SCCP o 107

Scientific Committee on Consumer Products
SCCP
OPINION ON
Vitamin K1
phytonadione (INCI name)
The SCCP adopted this opinion by written procedure on 28 September 2007

SCCP/1105/07
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 Products (SCCP), 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).
SCCP
Questions concerning the safety of consumer products (non-food products intended for the
consumer).
In particular, the Committee addresses questions related to the safety and allergenic
properties of cosmetic products and ingredients with respect to their impact on consumer
health, toys, textiles, clothing, personal care products, domestic products such as
detergents and consumer services such as tattooing.
Scientific Committee members

Claire Chambers, Gisela Degen, Ruta Dubakiene, Ramon Grimalt, Bozena Jazwiec-Kanyion,
Vassilios Kapoulas, Jean Krutmann, Carola Lidén, Jean-Paul Marty, Thomas Platzek, Suresh
Chandra Rastogi, Jean Revuz, Vera Rogiers, Tore Sanner, Günter Speit, Jacqueline Van
Engelen, Ian White
Contact:
European Commission
Health & Consumer Protection DG
Directorate C: Public Health and Risk Assessment
Unit C7 - Risk Assessment
Office: B232 B-1049 Brussels
[email protected]
© European Commission 2007
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/ph_risk/risk_en.htm
2
SCCP/1105/07
ACKNOWLEDGMENTS
Dr. C. Chambers
Prof. G. Degen
Dr. B. Jazwiec-Kanyion
Prof. C. Lidén
Prof. V. Kapoulas
Prof. J.-P. Marty
Prof. T. Platzek
Dr. S.C. Rastogi
Prof. J. Revuz (rapporteur)
Prof. V. Rogiers
Prof. T. Sanner
Dr. J. van Engelen
Dr. I.R. White (chairman)
Keywords: SCCP, scientific opinion, vitamin K1, phytonadione, Directive 768/76/EEC, CAS
84-80-0, 11104-38-4, 81818-54-4
Opinion to be cited as: Opinion of the SCCP on vitamin K1 (phytonadione)
3
SCCP/1105/07
TABLE OF CONTENTS
ACKNOWLEDGMENTS ………………………………………………………………………………... 3
1. BACKGROUND …………………………………………………………………………………. 5
2. TERMS OF REFERENCE …………………………………………………………………………………. 5
3. OPINION …………………………………………………………………………………. 6
4. CONCLUSION …………………………………………………………………………………. 16
5. MINORITY OPINION …………………………………………………………………………………. 16
6. REFERENCES …………………………………………………………………………………. 17
4
SCCP/1105/07
1. BACKGROUND
Phytonadione (CAS 84-80-0) [INN phytomenadione] with the chemical name 2-methyl-3-
(3,7,11,15-tetramethyl-2-hexadecenyl)-1,4-naphthalenedione is used as a skin conditioner
in cosmetic products according to the Inventory.
Vitamin K1 is a synonym with phytonadione.
Apparently the current maximum use concentration of vitamin K1 is 2% in EU and 5% in

USA.
The basis for this evaluation is a notification made by France to the Commission and the
Member States. The French authorities have banned - by a decision dated the 12 January
2006 - the use of vitamin K1 in cosmetic products due to the sensitizing properties of the
substance. The ban is based on 5 cases of undesirable effects (allergic reactions) between
December 2003 and June 2004 from 3 products and a further 6 cases have been identified
between March 2004 and July 2004 from another product containing vitamin K1. The French
authorities also refer to 2 cases from Spain and Italy described in the scientific literature
accordingly in February and September 2005.
The ban is furthermore supported as vitamin K1 might be used as an injectable therapeutic

agent for therapeutic reasons.
The Commission has asked Member States and stakeholders for information.
Only the Belgian Authorities submitted the study "Evaluation of skin sensitisation potential
in mice using the local Lymph node assay (LLNA).
The Italian competent authority supports a closer look at the use of vitamin K1, particularly
in view of the fact that it is often used in combination with other substances (such as
retinol).
2. TERMS OF REFERENCE
1. Does the SCCP consider that Vitamin K1 [and its oxide] are safe for the consumers
when used in cosmetic products taken into account the provided data?
2. Does the SCCP recommend any restrictions to their safe use?
5
SCCP/1105/07
3. OPINION
3.1. Chemical and Physical Specifications
3.1.1. Chemical identity
3.1.1.1. Primary name and/or INCI name
Phytonadione (INCI name)
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-[(min 80%E,7RS,11RS)-3,7.11,15-tetrametyl-2-hexadecenyl]-1,4-naphthoquinone
2',3'-trans-phylloquinone
α-phylloquinone
2-methyl-3-phytyl-1,4-naphthoquinone
phytylmenadione
3-phytylmenadione
phytomenadione
antihemorrhagic vitamin
3.1.1.3. Trade names and abbreviations
Aquamephyton konakion
combinal k1 mephyton
k-ject mono-kay
kativ n monodion
kephton synthex p
kinadion
3.1.1.4. CAS / EINECS number
Vitamin K1
CAS EINECS *
84-80-0 201-564-2 (phytomenadione)

11104-38-4 234-330-3 (vitamin K1)
81818-54-4 279-833-9 (2-methyl-3-(3,7,11,15-tetramethylhexadec-2-enyl)-1,4-
naphthoquinone)
* The names in brackets refer only to the EINECS numbers
6
SCCP/1105/07
3.1.1.5. Structural formula
The formula indicates 2'-Trans-7R, 11R-stereoisomer
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), representing 12.5% in an equimolar mixture.
3.1.1.6. Empirical formula
Empirical formula: C31H46O2
3.1.2. Physical form
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
3.1.5. Impurities / accompanying contaminants
Commercial preparations may contain up to 20% of the biological inactive cis isomer.
Ref.: 1
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 trans-epoxyphylloquinone (not more than 4.0 percent). Phylloquinone
occurs in nature only as the 2', 3’-Trans-7R, 11R-stereoisomer.
Ref.: 2
HPLC chromatograms
Three chromatograms were provided without any 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
3.1.6. Solubility
500 mg/l water (22 °C)

500 mg/l hydrochloric acid 0.1 N (22 °C)
500 mg/l sodium hydroxide 0.1 N (22 °C))
7
SCCP/1105/07
500 mg/l glycerine (22 °C)

4500 mg/l DMSO (dimethyl sulfoxide) (22 °C)
11000 mg/l methanol (22 °C)
15000 mg/l acetonitrile (22 °C)
75000 mg/l ethanol (22 °C)
1 g/l n-octanol, diethyl ether, acetone, benzene, ethyl acetate, dichloromethane,
chloroform, n-hexane, cyclohexane, dioxane (22 °C)
Ref.: 3
3.1.7. Partition coefficient (Log Pow)
3.1.8. Additional physical and chemical specifications
Melting point: approx. - 20 °C

Boiling point: 140-145 °C
Density: 0.97 g/cm³
3.1.9. Stability
Stable to air and moisture, but decomposes in sunlight. Unaffected by dilute acids, but is
destroyed by solutions of alkali hydroxides and by reducing agents.
Ref.: 1
General Comments on physico-chemical characterisation
- The data provided on the physico-chemical characterisation of phytonadione is

insufficient.
- No data was provided on 'phytonadione-oxide'
- It is not clear from the submission to which substance the term 'phytonadione-oxide'
refers to. It might be phytonadione epoxide, CAS: 25486-55-9; EINECS: 247-022-9
3.2. Function and use
Phytonadione (phylloquinone) is present in plant sources, especially green leafy vegetables. It

is also present in small amounts in dairy products. It is synthesised by bacterial flora in the
jejunum and ileum. The amount synthesised in the gut contributes significantly towards the
daily requirement of the vitamin.
Vitamin K is involved in blood clotting, bone and kidney metabolism. Roles in cell signalling
and brain lipid metabolism have also been proposed. Because vitamin K is widespread in the
diet and provided by bacteria, deficiency is generally secondary to conditions such as mal-
absorption. Newborn babies have low levels of vitamin K, which may result in haemorrhagic
disease of the newborn.
There may be decreased utilisation of the vitamin in the production of the vitamin K-
dependent clotting factors during any form of acute or chronic liver disease. This is as a
result of the destruction of the rough endoplasmic reticulum in the hepatocyte. Patients with
hypoprothrombinaemia related to hepatic disorders usually respond to daily parenteral
doses of 10 mg of vitamin K for three days. If no response to this treatment is noted this
suggests serious hepatocellular damage. (Basu and Dickerson, 1996).
Ref.: 4
8
SCCP/1105/07
The physiological activity of phylloquinone is based on its ability to change between its
oxidized (quinone and 2,3-epoxide) and reduced (hydroquinone) forms. The major role of
phylloquinone is the post-translational addition of a carboxyl-group into the γ-position of
glutamate residues of specific proteins. In this respect, the prime physiological relevance of
phylloquinone is the synthesis of coagulation proteins (Ferland, 1998; Olson, 1999 and
2000).
Whereas the vitamin K-dependent coagulation proteins are all synthesised in the liver,
vitamin K is also essential for the synthesis of a number of proteins produced in extra-
hepatic tissues. Examples of the latter group of proteins include:
• the bone Gla-protein, osteocalcin, which is exclusively synthesised by osteoblasts and

odontoblasts, and which is a negative regulator of bone formation;
• matrix Gla-protein (MGP), which is synthesised in most soft tissues, but
predominantly in cartilage (by chondrocytes) and in vessel wall (by vascular smooth
muscle cells) and which is a potent inhibitor of soft tissue calcification;
• growth arrest-specific gene 6 protein (Gas6), which is a ligand for tyrosine kinases
and has strong apoptopic activity in cultured cells.
Ref.: 5
Claimed uses for Vitamin K1 as a cosmetic include skin lightening, periorbital hyper
pigmentation, treatment of actinic and traumatic purpura and treatment of bruising after
laser treatment.
The SCCP is aware of cosmetic products on the market with Vitamin K1 concentrations as
high as 8%.
The company that has submitted safety data for this evaluation declares that: "following
AFSSAPS recommendations and our own observations…no product […] contains Vitamin K
since 1 January 2005”. It also stated that from this date, an oxidised form of Vitamin K1
was used instead. No data was provided about the formula of oxidised Vitamin K1.
Ref.: 6
9
SCCP/1105/07
3.3. Toxicological Evaluation
Due to the background of the mandate, this evaluation is focused on skin sensitisation
aspects as submitted in the dossier and does not consider general toxicity data.
3.3.1. Acute toxicity
3.3.1.1. Acute oral toxicity
No data submitted
3.3.1.2. Acute dermal toxicity
No data submitted
3.3.1.6. Acute inhalation toxicity
No data submitted
3.3.2 Irritation and corrosivity
3.3.2.1. Skin irritation
No data submitted
3.3.2.2. Mucous membrane irritation
No data submitted
3.3.3. Skin sensitisation
Murine Local Lymph Node Assay (LLNA) for Vitamin K1
Guideline: OECD 429

Species/strain: CBA/J mouse, nulliparous and non-pregnant females.
Group size: 7 groups of 4 animals
Test substance: vitamin K
Batch: 20040510
Purity: 98.96% (full isomeric composition not clarified, % active ingredient
unknown)
Concentrations: 5, 10, 25, 50, 100% in acetone/olive oil (4/1; v/v)
Positive control: α-hexylcinnamaldehyde (HCA)
GLP: in compliance
Results
Vitamin K1 was non-irritant in the preliminary test. The highest concentration retained for
the main test was the maximal practicable concentration (100%).
In the main test, twenty-eight female CBA/J mice were allocated to seven groups: five
treated groups of four animals receiving the test item Vitamin K (isomeric mixture) at the
concentration of 5, 10, 25, 50 or 100%, one negative control group of four animals
receiving the vehicle (mixture acetone/olive oil (4/1; v/v)), one positive control group of
four animals receiving alpha-hexylcinnamaldehyde (HCA) at the concentration of 25%.
10
SCCP/1105/07
Proliferation assay
No lympho-proliferation was noted at any of the test concentrations, while significant
lympho-proliferation was observed with HCA at 25%.
The results are presented in the following table:
Treatment Concentration Irritation level Stimulation Index

(%) (SI)
Test item 5 non-irritant 1.78
HCA 25 - 11.18
Conclusion
Under these experimental conditions, Vitamin K1 (isomeric mixture) did not induce delayed
contact hypersensitivity in the murine Local Lymph Node Assay.
Ref.: 7
Murine Local Lymph Node Assay (LLNA) for Vitamin Khv( irradiated Vitamin K1)
Guideline: OECD 429

Species/strain: CBA/J mouse, nulliparous and non-pregnant females.
Group size: 7 groups of 4 animals
Test substance: vitamin K(hv)
Batch: 20040510
Purity: 98.96% (full isomeric composition not clarified, % active ingredient
unknown)
Concentrations: 5, 10, 25, 50, 100% in acetone/olive oil (4/1; v/v)
Positive control: α-hexylcinnamaldehyde (HCA)
GLP: in compliance
Results
Vitamin K1 was non-irritant in the preliminary test. The highest concentration retained for
the main test was the maximal practicable concentration (100%).
In the main test, twenty-eight female CBA/J mice were allocated to seven groups: five
treated groups of four animals receiving the test item Vitamin K at the concentration of 5,
10, 25, 50 or 100%, one negative control group of four animals receiving the vehicle
(mixture acetone/olive oil (4/1; v/v)), one positive control group of four animals receiving
α-hexylcinnamaldehyde (HCA), at the concentration of 25%.
Proliferation assay
No lympho-proliferation was noted at any of the test concentrations, while significant
lympho-proliferation was observed with HCA at 25%.
11
SCCP/1105/07
The results are presented in the following table:
Treatment Concentration Irritation level Stimulation Index

(%) (SI)
HCA 25 - 8.54
Conclusion
Under our experimental conditions, the test item Vitamin K hv did not induce delayed
contact hypersensitivity in the murine Local Lymph Node Assay.
Ref.: 8
Comment
The batch and the analytical certificate provided was that for the non-irradiated form of
Vitamin K (isomeric mixture). No data about the isomeric composition of the test substance
in both tests are provided. Therefore, no conclusion can be made regarding the sensitising
potential by LLNA vitamin K1, either irradiated or non-irradiated before use.
3.3.4. Dermal / percutaneous absorption
No data submitted
3.3.5. Repeated dose toxicity
3.3.5.1. Repeated Dose (28 days) oral / dermal / inhalation toxicity
No data submitted
3.3.5.2. Sub-chronic (90 days) oral / dermal / inhalation toxicity
No data submitted
3.3.5.3. Chronic (> 12 months) toxicity in mice
No data submitted
3.3.6. Mutagenicity / Genotoxicity
3.3.6.1. Mutagenicity / Genotoxicity in vitro
No data submitted
3.3.6.2. Mutagenicity / Genotoxicity in vivo
No data submitted
12
SCCP/1105/07
3.3.7. Carcinogenicity
No data submitted
3.3.8. Reproductive toxicity
3.3.8.1. One generation reproduction toxicity
No data submitted
3.3.8.2. Teratogenicity
No data submitted
3.3.9. Toxicokinetics
No data submitted
3.3.10. Photo-induced toxicity
3.3.10.1. Phototoxicity / photoirritation and photosensitisation
In vitro assessment of phototoxic potential using human reconstructed epidermis
Guideline: /
Tissue: human reconstituted epidermis [SKINETHIC™]
N° of chambers: 6
Test substance: vitamin K1 phytonadione
Batch: 03.581
Purity: /
Concentrations: 100% and diluted to 10 and 1% in paraffin oil
GLP: /
A toxicity assay was carried out using SKINETHIC cultures (0.63 cm2 epidermis). The test
product was tested as supplied (i.e, 100%) and diluted to 10 and 1% (v/v) in paraffin oil.
Reconstituted epidermis (REp) was treated overnight (approximately 18h). The toxic effect was
assessed by using the MTT assay. No significant cytotoxicity was observed in epidermis. Taking
into account these results, the test substance was to be applied undiluted on the culture surface, for
a 24h incubation period prior to UV exposure.
Test product (6.3µl /epidermis) was applied directly onto the surface of tissues. Control and
treated REps were incubated at 37°C for 24 hr and subsequently washed with HBSS. REps
were irradiated with UVA dose 6 J/cm2 (3 biopsies/UVA dose), while 2 REps of each
experimental group were kept at room temperature in the dark during UVA exposure (dark
control). After further incubation at 37° C for 24h, viability was assessed by a MTT test.
Results
CONTROL TREATED
0 6 J/cm2 0 6 J/cm2
OD570 (mean) 0.899 0.871 0.861 0.323

St. Dev. 0.005 0.008 0.011 0.011
13
SCCP/1105/07
CONTROL TREATED
0 6 J/cm2 0 6 J/cm2
Viability 100% 97% 100% 38%
Cytotoxicity 3% 62%
Conclusion
Vitamin K1 (phytonadione) can be considered as phototoxic in vitro.
Ref.: 9
Comments
In this study, no positive controls were used. The isomeric composition of the test
compound was not reported.
The method which was used is not a validated in vitro method for the assessment of
phototoxic potential. The 3T3 NRU Phototoxicity test (OECD 432) should have been used
instead.
3.3.10.2. Phototoxicity / photomutagenicity / photoclastogenicity
No data submitted
3.3.11. Human data
Patch tests with two isomers of Vitamin K were applied on the back of 107 healthy
volunteers. No reaction was observed after 48 and 72 hours (only statement, no data
provided).
Ref.: 10
Comment
References 11 and 12 describe a therapeutic use of vitamin K and were considered not
relevant for risk assessment.
There have been unspecified adverse skin reactions reported from the topical use of vitamin
K containing products (6 case reports in France, 2 in Belgium, 1 in Spain and 1 in Italy).
The product manufacturer considered these adverse reactions to be secondary to the use of
the products on injured skin, which is not recommended. The estimated frequency was 2.5
to 4 cutaneous intolerance for 100 000 sold products (Vitamin K1, 1 and 2%).
Ref.: 13
The French authorities, in a report of the Commission de cosmétologie, noted 11 cases of

adverse effects after topical application of Vitamin K1 containing products in France, including
the 6 cases reported in the cosmetovigilance report from the manufacturer (Ref. 13). Amongst
these, two cases were reported with products containing oxidised Vitamin K1.
Ref.: 14
Contact dermatitis due to topical cosmetic use of Vitamin K1
A 27-year-old woman developed dermatitis of the face, particularly in the periorbital area. For
4 months, she had used a cosmetic treatment of the face to decrease periorbital hyper-
pigmentation, Auriderm K2® cream, a mixture containing vitamin K1 and retinol. Patch tests
showed a positive reaction to Auriderm K2® cream. Patch tests with the ingredients of the
14
SCCP/1105/07
cosmetic cream were positive to vitamin K1 2% pet. (D2+/ D3++) and trans-vitamin K 2%
pet (D2+/D3+++).
This was the first report of allergic contact dermatitis due to vitamin K1 from topical cosmetic
use.
Ref.: 17
A 45 year old woman developed a severe eczematous reaction on her face where she had been
applying a clarifying cream. A repeated open application test (ROAT) on her forearm was
positive. Patch testing of the cream’s ingredients showed positive reactions to vitamin K1.
At 1% and 10% in petrolatum; controls were negative.
Ref.: 16
2 cases of eyelid dermatitis cause by Vitamin K1 in a cosmetic cream (Ureadin® facial

contour) were reported in women using the cream for 3-4 weeks. Patch tests to the
Ureadin® cream (+++) and Vitamin K1 (+++) were positive but the cream without the
vitamin was negative; 15 control subjects showed no reactions.
The patch test preparation of vitamin K1 was 1 mg/ml aqueous.
Ref.: 20
Eczematous hypersensitivity from aqueous vitamin K injection
A case was reported of an eczematous reaction following injection with vitamin K1 for
treatment of warfarin-induced hypoprothrombinemia.
Ref.: 18
Type IV hypersensitivity to vitamin K
The day after intramuscular injection of vitamin K1 (phytomenadione) into her thigh, a 27-
year-old-woman with normal liver function developed a relapsing and remitting eczematous
reaction localized to the injection site, and later a further eczematous reaction under an
adhesive dressing (Duoderm®). On patch testing, she was positive to vitamin K1 and cross-
reacted to vitamin K4; she was also positive to colophonium and to ester gum rosin, the
dressing adhesive. Recurrent angioedema persisted for several months and, 2 years later,
symptoms were still occurring over the injection sites. Structure-activity relationships
among vitamin K allergens are discussed.
Ref.: 19
Between 1964 and 1994, at least 52 patients with cutaneous adverse effects of vitamin K
were described in the European and North American literature, with 94 cases in the
Japanese literature. A review of the details of these patients, primarily from therapeutic use
of Vitamin K1, is given and 2 new therapeutic use cases reported. Adverse effects were
seen not only in patients with liver-function disturbances but also in patients without liver
diseases, and occur mostly after intramuscular or subcutaneous administration of vitamin
K1, independent of the total dose. Patch and intracutaneous tests often give positive
reactions. The mechanism of action was considered in many patients to be a delayed-type
hypersensitivity reaction.
Intramuscular and subcutaneous injections of Vitamin K1 have induced three types of

cutaneous reactions:
• 10-14 days after injection eczematous reactions. The allergic mechanism was confirmed
in several patients by intradermal and/or epicutaneous testing. There were positive
patch test reactions with Vitamin K1; Vitamin K3 was negative
15
SCCP/1105/07
• Scleroderma-like patches at site of former injection several months or year after

injection. Sensitization was proven in 4 patients by intradermal tests.
• Urticaria
Additionally, 5 individuals exposed to vitamin K1 in the occupational setting and who

developed contact dermatitis on their hands and faces are recorded.
Ref.: 15
3.3.12. Special investigations
No data submitted
3.3.13. Safety evaluation (including calculation of the MoS)
Not applicable
3.3.14. Discussion
According to the applicant, since 2005 vitamin K has been replaced in their products by
“oxidised” Vitamin K. The applicant claims that “oxidised” Vitamin K is photo-stable in
contrast to Vitamin K, which is considered to produce sensitising by-products after UV
irradiation. However, experimental data to support this is absent from the submission.
The dossier presented to the SCCP is incomplete and does not permit a proper evaluation of
Vitamin K1 or “oxidised” Vitamin K1.
For “oxidised” Vitamin K1, the chemical identity of the substance has not been specified and
no experimental data on the sensitising potential or other toxicological endpoints has been
provided.
The LLNA test performed on UV irradiated Vitamin K, which should contain sensitising
photo-degradation products, was negative.
There are a number of clinical case reports concerning cutaneous sensitisation to Vitamin
K1. Although the risk of such allergy is small, Vitamin K1 can be a life-saving therapeutic
agent. In cases of pre-existing sensitisation caused by topical application of Vitamin K1 in
cosmetics, an individual might not be able to receive Vitamin K1 therapeutically.
4. 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.
5. MINORITY OPINION
Not applicable
16
SCCP/1105/07
6. REFERENCES
1. Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and

Biologicals. Rahway, NJ: Merck and Co., Inc., 1989, p. 1580
2. IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Geneva: World Health Organization, International Agency for Research on Cancer,
1972-present. (Multivolume work)., p. V76 424 (2000)
3. HSDB - Hazardous Substances Data Bank (http://toxnet.nlm.nih.gov/cgi-
bin/sis/htmlgen?HSDB)
4. Expert Group on Vitamins and Minerals. Revised review of vitamin K. doc. n°
EVM/01/09, revised aug 2002
5. Scientific Committee on Food. Opinion on the Tolerable Upper Intake Level on Vitamin
K. doc. n° SCF/CS/NUT/UPPLEV/32 Final. 4 April 2003.
6. AURIGA International, letter to Mrs J. Meunier. Service Denrées alimentaires, aliments
pour animaux et autres produits de consommation. Brussels,11 July 2006
7. Sire G. Vitamin K. Evaluation of skin sensitization potential in mice using the local lymph
node assay. CIT, France. Study number 31769 TSS, 26 January 2007
8. Sire G. Vitamin K hv. Evaluation of skin sensitization potential in mice using the local
lymph node assay (LLNA). CIT, France. Study number 31771 TSS; 26 January 2007
9. Boue-Grabot, M., Halaviat, B. Vitamine K1 Phytonadione. In vitro assessment of
phototoxic potential using human reconstructed epidermis. Bio HC, France. Report
PTCE 03.581. 13 July 2006
10. Heenen M. Rapport sur les réactions d'irritation observées après la pose de patch tests
de 2 isomères de la vitamine K. ULB, Brussels. Ref. adm/heenen/1102. 21.11.2002
11. Cesarini J.P. Rapport d'essai clinique du protocole Auriderm k5® sur les plaies
provoquees, standardisees chez l'homme. Unpublished report. 5.10.1999.
12. Cesarini J.P. Rapport d'essai clinique avec Auriderm® K5. unpublished report.
27.02.1999
13. AURIGA International. Cosmetovigilance. unpublished report
14. Avis de la Commission de cosmetology n° 25. France. 29 September 2005
15. Bruynzeel I., Hebeda CL, Folkers E., Bruynzeel DP. Cutaneous hypersensitivity
reactions to vitamin K: 2 case reports and a review of the literature. Contact
Dermatitis. 1995 Feb; 32(2):78-82
16. Serra-Baldrich E., Dalmau J., Pla C., Muntanola A.A. Contact dermatitis due to a
clarifying cream. Contact Dermatitis 2005 53(3), 174-175
17. Veneziano L., Simonetta S., Voudouris S., Tosti A. Contact dermatitis due to topical
use of vitamin K. Contact Dermatitis 2005. 52(2), 113-114
18. Keough G.C., English J.C., Meffert J.J., Eczematous hypersensitivity from aqueous
vitamin K injection. Cutis 1998 Feb; 61(2): 81-83
19. Sommer S., Wilkinson S.M., Peckham D., Wilson C. Type IV hypersensitivity to vitamin
K. Contact dermatitis 2002. 46(2), 94-96
20. Ruiz-Hornillos FJ, Prieto A, De Castro FJ et al. Allergic contact dermatitis due to
vitamin K1 contained in a cosmetic cream. Contact Dermatitis 2006. 55: 246-247
17

SCCP o 107

Uploaded by

Copyright:

Available Formats

SCCP o 107

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

SCCP o 107

Uploaded by

Copyright:

Available Formats

Scientific Committee on Consumer Products

The SCCP adopted this opinion by written procedure on 28 September 2007

About the Scientific Committees

Scientific Committee members

© European Commission 2007

Opinion to be cited as: Opinion of the SCCP on vitamin K1 (phytonadione)

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

5. MINORITY OPINION …………………………………………………………………………………. 16

Vitamin K1 is a synonym with phytonadione.

Apparently the current maximum use concentration of vitamin K1 is 2% in EU and 5% in

The ban is furthermore supported as vitamin K1 might be used as an injectable therapeutic

2. Does the SCCP recommend any restrictions to their safe use?

3.1. Chemical and Physical Specifications

3.1.1. Chemical identity

3.1.1.1. Primary name and/or INCI name

Phytonadione (INCI name)

3.1.1.2. Chemical names

1,4-naphthalenedione, 2-methyl-3-(3,7,11,15-tetramethyl-2-hexadecenyl)-, (r-(r*,r*-(e)))

3.1.1.3. Trade names and abbreviations

3.1.1.4. CAS / EINECS number

84-80-0 201-564-2 (phytomenadione)

* The names in brackets refer only to the EINECS numbers

3.1.1.5. Structural formula

The formula indicates 2'-Trans-7R, 11R-stereoisomer

3.1.1.6. Empirical formula

Empirical formula: C31H46O2

3.1.2. Physical form

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

3.1.5. Impurities / accompanying contaminants

Commercially available phytonadione (phylloquinone) is prepared synthetically and may

500 mg/l water (22 °C)

500 mg/l glycerine (22 °C)

3.1.7. Partition coefficient (Log Pow)

3.1.8. Additional physical and chemical specifications

Melting point: approx. - 20 °C

General Comments on physico-chemical characterisation

- The data provided on the physico-chemical characterisation of phytonadione is

3.2. Function and use

Phytonadione (phylloquinone) is present in plant sources, especially green leafy vegetables. It

• the bone Gla-protein, osteocalcin, which is exclusively synthesised by osteoblasts and

3.3. Toxicological Evaluation

3.3.1. Acute toxicity

3.3.1.1. Acute oral toxicity

3.3.1.2. Acute dermal toxicity

3.3.1.6. Acute inhalation toxicity

3.3.2 Irritation and corrosivity

3.3.2.1. Skin irritation

3.3.2.2. Mucous membrane irritation

3.3.3. Skin sensitisation

Murine Local Lymph Node Assay (LLNA) for Vitamin K1

Guideline: OECD 429

The results are presented in the following table:

Treatment Concentration Irritation level Stimulation Index

Test item 5 non-irritant 1.78

Test item 10 non-irritant 2.10

Test item 25 non-irritant 0.80

1,4-naphthalenedione, 2-methyl-3-(3,7,11,15-tetramethyl-2-hexadecenyl)-, (r-(r,r-(e)))