EFSA Journal 2013;11(2):3103
SCIENTIFIC OPINION
Scientific Opinion on the safety and efficacy of vitamin C (ascorbic acid and
sodium calcium ascorbyl phosphate) as a feed additive for all animal species
based on a dossier submitted by VITAC EEIG1
EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP)2, 3
European Food Safety Authority (EFSA), Parma, Italy
ABSTRACT
Vitamin C (formerly known as antiscorbutic vitamin) is essential for primates, guinea pigs and fish. Vitamin C,
in the form of ascorbic acid and sodium calcium ascorbyl phosphate, is safe for all animal species. Setting a
maximum content in feed and water for drinking is not considered necessary. Data on the vitamin C
consumption of consumers are based on the levels of vitamin C in foodstuffs, including food of animal origin,
produced in accordance with current EU legislation on the supplementation of feed with vitamin C. The
exposure is far below the guidance level. Any potential contribution of the use of vitamin C in feed is therefore
already considered in the above data. Consequently, the use of vitamin C in animal nutrition is not of concern for
consumer safety. In the absence of inhalation toxicity studies it would be prudent to assume that inhalation of
dust from the additives presents a health hazard to workers and measures should be taken to minimise inhalation
exposure. In the absence of data, ascorbic acid and sodium calcium ascorbyl phosphate should be considered as
irritant to skin and eyes and as dermal sensitisers. The supplementation of feed with vitamin C does not pose a
risk to the environment. Ascorbic acid and sodium calcium ascorbyl phosphate are regarded as effective sources
of vitamin C when added to feed or water for drinking.
© European Food Safety Authority, 2013
KEY WORDS
Nutritional additive, vitamins and provitamins, vitamin C, ascorbic acid, sodium calcium ascorbyl phosphate,
safety
1
2
3
On request from the European Commission, Question No EFSA-Q-2011-00250, adopted 30 January 2013. Revision 1 – 21
February 2013: minor editorial changes.
Panel members: Gabriele Aquilina, Alex Bach, Vasileios Bampidis, Maria De Lourdes Bastos, Gerhard Flachowsky, Josep
Gasa-Gasó, Mikolaj Antoni Gralak, Christer Hogstrand, Lubomir Leng, Secundino López-Puente, Giovanna Martelli,
Baltasar Mayo, Derek Renshaw, Guido Rychen, Maria Saarela, Kristen Sejrsen, Patrick Van Beelen, Robert John Wallace
and Johannes Westendorf. Correspondence: FEEDAP@efsa.europa.eu
Acknowledgement: The Panel wishes to thank the members of the Working Group on Vitamins, including Georges Bories,
Jürgen Gropp, Alberto Mantovani and the late Reinhard Kroker, for the preparatory work on this scientific opinion.
Suggested citation: EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) ; Scientific
Opinion on the safety and efficacy of vitamin C (ascorbic acid and sodium calcium ascorbyl phosphate) as a feed additive for
all animal species based on a dossier submitted by VITAC EEIG. EFSA Journal 2013;11(2):3103. [25 pp.]
doi:10.2903/j.efsa.2013.3103. Available online: www.efsa.europa.eu/efsajournal
© European Food Safety Authority, 2013
Vitamin C for all animal species
SUMMARY
Following a request from the European Commission, the Panel on Additives and Products or
Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and
efficacy of vitamin C in the form of ascorbic acid and sodium calcium ascorbyl phosphate as a
nutritional additive for all animal species. Ascorbic acid and sodium calcium ascorbyl phosphate are
intended for addition to feed. Ascorbic acid is also intended for use in water for drinking.
Vitamin C (formerly known as antiscorbutic vitamin) is essential for primates, guinea pigs and fish. It
is involved in the synthesis of collagen and in incorporating iron into ferritin. It is required for
neutrophil function and decreases circulating glucocorticoids. Vitamin C is thought to play a critical
role in the immune response.
Vitamin C, in the form of ascorbic acid and sodium calcium ascorbyl phosphate, is safe for all animal
species. Setting a maximum content in feed and water for drinking is not considered necessary.
Data on the vitamin C consumption of consumers are based on the levels of vitamin C in foodstuffs,
including food of animal origin, produced in accordance with current EU legislation on the
supplementation of feed with vitamin C. The exposure is far below the guidance level. Any potential
contribution of the use of vitamin C in feed is therefore already considered in the above data.
Consequently, the use of vitamin C in animal nutrition is not of concern for consumer safety.
The FEEDAP Panel concludes that in the absence of inhalation toxicity studies it would be prudent to
assume that inhalation of dust from the additives presents a health hazard to workers and measures
should be taken to minimise inhalation exposure. In the absence of data, ascorbic acid and sodium
calcium ascorbyl phosphate should be considered as irritant to skin and eyes and as dermal sensitisers.
The supplementation of feed with vitamin C does not pose a risk to the environment.
Owing to the long history of use and its established nutritional role in domestic animals, ascorbic acid
and sodium calcium ascorbyl phosphate are regarded as effective sources of vitamin C. This
conclusion includes the use of ascorbic acid in water for drinking.
The FEEDAP Panel made some recommendations concerning the nomenclature and the specifications
of the substances under application.
EFSA Journal 2013;11(2):3103
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Vitamin C for all animal species
TABLE OF CONTENTS
Abstract .................................................................................................................................................... 1
Summary .................................................................................................................................................. 2
Table of contents ...................................................................................................................................... 3
Background .............................................................................................................................................. 4
Terms of reference.................................................................................................................................... 5
Assessment ............................................................................................................................................... 8
1. Introduction ..................................................................................................................................... 8
2. Characterisation ............................................................................................................................... 8
2.1. Ascorbic acid obtained by fermentation and subsequent chemical synthesis ........................... 8
2.1.1. Manufacturing process ....................................................................................................... 8
2.1.2. Characteristics of the active substance ............................................................................... 9
2.2. Sodium calcium ascorbyl phosphate ....................................................................................... 10
2.3. Stability and homogeneity ...................................................................................................... 11
2.3.1. Stability of ascorbic acid .................................................................................................. 12
2.3.2. Stability of sodium calcium ascorbyl phosphate .............................................................. 12
2.3.3. Homogeneity .................................................................................................................... 13
2.4. Physico-chemical incompatibilities in feed ............................................................................ 13
2.5. Conditions of use .................................................................................................................... 13
2.6. Evaluation of the analytical methods by the European Union Reference Laboratory (EURL) 13
3. Safety ............................................................................................................................................. 13
3.1. Safety for the target species .................................................................................................... 14
3.1.1. Conclusions on the safety of vitamin C for the target species .......................................... 14
3.2. Safety for the consumer .......................................................................................................... 15
3.2.1. Absorption, distribution, metabolism and excretion (ADME) ......................................... 15
3.2.2. Toxicological studies ........................................................................................................ 15
3.2.3. Assessment of consumer safety ........................................................................................ 16
3.3. Safety for the user ................................................................................................................... 17
3.3.1. Effects on the respiratory system...................................................................................... 17
3.3.2. Effects on the eyes and skin ............................................................................................. 17
3.3.3. Conclusions on user safety ............................................................................................... 17
3.4. Safety for the environment...................................................................................................... 17
4. Efficacy.......................................................................................................................................... 17
5. Post-market monitoring ................................................................................................................. 18
Conclusions and recommendations ........................................................................................................ 18
Documentation provided to EFSA ......................................................................................................... 19
References .............................................................................................................................................. 19
Appendices ............................................................................................................................................. 22
Appendix A ............................................................................................................................................ 22
Appendix B ............................................................................................................................................ 24
EFSA Journal 2013;11(2):3103
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Vitamin C for all animal species
BACKGROUND
Regulation (EC) No 1831/20034 establishes the rules governing the Community authorisation of
additives for use in animal nutrition. In particular, Article 4(1) of that Regulation lays down that any
person seeking authorisation for a feed additive or for a new use of a feed additive shall submit an
application in accordance with Article 7; in addition Article 10(2) of that Regulation also specifies that
for existing products within the meaning of Article 10(1), an application shall be submitted in
accordance with Article 7, at the latest one year before the expiry date of the authorisation given
pursuant to Directive 70/524/EEC for additives with a limited authorisation period, and within a
maximum of seven years after the entry into force of this Regulation for additives authorised without
time limit or pursuant to Directive 82/471/EEC.
The European Commission received a request from the VITAC EEIG Vitamins Authorisation
Consortium5 for (i) authorisation of a new use (i.e. use in water for drinking) of vitamin C in the form
of L-ascorbic acid and (ii) re-evaluation of authorisation of vitamin C in the form of L-ascorbic acid
and ascorbyl monophosphate calcium sodium salt, when used as a feed additive for all animal species
(category: nutritional additive; functional group: vitamins, provitamins and chemically well-defined
substances having similar effect) under the conditions mentioned in Table 1a,b.
According to Article 7(1) of Regulation (EC) No 1831/2003, the Commission forwarded the
application to the European Food Safety Authority (EFSA) as an application under Article 4(1)
(authorisation of a feed additive or new use of a feed additive) and under Article 10(2) (re-evaluation
of an authorised feed additive). EFSA received directly from the applicant the technical dossier in
support of this application.6 According to Article 8 of that Regulation, EFSA, after verifying the
particulars and documents submitted by the applicant, shall undertake an assessment in order to
determine whether the feed additive complies with the conditions laid down in Article 5. The
particulars and documents in support of the application were considered valid by EFSA as of 20 April
2011.7
Vitamin C in the form of L--ascorbic acid, sodium L-ascorbate, calcium L-ascorbate, 6-palmityl Lascorbic acid and ascorbyl monophosphate calcium sodium salt has been authorised without time limit
under Council Directive 70/524/EEC8 for its use for all animal species as a nutritional additive and in
the form of L-ascorbic acid sodium L-ascorbate, calcium L-ascorbate and 6-palmityl L-ascorbic acid as
technological additive (antioxidant).
The Scientific Panel on Dietetic Products, Nutrition and Allergies (NDA) expressed an opinion on the
tolerable upper intake level of vitamin C (L-ascorbic acid, its calcium, potassium and sodium salts and
L-ascorbyl-6-palmitate) (EFSA, 2004).
The Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food
(AFC) issued an opinion on calcium ascorbate with a content of threonate for use as source of vitamin
C in food supplements (EFSA, 2007). A statement on the safety of calcium ascorbate with a content of
threonate produced by a new manufacturing process as a source of vitamin C in food supplements has
been published by EFSA in 2011 (EFSA, 2011a).
The Panel on Food Additives and Nutrient Sources added to food (ANS) issued an opinion on calcium
ascorbate, magnesium ascorbate and zinc ascorbate added for nutritional purposes in food supplements
(EFSA, 2009a), another opinion on the inability to assess the safety of vitamin C-enriched yeast for
4
5
6
7
8
Regulation (EC) 1831/2003 of the European Parliament and of the Council of 22 September 2003 on additives for use in
animal nutrition. OJ L 268, 18.10.2003, p. 29.
VITAC EEIG Vitamins Authorisation Consortium, Avenue Louise 130A, B-1050 Brussel, Belgium. Companies: ORFFA
International BV, The Netherlands; Trouw Nutrition International BV, The Netherlands.
EFSA Dossier reference: FAD-2010-0214.
A new mandate was received in EFSA in March 2011.
Commission List of the authorised additives in feedingstuffs published in application of Article 9t (b) of Council Directive
70/524/EEC concerning additives in feedingstuffs (2004/C 50/01). OJ C 50, 25.2.2004, p. 1.
EFSA Journal 2013;11(2):3103
4
Vitamin C for all animal species
nutritional purposes as a source of vitamin C in food supplements and the bioavailability of vitamin C
from this source, based on the supporting dossier (EFSA, 2009b) and another opinion on the use of
sodium ascorbate as a food additive in vitamin D preparations intended to be used in formulae and
weaning food for infants and young children (EFSA, 2010a). Ascorbates will be re-evaluated by the
ANS Panel as part of the food additives re-evaluation programme specified under Regulation (EU) No
257/2010.9 This opinion is expected to be delivered by the end of 2015. Ascorbyl fatty acid esters will
be re-evaluated by the ANS Panel as part of the food additives re-evaluation programme specified
under Regulation (EU) No 257/2010. This opinion is expected to be delivered by the end of 2015.
The NDA Panel expressed four opinions on the substantiation of several health claims pursuant to
Article 13(1) of Regulation (EC) No 1924/200610 (EFSA, 2009c, 2010b, c, 2011b).
TERMS OF REFERENCE
According to Article 8 of Regulation (EC) No 1831/2003, EFSA shall determine whether the feed
additive complies with the conditions laid down in Article 5. EFSA shall deliver an opinion on the
safety for the target animals, consumer, user and the environment and the efficacy of vitamin C in the
form of L-ascorbic acid and ascorbyl monophosphate calcium sodium salt, when used under the
conditions described in Table 1a,b.
9
Commission Regulation (EU) No 257/2010 of 25 March 2010 setting up a programme for the re-evaluation of approved
food additives in accordance with Regulation (EC) No 1333/2008 of the European Parliament and of the Council on food
additives. OJ L 80, 26.3.2010, p. 29.
10
Regulation (EC) No 1924/2006 of the European Parliament and of the Council of 20 December 2006 on nutrition and
health claims made on foods. OJ L 404, 30.12.2006, p. 9.
EFSA Journal 2013;11(2):3103
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Vitamin C for all animal species
Table 1a: Description and conditions of use of the additive as proposed by the applicant
Additive
Table 1:
Vitamin C / L-Ascorbic acid
Registration number/EC No/No
(if appropriate)
E300
Category of additive
3. Nutritional Additives
Functional group(s) of additive
a. Vitamins, provitamins and chemically well defined substances
having a similar effect
Description
Composition, description
L-ascorbic acid
Trade name (if appropriate)
Chemical
formula
Purity criteria
(if appropriate)
C6H8O6
Min 99.0%
Method of analysis
(if appropriate)
Assay, as mentioned in
current European
Pharmacopoeia method
Not appropriate
Name
of
the
holder
authorisation (if appropriate)
of
Not appropriate
Conditions of use
Species
category
animal
or
of
Minimum content
Maximum content
Withdrawal period
(if appropriate)
Maximum Age
mg/kg of complete feedingstuffs
All animal
species and
categories
No restrictions during all life
cycle
Not applicable
Not applicable
Not appropriate
Other provisions and additional requirements for the labelling
Specific conditions or restrictions for use
(if appropriate)
Only for manufacture of animal feeds.
Specific conditions or restrictions for
handling (if appropriate)
Not appropriate
Post market monitoring
(if appropriate)
No specific requirements other than the traceabiliity and
complaint system implemented in compliance with the
requirements of Regulation (EC) No. 183/2005.
Specific
conditions
for
use
in
complementary feedingstuffs or water
(if appropriate)
Applicable in premixtures, feedingstuffs & water.
Maximum Residue Limit (MRL) (if appropriate)
Marker residue
Species or category of
animal
Target tissue(s) or
food products
Maximum content in
tissues
Not appropriate
Not appropriate
Not appropriate
Not appropriate
EFSA Journal 2013;11(2):3103
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Vitamin C for all animal species
Table 1b: Description and conditions of use of the additive as proposed by the applicant
Additive
Vitamin C / Ascorbyl monophosphate Calcium sodium salt
Registration number/EC No/No
(if appropriate)
Not appropriate
Category of additive
3. Nutritional Additives
Functional group(s) of additive
a. Vitamins, provitamins and chemically well defined substances
having a similar effect
Description
Composition, description
Chemical
formula
Purity criteria
(if appropriate)
Ascorbyl monophosphate calcium
sodium salt
C6H6O9P CaNa
Min. 35.0% of Lascorbic acid bound
to phosphate
Trade name (if appropriate)
Method of analysis
(if appropriate)
Additive:
Spectrophotometric
method
Premixtures&Feed:
reversed-phase HPLC-UV
Not appropriate
Name
of
the
holder
authorisation (if appropriate)
of
Not appropriate
Conditions of use
Species
category
animal
or
of
Minimum content
Maximum content
Withdrawal period
(if appropriate)
Maximum Age
mg/kg of complete feedingstuffs
All animal
species and
categories
No restrictions
- during all life
cycle
Not applicable
Not applicable
Not appropriate
Other provisions and additional requirements for the labelling
Specific conditions or restrictions for use
(if appropriate)
Only for manufacture of animal feeds.
Specific conditions or restrictions for
handling (if appropriate)
Not appropriate
Post market monitoring
(if appropriate)
No specific requirements other than the traceabiliity and
complaint system implemented in compliance with the
requirements of Regulation (EC) No. 183/2005.
Specific
conditions
for
use
in
complementary feedingstuffs or water
(if appropriate)
Applicable in premixtures & feedingtuffs.
Maximum Residue Limit (MRL) (if appropriate)
Marker residue
Species or category of
animal
Target tissue(s)
or food products
Maximum content in
tissues
Not appropriate
Not appropriate
Not appropriate
Not appropriate
EFSA Journal 2013;11(2):3103
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Vitamin C for all animal species
ASSESSMENT
This opinion is based in part on data provided by a consortium of companies involved in the
production/distribution of vitamin C in the form of ascorbic acid and sodium calcium ascorbyl
phosphate. It should be recognised that these data cover only a fraction of existing additives containing
vitamin C in the form of ascorbic acid and sodium calcium ascorbyl phosphate. The application is for
the active substance and the composition of the additive formulations is not the subject of the
application. The Panel has sought to use the data provided together with data from other sources to
deliver an opinion.
The application contains data from one source of ascorbic acid obtained by fermentation and
subsequent chemical synthesis and from one source of sodium calcium ascorbyl phosphate obtained
by chemical synthesis.
1.
Introduction
The term vitamin C is used as generic description of ascorbic acid (reduced form) and
dehydroascorbic acid (oxidised form). Only the L-isomer of both forms has vitamin activity. Vitamin
C is widely distributed and occurs in large quantities in feeds of plant origin that are most relevant for
animal nutrition, particularly in green feeds and silages. Vitamin C is involved in the synthesis of
collagen and in incorporating plasma iron into ferritin. It is required for neutrophil function and
decreases circulating glucocorticoids. Thus, vitamin C is thought to play a critical role in the immune
response. It also reduces oxidised tocopherol to its active form in liver.
The antioxidant property of vitamin C is also utilised when protection against oxidation of food or
feed during manufacturing and storage is required.
Vitamin C in the form of L-ascorbic acid (hereafter referred to as ascorbic acid) and ascorbyl
monophosphate calcium sodium salt (hereafter referred to as sodium calcium ascorbyl phosphate) is
included in the European Union Register of Feed Additives pursuant to Regulation (EC) No
1831/2003 and foreseen for re-evaluation. It is authorised for use in all animal species without a time
limit as a nutritional additive and in the case of ascorbic acid as a technological additive (antioxidant).
No maximum levels of vitamin C in feeds are established in the EU.
The applicant asks for the re-evaluation of the use of vitamin C in the form of ascorbic acid and
sodium calcium ascorbyl phosphate as an additive to feed and for a new use of vitamin C in the form
of ascorbic acid (use in water for drinking). The substance is intended as nutritional additive under the
functional group vitamins, pro-vitamins and chemically well-defined substances having similar
effects, for all animal species and categories.
Ascorbic acid (E300) is approved for food use as vitamin and antioxidant whereas sodium calcium
ascorbyl phosphate is not approved for use in food (details see Appendix B).
Ascorbic acid is described in the European Pharmacopoeia (PhEur) as Monograph (MG) 0253.
2.
Characterisation
2.1.
Ascorbic acid obtained by fermentation and subsequent chemical synthesis
2.1.1.
Manufacturing process
Two fermentation steps and a chemical synthesis are involved in the production of ascorbic acid. In a
first fermentation step, sorbitol is converted to sorbose by Gluconobacter oxydans. In the second step,
mixed strains of Bacillus megaterium and Ketogulonicigenium vulgare are used to convert sorbose to
sodium 2-keto-L-gulonic acid. The latter is extracted by ultrafiltration, purified by ion exchange,
concentrated and crystallised. Crude ascorbic acid is chemically synthesised from this intermediate via
EFSA Journal 2013;11(2):3103
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Vitamin C for all animal species
esterification and lactonisation. The final product is obtained after several purification steps. The
applicant provided a flow-chart and detailed description of the media used for fermentation and the
synthetic process. Relevant material safety data sheets are submitted for the substrates/chemicals used.
The strain of Gluconobacter oxydans is deposited at the China General Microbiological Culture
Collection Centre of the Chinese Academy of Sciences (CGMCC) with the deposition number 7.30
(in-house identifier: R-30-10-12 or R-30-08-01).11 It has not been genetically modified.12 Strain
identity was established by the full 16S rRNA gene sequence, which, by comparison with sequences
recorded in databases, was unambiguously identified as Gluconobacter oxydans.13
According to the manufacturer, Bacillus megaterium and Ketogulonicigenium vulgare are symbiotic
and are therefore cultured in combination for the production of ascorbic acid. The strain mixture is
deposited at the CGMCC with the deposition number 7.31 (in-house identifier: 2980-10-12 or 298008-01).11 The strains have not been genetically modified.12 Their identity was established by the full
16S rRNA gene sequence and cell shape and, by comparison with sequences recorded in databases,
were unambiguously identified as Bacillus megaterium (2980-10-12-1) and Ketogulonicigenium
vulgare (2980-10-12-2).13
The microorganism Gluconobacter oxydans is not known to produce toxins, virulence factors or
antibiotics. Data on antibiotic resistance of the production strains were not provided. The strain
Bacillus megaterium has been tested to be free of antibiotic resistance.14 The battery of antibiotics
tested was that recommended by the EFSA (EFSA, 2012). All minimum inhibitory concentration
values for the Bacillus megaterium strain fell below the corresponding cut-off values. The toxigenic
potential of Bacillus megaterium was not provided. Several strains used in the production of 2-keto-Lgulonic acid and classified as α-subclass of Proteobacteria were compared by Urbance et al. (2001).15
They were shown to share common characteristics and not to harbour resistance genes to antibiotics.
The FEEDAP Panel notes that (i) the additive has a purity of 99.9 %, (ii) the absence of the production
organism in the additive is stated by the applicant16 and (iii) different purification steps are used in the
production of the additive (ultrafiltration, ion exchange and crystallisation of the sodium 2-keto-Lgulonic acid, additional crystallisation of ascorbic acid). It concludes that the presence of any impurity
from the fermentation process in the final product (including DNA fragments and virulence factors
potentially produced by strains involved in the fermentation process) is highly unlikely.
2.1.2.
Characteristics of the active substance
Ascorbic acid (International Union of Pure and Applied Chemistry (IUPAC) name (5R)-[(1S)-1,2dihydroxyethyl]-3,4-dihydroxyfuran-2(5H)-one; synonyms L-ascorbic acid, vitamin C) is identified by
the Chemical Abstracts Service (CAS) number 50-81-7 and the European Inventory of Existing
Chemical Substances (EINECS) number 200-066-2. The structural formula of ascorbic acid is shown
in Figure 1.
11
Technical dossier/Section II/Annex 2.11 and Supplementary Information/July 2012/Annex D.
Supplementary information/July 2012/Annex B.
13
Supplementary information/July 2012/Annex C.
14
Supplementary information/July 2012/Annex F.
15
Technical dossier/Section II/Ref. 2.2.02.
16
Technical dossier/Section II/Annex 2.7.
12
EFSA Journal 2013;11(2):3103
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Vitamin C for all animal species
Figure 1: Structural formula of ascorbic acid
The molecular formula of ascorbic acid is C6H8O6 and its molecular weight is 176.12. It has a melting
point of 191–192 °C, shows a bulk density of approximately 1.65 g/cm3 and is soluble in water (1 g
dissolves in 3 mL). It has two pKa values: 4.2 and 11.6. The pH of a 5 % (w/v) solution in water is
2.2–2.5.
Ascorbic acid occurs as white or almost white crystals or as a crystalline powder and is almost
odourless. Ascorbic acid is described in the European Pharmacopoeia (PhEur 7.0, 0253) as having a
purity of 99.0–100.5 % ascorbic acid, less than 0.2 % related substances (impurity E, oxalic acid),
sulphated ash < 0.1 % and heavy metals (expressed as lead) < 10 mg/kg.
By specification, the active substance contains at least 99.0 % ascorbic acid. Analysis of five batches
of the ascorbic acid under application showed an average (± SD) content of ascorbic acid of
99.9 ± 0.1 %, compliant with PhEur 0253.17 Heavy metals content was < 20 mg/kg; however, the lead
content was determined to be < 2 mg/kg. However, in three other batches, the heavy metals content
(expressed as lead) was < 3 mg/kg. Data on total plate count, yeast and moulds indicate that the
product is naturally free of microbial contamination; Escherichia coli, Salmonella and Staphylococcus
aureus were absent.18 The final product is free of the producing microorganisms.19 Product batches are
routinely screened for contaminants and impurities (including absence of antibiotic activity).20 Final
formulations are also monitored for aflatoxins (B1, B2, G1 and G2), which were below the limits of
detection (LOD) in one batch (LODs range from 0.15 to 0.30 µg/kg).21 Methanol (specification ≤
500 mg/kg) was in the range of 118–171 mg/kg in five batches.
Three batches of ascorbic acid were analysed for particle size distribution by laser diffraction. The
fraction of particles below 50 µm was between 6.2 and 7.1 % (v/v).22 The substance showed a dusting
potential of 1.14 g/m3.23
2.2.
Sodium calcium ascorbyl phosphate
Sodium calcium ascorbyl phosphate is obtained by esterification of ascorbic acid (alone or in
combination with sodium ascorbate). Adding calcium hydroxide and sodium trimetaphosphate and
further processing steps result in the final product. Different calcium sodium ascorbyl phosphates may
result from this manufacturing process (see Figure 2). The applicant provided a flow-chart and
detailed description of the synthetic process. Control measures are in place.
Sodium calcium ascorbyl phosphate (chemical name sodium-, calcium-L-ascorbyl phosphate) is not
identified by a CAS number or an EINECS number. The structural formula of sodium calcium
ascorbyl phosphate is shown in Figure 2.
17
Technical dossier/Section II/Annex 2.1
Technical dossier/Section II/Annex 2.5.
19
Technical dossier/Section II/Annex 2.7.
20
Technical dossier/Section II/Annex 2.16.
21
Technical dossier/Section II/Annex 2.6.
22
Technical dossier/Section II/Annex 2.12.
23
Technical dossier/Supplementary Information September 2011/Annex A.
18
EFSA Journal 2013;11(2):3103
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Vitamin C for all animal species
Figure 2: Structural formula of sodium calcium ascorbyl phosphate
The empirical molecular formula of sodium calcium ascorbyl phosphate is C6H6O9P·CaNa and it has a
molecular weight of 316. It has a flash point of > 60 °C, and a bulk density of approximately
0.65 g/cm3. No additional information is available.
Sodium calcium ascorbyl phosphate is cream-coloured, spray-dried powder consisting of the
phosphorylated sodium/calcium salt of ascorbic acid. It is specified to contain at least 35 % ascorbic
acid bound to phosphate. The main analysed composition of sodium calcium ascorbyl phosphate is
summarised in Table 2.24
Table 3:
Main composition of sodium calcium ascorbyl phosphate (five batches)
Item
Range (%)
Item
Range (%)
Ascorbate bound to phosphate*
36.0–39.3
Phosphorus
9.7–10.5
Calcium
12.7–13.3
Sodium
8.3–8.7
*Sum of monophosphate, low amount of diphosphate and trace amount of triphosphate.
Water content in the five batches was between 0.1 and 5.1 %; however, the applicant stated that water
may be up to 10.2 % in the case of dihydrate forms of sodium calcium ascorbyl phosphate.
Analysis of impurities in three batches of the additive found arsenic < 1.0 mg/kg, cadmium
< 0.13 mg/kg, lead < 0.27 mg/kg, mercury < 0.02 mg/kg;25 dioxin levels ranged from < 0.1 to
0.37 ng/WHO-PCDD/F-TEQ/kg and dioxin-like polychlorinated biphenyls (PCBs) were
< 0.33 ng/WHO-PCDD/F-TEQ/kg.26
One batch of sodium calcium ascorbyl phosphate was analysed for particle size distribution by laser
diffraction. The fraction of particles below 50 µm was 25.1 % (v/v).27 The substance showed a dusting
potential of 70.7 g/m3.28
2.3.
Stability and homogeneity
Vitamin C is sensitive to active oxygen, oxygenated nitrogen compounds, oxygenating enzymes, bases
and metals.
24
Technical dossier/Section II/Annex 2.2.
Technical dossier/Section II/Annex 2.9.
26
Technical dossier/Section II/Annex 2.8.
27
Technical dossier/Section II/Annex 2.13.
28
Technical dossier/Supplementary Information September 2011/Annex B.
25
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Vitamin C for all animal species
2.3.1.
Stability of ascorbic acid
2.3.1.1. Shelf-life
Ascorbic acid (three batches, stored in aluminium bags) was demonstrated to have a shelf-life of 36
months at 25 ± 2 °C. Shelf-life under accelerated conditions at 40 ± 2 °C was shown to be six
months.29
2.3.1.2. Stability in premixtures, feed and water for drinking
No data on stability of ascorbic acid in premixtures and feed were provided by the applicant.
According to the published literature (Coelho, 2002), the stability of the additive in premixtures
depends on the presence of trace elements and choline. Recovery of ascorbic acid after six months’
storage in a vitamin premixture without choline chloride was 90 %, with choline chloride 45 %, in a
vitamin trace element premixture without choline chloride 35 %, and with choline chloride 17 %.
These data indicate insufficient stability of ascorbic acid in the presence of choline chloride and of
inorganic compounds of trace elements.
The retention of ascorbic acid during feed processing is inversely correlated with the temperature
applied during pelleting or extrusion. The recovery of ascorbic acid after pelleting was 65 % at 66–
70 C and 15 % at 116–120 C, after extrusion 57 % at 91–95 C and 5 % at 141–145 C (Coelho,
2002). In the preparation of feed for poultry (Dozier, 2002),30 a similar influence on the retention of
ascorbic acid has been described for the temperature of conditioning, expanding and extrusion. The
retention of ascorbic acid decreased by 30.8 % (40 % Coelho) when the conditioning temperature was
changed from 70 to 110 C, by 68.1 % when the expanding temperature raised from 95 to 145 C, and
by 87.7 % when extrusion temperature was changed from 115 to 165 C (Dozier, 2002).
The stability of crystalline ascorbic acid when added to commercial fish feed was studied by Marchetti
et al. (1999). Initial concentrations of 207 mg/kg were reduced to 107 mg/kg by pelleting (by 48 %)
and to 41 mg/kg by extrusion (by 80 %). During storage for 30 days in paper bags at room
temperature, the pelleted feed lost another 50 % of the remaining ascorbic acid content. In extruded
feed only 17 mg ascorbic acid/kg feed could be found after three months (< 10 % of the initial
content).
The stability of ascorbic acid (one batch) in water for drinking at a concentration of 1 % and 10 % was
studied when stored for up to one week at room temperature in a dark place.31 Although the data
demonstrate stability, the extrapolation to practical concentration of ascorbic acid in water for drinking
(about 100 to 1 000 times lower) has a high margin of uncertainty.
2.3.2.
Stability of sodium calcium ascorbyl phosphate
2.3.2.1. Shelf-life
Sodium calcium ascorbyl phosphate (three batches) was demonstrated to have a shelf-life of 36
months at 25 ± 2 °C. Shelf-life under accelerated conditions at 40 ± 2 °C was shown to be six
months.32
2.3.2.2.
Stability in premixtures and feed
Three batches of vitamin premixtures for pigs, ruminants and fish containing 1 250, 500 and
100 000 mg ascorbic acid/kg, respectively, showed essentially no degradation after six months’
29
Technical dossier/Section II/Annexes 2.32 and 2.33.
Technical dossier/Section II/Ref. 2.4.01.
31
Technical dossier/Section II/Annex 2.34.
32
Technical dossier/Section II/Annex 2.35.
30
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Vitamin C for all animal species
storage either at room temperature or at 40 C.33 Two premixtures for pigs and ruminants contained
trace elements.
Stability of sodium calcium ascorbyl phosphate was tested in complete feed for pigs for fattening. The
initial concentration was 207 mg ascorbic acid/kg feed. After storage for three months in polyethylene
bottles at room temperature, the content of ascorbic acid from sodium calcium ascorbyl phosphate was
reduced by about 20 % in both types of feed.34
2.3.3.
Homogeneity
Based on a statistical method (Jansen, 1992), the coefficient of variation for homogeneity of ascorbic
acid and sodium calcium ascorbyl phosphate in poultry feed was calculated to be around 8.9 % and
1.3 %, respectively. However, this method has been developed to test the working accuracy of mixing
equipment and it is not accepted by the FEEDAP Panel as a valid method for assessing the
homogeneity of distribution of additives in feeds.
Ascorbic acid is highly soluble in water. Therefore, homogeneity in water for drinking does not need
to be demonstrated.
2.4.
Physico-chemical incompatibilities in feed
Ascorbic acid is sensitive to light, temperature and humidity. Its activity as an antioxidant may lead to
further decomposition if oxidising agents are present in feed. No physico-chemical incompatibilities or
interactions have been reported between ascorbic acid or sodium calcium ascorbyl phosphate and feed
materials or carriers when the additive was added to premixtures and feed. No such incompatibilities
or interactions are expected.
2.5.
Conditions of use
Vitamin C in the form of ascorbic acid and sodium calcium ascorbyl phosphate is to be used in all
animal species and categories without maximum limit. Ascorbic acid and sodium calcium ascorbyl
phosphate are intended for use in feed (premixtures, complete or complementary feeds). Ascorbic acid
is also authorised for use in water for drinking.
2.6.
Evaluation of the analytical methods by the European Union Reference Laboratory
(EURL)
EFSA has verified the EURL report as it relates to the methods used for the control of ascorbic acid
and sodium calcium ascorbyl phosphate in animal feed. The Executive Summary of the EURL report
can be found in Appendix A.
3.
Safety
According to Regulation (EC) No 429/2008, tolerance, metabolism and residue, and toxicological
(concerning consumer safety) studies are not required for vitamins, pro-vitamins and chemically
defined substances having similar effects which are already authorised as feed additives under
Directive 70/524/EEC and which do not have the potential to accumulate, which the FEEDAP Panel
considers is the case for vitamin C.
According to Regulation (EC) No 429/2008, toxicological studies are not required for additives
already authorised unless these are produced by fermentation. For fermentation products, genotoxicity
and subchronic toxicity studies must be provided, unless the active substance is separated from the
crude fermentation product and is highly purified; or the production organism has a history of apparent
safe use and there is sufficient knowledge of its biology to exclude a potential for the production of
toxic metabolites. Although ascorbic acid is produced by fermentation, throughout its manufacturing
33
34
Technical dossier/Section II/Annex 2.36.
Technical dossier/Section II/Annex 2.36.
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Vitamin C for all animal species
process, it is separated from the crude fermentation product and highly purified and the presence of
harmful impurities related to the fermentation process is unlikely (see Section 2.1.1).
3.1.
Safety for the target species
In general, domestic animals such as poultry, ruminants, swine, horses, dogs and cats have the ability
to biosynthesise ascorbic acid, and hence there is no requirement established by the National Research
Council, but ascorbic acid is essential for primates, guinea pigs and some fish species. The
requirements are for guinea pigs 200 mg/kg (NRC, 1995) and for fish 25–50 mg/kg purified diets
(NRC, 1993). Allowances for vitamin C have been proposed (see McDowell, 2000) in the range of
50–60 mg/kg feed for poultry, 150–300 mg/kg feed for pigs and 30–500 mg/kg feed for fish. Vitamin
supplementation of commercial compound feed is mostly oriented towards recommended allowances
in the range of 100–200 mg/kg for poultry, 50–200 mg/kg for pigs (including reproductive pigs), 150–
250 mg/kg for fish and 80–120 mg/kg feed for pets (AWT, 2002). The survey of Whittemore et al.
(2002) did not identify vitamin C supplementation to feedingstuffs for piglets and pigs. A survey on
vitamin supplementation of commercial feeds for pigs and poultry in Europe (Belgium, Denmark,
Germany, Italy, Netherlands, Portugal, Spain and United Kingdom) identified in Germany a range of
20–90 mg ascorbic acid/kg poultry diet and of 15–160 mg/kg piglet diet. However, only some feed
manufacturers add vitamin C. Higher use levels are found in the Mediterranean countries (up to
150 mg/kg broiler feed, up to 400 mg/kg sow feed), probably for climatic reasons, to minimise heat
stress (Gropp, 1994).
Oral supplementation of 1 or 2 g vitamin C/day to preruminant calves elevated plasma concentrations
of ascorbic acid compared with no supplemental vitamin C (Hidiroglou et al., 1995). The 2 g
supplementation rate tended to increase plasma concentrations of ascorbic acid above the 1 g rate but
the difference was not statistically consistent during the 35-day experiment. Data are lacking on the
effect of oral supplementation of vitamin C in cattle. Most orally ingested ascorbic acid is destroyed in
the rumen, but newer formulations of vitamin C may provide some protection from ruminal
metabolism. With sheep, oral supplementation of 4 g/day of various forms of vitamin C for 28 days
significantly increased plasma ascorbic acid concentrations (Hidiroglou et al., 1997).
There is very little information on any toxicity signs associated with excess ascorbic acid intake in
domestic animals. The NRC (1987) reviewed a number of studies in which ascorbic acid was orally
administered. No effects were found after application (i) to growing poultry of between 0.3 and 3.3 g
ascorbic acid/kg feed for up to one year, (ii) to pigs of 1 g ascorbic acid/kg for 28 days or 10 g/kg for 7
days, or (iii) to fish (catfish and trout) of 1–10 g/kg diet for 16–21 weeks. Osteodystrophy was found
in dogs treated with 1 g/day for 46 days. Guinea pigs treated with 8.7 g/kg diet for 43 days developed
decreased bone density. Bone demineralisation was also found in guinea pigs at a dose of 0.057 g/kg
body weight (bw) per day (Parker et al., 1979). Excessive doses of ascorbic acid also have adverse
effects on reproduction, as seen in studies in minks (0.1–0.2 g/kg bw over 70 days), in which anaemia
and reduction in the size and number of offspring were observed (Ender and Helgebostad, 1972).
Excess ascorbic acid intakes in laboratory animals (and in humans) have been reported to produce a
variety of toxic signs or symptoms including allergic responses, oxaluria, uricosuria, and interference
with mixed-function oxidase systems.
3.1.1.
Conclusions on the safety of vitamin C for the target species
Vitamin C in the form of ascorbic acid and sodium calcium ascorbyl phosphate is safe for all animal
species. Considering the large variation in the use levels of ascorbic acid (20–500 mg/kg feed, in
exceptional cases up to 1 000 mg/kg feed) and the fact that previous safety studies on domestic
animals have been performed with the less stable ascorbic acid, it is not possible to identify a precise
common margin of safety for vitamin C. However, the FEEDAP Panel does not see any reason to
introduce a maximum content in feed for vitamin C in the form of ascorbic acid and sodium calcium
ascorbyl phosphate to ensure animal safety.
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Vitamin C for all animal species
3.2.
Safety for the consumer
3.2.1.
Absorption, distribution, metabolism and excretion (ADME)
The following summary on the absorption, distribution, metabolism and excretion (ADME) of
ascorbic acid is based on the reviews of the Scientific Panel on Dietetic Products, Nutrition and
Allergies (NDA) on the Upper Tolerable Intake of Vitamin C (EFSA, 2004) and of McDowell (2000).
Gastrointestinal absorption of low doses of vitamin C is efficient, and occurs in the small intestine via
a sodium-dependent active transport mechanism. The extent of absorption of vitamin C is 80–90 % at
the usual intakes from food of 30–180 mg/person per day, but because the transporter is saturable,
absorption efficiency gradually decreases at higher intakes. Intakes above 1 g/day would be associated
with negligible increased uptake and tissue levels in humans, but there is an increased risk of adverse
gastrointestinal effects. High doses are also absorbed by passive diffusion, which is the main
absorption route in animals that are not prone to scurvy.
In humans, vitamin C is readily oxidised to dehydroascorbic acid, which can be reduced back to
ascorbic acid or hydrolysed to diketogulonic acid and then oxidised to oxalic acid, threonic acid,
xylose, xylonic acid and lyxonic acid. Some oxidation to carbon dioxide occurs at high doses, possibly
as a result of metabolism of unabsorbed ascorbate by the intestinal microflora. Ascorbic acid may also
undergo limited conjugation with sulphate to form ascorbate-2-sulphate, which is excreted in the
urine. Unchanged ascorbic acid and its metabolites are excreted in the urine. In guinea pigs, rats and
rabbits, carbon dioxide is the major excretory mechanism for vitamin C.
Ascorbic acid is widely distributed in most tissues of the body, both in animals capable of synthesising
ascorbic acid as well as in those dependent on an adequate dietary amount of vitamin C. There exists
an equilibrium between ascorbic acid and dehydroascorbic acid, dependent on the redox status of the
cells.
There are no data on the ADME of esterified forms of vitamin C, such as ascorbyl phosphate in
mammals. In contrast, many data are available for fish. In vitro data obtained by Miyasaki et al. (1993)
with ligated intestinal segments and a comprehensive review of Dabrowski et al. (1994) suggest that
(i) ascorbyl phosphate is protected against oxidation in the intestinal lumen, (ii) it is at least partially
hydrolysed in the intestine and, therefore, (iii) absorbed as ascorbic acid and as ascorbyl phosphate,
which is hydrolysed in tissues. In summary, tissue deposition of ascorbic acid in fish is more efficient
after the administration of ascorbyl phosphate than of ascorbic acid.
From the study of Pardue and Brake (1993), who administered graded levels of ascorbic acid and
ascorbyl-2-polyphosphate (mostly ascorbyl 2-triphosphate) in feed and water to chickens, it can be
concluded that the polyphosphate shows the same ascorbic acid bioavailability as ascorbic acid based
on the elevation of plasma concentrations. The consequences of administration of ascorbic acid and
ascorbyl-2-polyphosphate on the concentration of ascorbic acid in plasma and muscle tissues of
heifers after 31 days was investigated by MacLeod et al. (1999). Doses of 20 g/day ascorbic acid
equivalents from both sources per day resulted in an increase in plasma concentrations, whereas only
the administration of ascorbyl 2-polyphosphate resulted in an increase in muscle tissue concentration.
3.2.2.
Toxicological studies
The applicant referred to scientific opinions of the Expert Group on Vitamin and Minerals (EVM,
2003) and of the NDA Panel (EFSA, 2004), with comprehensive overviews of the toxicological profile
of vitamin C including data and effects in humans and animals. The data came from studies in vitro
and in laboratory animals and a considerable number of studies in humans, which have been reviewed
by EFSA (2004). Many of these studies considered the known gastrointestinal and renal effects of
vitamin C toxicity, but showed some shortcomings in the design and protocol. Adequate data defining
the dose–response relationship for each of these adverse effects were not available. Oral doses of up to
1 g/kg bw per day had no detrimental effect on pregnancy in rats and mice (EVM, 2003). The
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Vitamin C for all animal species
available human data suggest that supplementary doses of about 1 g/person per day in addition to
normal dietary intakes are not associated with adverse gastrointestinal effects, but that acute
gastrointestinal effects may occur at doses of 3–4 g/person per day or greater (EFSA, 2004). There
was conflicting evidence of an association between vitamin C intake and breast cancer prevalence in
humans: different studies showed increased or decreased risk at high intakes (EFSA, 2004).
Studies of the possible genotoxicity of vitamin C gave inconsistent results and the EFSA NDA Panel
could not draw any conclusions on the capacity of high intake of vitamin C to induce gene and
chromosomal mutations. The significance of these observations was considered to be unclear and
requires further study (EFSA, 2004).
3.2.3.
Assessment of consumer safety
3.2.3.1. Tolerable upper intake level (UL)
In humans, vitamin C is an essential dietary component, authorised for use in food and dietary
supplements. It is a permitted antioxidant in food with no specified limits on the levels of use. The
twenty-fifth report of the Joint FAO/WHO Expert Committee on Food Additives (WHO, 1981)
identified a group Acceptable Daily Intake (ADI) ―not specified‖ for use of ascorbic acid and its
calcium, potassium and sodium salts as antioxidants in food.
The NDA Panel (EFSA, 2004) could not identify a tolerable upper intake level of vitamin C (Lascorbic acid, its calcium and sodium salts and ascorbyl palmitate). However, dietary intakes reported
in EU countries were not considered to represent a cause for concern. The NDA Panel (EFSA, 2004)
noted that there is no information on the risk in susceptible subgroups (individuals who are
heterozygous for haemochromatosis and thalassaemia or those with a predisposition to urinary or renal
stones). Although EFSA considered that there are insufficient data to establish an UL for vitamin C, a
previous review of vitamin C performed by the Food and Nutrition Board in the USA (IOM, 2000) has
recommended an upper safe level. Data on osmotic diarrhoea and gastrointestinal disturbance were
selected as the most relevant. The UL of 2 g/person per day was derived from a lowest observed
adverse effect level (LOAEL) of 3 g/person per day applying an uncertainty factor of 1.5. Based on
the same LOAEL, the Expert Group on Vitamins and Minerals in the UK (EVM, 2003) developed a
guidance level of 1 g/person per day (applying an uncertainty factor of 3 to the LOAEL).
3.2.3.2. Consumer exposure
Souci et al. (2008) identified vitamin C in liver of calf, cattle, sheep, pigs and chickens in the range
200 to 450 mg/kg fresh material. Vitamin C in kidney was about half of that in liver. The range for
cow milk is 10–24 mg vitamin C/L. No values for meat, fish and eggs were given. These
concentrations result predominantly from endogenous synthesis.
According to the NDA opinion (EFSA, 2004), the background intake (mean national intakes) of
vitamin C was in the range of 70 (Germany) to 151 (Germany) mg/person per day; most of the 97.5th
percentile values were in the range of 180 (Germany) to 224 (Sweden) mg/person per day. More
recent data are available from Germany (Nationale Verzehrsstudie II, 2008). The median ascorbic acid
intake was 130 mg/day in men and 135 mg/day in women. The 95th percentile for both sexes (adults
aged 35–64 years) was 320 mg/day. The main contributors are fruits, vegetables including potatoes
and alcohol-free beverages. Milk, cheese, meat and sausages together account for less than 10 % of the
daily intake. All intake data are far below the guidance level of the EVM (1 g/person per day).
Data on the vitamin C consumption of the population are based on vitamin C levels in foodstuffs,
including food of animal origin, produced in accordance with current EU legislation on the
supplementation of feed with vitamin C. Any potential contribution of the use of vitamin C in feed is
therefore already considered in the above data. The FEEDAP Panel also notes that a theoretical
increase in supplementation with vitamin C above current levels would not substantially alter its
concentration in animal tissues and products.
The use of vitamin C in animal nutrition is not of concern for consumer safety.
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Vitamin C for all animal species
3.3.
Safety for the user
3.3.1.
Effects on the respiratory system
The moderate to high dusting potential and the high proportion of particles of diameter < 50 µm
indicate a potential for workers to inhale dust from ascorbic acid and sodium calcium ascorbyl
phosphate.
No acute inhalation toxicity study was available. The International Chemical Safety Card from the
International Programme on Chemical Safety (IPCS, 2003) indicates cough and sore throat as acute
hazards/symptoms upon inhalation of ascorbic acid.
It would be prudent to assume that inhalation of dust from the additives presents a health hazard to
workers and measures should be taken to minimise inhalation exposure.
3.3.2.
Effects on the eyes and skin
Ascorbic acid is frequently used as an ingredient in cosmetic products (as antioxidant/buffering agent).
From available studies there is no evidence that ascorbic acid causes dermal toxicity in humans or
guinea pigs (CIR, 2005). Furthermore, in rabbits, the percentage of ulceration or perforation in eyes
subjected to severe alkali burns and 10 % topical ascorbic acid was significantly lower than in controls
receiving no ascorbic acid (CIR, 2005).
With respect to sodium calcium ascorbyl phosphate, no information was found (either in the peerreviewed literature or in governmental safety assessments) regarding the potential toxicity of this
substance to the eyes/skin.
No laboratory animal studies of irritation of skin or eyes or of skin sensitisation were available. In the
absence of information on the potential of ascorbic acid and sodium calcium ascorbyl phosphate to
cause irritation or sensitisation it would be prudent to regard both substances as being potentially
harmful by exposure to skin or eyes and to take appropriate action to minimise such exposure of
workers.
3.3.3.
Conclusions on user safety
The FEEDAP Panel concludes that in the absence of inhalation toxicity studies it would be prudent to
assume that inhalation of dust from the additives presents a health hazard to workers and measures
should be taken to minimise inhalation exposure.
In the absence of data, ascorbic acid and sodium calcium ascorbyl phosphate should be considered as
irritant to skin and eyes, and as dermal sensitisers.
3.4.
Safety for the environment
Ascorbic acid occurs widely in most plants, including those used as feed material. In addition,
considering the rapid metabolism of ascorbic acid in animals, the use of ascorbic acid and sodium
calcium ascorbyl phosphate in animal nutrition is not expected to substantially increase the
concentration in the environment. Consequently, the supplementation of feed with vitamin C does not
pose a risk to the environment.
4.
Efficacy
According to Regulation (EC) No 429/2008, efficacy studies are not required for vitamins, provitamins and chemically well-defined substances having similar effects which are already authorised
as feed additives. Sodium calcium ascorbyl phosphate undergoes dephosphorylation mostly after
absorption to become the active vitamin. Owing to the long history of use and its established
nutritional role in domestic animals, ascorbic acid and sodium calcium ascorbyl phosphate are
regarded as effective sources of vitamin C. This conclusion includes the use of ascorbic acid in water
EFSA Journal 2013;11(2):3103
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Vitamin C for all animal species
for drinking. Data on requirements, allowances and recommendations for feed supplementation are
easily accessible as standard literature for animal nutrition experts.
5.
Post-market monitoring
The FEEDAP Panel considers that there is no need for specific requirements for a post-market
monitoring plan other than those established in the Feed Hygiene Regulation35 and Good
Manufacturing Practice.
CONCLUSIONS AND RECOMMENDATIONS
CONCLUSIONS
Vitamin C, in the form of ascorbic acid and sodium calcium ascorbyl phosphate, is safe for all animal
species. Setting a maximum content in feed and water for drinking is not considered necessary.
Data on the vitamin C consumption of consumers are based on the levels of vitamin C in foodstuffs,
including food of animal origin, produced in accordance with current EU legislation for the
supplementation of feed with vitamin C. The exposure is far below the guidance level. Any potential
contribution of the use of vitamin C in feed is therefore already considered in the above data.
Consequently, the use of vitamin C in animal nutrition is not of concern for consumer safety.
The FEEDAP Panel concludes that in the absence of inhalation toxicity studies it would be prudent to
assume that inhalation of dust from the additives presents a health hazard to workers and measures
should be taken to minimise inhalation exposure. In the absence of data, ascorbic acid and sodium
calcium ascorbyl phosphate should be considered as irritant to skin and eyes, and as dermal sensitisers.
The supplementation of feed with vitamin C does not pose a risk to the environment.
Owing to the long history of use and its established nutritional role in domestic animals, ascorbic acid
and sodium calcium ascorbyl phosphate are regarded as effective sources of vitamin C. This
conclusion includes the use of ascorbic acid in water for drinking.
RECOMMENDATIONS
The common names of the additives under assessment, easily understandable by the user, should
follow a consistent nomenclature. Assuming that all additives are listed under vitamin C, it is therefore
proposed to call:
L-ascorbic acid:
ascorbic acid
ascorbyl monophosphate calcium sodium salt: sodium calcium ascorbyl phosphate.
For ascorbic acid, the FEEDAP Panel proposes to use the specifications according to PhEur (MG
0253) considering purity and substance-related impurities and other impurities (sulphated ash) and the
specifications according to Regulation (EC) 231/201236 for lead, mercury and arsenic.
The specification for heavy metals (lead, cadmium and mercury) and arsenic for sodium calcium
ascorbyl phosphate should be adjusted to the analytical values, i.e. < 1 mg/kg for the four elements.
35
Regulation (EC) No 183/2005 of the European Parliament and of the Council of 12 January 2005 laying down
requirements for feed hygiene. OJ L 35, 8.2.2005, p. 1.
36
Commission Regulation (EC) No 231/2012 of 9 March 2012 laying down specifications for food additives listed in
Annexes II and III to Regulation (EC) No 1333/2008 of the European Parliament and of the Council. OJ L 83 22.03.2012,
p. 1.
EFSA Journal 2013;11(2):3103
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Vitamin C for all animal species
DOCUMENTATION PROVIDED TO EFSA
1.
Vitamin C (L-ascorbic acid and ascorbyl monophosphate calcium sodium salt) as a feed additive
for all animal species. November 2010. Submitted by VITAC EEIG Vitamins Authorisation
Consortium.
2.
Vitamin C (L-ascorbic acid and ascorbyl monophosphate calcium sodium salt) as a feed additive
for all animal species. Supplementary information. September 2011. Submitted by VITAC
EEIG Vitamins Authorisation Consortium.
3.
Vitamin C (L-ascorbic acid and ascorbyl monophosphate calcium sodium salt) as a feed additive
for all animal species. Supplementary information. July 2012. Submitted by VITAC EEIG
Vitamins Authorisation Consortium.
4.
Evaluation report of the European Union Reference Laboratory for Feed Additives on the
methods of analysis for vitamin C.
5.
Comments from Member States received through the ScienceNet.
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magnesium ascorbyl phosphate, sodium ascorbate, and sodium ascorbyl phosphate as used in
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Vitamin C for all animal species
system during and after extreme physical exercise (ID 144), non-haem iron absorption (ID 132,
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APPENDICES
APPENDIX A
Executive Summary of the Evaluation Report of the European Union Reference Laboratory for
Feed Additives on the Method(s) of Analysis for Vitamin C37
In the current joint application, authorisation is sought for six forms of Vitamin C under Articles 4(1)
for L-ascorbic acid (E 300)1,2 and Ascorbyl monophosphate sodium1 under the category/functional
group 3(a) "nutritional additives/vitamins, pro-vitamins and chemically well defined substances
having a similar effect", and under Article 10(2) under the category/functional group 3(a) for Lascorbic acid (E 300)1,2 and Ascorbyl monophosphate calcium sodium1,2 and under 1(b) "technological
additives/antioxidants" for L-ascorbic acid1, Sodium L-ascorbate (E 301)1, Calcium L-ascorbate (E
302)1 and 6-Palmityl-L-ascorbic acid (E 304)1, according to the classification system of Annex I of
Regulation (EC) No 1831/2003.
According to the Applicants:
L-ascorbic acid is white crystal or crystalline powder with a minimum purity of 99 %;
Sodium L-ascorbate and Calcium L-ascorbate are white to yellowish crystalline powders with
a minimum purity of 99 %;
6-Palmityl-L-ascorbic acid is a white to yellowish white crystalline powder with a minimum
purity of 98 %;
Ascorbyl monophosphate sodium is a white powder with a minimum purity of 95%; and
Ascorbyl monophosphate calcium sodium is beige to cream coloured compound.
Specifically, authorisation is sought for the use of the six forms of Vitamin C for all animal species
and categories. The feed additives are intended to be incorporated to feedingstuffs directly or through
premixtures. Additionally, L-ascorbic acid and ascorbyl monophosphate sodium are to be used
directly in water. No minimum or maximum concentration levels of the feed additives in feedingstuffs
or water are recommended, similar to what was previously set in the regulation. However, typical
concentrations in feedingstuffs range from 50-400 mg/kg.
For the determination of active substances in the feed additives the EURL recommends for official
control four European Pharmacopoeia methods for the characterisation of L-ascorbic acid; Sodium Lascorbate; Calcium L-ascorbate and 6-Palmityl-L-ascorbic acid (Monographs 0253, 1791; 1182 and
0807, respectively), and the single-laboratory validated and further verified reversed phase High
Performance Liquid Chromatography (RP-HPLC) method, submitted by the Applicant, for the
determination of ascorbyl monophosphate in the feed additives (ascorbyl monophosphate sodium or
ascorbyl monophosphate calcium sodium).
Additionally the EURL recommends for official control the ring-trial validated CEN methods EN ISO
6869, based on Atomic Absorption Spectrometry (AAS) or EN 15510, based on Inductively Coupled
Plasma Atomic Emission Spectrometry (ICP-AES), for the quantification of total calcium and total
sodium in the relevant feed additives.
For the quantification of L-ascorbic acid, Sodium L-ascorbate and Calcium L-ascorbate in
premixtures and feedingstuffs the Applicants submitted a single-laboratory validated and further
verified titrimetric method. The following performance characteristics were reported:
37
The full report is available on the EURL website: http://irmm.jrc.ec.europa.eu/SiteCollectionDocuments/FinRep-FAD2010-0185+0214.pdf
1
FAD-2010-0185 2 FAD-2010-0214
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Vitamin C for all animal species
premixtures: - a recovery rate (Rrec) of 105%; - a relative standard deviation for
repeatability (RSDr) ranging from 3.5 to 3.9 %; and - a relative standard deviation for
intermediate precision (RSDip) of 4.1%;
feedingstuffs: - Rrec ranging from 82 to 103 %; - RSDr ranging from 2.7 to 10.1 %; - RSDip
ranging from 5.4 to 10.1 %; and a limit of quantification (LOQ) of 40 mg/kg feedingstuffs.
For the determination of ascorbyl monophosphate in premixtures and feedingstuffs (containing
ascorbyl monophosphate sodium or ascorbyl monophosphate calcium sodium) the Applicants
submitted a single-laboratory validated and further verified reversed phase High Performance Liquid
Chromatography coupled to UV detection at 254 nm (RP-HPLC-UV).
The following performance characteristics were reported:
premixtures: - Rrec ranging from 98 to 101 %; - RSDr ranging from 0.6 to 2.2 %; and RSDip ranging from 0.87 to 2.42 %;
feedingstuffs: - Rrec ranging from 100 to 105 %; - RSDr ranging from 0.15 to 6.7 %; - RSDip
ranging from 0.3 to 6.7 %; and LOQ = 28 mg/kg feedingstuffs.
Based on the satisfactory performance characteristics presented, the EURL recommends for official
control the single-laboratory validated and further verified titrimetric method and RPHPLC-UV
methods, for the determination of L-ascorbic acid, Sodium L-ascorbate, Calcium L-ascorbate and/or
ascorbyl monophosphates (originating from ascorbyl monophosphate sodium and ascorbyl
monophosphate calcium sodium) in premixtures and feedingstuffs.
For the determination of L-ascorbic acid in water the Applicants proposed two internationally
recognised methods: (i) the AOAC 967.21 titrimetric method developed for the determination of
ascorbic acid in vitamin preparations and juices; and (ii) the ring-trial validated High Performance
Liquid Chromatography coupled to UV detection at 265 nm (HPLC-UV) CEN method (EN 14130)
developed for determination of vitamin C in foodstuffs. Based on the performance characteristics
presented and the rationale that water is a simpler matrix than juices and foodstuffs, the EURL
recommends for official control the AOAC and the CEN methods for the determination of L-ascorbic
acid in water.
The Applicant (FAD-2010-0185) did not provide any analytical methods for the determination of 6Palmityl-L-ascorbic acid in premixtures and feedingstuffs, or the determination of ascorbyl
monophosphate sodium in water. Therefore the EURL cannot evaluate nor recommend any methods
for official control to determine 6-Palmityl-L-ascorbic acid in premixtures and feedingstuffs or
ascorbyl monophosphate sodium in water.
Further testing or validation of the methods to be performed through the consortium of National
Reference Laboratories as specified by article 10 (Commission Regulation (EC) No 378/2005) is not
considered necessary.
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APPENDIX B
List of authorisations of vitamin C other than feed additive
Ascorbic acid (E300), sodium L-ascorbate (E301), calcium L-ascorbate (E302) and 6-palmityl-Lascorbic acid (E304) are approved as food additives38 for use in a large variety of food with a wide
range of dry matter content and with no limitation (quantum satis).
L-Ascorbic
acid, sodium L-ascorbate, calcium L-ascorbate, potassium L-ascorbate and L-ascorbyl 6palmitate are authorised for use in food (Annex II to Regulation (EC) No 1925/2006,39 replaced by
Annex III to Regulation (EC) No 1170/2009)40 and food supplements (Annex II to Directive
2002/46/EC replaced by Annex II to Regulation (EC) No 1170/2009)41.
L-Ascorbic
acid, sodium L-ascorbate, calcium L-ascorbate, potassium L-ascorbate and L-ascorbyl 6palmitate can be used for the manufacturing of dietetic foods (Commission Regulation (EC) No
953/2009, Annex)42.
L-Ascorbic
acid, sodium L-ascorbate, calcium L-ascorbate, potassium L-ascorbate and L-ascorbyl 6palmitate can be used for the manufacturing of processed cereal-based foods and baby foods for
infants and young children (Commission Directive 2006/125/EC, Annex IV)43 and for the
manufacturing of infant formulae and follow-on formulae when reconstituted as instructed by the
manufacturer (Directive 2006/141/EC, Annex III)44.
L-Ascorbic
acid is authorised as an orphan product in human medicine (EU/3/08/531) for the treatment
of Charcot–Marie–Tooth disease type 1A (EMA, 2008).45
L-Ascorbic
acid is listed as an ingredient in cosmetic products as an antioxidant/buffering agent
(Commission Decision 2006/257/EEC).46
L-Ascorbic
acid, ascorbyl palmitate and ascorbyl stearate may be used in the manufacture of plastic
materials and articles (Commission Directive 2002/72/EC).47
38
European Parliament and Council Directive No 95/2/EC of 20 February 1995 on food additives other than colours and
sweeteners OJ L 61, 18.3.1995, p. 1.
39
Regulation (EC) No 1925/2006 of the European Parliament and of the Council of 20 December 2006 on the addition of
vitamins and minerals and of certain other substances to foods. OJ L 404 30.12.2006, p. 26.
40
Commission Regulation (EC) No 1170/2009 of 30 November 2009 amending Directive 2002/46/EC of the European
Parliament and of Council and Regulation (EC) No 1925/2006 of the European Parliament and of the Council as regards
the lists of vitamin and minerals and their forms that can be added to foods, including food supplements. OJ L 314
1.12.2009, p. 36.
41
Directive 2002/46/EC of the European Parliament and of the Council of 10 June 2002 on the approximation of the laws of
the Member States relating to food supplements. OJ L 183 12.7.2002, p. 51.
42
Commission Regulation (EC) 953/2009 of 13 October 2009 on substances that may added for specific nutritional purposes
in foods for particular nutritional uses. OJ L 269, 14.10.2009, p. 9.
43
Commission Directive 2006/125 EC of 5 December 2006 on processed cereal-based foods and baby-foods for infants and
young children. OJ L 339 6.12.2006, p. 16.
44
Commission Directive 2006/141 EC of 22 December 2006 on infant formulae and follow-on formulae and amending
Directive 1999/21/EC. OJ L 401 30.12.2006, p. 1.
45
EMEA - Committee for orphan medicinal products (COMP) (2008) Public summary of positive opinion for orphan
designation of ascorbic acid for the treatment of Charcot–Marie–Tooth disease type 1A. EMEA/COMP/265714/2008.
46
Commission Decision 2006/257/EC of 9 February 2009 amending Decision 96/335/EC establishing an inventory and a
common nomenclature of ingredients employed in cosmetic products. OJ L 97 5.04.2006, p. 1.
47
Commission Directive 2002/72/EC of 6 August 2002 relating to plastic materials and articles intended to come into contact
with foodstuffs. OJ L 220, 15.8.2002, p. 18.
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L-Ascorbic
acid and its ammonium, calcium, magnesium, potassium and sodium salts are authorised
for the manufacture of regenerated cellulose film intended to come into contact with foodstuffs
(Commission Directive 2007/42/EC).48
L-Ascorbic
acid addition is an authorised oenological practice (Commission Regulation (EC) No
606/2009).49
L-Ascorbic
acid is authorised as a food additive in the preparation of foodstuffs of plant and animal
(meat products) origin and sodium ascorbate is authorised for the preparation of foodstuffs of animal
origin (Commission Regulation (EC) No 889/2008).50
L-Ascorbic
acid is authorised for use as a biocide (Commission Regulation (EC) No 1451/2007).51
48
Commission Directive 2007/42/EC of 29 June 2007 relating to materials and articles made of regenerated cellulose film
intended to come into contact with foodstuffs. OJ L 172, 30.06.2007, p. 71.
49
Commission Regulation (EC) No 606/2009 of 10 July 2009 laying down certain detailed rules for implementing Council
Regulation (EC) No 479/2008 as regards the categories of grapevine products, oenological practices and the applicable
restrictions. OJ L 193, 24.7.2009, p. 1.
50
Commission Regulation (EC) No 889/2008 of 5 September 2008 laying down detailed rules for the implementation of
Council Regulation (EC) No. 834/2007 on organic production and labelling of organic products with regard to organic
production, labelling and control. OJ L 250, 18.9.2008, p. 1.
51
Commission Regulation (EC) No 1451/2007 of 4 December 2007 on the second phase of the 10-year work programme
referred to in Article 16(2) of Directive 98/8/EC of the European Parliament and of the Council concerning the placing of
biocidal products on the market. OJ L 325, 11.12.2007, p. 3.
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