Vitamin K1, also commonly known as phylloquinone, is the natural form of the fat-soluble vitamin K found in plants. Vitamin K is needed to complete the synthesis of blood coagulation proteins and for bone mineralization. Deficiency of vitamin K can lead to coagulopathies and uncontrolled bleeding. Purified vitamin K1 is synthesized and sold commercially. Although acceptable for use in infant formulas and other foods for human consumption, regulations regarding the use of vitamin K1 in animal foods are not definitively defined, but the need for its use is increasing. Menadione, a synthetic vitamin K-active substance, is acceptable by regulatory bodies for use in pet foods in the United States, but concerns regarding its safety by some consumer advocate organizations have hindered its inclusion in pet foods for a large segment of the industry.1–3 The information reported here provides support for the safe use of vitamin K1 in pet foods.
Regulatory Status of Vitamin K1
Under the Federal Food, Drug, and Cosmetic Act as enforced by the US FDA, an ingredient in a food must be approved as a food additive unless it is regarded as GRAS. For consideration as GRAS, a substance must be “generally recognized, among experts qualified by scientific training and experience to evaluate its safety, as having been adequately shown…to be safe under the conditions of its intended use.”4 This may be verified through scientific procedures or through a long history of safe use in food prior to January 1, 1958.
The Code of Federal Regulations includes extensive lists of substances the FDA regards as GRAS or that have been affirmed by the FDA as GRAS for use in animal foods.5,6 However, the FDA understands that it is impractical for it to list all GRAS substances that may be used in foods, so it regards common food ingredients (eg, salt, pepper, and sugar) as GRAS. Legally, a party may also determine whether a substance is GRAS on the basis of its own expert evaluation of the safety of the substance for its intended use. It is permitted, but not required, for the party to further submit a GRAS notification to advise the FDA of its determination.
Vitamin K1 is not expressly listed as GRAS in the Code of Federal Regulations, whether for use in food for human consumption or in animal foods. Furthermore, to the authors' knowledge, it has not been the subject of a GRAS notification. However, it is a commonly used ingredient in a variety of human foods, particularly in vitamin supplements. In fact, FDA regulations require infant formulas to contain a source of vitamin K, and it must be added in the form of phylloquinone.7 In a notice in the Federal Register about proposed amendment of regulations on infant formulas, the FDA recognizes its seemingly contradictory position when it states, “Vitamin K…is required to be a part of an infant formula.and, in the form of phylloquinone, is considered to be safe and suitable for infant formulas when used in accordance with prescribed levels…, although no source of vitamin K, such as phytonadione or phylloquinone, has been listed or affirmed as GRAS by the agency.”8
The status for use of vitamin K1 in animal foods, especially foods formulated for dogs and cats, is even less clear. The FDA recognizes the nutritional importance of vitamin K in the diet of animals and has approved some vitamin K-active substances as food additives, namely menadione dimethylpyrimidinol bisulfite9 and menadione nicotinamide bisulfite.10 Menadione, also referred to as vitamin K3, is a compound with a distinct chemical structure. Menadione expresses its effects on prevention of vitamin K deficiency only after it is chemically converted to an active form in the body. As such, the FDA does not refer to menadione-containing compounds as vitamin K per se.11
Conditions of approval for menadione dimethylpyrimidinol bisulfite and menadione nicotinamide bisulfite restrict their use to rations formulated for poultry or swine; hence, they are prohibited from being included in pet food formulations. There are also 2 vitamin K-active substances (ie, menadione and menadione sodium bisulfite complex) that are prior sanctioned for use in poultry feed, which means that on the basis of a history of safe use prior to when the food additive regulations were enacted in 1958, they received a formal FDA letter of acceptance for use.11 Again, use of these prior sanctioned ingredients in pet foods is not expressly allowed. However, in the case of menadione and menadione sodium bisulfite complex, the FDA has acknowledged that they can be used in foods for species other than those sanctioned and indicated it would exercise regulatory discretion with regard to enforcement action against pet foods containing menadione or menadione sodium bisulfite complex.11
The FDA recognizes evidence of safety for phylloquinone when consumed by animals, but the only context in which it is mentioned in regulatory documents is relative to its natural occurrence in plants.11 The FDA fails to acknowledge that phylloquinone is simply vitamin K (not a vitamin K-active substance as considered by the FDA) or that when held to the same production and purity standards as used in infant formulas and other foods for human consumption, commercially available synthetic vitamin K1 is safe for use in pet formulations as well.
Description, Properties, and Means for Manufacture of Vitamin K1
The empirical formula for vitamin K1 is C31H46O2, and it has a molecular mass of 450.68 g/mol (Figure 1). Synonyms for vitamin K1 include vitamin K (all-rac), phylloquinone (all-rac), phytomenadione (all-rac), and phytonadione (all-rac).
The chemical structure of vitamin K1 (also known as phylloquinone).
Citation: Journal of the American Veterinary Medical Association 252, 5; 10.2460/javma.252.5.537
The chemical structure of vitamin K1 (also known as phylloquinone).
Citation: Journal of the American Veterinary Medical Association 252, 5; 10.2460/javma.252.5.537
The chemical structure of vitamin K1 (also known as phylloquinone).
Citation: Journal of the American Veterinary Medical Association 252, 5; 10.2460/javma.252.5.537
Vitamin K1 is a viscous, oily liquid with an intense yellow color. It is insoluble in water, slightly soluble in ethanol, and freely soluble in ether, chloroform, fats, and oils. It occurs naturally in foodstuffs, particularly leafy greens (eg, spinach, kale, and collard) and cruciferous vegetables (eg, broccoli and brussels sprouts). However, commercially available vitamin K1, including that used in infant formulas, is most often produced by means of chemical synthesis. Steps in the synthesis of vitamin K1 by a commercial manufacturer and the specifications of the final product have been described12,13 (Appendix).
Commercial vitamin K1 may be stored in the unopened original container for 36 months from the date of manufacture or until the “best use before” date on the label. It is relatively stable to heat, but it is slowly degraded by exposure to oxygen, is fairly rapidly degraded by light, and decomposes when in contact with alkalis.
Discovery of Vitamin K1
Dam14 and McFarlane et al15 were the first to report clotting defects in chicks when the chicks were fed diets that contained fat-extracted fish and meat meals. In 1933, investigators reported that feeding 5 g of cabbage/young (5 to 6 weeks old) chick was able to correct a clotting defect when fish meal, ground yellow corn, yeast, ground oyster shell, and sardine or cod liver oils were fed.a Those authors incorrectly believed that this curative effect was the result of the vitamin C content of the cabbage.a However, provision of purified ascorbic acid (ie, vitamin C) failed to result in similar improvements in clotting; therefore, other dietary factors that prevented the clotting defect were investigated. Dam14 attempted to cure the defect with high doses of vitamins A and D as well as fish liver oil; however, after these treatments failed to cure the clotting defect, it was determined that an active component in vegetable and animal sources was involved, and it was called vitamin K (for the German word Koagulation).16,17 In 1939, the specific vitamin was isolated and identified as 2-methyl-3-phytyl-1,4-napthoquinone (ie, vitamin K1 or phylloquinone).18 It was soon realized that the chlorophyll-rich portions of plants such as cabbage, alfalfa, spinach, kale, and cauliflower were rich in vitamin K.19
Vitamin K1 Deficiency and Coagulopathies
The importance of the frequent use of fish, fish meal, and fish oils in early studies of vitamin K, especially as it related to commercial foods formulated for dogs and cats, was possibly unappreciated for almost 6 decades. Although there was a report20 in 1959 that fish oil would induce vitamin K deficiency in rats, it was not until 1996 that investigators reported21 on vitamin K deficiency in cats fed commercial fish-based diets. In that study,21 queens and kittens fed canned diets high in salmon or tuna died, and survivors had prolonged coagulation times. Necropsy revealed hepatic and gastrointestinal hemorrhages. In a series of experiments in that study,21 vitamin K1 was fed to cats and kittens (concentrations of 4 to 30 μg/kg [1.8 to 13.6 μg/lb] of diet). Despite concurrent antimicrobial treatment to reduce gastrointestinal microbial synthesis of vitamin K2, excessive amounts of dietary vitamins A and E to inhibit absorption of vitamins K1 and K2, feeding of salmon or herring oils, or a combination of these, the lowest amount of vitamin K1 (11 μg/kg [5 μg/lb] of diet) did not result in a clotting deficiency as determined on the basis of prolonged blood clotting times.
Other investigators subsequently reported that cats on a diet higher in n-3 fatty acid diet content (from menhaden fish oil) had increased toenail bleeding times as well as lower peak platelet aggregation.22 However, indices of intrinsic, extrinsic, and common coagulation pathways, as measured by use of the 1-stage prothrombin time, APTT, and fibrinogen concentration, reportedly did not differ. Unfortunately, those authors did not report data on specific long-chain n-3 fatty acid concentrations (only the ratio of 1.3:1 [for n-6 to n-3 fatty acids] was provided) or dietary vitamin K concentration or intake.22 In a report23 of 2 cats with probable vitamin K-deficient bleeding secondary to malabsorption as a result of lymphocytic-plasmacytic enteritis, it was indicated that the 1-stage prothrombin time and APTT are insensitive indicators of vitamin K deficiency and that prolonged times develop only after vitamin K-dependent coagulation factors decrease to approximately 35% of normal activity. A study24 of the effects of n-3 fatty acids in healthy dogs did not reveal impacts on coagulation; however, the lowest ratio was 5.3:1 (for n-6 to n-3 fatty acids), and the short-chain n-3 fatty acid α-linolenic acid from flax was used.24 A ratio that includes values for all dietary n-3 fatty acids is not comparable to the lowest ratios of n-6 to long-chain n-3 fatty acids that are used clinically. Excluding α-linolenic acid, which cannot be efficiently converted to long-chain n-3 fatty acids, would have substantially increased the lowest ratio in that study.24 Thus, it is possible that there may be a coagulopathy in dogs fed diets with an extremely low ratio of n-6 to long-chain n-3 fatty acids, especially when other risk factors are present.
In a study in 2000,25 investigators found that 21 of 24 cats with an abnormal PIVKA clotting time responded to vitamin K1 treatment within 3 to 5 days after receiving 2.5 to 5 mg/cat parenterally twice daily. Most of those cats had hepatic disease or inflammatory bowel disease. It is interesting that although 61 of 150 cats had a prolonged PIVKA clotting time, only 17 of 121 cats had a prolonged APTT and only 10 of 113 had a low fibrinogen concentration. Of the 24 cats treated with vitamin K1, 10 had bleeding tendencies before treatment. In another study,26 50% of cats with liver disease and a prolonged prothrombin time had a coagulopathy attributable to vitamin K deficiency.
The AAFCO nutrient profiles only require that vitamin K be added to diets formulated for cats if the diet contains > 25% fish on a dry-matter basis.27 The AAFCO makes no recommendations for fish oil inclusion that could result in a ratio lower than 1.3:1 and does not set any upper maximum ratio or requirement for eicosapentaenoic acid and docosahexaenoic acid. No minimum requirement for vitamin K or maximum requirements for eicosapentaenoic acid and docosahexaenoic acid have been set by AAFCO for dog foods. The 2006 NRC recommendations,28 which served as the basis for the updated 2016 AAFCO nutrient profiles, suggest that gastrointestinal microbial synthesis in dogs should provide the necessary amount of vitamin K.
Higher Requirements for Vitamin K
Deficiencies of fat-soluble vitamins, including vitamin K, can be a concern in human patients with exocrine pancreatic insufficiency, despite oral administration of pancreatic enzymes.29 Dietary excess of vitamin E (13.3 to 32 U/kg/d [6.0 to 14.5 U/lb/d] for 1 week) has been found to reduce vitamin K-dependent clotting factors and increase prothrombin times for dogs fed fish (including fish oil) or for conditions in which gastrointestinal uptake of vitamin K was decreased because of reduced absorption or reduced microbial production resulting from antimicrobial treatment.30 The lowest vitamin E dose fed had a significant effect, and feeding studies of longer duration should be conducted. The pet food industry increasingly relies on mixed tocopherols with differing amounts of vitamin E biological activity as ingredients. These mixed tocopherols serve as antioxidants to prevent fat oxidation in dry extruded foods. Pet foods that are more expensive typically are defined by their increased energy density, which is largely attributable to a high fat content.31 In addition, as of 2016, AAFCO required for the first time that the long-chain n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid be included in some dog and cat diets. Finally, a low ratio of n-6 to long-chain n-3 fatty acids is recommended and used as a key nutritional management strategy for conditions such as renal disease and osteoarthritis as well as other inflammatory conditions such as inflammatory bowel disease. Higher amounts of dietary fat and n-3 fatty acids increase the need for antioxidants to prevent fat rancidity. Thus, there is an increased amount of vitamin E, especially from mixed tocopherols and fish oil or n-3 fatty acids, included in many pet foods. This creates more scenarios in which dietary fortification with vitamin K would be beneficial and likely protective. One example would be a dog or cat with inflammatory bowel disease that is receiving antimicrobial treatment and concurrently being fed a preserved pet food containing mixed tocopherols fortified with n-3 fatty acid-rich fish oil.
Unfortunately, regulations concerning the use of vitamin K have not been definitively clarified; thus, the pet food industry has been able to rely only on the inclusion of menadione compounds to provide vitamin K activity because, in the authors' experiences, inclusion of an adequate amount of green leafy vegetables is impractical. Menadione can have toxic effects after injection in horses,32 cats,33 and dogs.33–35 Vomiting, porphyrinuria, and occasional albuminuria have been reported when very high doses (30 to 60 mg/kg [13.6 to 27.3 mg/lb]) are fed to dogs.36 Menadione is not an approved food additive or otherwise sanctioned by the FDA for use in human foods because safety information sufficient to support such use has not been established. Reports of toxic effects, even for doses at least 312 times the NRC-recommended allowance for adult dogs,28 as well as other references to menadione toxicosis have resulted in some opposition to its use. Thus, use of purified and commercially available vitamin K1 would be seen by some as a preferable alternative to the use of menadione and menadione sodium bisulfite complex.
Arguments for the use of menadione compounds instead of vitamin K1 include better stability and lower costs.28 Although vitamin K1 is more heat stable than menadione, and both are adversely affected by oxygen and trace minerals, the binding of a compound such as menadione sodium bisulfite complex to an ion-exchange resin results in high thermal stability.37 The cost of vitamin K138 is approximately 35 times the cost for an equal mass of menadione sodium bisulfite.39 On the assumption that 2 to 4 times as much vitamin K1 is needed to address differences in shelf stability, this represents a cost that is 70 to 140 times that for menadione sodium bisulfite. However, it is worth mentioning that this represents 0.0001% (0.25 mg/250 g of dry-matter diet) of the 4,000-kcal/kg of dry-matter food for an adult cat or 0.000164% (0.41 mg/250 g of dry-matter diet) of the 4,000-kcal/kg of dry-matter food for an adult dog, as determined on the basis of 2006 NRC recommended allowances.28 The higher cost (an estimated 0.023% [0.000164% X 140 = 0.02296%]) for vitamin K1 may be acceptable to some pet food manufacturers and is not inherently cost prohibitive, even when higher amounts are included in diets. Thus, the result is that the net cost of fortifying pet food with vitamin K1 is higher, in part, because of needed overages.
Safety of Vitamin K1
The initial requirement of vitamin K1 established for puppies is ≥ 10 μg/kg (4.5 mg/lb) IV and for adult dogs is < 5 μg/kg (2.3 μg/kg) IV.40 These requirements were established by use of cholecystnephrostomy to reduce the ability to absorb vitamin K. This surgical procedure results in complete drainage of bile through the urinary tract and reduces the absorption of fat-soluble vitamin K, which leads to a deficiency. The maintenance IV dose of vitamin K1 necessary over several months to normalize prothrombin time was identified and used to establish dietary requirements.40 A subsequent study41 that involved the use of warfarin (which blocks vitamin K epoxide reductase and thus reduces the liver's ability to use vitamin K to produce functional blood clotting factors) to induce a need for vitamin K in dogs revealed that 2.2 mg of vitamin K1/kg (1 mg/lb) could be given orally for 3 consecutive days to normalize prothrombin time without any adverse effects. Oral administration of vitamin K1 at doses up to 10 mg/kg (104 times the NRC adult dog recommended allowance and 2,000 times the maintenance dose suggested in another study40) for 5 days did not result in adverse effects, including RBC oxidative stress.35
In the 1990s, oral administration of vitamin K1 to Devon Rex cats with reduced γ-glutamyl carboxylase activity was reported.42 This enzyme is involved in the oxidation of vitamin K hydroquinone and activation of coagulation factors. That report42 included administration of 5 mg of vitamin K1/d to a Devon Rex kitten, 5 mg of vitamin K1/d to an adult Devon Rex that was then maintained by long-term administration of 10 mg of vitamin K1 twice weekly, and 10 mg of vitamin K1/d to a related adult Devon Rex. Similarly, a 4-year-old male Devon Rex received 5 mg of vitamin K1/d for a few days and then was maintained by administration of 2.5 mg of vitamin K1/d, with the cat remaining fit and well.43 The aforementioned extensive experiments on oral supplementation with vitamin K1 were also conducted on cats.21 In that study,21 feeding trials of cats were conducted with doses of vitamin K1 between 4 and 30 μg of vitamin K1/kg (1.8 and 13.6 μg/lb) of diet.
To the authors' knowledge, there are no reports of hypervitaminosis K or toxic effects in dogs or cats fed synthesized vitamin K1. After an extensive review of the literature was conducted, the NRC concluded in 1987 that phylloquinone, which is a natural form of vitamin K, has no adverse effects when administered to animals in massive doses by any route.44
Clinical Summary
Vitamin K1 is the form of the fat-soluble vitamin K found in plants, and it is the safest form of vitamin K. Purified and synthetic vitamin K1 is commercially available. Vitamin K1 can be safely fed to dogs and cats without restriction. Thus, vitamin K1 manufactured in accordance with specifications set forth for use in infant formulas and other foods for human consumption has been determined via scientific procedures to be GRAS for its intended use in foods formulated for dogs and cats, including its use in nutritional supplement-type products for those species. Fortifying diets with vitamin K1 can prevent a potential coagulopathy for animals that are consuming increasingly common types of pet foods and that have increasingly common medical conditions. Menadione and menadione sodium bisulfite complex are considered acceptable by regulatory bodies for use in pet foods in the United States; however, their safety has been challenged by some consumer advocate organizations, which has limited their usefulness in commercial formulations needed to address potential vitamin K deficiencies. Therefore, we believe that the addition of vitamin K1 to pet diets should be encouraged and supported in veterinary nutrition.
Acknowledgments
No third-party funding or support was received in connection with the writing or publication of the manuscript.
Dr. Delaney is co-owner of Balance IT, which distributes multimineral and multivitamin premixes for the fortification of pet food. Dr. Dzanis is CEO of Regulatory Discretion Inc, which is a consulting company for the animal feed, pet food, and related industries in matters relating to nutrition, labeling, and regulation.
ABBREVIATIONS
| AAFCO | Association of American Feed Control Officials |
| APTT | Activated partial thromboplastin time |
| GRAS | Generally recognized as safe |
| NRC | National Research Council |
| PIVKA | Protein induced by vitamin K absence |
Footnotes
Holst WF, Holbrook ER. A “scurvy-like” disease in chicks (abstr). Science 1933;77:354.
References
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Appendix
Steps in the synthesis of vitamin K1 and specifications for the final product.
| Synthesis |
| Specifications |
Ph.Eur = European Pharmacopeia. USP = United States Pharmacopeia.
