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Ascorbic acid

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main Brand names/main trade names
   1.6 Main Manufacturers/main importers
   1.7 Presentation/formulation
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First-aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
         3.3.1.1 Colour
         3.2.1.2 State/Form
         3.3.1.3 Description
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailabality
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. Additional information
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    1.  NAME
 
        1.1  Substance 
 
             Ascorbic acid
 
        1.2  Group 
 
             ATC Code:  A11GA Ascorbic acid (Vit C), Plain
 
        1.3  Synonyms 
 
             Antiscorbic vitamin
             Antiscorbutic vitamin
             L(+)-Ascorbic acid
             L-threo-hex-2-enonic acid, gamma lactone
             3-keto-L-gulofuranolactone
             L-3-ketothreohexuronic acid lactone
             3-oxo-L-gulofuranolactone
             Vitamin C
             L-xyloascorbic acid
 
        1.4  Identification numbers 
 
             1.4.1  CAS number 
 
                    50-81-7
 
             1.4.2  Other numbers 
 
                    RTECS:    CI7650000
 
        1.5  Main Brand names/main trade names
 
             Cebid; Cebion; Cantaxin; Celaskon; Cevalin; Cevatine; 
             Cevimin; Cevite; Cewin; Cipca; Cebicure; C-Vimin; Cevitamin; 
             Testascorbic; Allercorb; Cecon; Cetebe; Ce-Vi-Sol; Ascorin; 
             Ascorteal; Cegiolan; Adenex; Ascorvit; Cevex; Lemascorb; 
             Ciamin; Hybrin; Vitacee; Cantan; Catavin C; Celin; Cenetone; 
             Cescorbat; Cereon; Cergona; Cetemican; Cetamide; Planavit C; 
             Colascor; Concemin; Duoscorb; Scorbacid; Davitamon C; 
             Proscorbin; Redoxon; Scorbu-C; Ribena; Vicalet; Vitacin; 
             Vitacimin; Vitascorbol; Xitrix; Cevitan; Laroscorbine.
 
        1.6  Main Manufacturers/main importers 
 
             To be added by Center using the monograph.
 
        1.7  Presentation/formulation 
 
             To be added by Center using the monograph.
 
 
 
 
    2.  SUMMARY 
 
        2.1  Main risks and target organs
 
             The main target organs for toxicity are found in the 
             gastrointestinal, renal and haematological systems.
 
        2.2  Summary of clinical effects
 
             In individuals with glucose-6-phosphate dehydrogenase 
             (G-6-PD) deficiency, haemolytic anaemia may develop after 
             administration of ascorbic acid.  In individuals predisposed 
             to renal stones, chronic administration of high doses may 
             lead to renal calculi formation. In some cases, acute renal 
             failure may be observed under both conditions.
 
        2.3  Diagnosis
 
             Diagnosis of poisoning is done clinically and by 
             laboratory investigations.  Following chronic administration 
             of large doses, the patient may present with difficulty in 
             urination, pain and blood in the urine.  Acute overdose in G- 
             6-PD deficient patients may present with hemolytic anaemia 
             and symptoms of acute renal failure.  The pertinent 
             laboratory investigation needed is as follows: complete blood 
             count, peripheral smear to rule out megaloblastic anaemia, 
             Coomb's test, G-6-PD test, serum uric acid, blood urea 
             nitrogen, creatinine, urinalysis, urine pH.  Determination of 
             vitamin C level in the body fluids is not useful for 
             diagnosis.  Serum electrolytes determination are useful when 
             renal failure or diarrhoea is present.
 
        2.4  First-aid measures and management principles
 
             When overdose has occurred, stop further administration 
             of vitamin C. Provide supportive treatment.
 
    3.  PHYSICO-CHEMICAL PROPERTIES
 
        3.1  Origin of the substance
 
             Ascorbic acid is of both natural and synthetic 
             origin.
             
             Natural origin: ascorbic acid is found in fresh fruit and 
             vegetables. Citrus fruits are a particularly good source of 
             ascorbic acid and also hip berries, acerola and fresh tea 
             leaves.
 
 
 
        3.2  Chemical structure
 
             Chemical name:           L-Ascorbic acid;
                                      L-xyloascorbic acid;
                                      3-oxo-L-gulofuranolactone (enol form);
                                      L-3-ketothreohexuronic acid lactone;
             
             Relative molecular mass: 176.1
             
             Molecular formula:       C6H8O6
 
        3.3  Physical properties
 
             3.3.1  Properties of the substance
 
                    3.3.1.1  Colour
 
                             Ascorbic acid exists as colourless, 
                             or  white or almost white crystals.
 
                    3.2.1.2  State/Form
 
                             Crystalline. 
 
                    3.3.1.3  Description
 
                             It is odourless or almost 
                             odourless.
                             
                             It has a pleasant, sharp acidic taste.
                             
                             It is freely soluble in water and sparingly 
                             soluble in ethanol. It is practicaly 
                             insoluble in ether  and chloroform.
                             
                             Ascorbic acid has pKa values of 4.2 and 
                             11.6.
                             
                             Ascorbic acid has a melting temperature of 
                             190C with decomposition (Moffat, 1986).
                             
                             A solution of ascorbic acid in sodium 
                             hydroxide, sodium carbonate, or sodium 
                             bicarbonate has a pH of 5.5-7.0.
                             
                             A 5% solution in water has a pH of 2.2- 
                             2.5.
                             
 
 
 
                             In impure preparations and in many natural 
                             products the vitamin oxidises on exposure to 
                             air and light (McEvoy, 1993)
 
             3.3.2  Properties of the locally available formulation
 
                    To be filled in by centre using the monograph.
 
        3.4  Other characteristics
 
             3.4.1  Shelf-life of the substance
 
                    Refer to local formulation.
 
             3.4.2  Shelf-life of the locally available formulation
 
                    Refer to local formulary.
 
             3.4.3  Storage conditions
 
                    Ascorbic acid should be protected from air and 
                    light and be stored in a tightly closed, non-metallic 
                    container (McEvoy, 1993).
 
             3.4.4  Bioavailabality
 
                    To be added by centre using the 
                    monograph.
 
             3.4.5  Specific properties and composition
 
                    Ascorbic acid solution is rapidly oxidised in 
                    air and alkaline media. Ascorbic acid gradually 
                    darkens upon exposure to light; however slight 
                    colouration does not impair  the therapeutic activity 
                    of ascorbic acid injection. Even in the absence of 
                    light, ascorbic acid is gradually degraded on exposure 
                    to a humid atmosphere, the decomposition being faster 
                    at higher temperatures. In concentrations greater than 
                    100 mg/mL, ascorbic acid may undergo decomposition 
                    with the production of carbon dioxide. Since increased 
                    pressure may develop after prolonged storage, ampules 
                    containing ascorbic acid injection should be opened 
                    carefully.
 
 
 
 
    4.  USES
 
        4.1  Indications
 
             4.1.1  Indications
 
             4.1.2  Description
 
                    Prevention  and treatment of scurvy. It has 
                    been  used as a urinary acidifier and in correcting 
                    tyrosinemia in premature infants on high-protein 
                    diets. The drug may be useful to treat idiopathic 
                    methemoglobinemia.
 
        4.2  Therapeutic dosage
 
             4.2.1  Adults
 
                    In adults with scurvy as little as 10 mg daily 
                    will result in complete improvement; however, this 
                    amount may not provide optimum health over long 
                    periods of time. In adults, oral or parenteral 
                    administration of 100 to 250 mg of ascorbic acid 1 to 
                    2 times daily for several days will reverse the 
                    skeletal changes and haemorrhagic disorders associated 
                    with scurvy within 2 days to 3 weeks (McEvoy, 
                    1993).
                    
                    As a urinary acidifying agent in adults, 4 to 12 g of 
                    ascorbic acid daily in divided doses (McEvoy, 
                    1993).
                    
                    In idiopathic methemoglobinemia, 300 to 600 mg of 
                    ascorbic acid per day orally in divided doses (McEvoy, 
                    1993).
 
             4.2.2  Children
 
                    In infants or children with scurvy, oral or 
                    parenteral administration of 100 to 300 mg of ascorbic 
                    acid daily in divided doses for several days results 
                    in rapid recovery (McEvoy, 1993).
                    
                    To reduce tyrosinemia in premature infants on high- 
                    protein diets, administer 100 mg of ascorbic acid per 
                    day (orally or IM) (McEvoy, 1993).
 
        4.3  Contraindications
 
             Ascorbic acid is contraindicated in patients with 
             hyperoxaluria (Dollery, 1991) and G-6-PD deficiency.
 
 
 
 
    5.  ROUTES OF ENTRY
 
        5.1  Oral
 
             Ascorbic acid is usually administered orally in 
             extended-release capsule form, tablets, lozenges, chewable 
             tablets, solutions and extended-release tablets and capsules 
             (McEvoy, 1993).
 
        5.2  Inhalation
 
             Not known
 
        5.3  Dermal
 
             Not known
 
        5.4  Eye
 
             Not known
 
        5.5  Parenteral
 
             When oral administration is not feasible or when 
             malabsorption is suspected, ascorbic acid may be administered 
             intramuscularly, intravenously, or subcutaneously (McEvoy, 
             1993).
 
        5.6  Others
 
             Not known
 
    6.  KINETICS
 
        6.1  Absorption by route of exposure
 
             Ascorbic acid is readily absorbed after oral 
             administration but the proportion does decrease with the dose 
             (Dollery, 1979).GI absorption of ascorbic acid may be reduced 
             in patients with diarrhoea or GI diseases.
 
        6.2  Distribution by route of exposure
 
             Normal plasma concentrations of ascorbic acid are about 
             10 to 20 g/mL. Total body stores of ascorbic acid have been 
             estimated to be about 1.5 g with about a  30 to 45 mg daily 
             turnover (McEvoy, 1993).
             
             Plasma concentrations of ascorbic acid rise as the dose 
             ingested is increased  until a plateau is reached with doses 
             of about 90 to 150 mg daily (McEvoy, 1993).
             
 
 
 
             Ascorbic acid becomes widely distributed in body tissues with 
             large concentrations  found in the liver, leukocytes, 
             platelets, glandular tissues, and the lens of the eye. In the 
             plasma about 25% of the ascorbic acid is bound to 
             proteins.
             
             Ascorbic acid crosses the placenta; cord blood concentration 
             are generally 2 to 4 times the concentration in maternal 
             blood. Ascorbic acid is distributed into milk. In nursing 
             mothers on a normal diet the milk contains 40 to 70 g/mL of 
             the vitamin (McEvoy, 1993).
 
        6.3  Biological half-life by route of exposure
 
             The plasma half-life is reported to be 16 days in 
             humans. This is different in people who have excess levels of 
             vitamin C where the  half-life is 3.4 hours (Dollery, 
             1991).
 
        6.4  Metabolism
 
             Ascorbic acid is reversibly oxidised to dehydroascorbic 
             acid in the body. This reaction, which proceeds by removal of 
             the hydrogen from the enediol group of ascorbic acid, is part 
             of the hydrogen transfer system (Dollery, 1991).The two forms 
             found in body fluids are physiologically active. Some 
             ascorbic acid is metabolised to inactive compounds including 
             ascorbic acid-2-sulfate and oxalic acid (McEvoy, 1993; 
             Dollery, 1991).
 
        6.5  Elimination by route of exposure
 
             The renal threshold for ascorbic acid is approximately 
             14 g/mL, but this level  varies among individuals. When the 
             body is saturated with ascorbic acid and blood concentrations 
             exceed the threshold, unchanged ascorbic acid is excreted in 
             the urine. When tissue saturation and blood concentrations of 
             ascorbic acid are low, administration of the vitamin results 
             in little or no urinary excretion of ascorbic acid. Inactive 
             metabolites of ascorbic acid such as ascorbic acid-2-sulfate 
             and oxalic acid are excreted in the urine (McEvoy, 1993).
             
             Ascorbic acid is also excreted in the bile but there is no 
             evidence for enterohepatic circulation (Dollery, 1991)
 
 
 
    7.  PHARMACOLOGY AND TOXICOLOGY
 
        7.1  Mode of action
 
             7.1.1  Toxicodynamics
 
                    Hyperoxaluria may result after administration 
                    of ascorbic acid  (Swartz et al, 1984; Reznik et al, 
                    1980) Ascorbic acid may cause acidification of the 
                    urine, occasssionally leading to precipitation of 
                    urate, cystine, or oxalate stones, or other drugs in 
                    the urinary tract. Urinary calcium may increase, and 
                    urinary sodium may decrease after 3 to 6 g of ascorbic 
                    acid daily. Ascorbic acid reportedly may affect 
                    glycogenolysis and may be diabetogenic but this is 
                    controversial (MvEvoy, 1993).
 
             7.1.2  Pharmacodynamics
 
                    In humans, an exogenous source of ascorbic acid 
                    is required for collagen formation and tissue repair. 
                    Vitamin C is a co-factor in many biological processes 
                    including the conversion of dopamine to noradrenaline, 
                    in the hydroxylation steps in the synthesis of adrenal 
                    steroid hormones, in tyrosine metabolism, in the 
                    conversion of folic acid to folinic acid, in 
                    carbohydrate metabolism, in the synthesis of lipids 
                    and proteins, in iron metabolism, in resistance to 
                    infection, and in cellular respiration.
                    
                    Vitamin C may act as a free oxygen radical scavenger 
                    (Dollery, 1991). The usefulness of the antioxidant 
                    properties of vitamin C in reducing coronary heart 
                    disease were found not to be  significant (Stampfer et 
                    al., 1993; Rimm et al., 1993).
 
        7.2  Toxicity
 
             7.2.1  Human data
 
                    7.2.1.1  Adults
 
                             Diarrhoea may occur after oral 
                             dosage of  1 g or more daily or greater. 
                             Doses greater than 600 mg to have a diuretic 
                             action. Doses of  8 g daily decrease serum 
                             uric acid. A pregnant woman taking more than 
                             5 g daily may undergo an abortion (Dollery, 
                             1991).
 
 
 
 
                    7.2.1.2  Children
 
                             No data available.
 
             7.2.2  Relevant animal data
 
                    Not relevant
 
             7.2.3  Relevant  in vitro data
 
                    Not relevant
 
        7.3  Carcinogenicity
 
             It has been reported that there is no evidence of 
             carcinogenicity (Dollery, 1991). However, some studies 
             suggest that vitamin C may amplify the carcinogenic effect of 
             other agents. Scwartz et al. (1993) report that L-ascorbic 
             acid increases the oral carcinoma size induced by 
             dimethylbenz(a)anthracene. Also, butylated hydroxyanisole 
             induced forestomach carcinogenesis in rats (Shibata et al., 
             1993) and the K2CO3 induced promotion of bladder 
             carcinogenesis in rats (Fukushima et al., 1991) were both 
             amplified by the administration of ascorbic acid.
 
        7.4  Teratogenicity
 
             There is no evidence of teratogenicity (Dollery, 
             1991).
 
        7.5  Mutagenicity
 
             Ascorbic acid is reported to increase the rate of 
             mutagenesis in cultured cells but this only occurs in 
             cultures with elevated levels of Cu2+ or Fe2+ . This 
             effect may be due to the ascorbate induced generation of 
             oxygen-derived free radicals. However, there is no evidence 
             of ascorbate induced mutagenesis  in vivo (Diplock, 
             1995).
 
        7.6  Interactions
 
             Concurrent administration of more than 200 mg of 
             ascorbic acid per 300 mg of elemental iron increases 
             absorption of iron from the GI tract.
             
             Increased urinary excretion of ascorbic acid and decreased 
             excretion of aspirin occur when the drugs are administered 
             concurrently (McEvoy, 1993). Ascorbic acid increases the 
             apparent half-life of paracetamol (Dollery, 1991)
             
 
 
 
             Ascorbic acid is incompatible in solution with 
             aminophyllyine, bleomycin, erythromycin, lactobionate, 
             nafcillin, sodium nitrofurantoin, conjugated oestrogens, 
             sodium bicarbonate, sulfafurazole  diethanolamine, 
             chloramphenicol sodium succinate, chlorothiazide sodium and 
             hydrocortisone sodium succinate (Dollery, 1991).
             
             Interference with anticoagulant therapy has been reported 
             (Dollery, 1991).
 
        7.7  Main adverse effects
 
             The daily use of high doses  may lead to the formation 
             of kidney oxalate stones (Dollery,  1991). High dose usage of 
             vitamin C may also result in disturbed water and electrolyte 
             balance, increased red cell lysis, rebound scurvy, renal 
             calcification and suppression of cobalamine activity 
             (Dollery, 1991).
             
             Haemolysis occurs in patients with G-6-PD deficiency 
             following large doses of ascorbic acid either intravenously 
             or in soft drinks (Reynolds, 1993).
 
    9.  CLINICAL EFFECTS
 
        9.1  Acute poisoning
 
             9.1.1  Ingestion
 
                    No data available.
 
             9.1.2  Inhalation
 
                    No data available.
 
             9.1.3  Skin exposure
 
                    No data available.
 
             9.1.4  Eye contact
 
                    No data available.
 
             9.1.5  Parenteral exposure
 
                    Haemolytic anaemia and renal failure were 
                    observed following intravenous daily doses of 80 g 
                    administered for two days to a patient with G-6-PD 
                    deficiency (Campbell et al., 1975).  Acute oxalate 
                    nephropathy and renal failure were also observed 
                    following a single intravenous dose of 45 g 
                    administered to a patient with nephrotic syndrome 
                    (Lawton et al., 1985).
 
 
 
             9.1.6  Other
 
                    No data available.
 
        9.2  Chronic poisoning
 
             9.2.1  Ingestion
 
                    Diarrhoea has been reported as a side effect 
                    following long term use of vitamin C.  Precipitation 
                    of urinary stones leading to  renal failure and 
                    haemolytic anaemia may develop in some high risk 
                    patients.
 
             9.2.2  Inhalation
 
                    No data available.
 
             9.2.3  Skin exposure
 
                    No data available.
 
             9.2.4  Eye contact
 
                    No data available.
 
             9.2.5  Parenteral exposure
 
                    Probably the same as in chronic overdose by 
                    ingestion.
 
             9.2.6  Other
 
        9.3  Course, prognosis, cause of death
 
             Death has been reported in two cases. These cases were 
             patients with primary systemic illness (see Section 11). The 
             common feature is acute renal failure.
             
             With the development of acute renal failure following 
             disseminated intravascular coagulation and haemolytic anaemia 
             or from precipitation of renal stones, oliguria, fluid 
             retention, pulmonary edema, ventricular arrhythmia and death 
             may result.
 
 
 
 
        9.4  Systematic description of clinical effects
 
             9.4.1  Cardiovascular
 
                    No data available.
 
             9.4.2  Respiratory
 
                    No data available.
 
             9.4.3  Neurological
 
                    9.4.3.1  CNS
 
                             No data available
 
                    9.4.3.2  Peripheral nervous system
 
                             No data available
 
                    9.4.3.3  Autonomic nervous system
 
                             No data available
 
                    9.4.3.4  Skeletal and smooth muscle
 
                             No data available
 
             9.4.4  Gastrointestinal
 
                    Diarrhoea has been reported following daily 
                    oral dose of 1 g (Anon., 1984) and from 4 g 
                    administered daily for 7 days (Stein et al., 
                    1976).
 
             9.4.5  Hepatic
 
                    No data available
 
             9.4.6  Urinary
 
                    9.4.6.1  Renal
 
                             Increased urinary oxalate excretion 
                             occured following 4 g of ascorbic acid daily 
                             in divided doses (Briggs et al., 1973).
                             
                             Precipitation of cysteine or oxalate stones 
                             can develop in susceptible individuals 
                             following daily oral doses of greater than 4 
                             g administered for months (Lamden & 
                             Chrystonski 1954, Roth and Breitenfield 
 
 
 
                             1977).  Uricosuria was seen following  intake 
                             of 4 g single oral dose or chronic daily 
                             administration of 8 g up to 7 days (Stein et 
                             al., 1976). This appeared to be a dose 
                             dependent property.  Alteration of urine pH 
                             to acidic levels may potentially interfere 
                             with the excretion of some concurrent drugs. 
                             Interstitial nephritis during total 
                             parenteral nutrition (TPN) has been reported 
                             (Schwartz et al., 1984).  Acute renal 
                             failure, manifesting as oliguria, anuria and 
                             rising serum creatinine, can occur secondary 
                             to tubular obstruction with calcium oxalate 
                             crystals following a single intravenous dose 
                             of 45 g ascorbic acid in patients with 
                             primary amyloidosis and nephrotic syndrome 
                             (Lawton et al., 1985).  Acute renal failure 
                             is also observed following intravascular 
                             hemolysis and disseminated intravascular 
                             coagulation (DIC) in individuals with G-6-PD 
                             deficiency given 80 gm intravenously for 2 
                             days (Campbell et al., 1975).
 
                    9.4.6.2  Other
 
                             No data available.
 
             9.4.7  Endocrine and reproductive systems
 
                    When taken with oral contraceptive pills, 
                    megadoses of vitamin C (1 g) taken for 7 days enhanced 
                    the effects of contraceptive steroids 
                    (ethinyloestradiol) such as high density lipoprotein 
                    (HDL)-cholesterol and plasma proteins, sex-hormone 
                    binding globulin and caeruloplasmin (Briggs, 
                    1981).
 
             9.4.8  Dermatological
 
                    No data available
 
             9.4.9  Eye, ear, nose, throat: local effects
 
                    Ascorbic acid can change the pH of the saliva 
                    so that calcium was lost from the tooth enamel leading 
                    to dental enamel erosion.  This was attributed to 
                    daily ingestion of chewable ascorbic acid tablets over 
                    a period of 3 years (Giunta, 1983).
 
 
 
 
             9.4.10 Haematological
 
                    Megaloblastic anaemia may potentially develop 
                    following megadoses of ascorbic acid taken over 
                    several years.  This is because vitamin C destroys 
                    vitamin B12 in the diet (Herbert & Jacob, 1974). 
                    Haemolytic anaemia may develop as a consequence of 
                    reducing activity of ascorbic acid on red blood cell 
                    or in patients with G-6-PD deficiency administered 
                    with intravenous dose of 80 g for two days (Nutri. 
                    Rev., 1976; Campbell et al., 1975).
 
             9.4.11 Immunological
 
                    No data available.
 
             9.4.12 Metabolic
 
                    9.4.12.1 Acid-base disturbances
 
                             No data available.
 
                    9.4.12.2 Fluid and electrolyte disturbances
 
                             Fluid retention, hyponatremia and 
                             hypochloremia may develop as a result of an 
                             overdose of vitamin C given to the patients 
                             with illnesses such as primary renal disease 
                             (Lawton et al., 1985).
 
                    9.4.12.3 Others
 
                             No data avilable.
 
             9.4.13 Allergic reactions
 
                    No data available.
 
             9.4.14 Other clinical effects
 
                    No data available.
 
             9.4.15 Special risks
 
                    Scurvy may develop in infants born to mothers 
                    taking large doses of vitamin C (Herbert, 1979).  This 
                    is because of rapid degradation of  ascorbic acid in 
                    food by these infants who have increased their 
                    metabolism.  American blacks, Sephardic Jews, 
                    Orientals with congenital G-6-PD deficiency are at 
                    risk for developing serious effects like hemolytic 
                    anemia following short term high dose administration 
 
 
 
                    of ascorbic acid (Herbert 1979; Campbell et al 1975). 
                    Patients with gout and hyperuricemia are considered 
                    special risk when prescribed ascorbic acid (Mitch et 
                    al., 1980).
 
        9.5  Other
 
             No data availbale.
 
        9.6  Summary
 
    10. MANAGEMENT
 
        10.1 General principles
 
             When overdose has occurred, stop further administration 
             of ascorbic acid.  Provide supportive treatment.
 
        10.2 Relevant laboratory analyses
 
             (to harmonize with section 8)
 
             10.2.1 Sample collection
 
             10.2.2 Biomedical analysis
 
                    Serum electrolytes. BUN, creatinine, 
                    urinalysis, complete blood count, peripheral smear, 
                    Coomb's test, G6PD test.
 
             10.2.3 Toxicological analysis
 
             10.2.4 Other investigations
 
        10.3 Life supportive procedures and symptomatic/specific treatment
 
             Assess the airway, breathing, and circulation status of 
             the patient.  Maintain a clear airway.  Aspirate secretions 
             from airway and provide oxygen when needed.  Provide 
             endotracheal intubation and assisted ventilation when 
             necessary.  Maintain an intravenous route and administer 
             intravenous fluids when necessary.  Correct any circulatory 
             disturbance.  Monitor blood pressure.  Monitor and maintain 
             fluid and electrolyte balance.  Monitor renal function. 
             Monitor acid-base balance.  Control cardiac arrhythmia with 
             proper therapeutic regimen.
 
        10.4 Decontamination
 
             Because ascorbic acid is rapidly absorbed orally, gut 
             decontamination is probably of no value beyond two hours 
             following overdose by ingestion.
 
 
 
        10.5 Elimination
 
             By increasing fluid intake to promote diuresis, vitamin 
             C can be eliminated, as well as preventing renal damage due 
             to precipitation with stones or crystals.
 
        10.6 Antidote treatment
 
             There is no antidote for ascorbic acid overdose.
 
             10.6.1 Adults
 
                    No data available.
 
             10.6.2 Children
 
                    No data available.
 
        10.7 Management discussion
 
             In patients who have used megadoses of ascorbic acid, 
             and are dependent on vitamin C, tapering by 10 to 20% daily 
             and maintaining at lower doses  prior to discontinuation, may 
             help prevent scurvy.  There are no controlled studies to 
             substantiate the claim for the beneficial effects from 
             megadosing with ascorbic acid (Ovesen, 1984).
 
    11. ILLUSTRATIVE CASES
 
        11.1 Case reports from literature
 
             A 58 year old woman with primary amyloidosis and 
             nephrotic syndrome was given a single intravenous dose of 45 
             g ascorbic acid.  Four days later, she became anuric, 
             developed fluid retention, hyponatremia, hypochloremia, 
             elevated creatinine, hemoglobinuria and calcium oxalate 
             crystalluria, hypotension, pulmonary edema.  She underwent 
             hemodialysis but died after developing intractable 
             ventricular fibrillation (Lawton et al., 1985).
             
             A 68 year old black man was given 80 g ascorbic acid 
             intravenously for 2 days for burn injuries.  Three days 
             later, he became oliguric and had dark urine.  Erythrocyte G- 
             6-PD testing showed low activity for red cells. 
             Haemodialysis was instituted but the patient developed DIC 
             syndrome and died on the 22nd hospital day (Campbell et al., 
             1975).
             
             A ten fold increase in urinary oxalate has been reported 
             following a short course of 4 g vitamin C daily in a young 
             man (Briggs et al., 1973).
             
 
 
 
             A 23 year old male had increased urinary oxalate following 4 
             g of ascorbic acid (Briggs, 1976).
             
             A 21 year old male had elevated urine oxalate levels (76 to 
             127 mg/24Hr) after taking 1 g of ascorbic acid for many 
             months.  Levels dropped after stopping vitamint C (Roth & 
             Breitenfield, 1977).
 
        11.2 Internally extracted data on cases
 
        11.3 Internal cases
 
    12. Additional information
 
        12.1 Availability of antidotes
 
             No data available.
 
        12.2 Specific preventive measures
 
             No data available.
 
        12.3 Other
 
             No data availble.
 
    13. REFERENCES
 
        Anon (1984) Toxic effects of vitamin overdose. Med. Lett. 
        Drugs Ther. 26(667):73-74.
        
        Briggs, MH (1976) Vit C- induced hyper oxaluria. Lancet. (Jan 17, 
        1976) p. 154
        
        Briggs, MH (1981) Megadose Vitamin C & metabolic effects of the 
        pill. BMJ 283: 1547
        
        Briggs, MH, Garcia-Webb P,  Daviss P (1973) Urinary oxalate and 
        vitamin-C supplement.  Lancet ii: 201
        
        Campbell GD, Steinberg MH & Bower JD (1975) Ascorbic acid-induced 
        hemolysis in G-6-PD deficiency. Ann of. Int. Med. 82:810
        
        Diplock AT (1995) Safety of antioxidant vitamins and Beta- 
        carotene. Am. J. Clin. Nutr. 62(suppl): 1510S-6S.
        
        Dollery C (1991) Therapeutic Drugs, Volume 1, Churchill 
        Livingstone, London, A181-A185.
        
        Fukushima S, Kurata Y, Hasegawa R, Asamoto M, Shibata MA, Tamano S 
        (1991) L-ascorbic acid amplification of bladder carcinogenesis 
        promotion by K2CO3. Cancer Res. 51(10):2548-51.
        
 
 
 
        Giunta JL (1983) Dental erosion resulting from chewable vitamin C 
        tables. J. Am. Dent. Assoc.  107:253-256.
        
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        acid. JAMA 230:241-242.
        
        Herbert VD (1979) Megavitamin therapy. NY State J. Med. 79:278- 
        9.
        
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        Moffat AC (1986) Clarke's isolation and identification of drugs in 
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        Nutri. Rev (1976) 34:236-237
        
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        Shibata MA, Hirose M, Kagawa M, Boonyaphiphat P, Ito N (1993) 
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        BHA-induced forestomach carcinogenesis in rats. Carcinogenesis 
        14(2):275-80.
        
        Stampfer MJ, Hennekens, CH, Manson JE, Colditz GA, Rosner B, 
        Willett WC (1993) Vitamin E Consumption and the risk of coronary 
        disease in women.. New Engl. J. Med. 328(20): 1444-49.
        
        Stein HB, Hasa A & Fox IH (1976) Ascorbic acid-induced uricosuria: 
        a consequence of megavitamin therapy. Ann of Int Med 84:385- 
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        Swartz RD, Wesley JR, Somermeyer MG et al (1984) Hyperoxaluria & 
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        total parenteral nutrition. Ann Int. Med 100:530-531
 
    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), 
        COMPLETE ADDRESS(ES)
 
        K. Hartigan-Go
        National Poisons Control & Information Services
        Philippine General Hospital
        Manila, Philippines
        
        tel  63-2-5241078
        Fax  63-2-5260062
        
        Peer review: Berlin, October 1995
 
        Finalised: IPCS, September 1996
    


    See Also:
       Toxicological Abbreviations
       Ascorbic acid (ICSC)
       ASCORBIC ACID (JECFA Evaluation)