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International Agency for Research on Cancer (IARC) - Summaries & Evaluations

VITAMIN K SUBSTANCES
(Group 3)

For definition of Groups, see Preamble Evaluation.

VOL.: 76 (2000) (p. 417)

Vitamin K (generic)
CAS No.
: 12001-79-5
Chem. Abstr. Name: Vitamin K

Vitamin K1 (generic)
CAS No.
: 11104-38-4
Chem. Abstr. Name: Vitamin K1

Phylloquinone
CAS No.
: 84-80-0
Chem. Abstr. Name: 2-Methyl-3-[(2E,7R,11R)-3,7,11,15-tetramethyl-2-hexadecenyl]-1,4-naphthalenedione

Menaquinone-4
CAS No.
: 863-61-6
Chem. Abstr. Name: 2-Methyl-3-[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl]-1,4-naphthalenedione

Vitamin K2 (generic)
CAS No.
: 11032-49-8
Chem. Abstr. Name: Vitamin K2

Menadione
CAS No.
: 58-27-5
CAS No.: 1,4-Naphthalenedione, 2-methyl-

Menadione sodium bisulfite
CAS No.
: 130-37-0
Chem. Abstr. Name: 1,2,3,4-Tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonic acid, sodium salt

Menadione sodium bisulfite trihydrate
CAS No.: 6147-37-1
Chem. Abstr. Name: 1,2,3,4-Tetrahydro-2-methyl-1,4-dioxo-2-naphthalenesulfonic acid, sodium salt, trihydrate

Menadiol
CAS No.
: 481-85-6
Chem. Abstr. Name: 2-Methyl-1,4-naphthalenediol

Menadiol sodium phosphate
CAS No.
: 131-13-5
Chem. Abstr. Name: 2-Methyl-1,4-naphthalenediol, bis(dihydrogen phosphate), tetrasodium salt

Menadiol sodium phosphate hexahydrate
CAS No.
: 6700-42-1
Chem. Abstr. Name: 2-Methyl-1,4-naphthalenediol, bis(dihydrogen phosphate), tetrasodium salt, hexahydrate

Acetomenaphthone
CAS No.
: 573-20-6
Chem. Abstr. Name: 2-Methyl-1,4-naphthalenediol, diacetate

5.  Summary of Data Reported and Evaluation

5.1 Exposure data

The term ‘vitamin K’ refers to a group of 2-methyl-1,4-naphthoquinone derivatives which can fulfil an essential co-factor function in humans in the biosynthesis of a number of calcium-binding proteins, some of which are essential for haemostasis. In nature, vitamin K occurs as phylloquinone in plants and as menaquinones produced by bacteria. The major dietary sources of vitamin K are green leafy vegetables and certain vegetable oils. Clinically, vitamin K is used primarily to prevent or cure deficiency-related bleeding in newborns and patients with malabsorption syndromes and to reverse the anticoagulative effects of vitamin K antagonists.

5.2 Human carcinogenicity data

An association between childhood leukaemia and vitamin K prophylaxis given by the intramuscular route was found in two reports but was not confirmed in a number of studies in various countries. A major limitation of most of the studies is that the fact of intramuscular administration of vitamin K was difficult to establish retrospectively for a substantial proportion of subjects, although the results of the analyses based on individual records and on imputed hospital policies for vitamin K administration are similar. In the studies in which a suggestion of an association was observed, selection bias may have accounted for the result. The possibility cannot be entirely excluded of a small increase in the risk for acute lymphoblastic leukaemia occurring at ages around those of the peak incidence in childhood in children given intramuscular administration of vitamin K.

The few studies that investigated oral administration of vitamin K found no increase in the relative risk for leukaemia.

5.3 Animal carcinogenicity data

No adequate study on the carcinogenicity of vitamin K substances was available to the Working Group.

5.4 Other relevant data

Phylloquinone and menaquinones are absorbed from food into the lymphatic system and carried by triglyceride-rich lipoproteins in the blood. Menaquinones synthesized by the gut microflora may also be absorbed. Phylloquinone is rapidly cleared from the circulation by the liver, metabolized to metabolites with shortened side-chains and excreted in the bile and urine. In animals, menadione is absorbed predominantly by the portal route, does not accumulate in specific organs and is extensively excreted unchanged in the urine. A fraction of menadione is converted in tissues to menaquinone-4.

Phylloquinone rarely has toxic effects, and the few serious immunological complications observed have been attributed to the vehicle of solubilization. Menadione may cause haemolytic anaemia and induce cellular damage by arylating protein-bound and soluble thiols or by inducing oxidative stress.

No adverse effects have been reported in mothers or infants after administration of vitamin K during pregnancy, whereas vitamin K deficiency is teratogenic. The safety of vitamin K in pregnancy has not been adequately studied experimentally.

Neither phylloquinone nor menaquinones have been adequately studied for mutagenicity. Menadione acts as a bacterial mutagen in several specific strains of Salmonella typhimurium and Escherichia coli. In mammalian cells, menadione leads to DNA breakage, and there are isolated reports of chromosomal aberrations and sister chromatid exchange.

5.5 Evaluation

There is inadequate evidence in humans for the carcinogenicity of vitamin K substances.

There is inadequate evidence in experimental animals for the carcinogenicity of vitamin K substances.

Overall evaluation

Vitamin K substances are not classifiable as to their carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Synonyms

Phylloquinone

Menaquinone-4

Menadione

Menadione sodium bisulfite

Menadiol

Menadiol sodium phosphate

Menadiol sodium phosphate hexahydrate

Acetomenaphthone


Last updated: 9 June 2000





















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       Toxicological Abbreviations