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Tadapox


By T. Mirzo. University of Scranton.

Any flakes resulting from sure of 384 pounds per square inch of the operations described in this para- plunger face in contact with the can graph (c)(2)(xi) or in other parts of this contents buy 80 mg tadapox with mastercard. Hold this pressure for 1 addi- paragraph are to be weighed as free tional minute and then release the flakes order 80 mg tadapox with visa. Only fragments that were bro- pressure and disengage the plunger ken in the canning procedure are con- from the press shaft cheap tadapox 80 mg otc. If the can is of inder so that any free liquid is drained such size that its entire drained con- out generic 80mg tadapox overnight delivery. Loosen the pressed cake from ula, scrape free flakes gently from the the cylinder with a thin blade and re- outside of the cake. Weigh the aggre- move the entire pressed cake as gently gate free flakes that were broken from as possible, to keep the mass in a sin- the loin segments in the canning proce- gle cake during this operation. For can size 401×206 The weight of the portion examined Press cylinder: should approximately equal the weight Inside depth, approximately 41⁄8 inches. For can sizes differing rated by hand, care being taken to from those specified in this paragraph avoid breaking the pieces. The sepa- (c)(3)(i), special press cylinders and rated pieces are evenly distributed over plungers may be used. Special press the top sieve of the screen separation less than the outside diameters, at the equipment described in paragraph cylinders have inside diameters 1⁄10- (c)(3)(iv) of this section. Beginning inch double seam, for the can sizes for with the top sieve, lift and drop each which the cylinders are used; plunger sieve by its open edge three times. Combine and weigh the ma- paragraph (c)(2) (ix) and (xi) of this sec- terial remaining on the three top tion and paragraph (c)(3)(i) of this sec- sieves (11⁄2-inch, 1-inch, 1⁄2-inch tion is made from a previously sealed screens), and determine the combined 300×407 can. The cover, including the percentage retention by weight in rela- top seam, is cut out. The in paragraph (c)(2) (vi) to (x) of this press cylinders are made with a lip to section, inclusive, is made by so facilitate drainage of the liquid. Plung- mounting a hydraulic jack, in a strong ers have a threaded center hole, about frame, that it will press horizontally half as deep as the thickness of the against the center of the plunger in the plunger, for receiving a ringbolt to as- press cylinder used. The frame is so sist in removing the plunger from the braced that it does not change shape press cylinder. The gauge on cylinders and plungers are as follows: the hydraulic jack is so calibrated that it will indicate, for the plunger being For can size 211×109 used, when the plunger is pressing Press cylinder: against the contents of the press cyl- Inside depth, approximately 33⁄4 inches. The sides of each scribed in "Official Methods of Anal- sieve are formed, in a raised rim, from ysis of the Association of Official Ana- 3⁄4-inch × 1⁄8-inch metal strap. The lytical Chemists," which are incor- frame has tracks made of 3⁄8-inch angle porated by reference in accordance metal to support each sieve under each with 5 U. Subpart B—Requirements for Specific Subpart B—Requirements for Spe- Standardized Cacao Products cific Standardized Cacao Products 163. The following follow the name without intervening safe and suitable ingredients may be printed or graphic matter. Ammonium, gredients used in the food shall be de- potassium, or sodium bicarbonate, car- clared on the label as required by the bonate, or hydroxide, or magnesium applicable sections of parts 101 and 130 carbonate or oxide, added as such, or in of this chapter. The fat value (calculated from the respective content of the food may be adjusted by combined weights of the alkali ingredi- adding one or more of the optional in- ents used) than the neutralizing value gredients specified in paragraph (b)(1) of 3 parts by weight of anhydrous po- of this section to the cacao nibs. Phosphoric percent nor more than 60 percent by acid, citric acid, and L-tartaric acid, weight of cacao fat as determined by added as such, or in aqueous solution. For each 100 parts by weight of cacao (2) Optional alkali ingredients speci- nibs, used as such, or before shelling fied in paragraph (b)(2) of this section from the cacao beans, the total quan- may be used as such in the preparation tity of phosphoric acid used is not of chocolate liquor under the condi- greater than 0. The name of the of the chocolate liquor under the condi- food is "cacao nibs", "cocoa nibs", or tions and limitations specified in "cracked cocoa". The following "Processed with lll", the blank safe and suitable ingredients may be being filled in with the common or used: usual name of the specific alkali ingre- (1) Cacao fat and cocoas (breakfast dient used in the food. Ammonium, beans from which they are prepared, potassium, or sodium bicarbonate, car- are processed with neutralizing agents bonate, or hydroxide, or magnesium specified in paragraph (b)(2) of this sec- carbonate or oxide, added as such, or in tion, the name of the food shall be ac- aqueous solution; companied by the statement "Proc- (3) Neutralizing agents. Phosphoric essed with neutralizing agent" or acid, citric acid, and L-tartaric acid, "Processed with lll", the blank added as such, or in aqueous solution; being filled in with the common or (4) Spices, natural and artificial usual name of the specific neutralizing flavorings, ground whole nut meats, agent used in the food. The name of the clared on the label as required by the food is "chocolate liquor", "choco- applicable sections of parts 101 and 130 late", "unsweetened chocolate", "bit- of this chapter. Breakfast cocoa used in the preparation of the cacao contains not less than 22 percent by nibs and cocoas from which the choco- weight of cacao fat as determined by late liquor was prepared, the name of the method prescribed in §163. The following cific neutralizing ingredient used in safe and suitable ingredients may be the food. Ammonium, flavorings, or seasonings specified in potassium, or sodium bicarbonate, car- paragraphs (b)(4) and (b)(5) of this sec- bonate, or hydroxide, or magnesium tion are used in the chocolate liquor, carbonate or oxide, used as such, or in the label shall bear an appropriate aqueous solution; statement, e. Phosphoric vored with lll", "Seasoned with acid, citric acid and L-tartaric acid, lll", or "With lll added", the used as such, or in aqueous solution; blank being filled in with the common (3) Spices, natural and artificial or usual name of the spice, flavoring, flavorings, and other seasonings that or seasoning used, in accordance with do not either singly or in combination §101. The name of the bined in a manner that is appropriate, food is "breakfast cocoa", or "high fat but not misleading. Lowfat cocoa is the (2) When any optional neutralizing food that conforms to the definition agent specified in paragraph (b)(2) of and standard of identity, and is subject this section is used, including those to the requirements for label declara- used in the preparation of the cacao tion of ingredients for breakfast cocoa nibs from which the breakfast cocoa in §163. Cocoa with dioctyl so- paragraph (b)(3) of this section are used dium sulfosuccinate for manufacturing in the breakfast cocoa, the label shall is the food additive complying with the provisions prescribed in §172. It conforms to the definition "Spice added", "Flavored with lll", and standard of identity, and is subject or "With lll added", the blank being to the requirements for label declara- filled in with the common or usual tion of ingredients, for breakfast cocoa name of the spice, flavoring, or sea- in §163. The name of the pears on the label so conspicuously as food additive is "cocoa with dioctyl so- to be easily seen under customary con- dium sulfosuccinate for manufac- ditions of purchase, the statements turing" to which is added any modifier prescribed in this paragraph showing of the word "cocoa" required by the optional ingredients used shall precede definition and standard of identity to or follow the name without intervening which the food additive otherwise con- printed or graphic matter. Each of the in- in a fabricated food, the phrase "for gredients used in the food shall be de- manufacturing" may be omitted from clared on the label as required by the any declaration of ingredients required applicable sections of parts 101 and 130 under §101. Cocoa is the food that by intimately mixing and grinding conforms to the definition and stand- chocolate liquor with one or more op- ard of identity, and is subject to the re- tional nutritive carbohydrate sweet- quirements for label declaration of in- eners, and may contain one or more of gredients for breakfast cocoa in the other optional ingredients specified §163. The name of the tracting from the weight of the choco- food is "cocoa" or "medium fat cocoa". The finished sweet chocolate con- lll", the blank being filled in with tains less than 12 percent by weight of the common or usual name of the spe- total milk solids based on those dairy cific alkali ingredient used in the food. The following "Spice added", "Flavored with lll", safe and suitable ingredients may be or "With lll added", the blank being used: filled in with the common or usual (1) Cacao fat; name of the spice, flavoring, or sea- (2) Nutritive carbohydrate sweet- soning used, in accordance with §101. Each of the in- condensed skim milk, nonfat dry milk; gredients used in the food shall be de- (iv) Concentrated buttermilk, dried clared on the label as required by the buttermilk; and applicable sections of parts 101 and 130 (v) Malted milk; or of this chapter. The name of the by intimately mixing and grinding food is "sweet chocolate", "sweet choc- cacao fat with one or more of the op- olate coating", "semisweet chocolate", tional dairy ingredients specified in "semisweet chocolate coating", "bit- paragraph (b)(2) of this section and one tersweet chocolate", or "bittersweet or more optional nutritive carbo- chocolate coating", as appropriate. I (4–1–10 Edition) one or more of the other optional in- "With lll added", the blank being gredients specified in paragraph (b) of filled in with the common or usual this section. White chocolate shall be name of the spice, flavoring, or sea- free of coloring material. Each of the in- as calculated by subtracting from the gredients used in the food shall be de- weight of the total fat the weight of clared on the label as required by the the milkfat, dividing the result by the applicable sections of parts 101 and 130 weight of the finished white chocolate, of this chapter. The following one or more of the other optional in- safe and suitable ingredients may be gredients specified in paragraph (b) of used: this section. The finished (v) Malted milk; milk chocolate contains not less than (3) Emulsifying agents, used singly or 3. The following of chocolate, milk, or butter; safe and suitable ingredients may be (5) Antioxidants; and used: (6) Whey or whey products, the total (1) Cacao fat; amount of which does not exceed 5 per- (2) Nutritive carbohydrate sweet- cent by weight. The name of the (3) Spices, natural and artificial food is "white chocolate" or "white flavorings, ground whole nut meats, chocolate coating. Each of the in- (ii) Milk, concentrated milk, evapo- gredients used in the food shall be de- rated milk, sweetened condensed milk, clared on the label as required by the dried milk; and applicable sections of parts 101 and 130 (iii) Skim milk, concentrated skim of this chapter. Buttermilk chocolate (5) Emulsifying agents, used singly or is the food that conforms to the stand- in combination, the total amount of ard of identity, and is subject to the re- which does not exceed 1. The name of the food is "buttermilk chocolate", "but- or "Processed with lll", the blank being filled in with the common or termilk chocolate coating", "sweet buttermilk chocolate", "sweet butter- usual name of the specific neutralizing agent used in the food. Skim milk chocolate "Spice added", "Flavored with lll", is the food that conforms to the stand- or "With lll added", the blank being ard of identity, and is subject to the re- filled in with the common or usual quirements for label declaration of in- name of the spice, flavoring, or sea- gredients for milk chocolate in soning used, in accordance with §101. I (4–1–10 Edition) added beyond that amount that is nor- ments for label declaration of ingredi- mally present in the specified dairy in- ents for sweet chocolate in §163. The name of the (1) In the preparation of the product, food is "skim milk chocolate", "skim cocoa or a mixture of cocoa and choco- milk chocolate coating", "sweet skim late liquor is used in such quantity milk chocolate", or "sweet skim milk that the finished food contains not less chocolate coating". Mixed dairy product specified in paragraph (b) of this sec- chocolates are the foods that conform tion are used; and to the standard of identity, and are (3) The requirement in §163. The fats, oils, and stearins (iii) Any dairy ingredients specified may be hydrogenated; in §163. The name of the referred to in paragraph (a)(1) of this food is "sweet cocoa and vegetable fat section, exclusive of any added sweet- coating". Alternatively, the common ener or other dairy-derived ingredient or usual name of the vegetable derived that is added beyond that amount that fat ingredient may be used in the name is normally present in the specified of the food, e. The name of the conforms to the definition and stand- food is "chocolate", or "chocolate ard of identity, and is subject to the re- coating", preceded by the designation quirements for label declaration of in- of the type of milk ingredients used as gredients for sweet chocolate in prescribed in paragraph (a) of this sec- §163. Sweet cocoa and vege- cluding only those dairy ingredients re- table fat coating is the food that con- ferred to in §163. The lll oil coating", the blank being fats, oils, and stearins may be hydro- filled in with the common or usual genated; name of the specific vegetable fat used. The name of the Subpart A [Reserved] food is "sweet chocolate and vegetable Subpart B—Requirements for Specific fat coating". Alternatively, the com- Standardized Tree Nut and Peanut mon or usual name of the vegetable de- Products rived fat ingredient may be used in the name of the food, e. The ingredient when used shall be present oils, fats, and stearins may be hydro- in a quantity not less than 2 percent genated; and not more than 80 percent by weight (2) Safe and suitable dairy-derived in- of the finished food. For purposes of gredients; and this section, each kind of tree nut and (3) Safe and suitable bulking agents, peanut is an optional ingredient that formulation aids, humectants, and may be prepared by any suitable meth- texturizers. The finished food may food is "milk chocolate and vegetable contain one or more of the optional fat coating" or "skim milk chocolate nonnut ingredients provided for in and vegetable fat coating", as appro- paragraph (c) of this section. I (4–1–10 Edition) (b) The optional shelled nut ingredi- than 16 ounces, enough containers to ents referred to in paragraph (a) of this provide a total quantity of at least 24 section are: pounds of nuts. Calculate the av- combination of two or more such vari- erage percentage of each nut ingredient eties. If the average percent found (c) The optional nonnut ingredients for each nut ingredient present is 2 per- referred to in paragraph (a) of this sec- cent or more and none of the individual tion consist of suitable substances that nut ingredients exceeds 80 percent by are not food additives as defined in sec- weight of the finished food, the lot will tion 201(s) of the Federal Food, Drug, be deemed to be in compliance with the and Cosmetic Act; or if they are food percentage requirements of paragraph additives as so defined, they are used in (a) of this section. If the average per- conformity with regulations estab- cent found for a single nut ingredient lished pursuant to section 409 of the exceeds 50 percent by weight of the fin- act. Nonnut ingredients that perform a ished food and the average percent useful function are regarded as suit- found is within the range indicated by able, except that color additives are the number declared on the label in ac- not suitable ingredients of the food. If the percentage of a single tree with the labeling requirements of this nut ingredient or the total peanut con- paragraph. Each of the in- ceeds 50 percent but not 60 percent, the gredients used in the food shall be de- statement "contains up to 60% lll" clared on the label as required by the or "contains 60% lll" or "60% applicable sections of parts 101 and 130 lll" shall immediately follow the of this chapter, except that: name "mixed nuts" and shall appear on (1) If the Spanish variety of peanuts the same background, be of the same is used, it shall be declared as "Spanish color or, in the case of multicolors, in peanuts".

Small amounts of activity were sometimes detected in liver generic 80mg tadapox otc, lung and kidney discount tadapox 80 mg free shipping, but no significant amounts were found in skin tadapox 80mg on-line, bone or muscle (Solvonuk et al purchase tadapox 80 mg with amex. A comparison of the tissue distribution of [14C]menadione and [14C]phylloquinone in rats after intravenous administration of a pharmacological dose (5 mg/kg bw) showed a much higher (24-fold) concentration of radiolabel in the livers of animals given phylloquinone than in those given menadione, and a fivefold greater accumulation of phylloquinone was found in the spleen. The rapid, extensive excretion of [14C]menadione in the urine was confirmed by Losito et al. They also showed that the urinary excretion of menadione (again unlike phyllo- quinone) was not dependent on an intact liver, as hepatectomized rats excreted the same amount of the dose (70%) as normal rats. A similar pattern was seen in rats given an intraperitoneal injection of about 2 μg of the water-soluble salt menadiol diphosphate; 17 h later, some 43% of the radiolabel had been excreted in urine and about 4% in faeces. The compound was not concentrated in any tissue but was distributed throughout all body organs, and the distribution was the same in vitamin K-replete and -deficient animals. This water-soluble compound underwent rapid conversion to lipid- soluble forms, and the compound and its metabolites were found generally to be asso- ciated with the membranous fractions of cells (Thierry & Suttie, 1969). After oral administration of menadione to rabbits, Richert (1951) isolated the sulfated compound 2-methyl-4-hydroxy-1-naphthyl sulfate and noted increased excretion of glucuronic acid. The chromatographic pattern in hepatectomized rats was different, but the major peak was shown to be a glucuronide conjugate, showing that animals have the capacity for extrahepatic conjugation of menadione with glucuronic acid (Losito et al. The early evi- dence that both menadione and phylloquinone could be converted in birds and rats has been reviewed (Martius, 1967). The enzymic alkylation of menadione to menaquinone- 4 was subsequently confirmed by more sophisticated techniques both in vivo in rats (Taggart & Matschiner, 1969) and in vitro in chick liver homogenates (Dialameh et al. The greatest alkylating activity was found in the microsomal fraction and was six to seven times higher in chick liver microsomes than in rat liver microsomes (Dialameh et al. Rare cutaneous reactions to another vitamin K preparation, AquaMephyton, have been reported and are suspected to be immunologically mediated (Sanders & Winkelmann, 1988). This preparation contains a polyoxyethylated fatty acid derivative as the emulsifying agent (Rich & Drage, 1982). Severe complications resulting in cardiopulmonary arrest were reported after intravenous injection of AquaMephyton (Rich & Drage, 1982). The increased erythrocyte breakdown may lead to hyperbilirubinaemia and kernicterus. These effects are clearly dose-dependent, as premature infants given 30 mg of menadiol sodium phosphate had higher serum bilirubin concentrations, more Heinz bodies, lower haemoglobin concentrations and lower erythrocyte counts than those given 1 mg. The toxic reactions are more pro- nounced and may lead to severe haemolysis in premature infants and in infants with a congenital defect of glucose 6-phosphate dehydrogenase. An explanation for the haemolytic toxicity of menadione is provided by studies showing the high reactivity of the 3-position of menadione with sulfhydryl compounds. Canady and Roe (1956) showed that when menadione is added to blood, it combines directly with blood proteins, probably by forming a thio ether at the 3-position. A later study showed that menadione reacts with both the haem groups and the β-93 thiol groups of haemoglobin and that it oxidizes the haem groups of oxyhaemoglobin, resulting in the formation of methaemoglobin (Winterbourn et al. With elucidation of the toxic properties of menadione in newborn infants and, in the 1960s, the industrial synthesis of natural K vitamins, use of menadione for vitamin K prophylaxis in the newborn was discontinued in most countries (Vest, 1966). This suggestion stemmed from their studies with menadione, which was shown to inhibit the conversion of benzo[a]pyrene to its more polar metabolites in rat liver microsomes in vitro. The inhi- bition showed a plateau (25% of control) at a concentration of 100 μmol/L [17 μg/mL]. With phylloquinone, no inhibition to polar metabolites was evident at concentrations up to 50 μmol/L [8. The weaker effect of phylloquinone at lower concentrations is perhaps due to its much greater lipophilicity and reduced penetration and solubility in microsomal membranes as compared with menadione; this explanation would also be consistent with the absence of a difference in solubility at higher concentrations of phylloquinone. In parallel studies, tumorigenesis was inhibited in mice treated with the vitamin K antagonist warfarin and in mice made vitamin K-deficient by dietary deprivation. In these experiments, the compounds were given either before or both before and after benzo[a]pyrene (Israels et al. This dose resulted in significant increases in splenic weight and decreased blood packed cell volume and haemoglobin concentration. There was no evidence that menadione caused haemaglobinaemia, suggesting that the haemo- lysis is not intravascular but is due to the destruction of damaged erythrocytes by cells of the reticuloendothelial system. This dose regime was generally well tolerated with no relevant haematological changes, although there was a signifi- cant increase in spleen weight. Many studies have been reported of the cytotoxicity of menadione in isolated and cultured cells of several types, including isolated rat hepatocytes (Mirabelli et al. The cytotoxicity of menadione has also been studied in iso- lated rat platelets (Chung et al. A characteristic finding in isolated rat hepatocytes treated with menadione is the appearance of numerous protrusions in the plasma membrane, known as blebs. Mena- dione produced a dose- and time-dependent increase in the frequency of cytoskeletal abnormalities; protein thiol oxidation seems to be intimately related to the appearance of surface blebs (Mirabelli et al. In a study of the efficacy of vitamin K for the prevention of the vitamin K deficiency induced by antiepileptic drugs, 16 women receiving antiepileptic drugs known to induce hepatic microsomal enzymes were treated orally with phylloquinone (Konakion) at 10 mg/day from the 36th week of pregnancy until delivery (mean, 29 days; range, 10–46). A control group of 20 epileptic women on similar antiepileptic drugs did not receive supplemental vitamin K. No adverse effects were observed in the infants of women given vitamin K supplementation. The median maternal plasma concentration of phylloquinone was raised 60-fold and the cord blood concentration was raised 15-fold, for a median maternal:cord blood ratio of 44 (Cornelissen et al. Six pregnant Sprague-Dawley rats were dosed with 10 mg/kg bw phylloquinone (Konakion) daily on days 9–20 of gestation, and the fetuses were delivered on day 21 and examined for external malformations and the presence of haemorrhages only. No adverse effects were noted when compared with a group of five untreated controls (Howe & Webster, 1990). The blood was taken 24 h after an intramuscular dose of 1 mg, at which time the plasma concentrations of phylloquinone ranged from 115 to 1150 ng/mL (mean, 536 ng/mL), compared with about 0. All three groups showed a lower variant frequency than a reference group of children aged 1–15 years. For ethical reasons, there was no control group of infants who had not received vitamin K prophylaxis, and the conclusion was therefore limited to a lack of association between the route of vitamin K administration and somatic mutation. It enhanced the frequency of sister chromatid exchange in cultured human maternal lymphocytes at concentrations that are relevant in vivo, and a similar increase in sister chromatid exchange frequency was observed in cultured lymphocytes from human placental blood. In fetal sheep that received a catheter in the femoral vein 10–15 days before term, phylloquinone significantly increased the frequency of sister chromatid exchange in peripheral blood lymphocytes sampled 24 h later. Menaquinone-4 but not phylloquinone inhibited osteoclastic bone resorption by inducing osteoclast apoptosis (Kameda et al. Menaquinone-4 and its derivatives also induced apoptosis in various human leukaemic cell lines (Yaguchi et al. Phylloquinone at a high concentration (200 μmol/L) inhibited the conversion of benzo- [a]pyrene to its more polar metabolites, a property it shares with menadione. Paradoxi- cally, at a lower concentration of phylloquinone (25 μmol/L), but not with menadione, the metabolism of benzo[a]pyrene was increased. In this system, therefore, whereas menadione consistently acts as a potential inhibitor of carcinogenesis, phylloquinone could either potentiate or inhibit it, depending on the concentration. The overall weaker inhibitory effect of phylloquinone could be due to the low solubility of this lipophilic compound, but it is difficult to explain the mechanism of the enhanced metabolism of benzo[a]pyrene at lower concentrations of phylloquinone. They concluded that vitamin K deficiency confers a protective effect against benzo[a]pyrene-induced tumour formation. They sub- sequently tendered the hypothesis that the low vitamin K status of normal newborns confers a biological advantage by reducing the risk of mutagenic events during a period of rapid cell proliferation (Israels et al. They concluded that the antioxidant effect is probably due to radical chain- breaking by vitamin K quinol and that dietary intake of vitamin K may strengthen cellular defences against oxidative stress. The toxicity may result directly from binding of menadione to a critical protein thiol (such as a membrane cation transporter) or indirectly from binding to and decreasing concentrations of reduced glutathione, thereby predisposing the cell to oxidative stress. An alternative mechanism whereby menadione may produce oxidative stress is by redox cycling, which ultimately results in the production of reactive oxygen species. Oxidative stress results when the production of reactive oxygen species exceeds the antioxidant defence mechanisms, which in turn may result in cellular injury and death through a variety of mechanisms. In human cancer cells, menadione-induced cell degeneration was consid- ered to result mainly from lipid peroxidative damage rather than from other mechanisms such as a depleted glutathione content (Chiou et al. It has been proposed that menadione causes mutations by generating active oxygen species from semiquinone radicals (e. Semiquinones can generate superoxide anion, which itself produces other active species, such as hydrogen peroxide and hydroxyl radical, through enzyme- and metal-catalysed reactions (Chesis et al. Cells in culture can, however, convert menadione to menaquinone-4, and there is already evidence that this plays a role in apoptosis. 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. 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. Phylloquinone is rapidly cleared from the circulation by the liver, metabolized to metabolites with shortened side- chains and excreted in the bile and urine. Phylloquinone rarely has toxic effects, and the few serious immunological compli- cations 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 muta- genicity. Menadione acts as a bacterial mutagen in several specific strains of Salmo- nella typhimurium and Escherichia coli. 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). Cancer, 76, 406–415 Rote Liste Sekretariat (1998) Rote Liste 1998, Frankfurt, Rote Liste Service GmbH, pp. Volume 31 Volume 40 Volume 51 Some Food Additives, Feed Some Naturally Occurring and Coffee, Tea, Mate, Methyl- Additives and Naturally Synthetic Food Components, xanthines and Methylglyoxal Occurring Substances Furocoumarins and Ultraviolet 1991; 513 pages 1983; 314 pages (out-of-print) Radiation 1986; 444 pages Volume 52 Volume 32 Chlorinated Drinking-water; Polynuclear Aromatic Volume 41 Chlorination By-products; Some Compounds, Part 1: Chemical, Some Halogenated Hydrocarbons Other Halogenated Compounds; Environmental and Experimental and Pesticide Exposures Cobalt and Cobalt Compounds Data 1986; 434 pages 1991; 544 pages 1983; 477 pages (out-of-print) Volume 42 Volume 53 Silica and Some Silicates Occupational Exposures in Volume 33 1987; 289 pages Insecticide Application, and Polynuclear Aromatic Some Pesticides Compounds, Part 2: Carbon Volume 43 1991; 612 pages Blacks, Mineral Oils and Some Man-Made Mineral Fibres and Nitroarenes Radon Volume 54 1984; 245 pages (out-of-print) 1988; 300 pages Occupational Exposures to Mists and Vapours from Strong Volume 34 Volume 44 Inorganic Acids; and Other Polynuclear Aromatic Alcohol Drinking Industrial Chemicals Compounds, Part 3: Industrial 1988; 416 pages 1992; 336 pages Exposures in Aluminium Production, Coal Gasification, Volume 45 Volume 55 Coke Production, and Iron and Occupational Exposures in Solar and Ultraviolet Radiation Steel Founding Petroleum Refining; Crude Oil 1992; 316 pages 1984; 219 pages and Major Petroleum Fuels 1989; 322 pages Volume 56 Volume 35 Some Naturally Occurring Polynuclear Aromatic Volume 46 Substances: Food Items and Compounds, Part 4: Bitumens, Diesel and Gasoline Engine Constituents, Heterocyclic Coal-tars and Derived Products, Exhausts and Some Nitroarenes Aromatic Amines and Mycotoxins Shale-oils and Soots 1989; 458 pages 1993; 599 pages 1985; 271 pages Volume 47 Volume 57 Volume 36 Some Organic Solvents, Resin Occupational Exposures of Allyl Compounds, Aldehydes, Monomers and Related Hairdressers and Barbers and Epoxides and Peroxides Compounds, Pigments and Personal Use of Hair Colourants; 1985; 369 pages Occupational Exposures in Some Hair Dyes, Cosmetic Paint Manufacture and Painting Colourants, Industrial Dyestuffs 1989; 535 pages and Aromatic Amines Volume 37 1993; 428 pages Tobacco Habits Other than Volume 48 Smoking; Betel-Quid and Areca- Some Flame Retardants and Volume 58 Nut Chewing; and Some Related Textile Chemicals, and Exposures Beryllium, Cadmium, Mercury, Nitrosamines in the Textile Manufacturing and Exposures in the Glass 1985; 291 pages Industry Manufacturing Industry 1990; 345 pages 1993; 444 pages Volume 38 Tobacco Smoking Volume 49 Volume 59 1986; 421 pages Chromium, Nickel and Welding Hepatitis Viruses 1990; 677 pages 1994; 286 pages Volume 39 Some Chemicals Used in Plastics Volume 50 Volume 60 and Elastomers Pharmaceutical Drugs Some Industrial Chemicals 1986; 403 pages 1990; 415 pages 1994; 560 pages Volume 61 Volume 70 Supplement No. In the past 3 decades there has been vast expansion in the range of new drugs and their formulatons.