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The EFSA Journal (2008) 761, 1-11
Magnesium L-lysinate, calcium L- lysinate, zinc L- lysinate as sources for
magnesium, calcium and zinc added for nutritional purposes in food
supplements1
Scientific Opinion of the Panel on Food Additives, Flavourings, Processing
Aids and Materials in Contact with Food
(Questions No EFSA-Q-2005-142, EFSA-Q-2005-127, EFSA-Q-2005-218)
Adopted on 08 July 2008
PANEL MEMBERS
F. Aguilar, H. Autrup, S. Barlow, L. Castle, R. Crebelli, W. Dekant, K.-H. Engel, N. Gontard, D.
Gott, S. Grilli, R. Gürtler, J.-C. Larsen, C. Leclercq, J.-C. Leblanc, F. X. Malcata, W. Mennes, M.R. Milana, I. Pratt, I. Rietjens, P. Tobback, F. Toldrá.
SUMMARY
Following a request from Commission, the Panel on Food Additives, Flavourings, Processing Aids
and Materials in Contact with Food (AFC Panel) was asked to deliver a scientific opinion on
magnesium L-lysinate, calcium L-lysinate, zinc L-lysinate as sources for magnesium, calcium and
zinc added for nutritional purposes in food supplements.
The present opinion deals only with the safety of a number of lysinates as sources for respectively
magnesium, calcium and zinc added for nutritional purposes to food supplements. The safety
evaluation of magnesium, calcium and zinc itself is outside the remit of the AFC Panel.
1
For citation purposes: Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact
with Food on a request from the Commission on magnesium L-lysinate, Calcium L-lysinate, Zinc L-lysinate as sources for
magnesium, calcium and zinc subject. The EFSA Journal (2008) 761, 1-11.
© European Food Safety Authority, 2008
Opinion on certain lysinates as sources for magnesium, calcium and zinc
Magnesium L-lysinate, calcium L-lysinate and zinc L-lysinate being salts of the amino acid Llysine, like other salts of organic acids, are soluble in water and are expected to dissociate. The
bioavailability of the respective cations is expected to be similar to that of other soluble sources of
these cations.
L-Lysine, following ingestion, is absorbed from the lumen of the small intestine into the
enterocytes. Some metabolism of L-lysine takes place within the enterocytes. The lysine that is not
metabolised is transported to the liver.
Regarding the exposure to lysine from these sources, if the lysinates are used to provide
respectively 250 mg Mg/day, 800 mg Ca/day and 15 mg Zn/day, the exposure to anionic lysine is
respectively about 3 g/day from magnesium L-lysinate, about 5.8 g/day from calcium L-lysinate
and about 0.034 g/day from zinc L-lysinate. These values are low compared to the level of lysine
in protein rich foods.
In a worst case assumption that the three lysinates would be used together in supplements as
sources of respectively magnesium, calcium and zinc at the Tolerable Upper Intake levels for the
cations, the Panel estimated the potential exposure to lysine to be up to 353 mg/kg bw/day for an
adult with a standard body weight of 60 kg.
Bearing in mind this is a worst case estimate, although the value is around twice the intake from
the normal diet, but considering the high NOAEL (the highest dose tested) in a rat study the Panel
does not have concerns.
The Panel concluded that the use of magnesium L-lysinate, calcium L-lysinate and zinc L-lysinate
used in food supplements as a source of respectively magnesium, calcium and zinc is not of safety
concern at the proposed use levels.
Key words:
Magnesium L-lysinate; calcium L-lysinate ; CAS N° 6150-68-1; zinc L-lysinate ; CAS N° 2333398-4.
The EFSA Journal (2008) 261, 2-11
Opinion on certain lysinates as sources for magnesium, calcium and zinc
TABLE OF CONTENTS
Panel Members............................................................................................................................................1
Summary .....................................................................................................................................................1
Table of Contents ........................................................................................................................................3
Background as provided by the Commission..............................................................................................4
Terms of reference as provided by the Commission ...................................................................................4
Acknowledgements .....................................................................................................................................4
Assessment ..................................................................................................................................................5
1. Introduction ........................................................................................................................................5
2. Technical data.....................................................................................................................................5
2.1.
Chemistry...................................................................................................................................5
2.2.
Specifications.............................................................................................................................6
2.3.
Manufacturing process...............................................................................................................6
2.4.
Methods of analysis in food.......................................................................................................6
2.5.
Reaction and fate in foods to which the source is added ...........................................................6
2.6.
Case of need and intended use ...................................................................................................6
2.7.
Exposure ....................................................................................................................................7
2.8.
Existing authorisations and evaluations.....................................................................................8
3. Biological and toxicological data .......................................................................................................8
3.1.
Bioavailability............................................................................................................................8
3.2.
Toxicological data......................................................................................................................8
3.2.1. Metabolism and kinetics........................................................................................................8
3.2.2. Toxicity data..........................................................................................................................9
4. Discussion...........................................................................................................................................9
Documentation provided to EFSA ............................................................................................................10
References .................................................................................................................................................10
Glossary / Abbreviations ...........................................................................................................................11
The EFSA Journal (2008) 261, 3-11
Opinion on certain lysinates as sources for magnesium, calcium and zinc
BACKGROUND AS PROVIDED BY THE COMMISSION
The European Community legislation lists nutritional substances that may be used for nutritional
purposes in certain categories of foods as sources of certain nutrients.
The Commission has received a request for the evaluation of magnesium L-lysinate, calcium Llysinate, zinc L-lysinate as a source for respectively magnesium, calcium and zinc added for
nutritional purposes in food supplements. The relevant Community legislative measures are:
•
Directive 2002/46/EC of the European Parliament and of the Council on the approximation
of the laws of the Member States relating to food supplements.2
TERMS OF REFERENCE AS PROVIDED BY THE COMMISSION
In accordance with Article 29 (1) (a) of Regulation (EC) No 178/2002, the European Commission
asks the European Food Safety Authority to provide a scientific opinion, based on its consideration
of the safety and bioavailability of magnesium L-lysinate, calcium L-lysinate, zinc L-lysinate as
sources for magnesium, calcium and zinc added for nutritional purposes in food supplements
intended for the general population.
ACKNOWLEDGEMENTS
The European Food Safety Authority wishes to thank the members of the Working Group for the
preparation of this opinion:
F. Aguilar, D. Boskou, D. Gott, S. Grilli, R. Guertler, K. Hulshof, J.C. Larsen, J.C. Leblanc, C.
Leclercq, A. Mortensen, D. Parent-Massin, I. Pratt, I. Rietjens, P. Tobback, G. Speijers, F. Toldra.
•
2
OJ L 183, 12.7.2002, p.51.
The EFSA Journal (2008) 261, 4-11
Opinion on certain lysinates as sources for magnesium, calcium and zinc
ASSESSMENT
1.
Introduction
The present opinion deals with the safety of a number of lysinates as sources for respectively
magnesium, calcium and zinc added for nutritional purposes to food supplements. The safety
evaluation of magnesium, calcium and zinc itself is outside the remit of this Panel.
2.
Technical data
2.1. Chemistry
Magnesium L-lysinate (synonym: L-Lysine, magnesium salt) has the empirical formula
(C6H13N2O2)2 Mg and as molecular mass: 314.68 Dalton. It is a white powder soluble in water. Its
structural formula is as follows:
O
H2
N
O
(CH2)4NH2
Mg
H2N(H2C)4
O
N
H2
O
Calcium L-lysinate (synonym: L-Lysine, calcium salt), CAS N° 6150-68-1, has the empirical
formula (C6H13N2O2)2 Ca and as molecular mass: 330.44 Dalton. It is a white powder slightly
soluble in water. Its structural formula is as follows:
O
H2
N
O
(CH 2)4NH2
Ca
H 2N(H 2C)4
N
H2
O
O
Zinc L-lysinate (synonym: L-Lysine, zinc salt), CAS N° 23333-98-4, has the empirical formula
(C6H13N2O2)2Zn and as molecular mass: 355.75 Dalton. It is a white powder slightly soluble in
water. Its structural formula is as follows:
The EFSA Journal (2008) 261, 5-11
Opinion on certain lysinates as sources for magnesium, calcium and zinc
O
H2
N
O
(CH2)4NH2
Zn
H2N(H2C)4
N
H2
O
O
2.2. Specifications
According to the petitioner, magnesium L-lysinate and calcium L-lysinate are not less than 97.5
pure on the anhydrous basis while zinc L-lysinate is not less than 98.0% pure.
For the three compounds the following impurities have been indicated: Arsenic (not more than 3
mg/kg), lead (not more than 3 mg/kg) and mercury (not more than 1 mg/kg).
For zinc L-lysinate it is indicated that other, unspecified, heavy metals are present at a level not
more than 10 mg/kg.
2.3. Manufacturing process
For the three compounds no details of the manufacturing process are provided by the petitioner. It
is only stated that magnesium L-lysinate is manufactured synthetically from a soluble magnesium
salt and L-lysine, calcium L-lysinate from a soluble calcium salt and L-lysine and that zinc Llysinate is manufactured from reacting l-lysine with zinc oxide in water.
2.4. Methods of analysis in food
The petitioner states that infrared spectrometry (IR) is the method used for the identification of the
compounds. Specific test methods for the identification of the three individual cations, (Mg2+, Ca2+
and Zn2+) based on precipitation are detailed by the petitioner in the application.
2.5. Reaction and fate in foods to which the source is added
The petitioner indicates that the three compounds are stable and remain available in foods, but no
data were provided.
2.6. Case of need and intended use
The three compounds are used to provide a source of respectively magnesium, calcium and zinc as
nutrients in food supplements.
According to the petitioner, magnesium L-lysinate, calcium L-lysinate and zinc L-lysinate are used
by manufacturers as ingredients in food supplement in the form of tablets, caplets, capsules,
chewable tablets, effervescent powders and liquids. The method of incorporation is determined by
the individual manufacturers as appropriate for the particular type of finished products. It is also
The EFSA Journal (2008) 261, 6-11
Opinion on certain lysinates as sources for magnesium, calcium and zinc
mentioned that the quantity of the different sources to be added to food supplements will be
determined by individual manufacturers.
The quantity of magnesium L-lysinate to be added to food supplements is normally the quantity
necessary to supply adults up to 250 mg Mg/day. However, the petitioner indicates that magnesium
salts are used in food supplements at levels providing up to 750 mg Mg/day (EVM, 2003)
The quantity of calcium L-lysinate incorporated in food supplements would normally supply up to
800 mg Ca/day.
The quantity of zinc L-lysinate incorporated in food supplements would normally supply up to 15
mg Zn/day.
2.7. Exposure
The petitioner states that the anticipated dietary exposure of the population to magnesium, calcium
or zinc in food supplements is by self-selection of products containing Multivitamins and
Multiminerals or as more specific combinations providing these elements.
As products containing magnesium L-lysinate, calcium L-lysinate and zinc L-lysinate are
manufactured by many different companies in the EU, according to the petitioner it is difficult to
obtain sales statistics to indicate the total exposure. Similarly, the total quantity of the above listed
lysinates sold to manufacturers for use in food supplements in Europe is also unknown
As indicated above, the quantity of magnesium L-lysinate to be added to food supplements for
adults will be up to 250 mg Mg/day. Based on this value, the exposure to lysine from this source is
calculated to be about 3 g lysine/day as lysinate.
In case the level used would be up to 750 mg Mg/day (EVM, 2003b), and if this quantity is
entirely supplied by magnesium L-lysinate, the exposure to anionic lysine would be about 9 g/day.
The Panel noted however, that for magnesium a Tolerable Upper Intake Level has been established
by the SCF: 250 mg per day for readily dissociable magnesium salts and compounds like
magnesium oxide, not including magnesium normally present in foods and beverages for adults
and children from 4 years on (SCF, 2001).
The quantity of calcium supplied by the addition of calcium L-lysinate to food supplements will be
up to 800 mg Ca/day. Such a supplementation would give a calculated exposure to anionic lysine
of about 5.8 g/day. The Tolerable Upper Intake level of calcium for adults is 2500 mg/day (SCF,
2003b). At this intake level the exposure to anionic lysine would be 18.1 g/day
Similarly, the quantity of zinc supplied by the addition of zinc L-lysinate to food supplements will
be up to 15 mg Zn/day. Such a supplementation gives a calculated exposure to anionic lysine of
about 0.034 g/day. The Tolerable Upper Intake level of zinc for adults is 25 mg Zn/day (SCF,
2003a). At this intake level the exposure to anionic lysine would amount to 0.056 g/day.
In a worst case assumption that the three lysinates would be used together in supplements as
sources of respectively magnesium, calcium and zinc at the Tolerable Upper Intake levels for the
cations, the Panel estimated the potential exposure to lysine would be up to 21.16 (3 + 18.1 +
0.056) g/day, corresponding to 353 mg/kg bw/day for an adult with a standard body weight of 60
kg.
The EFSA Journal (2008) 261, 7-11
Opinion on certain lysinates as sources for magnesium, calcium and zinc
L-lysine is an amino acid present in proteins. It is classified as an essential amino acid for humans.
Certain proteins are rich in L-lysine, e.g. meat (beef): about 23 g lysine/kg, whole raw eggs: about
9 g lysine/kg and milk: about 3 g lysine/kg. Proteins found in grains, cereals and their products are
typically low in L-lysine, e.g. whole white rice: about 2 g lysine/kg (Fennema, 1996).
Recent intake recommendations to meet the lysine requirement range from 64 to 30 mg/kg per day
for respectively 6 months old infants and adults (>18 years), respectively (WHO, 2007). Lysine
intake in the Western human diet is in the range of 40-180 mg/kg per day (Tomé and Bos, 2007).
2.8. Existing authorisations and evaluations
The SCF considered the use of L-amino acids generally acceptable provided the addition to food
does not give rise to a nutritional imbalance of the amino acids (SCF, 1990).
In 2001, The Scientific Committee on Food (SCF) issued an opinion on the Tolerable Upper Intake
level of magnesium. The Tolerable Upper Intake level of magnesium given by the SCF for adults
is 250 mg/day (SCF, 2001).
In 2003, the SCF issued an opinion on the Tolerable Upper Intake level of calcium. The Tolerable
Upper Intake level of calcium given by the SCF for adults is 2500 mg/day (SCF, 2003b).
In 2003, zinc was evaluated the UK Expert Group on Vitamins and Minerals (EVM, 2003a) and by
the SCF (SCF, 2003a). The Tolerable Upper Intake level of zinc given by the SCF for adults is 25
mg Zn/day (SCF, 2003a).
3.
Biological and toxicological data
3.1. Bioavailability
Magnesium L-lysinate, calcium L-lysinate and zinc L-lysinate are salts of L-lysine and, like other
salts of organic acids, soluble in water. No information was provided on the bioavailability of
magnesium, calcium and zinc from the L-lysinate sources however, their bioavailability is likely to
be similar to that of other soluble sources of these cations. The compounds are expected to
dissociate before absorption and to be absorbed in the intestine.
3.2. Toxicological data
3.2.1.
Metabolism and kinetics
The absorption and metabolic fate of magnesium, calcium and zinc cations has been thoroughly
described previously by the SCF and the EFSA (SCF 1990, 2001, 2003a, 2003b) and has recently
been compiled (EFSA, 2006).
L-Lysine, following ingestion, is absorbed from the lumen of the small intestine into the
enterocytes by an active transport process. Some metabolism of L-lysine takes place within the
enterocytes. The lysine that is not metabolized is transported to the liver via the portal circulation.
The EFSA Journal (2008) 261, 8-11
Opinion on certain lysinates as sources for magnesium, calcium and zinc
L-Lysine, in the liver, participates in protein biosynthesis along with other amino acids. It is the
exception to the general rule that the first step in catabolism of an amino acid is the removal of its
alpha-amino group by transamination to form the respective alpha-keto acid. L-Lysine is both a
glycogenic and a ketogenic amino acid. Some is metabolised to L-alpha-aminoadipic acid semialdehyde, which is further metabolised to acetoacetyl-CoA. It can participate in the formation of
D-glucose and glycogen, as well as lipids. It can also participate in the production of energy.
3.2.2.
Toxicity data
The toxicity of the cations magnesium, calcium and zinc has been evaluated by the SCF (SCF,
1990; SCF, 2001; SCF, 2003a; SCF 2003b; EVM, 2003a; EVM, 2003b)
Further, the SCF considered the use of L-amino acids generally acceptable provided the addition to
food does not give rise to a nutritional imbalance of the amino acids (SCF, 1990).
However, since the evaluation by the AFC Panel a 13-week oral toxicity study of L-lysine
hydrochloride in male and female Sprague-Dawley rats has been published (Tsubuku et al,.2004).
This study evaluated toxicological and behavioural effects of lysine during a dosing period. The
amino acid was incorporated into a standard diet at doses equal to 1.25%, 2.5%, and 5.0% (w/w).
A control group of rats received a standard diet. All diets were administered ad libitum for 13
consecutive weeks. To examine reversibility of any potential effects, the administration period was
followed by a 5-week recovery period during which only the standard diet was provided to all
animals. In male and female rats in each concentration group, no treatment-related changes were
observed in the clinical signs, body weights, diet consumption, water intake, ophthalmology, gross
pathology, organ weights, or histology. A lysine-related drop in serum concentration and an
increase in urine excretion of chlorides was a compensatory reaction to the ingested hydrochloride.
No functional, biochemical, or histological changes in renal function were found. The noobserved-adverse-effect level (NOAEL) for lysine was estimated at 5.0% in the diet for both
genders (male, 3.36 g/kg bw/day; female, 3.99 g/kg bw/day) as calculated by the authors.
4.
Discussion
The Panel noted that magnesium L-lysinate, calcium L-lysinate and zinc L-lysinate are salts of the
amino acid L-lysine and, like other salts of organic acids, soluble in water. The bioavailability of
the respective cations is likely to be similar to that of other soluble sources of the cations. The
compounds are expected to dissociate before absorption and to be readily absorbed in the intestine.
L-Lysine, following ingestion, is absorbed from the lumen of the small intestine into the
enterocytes. Some metabolism of L-lysine takes place within the enterocytes. The lysine that is not
metabolised is transported to the liver.
It can be calculated that if the three lysinates are used in supplements to provide respectively up to
250 mg Mg/day, up to 800 mg Ca/day and up to 15 mg Zn/day, the exposure to anionic lysine is
respectively about 3 g/day for magnesium L-lysinate as the source, about 5.8 g/day for calcium Llysinate as the source and about 0.034 g/day for zinc L-lysinate as the source. These values are low
compared to the level of lysine in protein rich foods.
The EFSA Journal (2008) 261, 9-11
Opinion on certain lysinates as sources for magnesium, calcium and zinc
In the worst case assumption that the three lysinates would be used together in supplements as
sources of respectively magnesium, calcium and zinc at the Tolerable Upper Intake levels for the
cations, the Panel estimated the potential exposure to lysine to be up to 353 mg/kg bw/day for an
adult with a standard body weight of 60 kg.
Bearing in mind this is a worst case estimate, although the value is around twice the intake from
the normal diet, but considering the high NOAEL (the highest dose tested) in the rat study, the
Panel does not have concerns.
CONCLUSIONS
The present opinion deals only with the safety of a number of lysinates as sources for respectively
magnesium, calcium and zinc added for nutritional purposes to food supplements. The safety
evaluation of magnesium, calcium and zinc itself is outside the remit of this Panel.
Magnesium L-lysinate, calcium L-lysinate and zinc L-lysinate being salts of the amino acid Llysine, like other salts of organic acids, are soluble in water and are expected to dissociate and the
bioavailability of the respective cations is expected to be similar to that of other soluble sources of
these cations.
The Panel concluded that the use of magnesium L-lysinate, calcium L-lysinate and zinc L-lysinate
used in food supplements as a source of respectively magnesium, calcium and zinc is not of safety
concern at the proposed use levels.
DOCUMENTATION PROVIDED TO EFSA
1. Application dossiers for magnesium L-lysinate, calcium L-lysinate and zinc L-lysinate.
Submitted by the ‘Health Food Manufacturers Association, UK’.
REFERENCES
EC, 2001. Commission Directive 2001/15/EC on substances that may be added for specific
nutritional purposes in foods for particular nutritional uses. Official Journal of the European
Communities L 52/19, 22.2.2001
EFSA, 2006. Tolerable Upper Intake Levels for Vitamins and Minerals. European Food Safety
Authority. February 2006.
EVM, 2003a (Expert Group on Vitamins and Minerals). Report on safe upper levels for vitamins
and minerals. Zinc. London, May 2003.
EVM, 2003b (Expert Group on Vitamins and Minerals). Report on safe upper levels for vitamins
and minerals. Magnesium. London, May 2003.
The EFSA Journal (2008) 261, 10-11
Opinion on certain lysinates as sources for magnesium, calcium and zinc
Fennema, O.R., 1996. Food Chemistry, 3rd Edition, p. 397, Marcel Dekker Inc. NewYork.
SCF, 1990. Report of the Scientific Committee for Food (25th Series). Opinion expressed on 18
May 1990.
SCF, 2001. Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of
Magnesium. http://ec.europa.eu/food/fs/sc/scf/out105_en.pdf
SCF, 2003a. Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of
Zinc (March 2003).
SCF, 2003b. Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of
Calcium. Expressed on 4 April 2003. SCF/CS/NUT/UPPLEV/64 Final. 23 April 2003.
Tomé, D. and Bos, C., 2007. Lysine Requirement through the Human Life Cycle. J. Nutr. 137,
1642S-1645S.
Tsubuku, S., Mochizuki, M., Mawatari, K., Smriga, M. and Kimura, T., 2004. Thirteen-week oral
toxicity study of L-lysine hydrochloride in rats. Int. J. Toxicol. 23(2), 113-118.
WHO, 2007. Protein and amino acid requirements in human nutrition: report of a joint
FAO/WHO/UNU expert consultation. WHO technical report Series, no. 935.
http://whqlibdoc.who.int/trs/WHO_TRS_935_eng.pdf
GLOSSARY / ABBREVIATIONS
AFC
Scientific Panel on food additives, flavourings, processing aids and materials
in contact with food.
bw
body weight
CAS
Chemical Abstract Service
EVM
Expert Group on Vitamins and Minerals, UK
NOAEL
No-Observed-Adverse-Effect Level
SCF
Scientific Committee for Food
WHO
World Health Organization
The EFSA Journal (2008) 261, 11-11