0

 

PND 4

 

Control

 

10.5(+/-)

7.5

 

7.9(+/-)8.1

 

92.1(+/-)8.1

 

97.6(+/-)6.0

 

99.6(+/-)1.5

 

1.0

(85/82)

 

1.0

(85/81)

 

50mg/kg

 

6.5(+/-)6.5

 

6.9(+/-)7.1

 

93.1(+/-)7.1

 

95.6(+/-)7.8

 

97.4(+/-)6.0

 

1.2

(87/75)

 

1.2

(86/72)

 

150mg/kg

 

7.1(+/-)5.1

 

8.4(+/-)11.1

 

91.6(+/-)

11.1

 

100.0(+/-)

0.0

 

99.1(+/-)2.3

 

0.9

87/96)

 

0.9

(86/95)

 

450mg/kg

 

4.8(+/-)4.9

 

5.5(+/-)6.3

 

94.5(+/-)6.3

 

99.0(+/-)2.3

 

96.8(+/-)5.9

 

1.1

(99/89)

 

1.1

(96/86)

 

 

Conclusions:
No dose-related effects were noted in reproduction function. The NOAEL was considered to be 450 mg/kg bw/day for reproduction toxicity study.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
450 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
19.6 mg/m³
Study duration:
subchronic
Species:
rat
Effect on fertility: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
11.25 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Additional information

Oral exposure

In a reliable one-generation study a repeated oral dose NOAEL of 450mg/kg/day in male and females was determined for effects on reproductive organs in the rat.

The NOAEL for reproductive endpoints is  the highest dose level administered (450 mg/kg bw for male and  females).

 

Dermal exposure:

For dermal exposure we taken that:

-the average weight of rats is 250g (200-300g),

-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg

 corrected dermal NOAEL=   oral NOAEL

450 mg/kg bw/day x 0.025 kg =                  

 NOAELrat  = 11.25 mg/kg bw/day

Inhalation exposure:

The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.

NOAEL rat            

 450 mg/kg bw/day

÷1.15 m3/kgbw

÷20m3/rat

NOAECrat  =  19.6 mg/m3 

 


Short description of key information:
There are conclusive but not suffcient data for the classification of substance Magnesium with regard to reproduction.
It is concluded that the substance Magnesium does not meet the criteria to be classified for human health hazards for Reproductive toxicity

Justification for selection of Effect on fertility via inhalation route:
Inhalation exposure:
The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.
NOAEL rat            
 450 mg/kg bw/day
÷1.15 m3/kgbw
÷20m3/rat
NOAECrat  =  19.6 mg/m3 
 

Justification for selection of Effect on fertility via dermal route:
Dermal exposure:
For dermal exposure we taken that:
-the average weight of rats is 250g (200-300g),
-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg
 corrected dermal NOAEL=   oral NOAEL
450 mg/kg bw/day x 0.025 kg =                  
 NOAELrat  = 11.25 mg/kg bw/day

Effects on developmental toxicity

Description of key information
There are conclusive but not suffcient data for the classification of substance  Magnesium)  with regard to Developmental toxicity / teratogenicity 
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
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 details are reported.
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

Table 1: Preliminary teratogenicity test of MgCl2.6H2O in rats

Parameter

Dose (mg/kg bw/day)

0 (control)

250

500

1000

No. of pregnant rats

4

4

4

4

No. of dead pregnant rats

0

0

0

2

No. of litters

4

4

4

2

No. of corpora luteaa)

14.5 ± 0.6

17.8 ± 2.1

16.5 ± 1.0

16.0 ± 2.8

No. of implantsa)

14.0 ± 0.8

14.5 ± 1.3

15.0 ± 0.8

14.0 ± 4.2

No. of live foetusesa)

14.0 ± 0.8

14.5 ± 1.3

15.0 ± 0.8

14.0 ± 4.2

           Sex ratio (male/female)

1.24

1.26

0.92

1.32

Foetal weight (g)a)

-

-

-

-

           Male

3.84 ± 0.09

3.75 ± 0.33

3.93 ± 0.15

3.82 ± 0.22

           Female

3.73 ± 0.18

3.58 ± 0.22

3.73 ± 0.26

3.68 ± 0.22

Mortality of implants (%)a)

1.8

5.0

7.4

6.9

No. of foetuses

-

-

-

-

           with gross malformation

0

0

1

1

a) Mean ± SD

 

Table 2: Foetal growth in pregnant rats treated with MgCl2.6H2O

Parameter

Dose (mg/kg bw/day)

0 (control)

200

400

800

No. of litters

22

22

22

22

No. of corpora luteaa)

373

370

361

362

           Mean ± SD

17.0 ± 1.6

16.8 ± 2.2

16.4 ± 2.1

16.5 ± 1.5

No. of implants

364

340

345

345

           Mean ± SD

16.5 ± 1.7

15.5 ± 3.2

15.7 ± 1.9

15.7 ± 1.8

           Implantation rate (%)a)

97.7 ± 4.5

91.4 ± 12.2

95.9 ± 6.6

95.4 ± 8.3

No. of live foetuses

346

326

324

332

           Mean ± SD

15.7 ± 1.5

14.8 ± 3.5

14.7 ± 1.8

15.1 ± 1.8

           Sex ratio (male/female)

1.28

1.15

1.23

1.38

Foetal weight (g)a)

 -

           Male

3.95 ± 0.22

3.98 ± 0.29

3.87 ± 0.21

3.98 ± 0.22

           Female

3.73 ± 0.25

3.75 ± 0.23

3.72 ± 0.20

3.81 ± 0.17

No. of dead implants

18

14

21

13

           Early death

18

14

21

13

           Late death

0

0

0

0

           Mortality (%)a)

4.8 ± 4.6

4.8 ± 5.8

5.9 ± 6.1

3.6 ± 5.7

a) Mean ± SD

 

Table 3: Gross malformations in the foetuses from pregnant rats treated with MgCl2.6H2O

Parameter

Dose (mg/kg bw/day)

0 (control)

200

400

800

No. of litters

22

22

22

22

No. of foetuses examined

346

326

324

332

No. of litters with malformed foetuses

3 (13.6%)

1 (4.55%)

3 (13.6%)

1 (4.55%)

No. of foetuses with malformationa)

3 (0.88%)

1 (0.32%)

4 (1.18%)

1 (0.25%)

           Anal atresia

0 (0.00%)

0 (0.00%)

1 (0.30%)

1 (0.25%)

           Dwarf

3 (0.88%)

1 (0.32%)

2 (0.61%)

0 (0.00%)

           Kinky tail

0 (0.00%)

0 (0.00%)

1 (0.27%)

0 (0.00%)

           Pes varus

0 (0.00%)

0 (0.00%)

1 (0.30%)

0 (0.00%)

           Rudimentary tail

0 (0.00%)

0 (0.00%)

1 (0.30%)

1 (0.25%)

a) Total number and mean incidence

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.
Executive summary:

Teratogenicity of magnesium chloride hexahydrate was examined in rats. The pregnant rats were sacrificed on day 20 of pregnancy and their foetuses were examined for malformation. It was found that magnesium chloride hexahydrate caused no increased incidences of foetal malformation, and no toxic signs in the pregnant rats and the foetuses. Even a dose of 800 mg/kg/day, considered the maximum non-fatal dose of magnesium chloride hexahydrate in pregnant rats, did not increase the incidence of teratogenicity. The no observed adverse effect level was estimated to be over 800 mg/kg/day for both pregnant rats and rat foetuses.This is because, although no effects from magnesium chloride hexahydrate are observed in maternal rats at a dose of 800 mg/kg/day, sedation, decreased body temperature, salivation, watery stool and mortality were observed at a dose of 1,000 mg/kg/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
800 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
34.8 mg/m³
Study duration:
subchronic
Species:
rat
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
20 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Additional information

Oral exposure

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.

NOAEL=800 mg/kg/day 

Dermal exposure:

For dermal exposure we taken that:

-the average weight of rats is 250g (200-300g),

-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg

 corrected dermal NOAEL=   oral NOAEL

800 mg/kg bw/dayx0.025 kg =                  

 NOAELrat  = 20 mg/kg bw/day

Inhalation exposure:

The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.

NOAEL rat            

 800 mg/kg bw/day

÷1.15 m3/kgbw

÷20m3/rat

NOAECrat  =  34.8mg/m3 


Justification for selection of Effect on developmental toxicity: via inhalation route:
Inhalation exposure:
The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.
NOAEL rat            
 800 mg/kg bw/day
÷1.15 m3/kgbw
÷20m3/rat
NOAECrat  =  34.8mg/m3 

Justification for selection of Effect on developmental toxicity: via dermal route:
Dermal exposure:
For dermal exposure we taken that:
-the average weight of rats is 250g (200-300g),
-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg
 corrected dermal NOAEL=   oral NOAEL
800 mg/kg bw/dayx0.025 kg =                  
 NOAELrat  = 20 mg/kg bw/day

Toxicity to reproduction: other studies

Additional information

Teratogenicity of magnesium ( as chloride hexahydrate) was examined in rats. The pregnant rats were sacrificed on day 20 of pregnancy and their foetuses were examined for malformation. It was found that magnesium chloride hexahydrate caused no increased incidences of foetal malformation, and no toxic signs in the pregnant rats and the foetuses. Even a dose of 800 mg/kg/day, considered the maximum non-fatal dose of magnesium chloride hexahydrate in pregnant rats, did not increase the incidence of teratogenicity. The no observed adverse effect level was estimated to be over 800 mg/kg/day for both pregnant rats and rat foetuses.This is because, although no effects from magnesium chloride hexahydrate are observed in maternal rats at a dose of 800 mg/kg/day, sedation, decreased body temperature, salivation, watery stool and mortality were observed at a dose of 1,000 mg/kg/day.

Justification for classification or non-classification

Based on the hazard assessment of Magnesium in section 2.1 and 2.2. in IUCLID 5.4., available data for the substance and following the “Guidance on Information Requirement and Chemical Safety Assessment R.8. Characterisation of dose [concentration]- response for human health” and according to the criteria described in Directive 67/548 and in the CLP Regulation:

Directive 67/548

Toxicity to reproduction/development

Repr. Cat. 1; R61 May cause harm to the unborn child.

Repr. Cat. 2; R61 May cause harm to the unborn child.

Repr. Cat. 3; R63 Possible risk of harm to the unborn child.

Toxicity to reproduction/fertility

 Repr. Cat. 1; R60 May impair fertility.

Repr. Cat. 2; R60 May impair fertility.

Repr. Cat. 3; R62 Possible risk of impaired fertility

 

CLP

Reproductive toxicity

Repr. 1A

Repr. 1B

Repr. 2

H360: May damage fertility or the unborn child <state specific effect if known > <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

H361: Suspected of damaging fertility or the unborn child <state specific effect if known> <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

 

 

 

It is concluded that the substance Magnesium does not meet the criteria to be classified for human health hazards for Reproductive toxicity

 

 

Additional information