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Exposure related observations in humans: other data

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Administrative data

Endpoint:
exposure-related observations in humans: other data
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: Well documented summary of data from a reliable source.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2001
Report date:
2001

Materials and methods

Type of study / information:
This document is an official opinion of the SCF (Scientific Committee on Food of the European Commission) on derivation of a tolerable upper intake level of magnesium compounds.
Endpoint addressed:
repeated dose toxicity: oral
Test guideline
Qualifier:
no guideline required
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Magnesium carbonate
EC Number:
208-915-9
EC Name:
Magnesium carbonate
Cas Number:
546-93-0
Molecular formula:
CH2O3.Mg
IUPAC Name:
magnesium carbonate
Details on test material:
This scientific opinion includes all easily dissociable magnesium salts (e.g. chloride or sulphate; included are compounds becoming readily dissociable after the reaction with gastric hydrochloric acid).

Method

Ethical approval:
not applicable
Details on study design:
In this document, the different aspects of oral magnesium supplementation are critically reviewed on the basis of different chapters:
- Nutritional background
- Biological considerations
- Hazard identification
- Dose-response assessment
- Derivation of a tolerable upper intake level
- Characterisation of risk
Exposure assessment:
measured
Details on exposure:
TYPE OF EXPOSURE: Only oral supplementation besides the "normal" dietary magnesium uptake are considered.

TYPE OF EXPOSURE MEASUREMENT: In the different studies reviewed in this opinion, biomonitoring was mainly conducted by magnesium quantification in blood and urine.

EXPOSURE LEVELS: Exposure levels taken into consideration for the assessment of adverse effects ranged from 180 mg Mg/day up to 1095 mg Mg/day. These values correspond to magnesium carbonate (MgCO3) levels of 624.5-3799 mg MgCO3/day.

EXPOSURE PERIOD: The exposure period of the different studies ranged from 1 to 72 weeks.

Results and discussion

Results:
Mild diarrhoea can be taken as the most sensitive non-desirable effect if Mg supplements are taken for nutritional purposes. However it must be kept in mind that adaptation of the bowel to higher oral Mg intake is known (Nadler et al., 1992; Stendig-Lindberg et al., 1993; Widman et al., 1993), that a mild laxative effect may be desirable (“four patients reported mild diarrhoea in the Mg group, and a similar number felt that their bowel function improved with less constipation”; Gullestadt et al., 1991), that mild laxative effects have been frequently observed also in the placebo groups (perhaps caused by taste adjusters, vehicles a.o.) (Sibai et al., 1989), that a given daily dose of Mg is better tolerated when it is divided into several portions, and finally that the galenic form (aqueous solution, capsules, tablets, etc.) may play a role. Data from the literature are summarized in Table 1 including children, pregnant women, tetanic, hypertensive and cardiac patients as well as volunteers. Papers were only considered when the presence or absence of “mild diarrhoea” was stated. Table 1 does not include Mg contained in food derived from plant or animal sources this being considered to be poorly dissociable (e.g. phytates).
As discussed, mild diarrhoea is the most sensitive non-desirable effect of orally administered easily dissociable magnesium salts. From the data presented in Table 1 one can conclude that mild diarrhoea occurs in a small percentage of adult subjects at oral doses of about 360/365 mg Mg per day, hence presenting the LOAEL.
No laxative effects have been observed in adult men and women -also during pregnancy and lactation- at doses up to 250 mg Mg per day. Therefore, this dose is considered as being the no-observed-adverse-effect level (NOAEL).

Toxic hypermagnesaemia, presenting e.g. with hypotension or muscular weakness, is only seen at oral Mg doses greater than 2,500 mg, i.e. doses exceeding the derived NOAEL by a factor of more than 10.

Any other information on results incl. tables

Table 1: Mild diarrhoea induced by daily oral magnesium supplements

Total Mg Dose * [mg/day]

Diarrhoea [n/total]

Subjects

 

Salt

Weeks

Ref.

Included as supporting data

Mean age

[yr] (range)

Gender

180

0/130

5.3-17.4

M/F

Asp. HCl#

3

1

x

245

0/112

8.1 (4-12)

M/F

Asp. HCl

3

2

x

245

0/181

4-12

M/F

Asp. HCl

3

3

 

250

0/31

58

F

Hydroxide

72

4

x

365

0/17

52 (33-66)

M/F

Asp. HCl

4

5

x

365

0/39

40 (20-59)

M/F

Asp. HCl

8

6

x

365

1/278

28 (20-38)

F

Asp. HCl

26

7

x

365

4/17

71 (56-88)

nd

Lactate, Citrate

6

8

x

365

4/22

62

M/F

Hydroxide

12

9

x

384

1/25

21

F

Chloride

4

10

x

384

2/21

63 (42-73)

M/F

Chloride

6

11

x

400

2/20

46 (26-65)

M/F

Chloride, Oxide

8

12

x

476

18/50

30 (21-50)

M/F

Oxide

8.5

13

 

480

2/12

16 (11-21)

M/F

Asp. HCl

12

14

x

480

2/37

28.5±4.5

F

Asp. HCl

4

15

x

500

2/20

57

M/F

Oxide

12

16

x

576

0/5

54 (38-75)

M/F

Oxide

6

17

x

970

Adaption

50

M/F

Hydroxide

3x3

18

x

1095

8/8

nd

M/F

Asp. HCl

1

19

x

* Referred to elemental Mg; nd = no data; M = males; F = females;#Asp. = aspartate.

 

References:

  1. Classen et al. (1986) Der Kinderarzt 17: 1565-1568.
  2. Schimatschek et al. (1997) Der Kinderarzt 28: 196-203.
  3. Schimatschek et al. (2001) Kinder- und Jugendmedizin [in press]
  4. Stendig-Lindberg et al. (1993) Magnesium Res 6: 155-163.
  5. Cappuccio et al. (1984) Brit Med J 291: 235-238.
  6. Plum-Wirell et al. (1994) Magnesium Res 7: 277-283.
  7. Spätlinget al.(1988) Brit J Obstet Gynaecol 95: 120-125.
  8. Gullestad et al. (1991) Magnes Trace Elem 10: 11-16.
  9. Rasmussen et al. (1989) Arch Int Med 149: 1050-1053.
  10. Ricci et al.(1991) Am J Obstet Gynecol165: 603-610.
  11. Bashir et al. (1993) Am J Cardiol 72: 1156-1162.
  12. Nadler et al. (1992) Diabetes Care 15: 835-841.
  13. Marken et al. (1989)Atherosclerosis 77: 37-42.
  14. Rueddel et al.(1990) Magnesium Res 3: 103-107.
  15. Spätling et al. (1998) Geburtsh u Frauenheilk 58: 561-565.
  16. Daly et al. (1990) Magnesium-Bull 12: 149-154.
  17. Spencer et al. (1994) J Am Coll Nutr 13: 485-492.
  18. Widman et al. (1993) Am J Hypertens 6: 41-45.
  19. Muehlbauer et al. (1991) Eur J Clin Pharmacol 40: 437-438.

Applicant's summary and conclusion

Conclusions:
After oral supplementation with easily dissociable magnesium compounds, diarrhoea seems to be the most sensitive non-desirable effect. After reviewing 19 different human studies (including children, pregnant women, hypertensive and cardiac patients as well as volunteers) no laxative effects have been observed in adult men and women - also during pregnancy and lactation - at supplementary doses up to 250 mg Mg per day. Therefore, this dose is considered as being the no-observed-adverse-effect level (NOAEL). In a small percentage of adult subjects, mild diarrhoea occurs at oral doses of about 365 mg Mg per day, hence presenting the LOAEL.
These values, which are based on and apply to magnesium supplementation, i.e. on top of normal dietary intake of magnesium from its presence in food and bevereages, can be converted into the respective NOAEL and LOAEL values of 14.5 and 21.1 mg/kg bw/day for magnesium carbonate.
Executive summary:

This document is an official opinion of the SCF (Scientific Committee on Food of the European Commission) on derivation of a tolerable upper intake level of magnesium compounds, including all easily dissociable magnesium salts (also compounds becoming readily dissociable after the reaction with gastric hydrochloric acid). Different aspects of oral magnesium supplementation are critically reviewed on the basis of different chapters: Nutritional background, Biological considerations, Hazard identification, Dose-response assessment, Derivation of a tolerable upper intake level, and Characterisation of risk.

The review of 19 differentially conducted studies (including children, pregnant women, hypertensive and cardiac patients as well as volunteers) revealed that mild diarrhoea can be taken as the most sensitive non-desirable effect if Mg supplements are taken orally. From the data presented it can be concluded that mild diarrhoea occurs in a small percentage of adult subjects at supplementary oral doses of about 365 mg Mg per day, hence presenting the LOAEL. No laxative effects have been observed in adult men and women – also during pregnancy and lactation – at supplementary doses up to 250 mg Mg per day. Therefore, this dose is considered as being the no-observed-adverse-effect level (NOAEL). Toxic hypermagnesaemia, presenting e.g. with hypotension or muscular weakness, is only seen at oral Mg doses greater than 2,500 mg, i.e. doses exceeding the derived NOAEL by a factor of more than 10.

As all easily dissociable magnesium salts are included in this opinion, these values can also be applied to magnesium carbonate. It is therefore legitimate to derive a NOAEL/LOAEL for oral intake of magnesium carbonate from these data. Based on dose conversion of the magnesium data, the NOAEL and LOAEL for magnesium carbonate are 14.5 and 21.1 mg/kg bw/day, respectively.

The SCF UL of 250 mg Mg/day is based on and applies to magnesium supplementation, i.e. intake on top of normal dietary intake of magnesium from its presence in food and beverages. The NOAEL of 14.5 mg/kg bw/day for magnesium carbonate should therefore be viewed accordingly.