Ascorbic acid
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
190°C 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 µg/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 µg/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 µg/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.
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Willett WC (1993) Vitamin E Consumption and the risk of coronary
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Stein HB, Hasa A & Fox IH (1976) Ascorbic acid-induced uricosuria:
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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