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«SCCS/1313/10 24 March 2010 Scientific Committee on Consumer Safety SCCS OPINION ON Vitamin K1 (Phytonadione) The SCCS adopted this opinion at 6th ...»

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SCCS/1313/10

24 March 2010

Scientific Committee on Consumer Safety

SCCS

OPINION ON

Vitamin K1

(Phytonadione)

The SCCS adopted this opinion at 6th plenary meeting

of 23 March 2010

SCCS/1313/10, 24.3.10

Opinion on Vitamin K1 (phytonadione)

__________________________________________________________________________________

About the Scientific Committees

Three independent non-food Scientific Committees provide the Commission with the

scientific advice it needs when preparing policy and proposals relating to consumer safety, public health and the environment. The Committees also draw the Commission's attention to the new or emerging problems which may pose an actual or potential threat.

They are: the Scientific Committee on Consumer Safety (SCCS), the Scientific Committee on Health and Environmental Risks (SCHER) and the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) and are made up of external experts.

In addition, the Commission relies upon the work of the European Food Safety Authority (EFSA), the European Medicines Evaluation Agency (EMEA), the European Centre for Disease prevention and Control (ECDC) and the European Chemicals Agency (ECHA).

SCCS The Committee shall provide opinions on questions concerning all types of health and safety risks (notably chemical, biological, mechanical and other physical risks) of non-food consumer products (for example: cosmetic products and their ingredients, toys, textiles, clothing, personal care and household products such as detergents, etc.) and services (for example: tattooing, artificial sun tanning, etc.).

Scientific Committee members Jürgen Angerer, Ulrike Bernauer, Claire Chambers, Qasim Chaudhry, Gisela Degen, Gerhard Eisenbrand, Corrado Galli, Thomas Platzek, Suresh Chandra Rastogi, Vera Rogiers, Christophe Rousselle, Tore Sanner, Kai Savolainen, Jacqueline Van Engelen, Maria Pilar Vinardell, Rosemary Waring, Ian R. White Contact European Commission Health & Consumers Directorate C: Public Health and Risk Assessment Unit C7 - Risk Assessment Office: B232 B-1049 Brussels Sanco-Sc6-Secretariat@ec.europa.eu © European Union, 2010 ISSN 1831-4767 ISBN 978-92-79-12737-3 doi:10.2772/23121 ND-AQ-09-009-EN-N The opinions of the Scientific Committees present the views of the independent scientists who are members of the committees. They do not necessarily reflect the views of the European Commission. The opinions are published by the European Commission in their original language only.

http://ec.europa.eu/health/scientific_committees/consumer_safety/index_en.htm

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Opinion on Vitamin K1 (phytonadione) __________________________________________________________________________________

ACKNOWLEDGMENTS

Prof. J. Angerer Dr. U. Bernauer Dr. C. Chambers Dr. Q. Chaudhry Prof. G. Degen Dr. S.C. Rastogi Prof. V. Rogiers Prof. T. Sanner chairman Dr. J. van Engelen Prof. R. Waring Dr. I.R. White rapporteur Keywords: SCCS, scientific opinion, vitamin K1, phytonadione, CAS 84-80-0, 11104-38-4, 81818-54-4, EC 201-564-2, 234-330-3, 279-833-9, directive 76/768/EEC Opinion to be cited as: SCCS (Scientific Committee on Consumer Safety), Opinion on vitamin K1 (phytonadione), 23 March 2010

–  –  –

Opinion on Vitamin K1 (phytonadione) __________________________________________________________________________________

TABLE OF CONTENTS

ACKNOWLEDGMENTS ………………………………………………………………………………... 3

1. BACKGROUND …………………………………………………………………………………. 5

2. TERMS OF REFERENCE …………………………………………………………………………………. 5

3. OPINION …………………………………………………………………………………. 6

4. CONCLUSION …………………………………………………………………………………. 28

5. MINORITY OPINION …………………………………………………………………………………. 29

6. REFERENCES …………………………………………………………………………………. 29

–  –  –

Opinion on Vitamin K1 (phytonadione) __________________________________________________________________________________

1. BACKGROUND Due to a notification procedure by a member state on vitamin K1 triggered by cases of allergic reactions, a scientific evaluation of its use in cosmetic products was requested. The first scientific opinion on vitamin K1 (SCCP/1105/07) was adopted by the SCCP by written

procedure on 28 September 2007 with the following conclusion:

"Because of the inadequate nature of the dossier submitted, the SCCP is unable to provide an adequate safety evaluation for the use of vitamin K1 (phytonadione) and its "oxide" in cosmetic products. However, as such use may cause cutaneous allergy, individuals so affected may be denied an important therapeutic agent."

A complete dossier was submitted by November 2007. The applicant applied for the use of vitamin K1 - with the CAS 81818-54-4 and EINECS 279-833-9 and the chemical name 2methyl-3-(3,7,11,15-tetramethylhexadec-2-enyl)-1,4-naphthoquinone - in cosmetic products in a concentration up to a maximum of 1.0%.





A second opinion (SCCP/ 1187/08) was adopted by the SCCP at the 24 June 2008 with the conclusion: "The studies provided on the allergenic potential of Vitamin K1 did not supersede the concerns stated in opinion SCCP/1105/07. The SCCP maintains the view that use of Vitamin K1 in cosmetic products is not safe, since it may cause cutaneous allergy and individuals so affected may be denied an important therapeutic agent."

Following this opinion, additional, newly generated data on skin sensitisation was submitted, which has not been evaluated by the SCCS (formerly SCCP) together with some comments of stakeholders.

2. TERMS OF REFERENCE

1. Does the SCCS consider that the new scientific data submitted supersedes the concern about the allergenic potential of vitamin K1 when used in cosmetic products in a concentration up to 1.0%?

2. If yes, does the SCCS consider that vitamin K1 is safe when used in cosmetic product in a concentration up to 1.0%?

–  –  –

Opinion on Vitamin K1 (phytonadione) __________________________________________________________________________________

3. OPINION The data described in this opinion have been taken from three submissions. Submission I, which formed the basis of opinion SCCP/1105/07, did not provide adequate information on the chemical identity of the substance used and did not allow for a safety assessment of the substance. Nevertheless, the data contained in the dossier is included in this opinion for completeness. Submission II and III were submitted by a different applicant.

3.1. Chemical and Physical Specifications 3.1.1. Chemical identity According to the European Pharmacopoeia, Phytomenadione is a mixture of 2-methyl-3-[(2E)-(7R,11R)-3,7,11,15-tetramethylhexadec-2-enyl]naphthalene-1,4-dione (trans-phytomenadione), 2-methyl-3-[(2Z)-(7R,11R)-3,7,11,15-tetramethylhexadec-2-enyl]naphthalene-1,4-dione (cis-phytomenadione), and 2,3-epoxy-2-methyl-3-[(2E)-(7R,11R)-3,7,11,15-tetramethylhexadec-2-enyl]-2,3dihydronaphthalene-1,4-dione (trans-epoxyphytomenadione).

It contains not more than 4.0 per cent of trans-epoxyphytomenadione and not less than

75.0 per cent of trans-phytomenadione. The total of the three components is not less than

97.0 per cent and not more than the equivalent of 103.0 per cent.

3.1.1.1. Primary name and/or INCI name Phytonadione (INCI name) Phytomenadione (INN) 3.1.1.2. Chemical names 1,4-naphthalenedione, 2-methyl-3-(3,7,11,15-tetramethyl-2-hexadecenyl)-, (r-(r*,r*-(e))) 2',3'-trans-vitamin K1 2-methyl-3-[(7RS,11RS)-3,7,11,15-tetramethyl-2-hexadecenyl]-1,4-naphtoquinone;

2-methyl-3-[(7RS,11RS)-3,7,11,15-tetramethyl-2-hexadecenyl]-naphtalene-1,4-dione;

2',3'-trans-phylloquinone α-phylloquinone 2-methyl-3-phytyl-1,4-naphthoquinone phytylmenadione 3-phytylmenadione antihemorrhagic vitamin 3.1.1.3. Trade names and abbreviations

–  –  –

Opinion on Vitamin K1 (phytonadione) __________________________________________________________________________________

- Phytomenadione (all-rac)

- Phytonadione (all-rac)

- α-Phylloquinone (all-rac)

- Vitamin K (all-rac) 3.1.1.4. CAS / EC number

–  –  –

* The names in brackets refer only to the EC numbers 3.1.1.5. Structural formula The Vitamin K1 molecule has two geometrical isomers (cis-trans or (Z)-(E) isomers) plus two asymmetric carbon atoms (C7 and C11), each generating two enantiomers (R or S).

Thus, there are eight diastereoisomers (four in the trans- and four in the cis- configuration).

The name Vitamin K is appropriate only for the 2'-Trans-7R, 11R-stereoisomer (the others are not vitamins). The formula indicates the 2'-Trans-7R, 11R-stereoisomer.

3.1.1.6. Empirical formula Empirical formula: C31H46O2

–  –  –

Clear yellow to golden yellow viscous liquid 3.1.3. Molecular weight Molecular weight: 450.68 g/mol 3.1.4. Purity, composition and substance codes Submission II/III states that the applicant's Vitamin K1 preparation meets all requirements of the USP, FCC and Ph. Eur. when tested

according to these compendia:

• Purity (HPLC): vitamin K1 content 97.0 - 103.0 %, trans- vitamin K1 min. 75 %, cisvitamin K1 max. 15.0 %, vitamin K1 epoxyde max. 1.0 %

• Appearance: intense yellow, viscous oil.

• Solution 10% in trimethylpentane: clear

–  –  –

Opinion on Vitamin K1 (phytonadione) __________________________________________________________________________________

• Refractive index (589 nm, 25 °C): 1.523–1.526

• Reaction: passes test (USP)

• Heavy metals: max. 20 ppm

• Lead: max. 2 ppm

• Sulphated ash (residue on ignition): max. 0.1%

• Acid value: max. 2.0

• Menadione: max. 0.2%

• Other related substances: corresponds (Ph. Eur.) The applicant's Vitamin K1 preparation is declared to be CEP certified.

Comment No documentation for the characterisation of batches according to the above mentioned specifications has been provided.

3.1.5. Impurities / accompanying contaminants

–  –  –

Phylloquinone occurs in nature only as the 2', 3’-Trans-7R, 11R-stereoisomer. Commercially available phytonadione (phylloquinone) is prepared synthetically and may contain not only 2',3'-trans-phylloquinone (not less than 75%), but also 2',3'-cis-phylloquinone and transepoxyphylloquinone (not more than 4.0 percent).

Ref.: 2 In submission I, three HPLC chromatograms were provided without any further explanation or identification of the peaks. After 5 minutes and one hour irradiation with UV, several new unidentified peaks appeared on the chromatograms, which were also not described. No information on the nature of UV exposure of the test substance was given.

According to Eur Ph, Menadione is the principle impurity. No information on its actual content in commercial batches was provided in the dossier.

–  –  –

Vitamin K1 is insoluble in water, slightly soluble in ethanol, and freely soluble in ether, chloroform, fats and oils.

Comment No study is provided, quantitative data on the solubility is not provided.

–  –  –

Opinion on Vitamin K1 (phytonadione) __________________________________________________________________________________

3.1.7. Partition coefficient (Log Pow) No data submitted 3.1.8. Additional physical and chemical specifications

–  –  –

The stability of phytomenadione stored in aluminium cans under nitrogen was investigated

under the following conditions:

For long term storage condition studies samples of commercial lots are stored at 25°C + 2°C at 60% RH + 5% RH for 36 months.

For accelerated storage condition studies samples of commercial lots were stored at 40°C + 2°C at 75% RH + 5% RH for 6 months.

Under these storage conditions samples of phytomenadion are described to be stable:

trans-phytomenadione (84.4-86.4%, epoxy phytomenadione 0.15, total cis-, trans- and epoxy phytomenadione (97.8-100.3%) Vitamin K1 is slowly degraded by atmospheric oxygen, but is fairly rapidly degraded by light. It is relatively stable to heat, but is decomposed by alkalis. Due to these cognitions

and the results of the stability test programs the following is recommended:

The product may be stored for 36 months from the date of manufacture in the unopened original container (which is sealed under inert gas) and at a temperature below 15°C.

–  –  –

Comment Above mentioned data is presented in a summary document, but no documentation has been provided for this.

No information is available on the fate of vitamin K1 in cosmetic products under normal use conditions.

General Comments on physico-chemical characterisation

- The data provided on the physico-chemical characterisation of phytonadione is insufficient. Documentation of characterisation, determination of composition, purity and impurities is missing.

- Log Pow and quantitative data on the solubility are not provided.

- Vitamin K1 is slowly degraded by atmospheric oxygen and fairly rapidly degraded by light. No information on stability of phytomenadione in typical cosmetic formulations and under use conditions is available.

–  –  –

Opinion on Vitamin K1 (phytonadione) __________________________________________________________________________________

- According to the applicant of submission I, since 2005 "oxidised" Vitamin K1 has been used in products. It is not clear from the submission to which chemical substance the term 'phytonadione-oxide' refers to and no data was provided on this substance.



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