PHARMACEUTICALS
1. NAME
1.1 Substance
Retinol
1.2 Group
Vitamin A
1.3 Synonyms
15- apo-B-caroten-15-ol (3,7-dimethyl-9-(2,6,
6-trimethylcyclohex-1-enyl) nona- 2
anti-infective vitamin
Anti-xerophthalmic vitamin
Axerophtholum
Biosterol
Oleovitamin A
Retinal (vitamin A aldehyde)
vitamin A₁
1.4 Identification numbers
1.4.1 CAS number
68-26-8
1.4.2 Other numbers
Martindale online monograph link no. 7823-k
1.5 Brand names, Trade names
To be completed by each centre.
1.6 Manufacturers, Importers
A 313 (Chabre, France)
Acaren (Belgium)
Afaxin (Canada)
AFI-A diagnostikum (Nyco, Norway)
Alfa Monovit (Italy)
Alfatar (Arnaldi, Italy)
Alphalin (Lilly, USA)
Amirale (IDI, Italy)
Amplex-A (Spain)
A-Muslin (Mucos, Germany)
Anol Standard (Belgium)
A-OM (Spain)
Aquasol A (Argentina, Rover Canada, Armour USA)
Ariovit (Roche, Denmark)
Arovit (Belgium; Roche in France, Germany,
Italy, Netherland, South Africa, Spain,
Sweden, Switzerland)
Astrapin, oily form (Germany)
Atunol (Argentina)
Auxina A Masiva (Gayoso Wellcome, Spain)
Avibon (Theraplix, France)
A-Vicotrat (Heyl, Germany)
Avimin (Ferrosan, Denmark)
Avita (South Africa)
Avitam Masivo (Spain)
A-vitamin (DAK, Denmark)
Avitina (CT, Italy)
Axerol (Wander, Switzerland).
Isotretinoil (CAPS, South Africa).
Medox, Vitamin A tablet (CAPS, Zimbabwe)

To be completed by the centre.

2. SUMMARY
2.1 Main risks and target organs
The main risk is hypervitaminosis A which occurs both in young
children and adults receiving more than 100,000 units/daily
over several months or in acute poisoning.

Target organs are the skin, CNS, bone and liver.
2.2 Summary of clinical effects
Chronic vitamin A intoxication produces musculo-skeletal and
skin disorders, dry hair, alopesia, anemia, headache,
hepatomegaly, fever and gastrointestinal disturbanaces in the
adult. Headache, nausea, vomiting and irritability have been
observed after excessive consumption of animal liver
containing vitamin A or one dose of 1,500,000 IU. Toxicity is
reversible on withdrawal of vitamin A, but in children,
premature closure of epipyses of long bones may arrest bone
growth.

Infants aged 3-7 months who ingested 350,000 IU developed
vomiting, irritability, bulging fontanelles and elevated
cerebrospinal fluid pressure (Ellenhorn & Barceloux, 1988).

Toxicity usually occurs about 6 h after ingestion in acute
poisoning with vitamin A. Acute overdose also results in
hydrocephalus in infants and increased intracranial pressure
(pseudotumor cerebri) in older children and adults. Symptoms
of acute overdose include bleeding from gums or sore mouth and
a bulging soft spot on head. In babies, confusion or unusual
excitement, diarrhoea, dizziness, or drowsiness, double vision,
severe headache, severe irritability, peeling of skin,
especially on lips and palms, seizures, and severe vomiting
have been reported.
2.3 Diagnosis
The diagnosis is made by history of exposure to vitamin A and
the presence of nausea, vomiting, anorexia, headache,
irritability, engthema, prurities, fever, features of acute
vitamin A poisoning. There may be fatigue hepatosplenomegaly,
visual disturbances, skin lesions, dry hair, bleeding and
haematological abnormalities in chronic exposure.

In children raised intracranial pressure with bulging
fontanelles, papilloedema and diplopia may be symptoms of
chronic toxicity.

Laboratory analyses may show raised serum aspartate
transaminase (SGOT), alanine transaminase (SGPT), erythrocyte
sedimentation rate, serum calcium and alkaline phosphatase in
blood. Complete blood count may reveal haematological
abnormalities such as anaemia, leucopenia or leucocytosis, and
thrombocytopenia.
2.4 First aid measures and management principles
In acute poisoning by ingestion, induce emesis or perform
gastric lavage and administer activated charcoal.

In cases of eye contact, immediately irrigate with copious
amounts of water.

In severe overdoses, maintain clear airway, establish and
monitor breathing and circulatory functions. Reduce
intracranial pressure with mannitol or corticosteroids. Monitor
blood pressure, fluids, electrolytes, papilledema and CNS status.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Vitamin A ester concentrate (natural) consists of a natural
ester, or mixture of natural esters of retinol, or of a
solution of ester, or mixture of esters in arachis oil or
other suitable vegetable oil. It contains in 1 g not less
than 485,000 units of vitamin A and not less than 97.0% of the
number of units of vitamin A stated on the label. It may
contain a suitable antioxidant or mixture of antioxidants (BP
1988).

Synthetic vitamin A concentrate (oily form) consists of an
ester or mixture of esters of retinol (the acetate, propionate
or palmitate) prepared by synthesis. It may be diluted with a
suitable vegetable oil. It contains in 1 g not less than 500,
000 units of vitamin A and not less than 95.0% and not more
than 110.0% of the number of units of vitamin A stated on the
label. It may contain suitable stabilizing agents such as
antioxidants (BP 1988).

Synthetic vitamin A concentrate (powder form) consists of an
ester or mixture of esters of retinol (the acetate, propionate
or palmitate) prepared by synthesis and dispersed in a matrix
of gelatin, acacia or other suitable material. It contains in
1 g not less than 250,000 units of vitamin A and not less than
95.0% and not more than 115.0% of the number of units of
vitamin A stated on the label. It may contain suitable
stabilizing agents such as antioxidants (BP 1988).

Synthetic vitamin A concentrate (water-dispersible form)
consists of an ester or mixture of esters of retinol (the
acetate, propionate or palmitate) prepared by synthesis to
which suitable solubilizers have been added. It contains in 1
g not less than 100,000 units of vitamin A and not less than
95.0% and not more than 115.0% of the number of units of
vitamin A stated on the label. It may contain suitable
stabilizing agents such as antimicrobial preservatives and
antioxidants (BP 1988).
3.2 Chemical structure
Structural formula: C₂₀H₃O

Molecular weight: 286.5
3.3 Physical properties
3.3.1 Properties of the substance
- Vitamin A Ester Concentrate (Natural)

Characteristics: A yellow oil or mixture of oil
and crystalline material which yields an
homogenous yellow oil on warming with a faint
odour.

Solubility: Practically insoluble in water;
soluble or partly soluble in ethanol (96%);
miscible with chloroform, with ether and
petroleum spirit.

- Synthetic Vitamin A Concentrate (Oily Form)

Characteristics: A yellow to brownish-yellow
oily liquid with a faint and characteristic
odour.

Solubility: Practically insoluble in water;
soluble or partly soluble in absolute ethanol;
miscible with organic solvents. Partial
crystallization may occur in highly concentrated
solutions.

- Synthetic Vitamin A Concentrate (Water-dispersible Form)

Characteristics: a yellow or yellowish liquid of
variable opalescence and viscosity and a
characteristic odour. Highly concentrated
solutions may become cloudy at low temperatures
or take the form of a gel at room temperature.

Solubility: Soluble in water.

Melting points:
Vitamin A acetate about 57 °C
Vitamin A palmitate 28-30 °C.
3.3.2 Properties of the locally available formulation
To be completed by each centre.
3.4 Other characteristics
3.4.1 Shelf-life of the substance
Up to 2 years depending on the preparation.
3.4.2 Shelf-life of the locally available formulation
To be completed by each centre.
3.4.3 Storage conditions
Vitamin A ester concentrate (natural), synthetic Vitamin
A concentrates (oily, powder and water-miscible forms)
should be kept in an airtight container, protected from
light and stored at a temperature of 8°C to 15°C. Once
the container has been opened its contents should be
used as soon as possible; any part of the contents not
used at once should be protected by an atmosphere of an
inert gas.
3.4.4 Bioavailability
To be completed by each centre.
3.4.5 Specific properties and composition
To be completed by each centre.
4. USES
4.1 Indications
- Vitamin A deficiency (prophylaxis and treatment).

Vitamin A is indicated only for prevention or treatment
of Vitamin A deficiency states, which may occur as a

result of inadequate nutrition or intestinal
malabsorption in patients receiving an adequate balanced
diet. Dietary improvement is preferred over
supplementation whenever possible. Deficiency of
vitamin A may lead to keratomalacia, xerophthalmia, and
nyctalopia (night blindness). Requirements of vitamin A
may be increased and/or supplementation may be necessary
in the following persons or conditions (although
clinical deficiencies are usually rare) (Reynolds, 1989;
USP DI, 1989; McEvoy, 1988; Speight, 1987; Vanderveen,
1980).

- During prolonged stress or infection or chronic fever

In malabsorption syndromes associated with pancreatic
insufficiency (pancreatic disease, cystic fibrosis);
hepatic biliary tract disease (hepatic function
impairment, cirrhosis, obstructive jaundice); diseases
of the small intestine (coeliac disease, tropical sprue,
regional enteritis, persistent diarrhoea); or
postgastrectomy in patients with diabetes mellitus,
hyperthyroidism, or severe protein deficiency.

In general, Vitamin A absorption will be impaired in any
condition in which fat malabsorption (steatorrhoea) occurs.
In addition, conversion of dietary beta-carotene to vitamin A
may be impaired in diabetes mellitus and hyperthyroidism.

Supplementation with vitamin A is necessary in patients
receiving total parenteral nutrition (TPN); undergoing
rapid weight loss regimes; or in those with malnutrition,
because of inadequate dietary intake.

Requirements of all vitamins are increased during
pregnancy and breast-feeding. However, high doses of
vitamin A are teratogenic and there are few indications
for supplementation during pregnancy.

Requirements may be increased by the following
medications: cholestyramine, colestipol, mineral oil,
neomycin and sucralfate.

Vitamin A is not appropriate for the treatment of dry or
wrinkled skin, eye problems, or prevention or treatment
of infections not related to vitamin A deficiency.

Vitamin A dietary intake has been reported in a
population-based case-control study to have reduced the
risk of cervical cancer (Verreault et al, 1989).

- Dermatological disorders

The oral retinoids, or synthetic derivatives of vitamin
A, are used in the treatment of various dermatoses. The
most useful drugs are isotretinoin (13-cis-retinoic
acid) for nodulocystic acne and etretinate for

refractory psoriasis vulgaris. Retinoids are also
effective in the treatment of papulomatous dermatoses
other than psoriasis (e.g., inherited disorders of
keratinization), cutaneous T-cell lymphoma and in the
chemotherapy of cancer (Pasterino et al, 1988, Caffery &
Josephson, 1988). However, systemic administration of
these compounds is frequently associated with liver
toxicity, abnormalities of serum lipid profiles,
teratogenic effects and adverse mucocutaneous effects
(David et al, 1988). A potential role of vitamin A in
prevention of treatment of cancer has been suggested but
efficacy has not been proven.
4.2 Therapeutic dosage
4.2.1 Adults
A daily dietary intake of about 750 µg of vitamin A is
recommended for healthy adults. Dietary vitamin A is
derived from 2 sources: retinol is provided by dairy
products, eggs and fish liver oils (the most
concentrated natural source); pro-vitamin carotenoids
can be obtained from many plants.

In the treatment of xerophthalmia: Vitamin A palmitate
110 mg or vitamin A acetate 66 mg (200,000 units of
vitamin A) administered orally. The dose should be
repeated the next day followed by an additional dose
administered 1 to 2 weeks later.

When there is repeated vomiting or severe diarrhoea. a
water-miscible vitamin A palmitate 55 mg (100,000 units)
should be given by intramuscular injection instead of
the first oral dose.

In the prophylaxis of blinding xerophthalmia vitamin A
palmitate 110 mg of vitamin A acetate 66 mg (100,000
units) may be given by mouth every 4 to 6 months.

Note: Vitamin A injection should not be administered
intravenously because of the risk of anaphylactic shock
and death.
4.2.2 Children
The recommended daily intake in children aged 6 - 12
months is 300 µg.

Treatment of xerophthalmia: as adults, except in
children younger than 12 months for whom the dose is
halved.

In the prophylaxis of blinding xerophthalmia in children
less than 12 months old, vitamin A palmitate 55 mg or
vitamin A acetate 33 mg (100,000 units of vitamin A)
should be given by mouth. The dose should be repeated
every 4 to 6 months.

In children under 12 months, water miscible vitamin A
palmitate 27.5 mg (50,000 units) should be given by
intramuscular injection instead of the first oral dose

when this latter is not acceptable - for example in
nausea, diarrhoea, pre-operative and post-operative
conditions, in malabsorption syndromes or when ocular
damage is severe.

Note: Vitamin A injection should not be administered
intravenously because of the risk of anaphylactic shock
and death.
4.3 Contraindications
Caution is recommended in young children, who are usually more
sensitive to the effects of high doses of vitamin A. Normal
daily requirements vary according to age. Adequate and well-
controlled studies have not been done.

Excessive doses of vitamin A should be avoided in pregnancy
beccause of potential teratogenic effects (Reynolds, 1993).
5. ROUTES OF ENTRY
5.1 Oral
This is the most important route of entry.
5.2 Inhalation
No data available.
5.3 Dermal
Absorption of the retinoid tretinoin is minimal after
application of commercial
formulations to the skin.
5.4 Eye
No data available.
5.5 Parenteral
This route is used for patients with absorption problems, e.g:
coeliac disease and sprue.
5.6 Other
No data available.
6. KINETICS
6.1 Absorption by route of exposure
In oral doses that do not greatly exceed the physiological
requirements, vitamin A is readily and easily absorbed
provided fat absorption is normal. Absorption is incomplete
on administration of larger doses and in patients with fat
malabsorption, low protein intake or hepatic or pancreatic
disease. Water-miscible preparations of retinol or its esters
are absorbed more rapidly from the GI tract than oil
solutions. Retinol esters are hydrolysed in the GI lumen by
pancreatic enzymes. Retinol is absorbed and re-esterified
mainly to retinal palmitate. Fatty acid esters of retinol
enter the circulation by transport in chylomicrons of lymph.
Peak plasma concentrations of retinol esters occur about 4 - 5
hours after oral administration of retinol in an oil solution
and 3 - 4 hours after administration of a water miscible
retinol; higher plasma concentrations are obtained after
administration of a water miscible preparation of vitamin A
than after an oily solution. Normal serum concentrations of
retinol range from 300 to 700 ng/l adults and from 200 to 500
ng/l in infants (McEvoy, 1988).
6.2 Distribution by route of exposure
Retinal palmitate and small amounts of retinol and retinal are
stored in the liver. Small amounts of retinal palmitate are

stored in the kidney, lung, adrenal glands, retina and
intraperitoneal fat. Normal body stores of vitamin A are
sufficient to meet the body's requirements for several months.
Vitamin A passes into milk. Retinol in circulation is bound
to a specific globulin, retinol binding protein (RPB).
Release of retinol from the liver depends on several factors
including protein and zinc. RPB circulates as a complex with
a prealbumin protein and concentrations of RPB may be
decreased in patients with protein malnutrition. However, the
serum concentration of retinol is not a good index of hepatic
stores as these may be depleted. After taking a meal
deficient in vitamin A, normal serum concentrations are
maintained until the liver stores are depleted. On
administration to a patient deficient in vitamin A, vitamin A
correction occurs in the retina followed by accumulation in
the liver; serum concentrations remain normal until the liver
stores are saturated. Patients with glomerulonephritis or
lipoid nephrosis may have increased serum concentrations of
vitamin A because of RBP or storage abnormalities. If large
doses of vitamin A are administered after saturation of
storage sites, the binding capacity of RBP may be exceeded and
unbound retinol carried by lipoproteins may enter the
circulation. This unbound retinol may bring about many of the
toxic effects on cellular membranes from hypervitaminosis A
(McEvoy, 1988).
6.3 Biological half-life by route of exposure
By ingestion, 1.9 hours.
6.4 Metabolism
Retinol is conjugated with glucuronic acid; the B-glucuronide
undergoes enterohepatic circulation and oxidation to retinol
and retinoic acid. Retinoic acid undergoes decarboxylation
and conjugation with glucuronic acid.
6.5 Elimination by route of exposure
Retinol, retinoic acid and water-soluble metabolites are
excreted in faeces and urine. Normally no unchanged retinol
is excreted in urine. However, in patients with pneumonia or
chronic nephritis, unchanged vitamin A may be excreted (McEvoy,
1988).

20% to 50% of the absorbed retinol is eliminated in faeces and
urine as conjugation or oxidation products. Approximately 20%
is not absorbed and is eliminated in faeces (Hathcock et al,
1990).
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
Toxicity from a large dose of vitamin A is more common
in young children than in adults. A few hours after
administration of vitamin A at a dose of about 75,000
units/kg, irritability, drowsiness, vertigo, delirium,
coma, vomiting and diarrhoea may occur. Increased
intracranial pressure with bulging fontanelles in
infants, headache, papilloedema, exophthalmos and visual
disturbances have been reported. Erythema and general
peeling of the skin may occur a few days later and may
persist for several weeks. However, symptoms usually

disappear within a few days after the drug has been
discontinued.
7.1.2 Pharmacodynamics
Vitamin A is required for growth and bone development,
vision, reproduction and the integrity of mucosal and
epithelial surfaces. In the retina, retinol is
converted to the aldehyde, cis-retinal, which combines
with opsin to form rhodopsin, the visual pigment.
Vitamin A has been reported to act as a co-factor in
various reactions including mucopolysaccharide synthesis,
cholesterol synthesis and hydroxysteroid metabolism.
The retinoid tretinoin increases cell turnover. Vitamin
A deficiency leads to xerophthalmia, Bitot's spots,
keratomalacia, night blindness (nyctalopia),
hyperkeratosis of the skin, epithelial metaplasia of
mucous membranes and decreased resistance to infections.
Administration of vitamin A completely reverses signs of
vitamin A deficiency unless keratomalacia has resulted
in irreversible ocular damage.

Retinol esters are hydrolysed in the gastrointestinal
tract, absorbed as retinol and re-esterified mainly to
retinal palmitate. This is transported by chylomicrons
to the relevant tissues, including the retina, liver,
mucosa and epithelia. Retinol is metabolized by
conjugation pathways and excreted.
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
There have been reports of papilloedema
associated with vitamin A. Nodular liver
cirrhosis and portal hypertension occurred in a
36-year-old man 3.5 years after receiving
vitamin A 70 million units by mouth over 7 weeks
for psoriasis. Peripheral neuritis and pain
developed in 2 leprotic patients treated with
thiambutosine when vitamin A 15,000 and 120,000
units daily respectively were taken; nerve pain
stopped when the excess vitamin A was withdrawn.
Hypercalcaemia and skeletal changes occurred in
5 patients who had taken excess amounts of
vitamin A (David et al, 1986).

Congenital malformations associated with
maternal over-use of high doses of vitamin A
have also recently been reported (Bendich and
Langseth, 1989). However, no cause and effect
relationship has been established. Deficiency
of the vitamin during pregnancy has also been
associated with congenital abnormalities.

Reported cases of vitamin A toxicity are rare.
7.2.1.2 Children
Administration of more than 50,000 to 500,000 UI
daily for months has produced hepatosplenomegaly
(Babb & Kieraldo, 1978) and other effects.

Allergy to vitamin A especially in children, has
been reported and confirmed.
7.2.2 Relevant animal data
There is no evidence that vitamin A at any dose is
lethal to animals. However, both deficiency and excess
of vitamin A in pregnant animals are teratogenic.
7.2.3 Relevant in vitro data
No data available.
7.3 Carcinogenicity
- Animal data

In rats (and probably in man), vitamin A appears to play a
role in testosterone synthesis. If vitamin A increases
endogenous levels of this hormone, which may mediate the
development of prostatic cancer, this effect may be more
significant in older animals (and man) whose natural levels of
testosterone are declining (Dukes & Beeley, 1989).

- Human data

Although epidemiological studies have demonstrated a reduced
risk of certain cancers with increasing consumption of vitamin
A, there is strong evidence that vitamin A has the opposite
effect with regard to prostatic cancer. The risk
increases directly with the intake of vitamin A in men at all
ages, but the trend was strong in those of 70 years and older.
Vitamin A seems to influence tumour progression rather than
the early stages of carcinogenesis. The mechanism by which
vitamin A may enhance carcinogenesis is not yet established
(Dukes & Beeley, 1989).
7.4 Teratogenicity
The teratogenicity of vitamin A in both high and low doses is
well established in animals. However, it is uncertain whether
vitamin A is teratogenic in man. A 1983 case report suggested
that a multivitamin product containing vitamin A may have
caused a cleft palate in one infant; there may be an
association between the birth of two malformed children to
mothers who had taken excess vitamin A and the birth of 120
malformed children with deficiency of vitamin A; there has
been a case of a baby born with congenital xerophthalmia and
bilateral cleft because of deficiency of vitamin A in the
mother; excess intake in some mothers resulted in defects of
the urinary tract, urogenital system and microcephaly in the
infants (Briggs et al, 1986). There are few documented reports
in humans which link teratogenic consequences to high intakes
of supplemental retinol taken either acutely or chronically.
Until more is known about the mechanisms of placental transfer
and control as well as about the dose-related teratogenicity
of vitamin A at different stages of gestation, there are few
justifications for routine ingestion by fertile women of
supplemental vitamin A in excess of 8,000 to 10,000 IU.
Exceptions occur when clinical signs are evident and hospital
diets are unusually deficient (Underwood, 1989).

By contrast, the retinoids isotretinoin and etretinate are

highly teratogenic in man. Their use is contraindicated during
pregnancy and conception must be prevented for at least 4
weeks after use of isotretinoin and for at least 2 years after
use of etretinate.
7.5 Mutagenicity
7.6 Interactions
7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple Qualitative Test(s)
8.2.1.2 Advanced Qualitative Confirmation Test(s)
8.2.1.3 Simple Quantitative Method(s)
8.2.1.4 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
8.2.2.1 Simple Qualitative Test(s)
8.2.2.2 Advanced Qualitative Confirmation Test(s)
8.2.2.3 Simple Quantitative Method(s)
8.2.2.4 Advanced Quantitative Method(s)
8.2.2.5 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
8.3.1.2 Urine
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and their
interpretation
8.5 Overall Interpretation of all toxicological analyses and
toxicological investigations
8.6 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion

Doses of vitamin A that do not exceed the physiologic
requirements are not usually toxic (McEvoy, 1988).
However, acute intoxication has generally been observed
following ingestion of vitamin A-rich liver from the
polar bear, halibut or shark. The doses have been in
the range of one million units of vitamin A, but as low
as 30,000 IU in children. The symptoms occur 6 to24 h
after ingestion and are characterized by acute onset of
drowsiness, irritability, vertigo, headache, delirium
and convulsions, diarrhoea and intolerance to food. Long-
term administration of as little as 10,000 IU daily may
be sufficient to cause chronic hypervitaminosis A. The
main symptoms of chronic intoxication include malaise,
gastrointestinal complaints, changes in the skin and
mucous membranes, headache, tenderness and pain in the
bone and joints, and fever (Helsing, 1988).
Hypersensitivity reactions do not seem to occur.

Toxicity from large doses of vitamin A is more common in
young children than in adults. A few hours after
administration of 25,000 units/kg, severe irritability,
drowsiness, or vertigo, delirium, coma, vomiting and
diarrhoea may occur. Increased intracranial pressure
with bulging fontanelles in infants, headache,
papilloedema, exophthalmos, and visual disturbances have
been reported. Erythema and generalized peeling of the
skin occur a few days later and may persist for several
weeks. However, symptoms usually disappear within a few
days after the drug is discontinued (McEvoy, 1988;
Speight, 1987).
9.1.2 Inhalation
No data available.
9.1.3 Skin exposure
Skin reactions are more common after topical application
of the retinoids
etretinate, isotretinoin and tretinoin. The most common
cutaneous side effects are xerosis of the skin
associated with pruritus and sometimes with erythema,
skin hyperfragility and desquamation of the skin,
particularly of the palms and soles (David et al, 1988);
hair loss from scalp, eyebrows and/or eyelashes.
9.1.4 Eye contact
No data available.
9.1.5 Parenteral exposure
The same as for oral exposure.
9.1.6 Other
No data available.
9.2 Chronic poisoning
9.2.1 Ingestion
Chronic overdose results in hepatotoxicity, papilloedema,
intracranial hypertension, hypomenorrhoea, portal
hypertension, haemolysis and anaemia, radiographic bone
changes and, in children, premature closure of the
epiphyses. Toxicity is slowly reversible on withdrawal
of vitamin A, but may persist for several weeks. Bone
or joint pain fever, general feeling of bodily

discomfort or weakness, headache, increase in the volume
and frequency of urination, especially at night,
irritability, loss of appetite, stomach pain, unusual
tiredness and vomiting are also reported (David et al,
1988; USP DI 1989; McEvoy, 1988).
9.2.2 Inhalation
No data available.
9.2.3 Skin exposure
After repeated administration to the skin, the retinoid
tretinoin may cause drying or cracking of skin or lips,
increased sensitivity of skin to sunlight, loss of hair,
yellow-orange patches on soles of feet, palms of hands
or skin around nose and lips.
9.2.4 Eye contact
No data available.
9.2.5 Parenteral exposure
As for oral exposure.
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
Toxicity in both acute and chronic vitamin A is reversible on
withdrawal of vitamin A. In chronic overdose, toxicity may
persist for several weeks. In children, the premature closure
of ephphyses of the long bones may result in arrested bone
growth (Reynolds, 1993).

In general, most signs and symptoms of overdoes rsolve within
one week after withdrawal of vitamin A and appropriate
symptomatic treatment. Benign intracranial hypertension
resolves usually after symptomatic treatment. However,
papilloedema and skeletal abnormalities may persist for
several months and visual impairement (blindness) due to optic
atcoply may remain as a permanent sequela (Goldfrank, 1986).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Tachycardia, possibly secondary to fever (Helsing,
1988).
9.4.2 Respiratory
No information available.
9.4.3 Neurological
9.4.3.1 CNS
Acute symptoms of vitamin A poisoning include
drowsiness, sluggishness, irritability and
somnolence, severe headache and papilloedema.
In young children, raised intracranial pressure
with bulging of the fontanelles, papilloedema
and diplopia have been observed. Intracranial
hypertension may sometimes occur together with
skin and hair changes, pain in musculoskeletal
system and fatigue. Chronic daily doses of 3,
000,000 IU of vitamin A have induced central
nervous symptoms such as psychosis, with
pathological changes in the cerebrospinal fluid
(Helsing, 1988; USP DI 1989). Pseudotumour
cerebri (benign intracranial hypertension),
vertigo and papilloedema have occurred following

the daily intake of 10,000 - 20,000 IU for 2
years in adults; in children even few months of
treatment may suffice (Helsing, 1988; USP DI,
1989). Similar effects have been reported for
retinoids for both acute and chronic
intoxication (David et al, 1988; Reynolds,
1989).
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
Nausea, vomiting and anorexia are common symptoms of
acute vitamin A intoxication, as are dryness and scaling
of the lips, gingivitis and bleeding from the gums (USP
DI, 1989, Helsing, 1988).
9.4.5 Hepatic
Enlargement of the liver, spleen and lymph nodes have
been reported in adults (Helsing, 1988). Liver damage
due to vitamin A and its derivatives occurs after acute
poisoning; whether liver toxicity occurs after chronic
poisoning is still uncertain (David et al, 1988).
Excessive administration of vitamin A and its
derivatives can lead to fibrosis in the Disse space and
obstruction of sinusoidal blood flow, causing non-
cirrhotic portal hypertension and hepatocellular
dysfunction (Reynolds, 1989). Elevated serum
concentrations of aspartate transaminase (AST, SGOT),
alanine transaminase (ALT, SGPT) and occasionally lactic
dehydrogenase (GGT) and alkaline phosphatase have been
reported (David et al, 1988; McEvoy, 1988; Krishnaswany,
1987).
9.4.6 Urinary
9.4.6.1 Renal
In chronic intoxication, polyuria, increased
frequency of micturition, urinary incontinence,
enuresis and acute renal failure due to tubular
necrosis may occur (Dukes, 1984; USP DI, 1989).
Patients with renal dysfunction, in chronic
dialysis and haemodialyzed patients appear to
have increased circulating vitamin A levels.
9.4.6.2 Other
No data available.
9.4.7 Endocrine and reproductive systems
Hypomenorrhoea may be an early symptom of chronic
intoxication.
9.4.8 Dermatological
In acute intoxication, peeling of the entire skin can
occur as a delayed symptom. Among the early and most
commonly reported symptoms of chronic poisoning with
vitamin A and its derivatives are pruritus; erythema;
hyperkeratosis; dryness, haemorrhage and fissures of the
lips (Krishnaswany, 1987; McEvoy, 1988; USP DI, 1989;
Reynolds, 1989). A yellow to yellow-orange

discoloration of the skin, decreased tolerance to
sunlight, changes in pigmentation, hair loss and brittle
nails can occur (USP DI, 1989; Reynolds, 1989; Helsing,
1988). Spider angiomas and palmar erythema in patients
with serious hepatic damage due to chronic use of
vitamin A have also been reported.
9.4.9 Eye, ear, nose, throat: local effects
Eye: ocular toxicities involve the conjunctival membrane,
cornea and retina manifested by photophobia, palsy of
the ocular muscle, retinal haemorrhage and protrusio
bulbi, nystagmus, diplopia, dryness, irritation and
pain. These are due to raised intracranial pressure.
Intoxication can also lead to papilloedema, which in
some cases may be the only symptom (Helsing, 1988; David
et al, 1988). Anterior segment inflammation, contact
lens intolerance and altered refraction have also been
reported with the retinoid isotretinoin (Caffery &
Josephson, 1988).

Ear, nose, and throat: no data available.
9.4.10 Haematological
High doses of vitamin A reduce the stability of the
hypoprotein boundary layer of erythrocytes, which can
lead to haemolysis and anaemia. Neutropenia or
leucocytosis, thrombocytopenia, aplastic anaemia and
increased sedimentation rate have been reported after
high doses of vitamin A (McEvoy, 1988; USP DI, 1989;
Dukes, 1984).
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
Oedema and ascites are sometimes seen in
patients with chronic intoxication (Helsing,
1988). Polydipsia may also occur.
9.4.12.3 Others
Chronic intoxication with vitamin A has been
reported to cause hyperglycaemia, increased
alkaline phosphatase, hypoproteinuria,
hypoprothrombinaemia, increased
sulphobromphthalein retention, elevated serum
transaminases, low serum ascorbic acid,
decreased protein content of cerebrospinal
fluid, elevated urinary hydroxyproline, and
hypercalciuria. Continued vitamin A
administration or accumulation is associated
with an increase in serum cholesterol and
consequently might be linked with
atherosclerosis (Helsing, 1988).

Hyperlipidaemia: As a result of liver damage,
vitamin A and its derivatives produce a rise
in serum triglycerides and, in particular, in
very low density lipoproteins. The changes

are reversible on stopping treatment
(Krishnaswamy, 1987; David et al, 1988).
9.4.13 Allergic reactions
Hypersensitivity reactions do not seem to occur
(Hellriegel, 1984).
9.4.14 Other clinical effects
Excessive intake of vitamin A leads to accelerated
resorption of trabecular and cortical bone due to
increased osteoclast activity. Pain in bones and
joints is a common symptom. Bone tenderness with
complications such as periosteum, hyperostosis and, in
children, premature closure of the epiphyses of the
long bones causing growth arrest (Reynolds, 1989, USP
DI, 1989; Helsing, 1988). Similar effects have been
reported for vitamin A derivatives (David et al, 1988).
Skeletal deformities involving the lower limbs and the
spine were seen in a 15-month old girl who had received
during the previous few months a total dose of 10.5
million IU of vitamin A (Helsing, 1988).
9.4.15 Special risks
Pregnancy: Vitamin A in high doses induces congenital
abnormalities in the offspring of rats and has been
reported to impair learning ability in rat offspring.
In man, epidemiological data on teratogenicity is
lacking. However, human teratogenicity of synthetic
vitamin A derivatives such as isotretinoin is now well
accepted. Results from an epidemiological case-control
study on prenatal exposure to vitamin A alone or in
combination with other vitamins have indicated that a
teratogenic effect could exist for exposures to high
doses of vitamin A. Urinary tract malformations,
growth retardations, and early epiphyseal closure have
been reported in children whose mothers took excessive
amounts during pregnancy (Krishnaswany, 1987; USP DI,
1989; Rosa et al, 1986).

Breast-feeding: Problems in humans have not been
documented with intake of normal daily requirements;
however, vitamin A is excreted in breast milk (USP DI,
1989).

Enzyme deficiencies: No data available.
9.5 Other
No data available.
9.6 Summary
10. MANAGEMENT
10.1 General principles
Treatment is mainly supportive. Make a proper assessment of
the airway, breathing and neurological status of the
patient. Reduce intracranial pressure with mannitol or
corticosteroids.

After oral exposure, gastric lavage is indicated if more
than the therapeutic doses is ingested. Alternatively,
emesis is indicated unless the victim is comatose. A
cathartic may be administered.

Wash contaminated skin thoroughly with soap and water. If
the eyes are affected, irrigate with copious amounts of
water for 10 to 15 minutes and consult ophthalmologist if
pain persists.

Monitor patient for dark adaptation tests,
electronystagmogram, electroretinogram and plasma vitamin A
determinations. Hepatic and renal status should be
evaluated, especially in chronic exposure.
10.2 Relevant laboratory analyses
10.2.1 Sample collection
Blood sample and 24 h urine collection.
10.2.2 Biomedical analysis
Routine blood and urine analysis of retinol and
metabolites may confirm the severity of poisoning.

Monitor for haematologic effects, including
haemolysis, anaemia, thrombocytopenia and leucopenia.
Monitor serum AST (SGOT) and ALT (SGPT)
concentrations (McEvoy, 1988).
10.2.3 Toxicological analysis
Analysis of vitamin A in blood and urine may be done
by colorimetric or gas chromatography.
10.2.4 Other investigations
10.3 Life supportive procedures and symptomatic/specific
treatment
Maintain clear airway, establish and monitor breathing and
circulation.

Control seizures with IV diazepam or phenobarbital.

Reduce intracranial pressure with mannitol or corticostreoids.

Support other CNS functions. Neuroleptics may be required to
control psychotic reactions.

Monitor hepatic function.

Correct anaemia and other haematological abnormalities, if
necessary.
10.4 Decontamination
Ingestion: Gastric lavage and emesis are indicated if large
amounts are ingested.

Activated charcoal should be administered in usual doses of
30 to 100 g in adults and 15-30 g in children.

A saline cathartic (e.g. sodium sulphate) may be given in
doses of 20 to 30 g in adults and 150 mg/kg in children over
2 years. However, saline cathartics are contraindicated in
patients with impaired renal function.

Skin: wash exposed areas thoroughly with soap and water.

Eyes: irrigate eyes copious amounts of water for at least 15

min. Consult an ophthalmologist, if pain persists.
10.5 Elimination
Since the volume or frequency of urination may be increased,
especially at night, osmotic diuresis or haemodialysis has
been suggested.
10.6 Antidote treatment
10.6.1 Adults
There is no specific antidote available.
10.6.2 Children
There is no specific antidote available.
10.7 Management discussion
Vitamin E may increase the absorption, utilization and
storage of vitamin A and may protect against
hypervitaminosis A; however, these effects are
controversial (McEvoy, 1988).
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
- Hypercalcaemia caused by vitamin A toxicity was
observed in a 16-year-old patient. Diagnosis was difficult
because she denied recent ingestion of vitamin A and was
thought to be bulimic. Symptoms included vomiting,
diarrhoea, thirst and polyuria. She also developed a
dry scaly skin rash on her back, face and extremities. The
findings on physical examination were normal except for
multiple excoriations on her extremities, a dry scaly rash over
her upper arms, fissures at the corners of her mouth and
dry mucous membranes. Intravenous fluids and loop diuretics
lowered the serum calcium and ameliorated the symptoms of nausea
and vomiting temporarily. During the 10 days of this therapy,
the serum calcium never fell below 11.5 mg/dl. Oral prednisone
was then started and produced a prompt and lasting reduction of
the serum calcium to normal (Bergman et al, 1988).

- Plasma retinol levels and toxicity were evaluated in
thirteen metastatic breast cancer patients treated orally with
high dose (300,000 IU/day) retinal acetate in combination with
tamoxifen. During the first 2 months of treatment, a cumulative
increase of plasma retinol occurred; long-term systemic toxicity
was acceptable and included gastrointestinal symptoms, skin
toxicity and headache. These symptoms could be related to the
long-term increase of retinol systemic concentrations (Ressasco
et al, 1988).

- The teratogenicity of vitamin A has been repeatedly
reported in the literature and confirmed on the basis of several
cases of adverse pregnancy outcome associated with maternal
isotretinoin exposure. Teratogenic effects have been reported
after normal supplementation with vitamin A during pregnancy
(Lungarotti et al, 1987).

- A 7-year-old girl, a 13-year-old boy and a 26-year-old
woman, all with renal failure, developed biochemical and clinical
findings of vitamin A toxicity (hypervitaminosis A) while
receiving a total parenteral nutrition regime containing
vitamin A; the symptoms improved after withdrawal of vitamin A
from the regime. These cases demonstrate that patients with

renal failure may be at risk for symptomatic vitamin A toxicity,
if given standard supplementation (Gleghorn et al, 1986).

- A 29-year-old man developed hepatic cirrhosis as a
manifestation of vitamin A toxicity induced by the ingestion of
6 to 8 ounces of beef liver per week for 8 to 9 years. However,
a history of infectious mononucleosis was probably a contributing
factor. A 41-year-old woman developed chronichypervitaminosis A due to long-term use of special
regimen utilizing an emulsified vitamin A product containing
15,000 IU per drop (Inkeles et al, 1986).

- Vitamin A intake was assessed from dietary histories of
452 men with prostate cancer and 899 population controls in
Hawaii during the period 1977-1983. In the group of men less
than 70 years of age, there was no significant association
between vitamin A and the risk of prostate cancer. In the men
aged 70 or older, the risk correlated directly with the amount
of vitamin A consumed. The findings were consistent across the
5 ethnic groups and similar for the various components of
vitamin A and its metabolites but were somewhat stronger for
total carotenes than for total retinol. These data suggest
possible mechanisms for this risk enhancement by vitamin A in
the elderly men (Kolonel et al, 1987).
11.2 Internally extracted data on cases
To be completed by each centre.
11.3 Internal cases
To be completed by each centre.
12. Additional information
12.1 Availability of antidotes
No antidotes are available.
12.2 Specific preventive measures
No data available.
12.3 Other
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Bendich A & Langseth L (1989) Safety of vitamin A. American
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Bergman SM, O'Mailia J, Krane NK, Wallin JD (1988) Vitamin A-
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Caffery BE & Josephson JE (1988) Ocular side effects of
isotretinoin therapy. Journal of the American Optometric
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David M, Hodak E & Lowe NJ (1988) Adverse effects of retinoids.
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Dukes MNG & Beeley L (1989) Vitamin A and prostatic cancer.
Side effects of drugs. Annual 13, Elsevier, Amsterdam - New York,
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Gleghorn EE, Eisenberg LD, Hack S, Parton P, Merritt RJ (1986)
Observations of vitamin A toxicity in 3 patients with renal
failure receiving parenteral alimentation. American Journal of
Clinical Nutrition 44(1): 107-112 (June).

Goldfrank LR, Flomenbaum NE, Lewin NA, Weisman RS, Howland NA,
and Kulberg AG: Goldfrank's Toxicologic Emergencies (1988) 3rd
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Hathcock JN, Hattan DG, Jenkins NY et al (1990) Evaluation of
vitamin A toxicity. Am. J. Clin. Nutri. 52: 183 - 202.

Hellriegel KP (1984) Vitamins: Vitamin A (Retinol). In Dukes
MNG, Meyler's side effect of drugs. Tenth edition, Elsevier, 715-
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Helsing E (1988) Vitamins in: Dukes MNG. Meyler's side effects
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Inkeles SR, Connor WE, Illingworth DR (1986) Hepatic and
dermatologic manifestations of chronic hypervitaminosis A in
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Kolonel LN, Haukin JH, Yoshizawa CN (1987) Vitamin A and
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Krishnaswany K (1987) Diseases of a tropical environment. In:
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Lungarotti MS, Marinelli D, Mariano T, Calobro A (1987) Multiple
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McEvoy GK (1988) Vitamin A. Drug information 88. American
Hospital Formulary Service. The American Society of Hospital
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Pastorino U, Soresi E, Clerici M, Chiesa G, Belloni PA, Ongari M,
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retinol palmitate. Preliminary data from a randomized rial on
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Ressasco M, Canobbio L, Trave F, Valenti G, Mazzoni A, Gauti G,
Roccardo F, Nicolin A (1988) Plasma retinol levels and side
effects following high-dose retinal acetate in breast cancer
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Reynolds JEF (1989) Nutritional agents and vitamins: Martindale,
The Extra Pharmacopoeia, 29th edition, The Pharmaceutical Press,
London, 1250-1290.

Rosa FW, Wilk AL, Kelsey FO (1986) Teratogen update: vitamin A
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Underwood BA (1989) Teratogenicity of vitamin A. International
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USP DI. The United States Pharmacopoeial Convention Inc. (1989)
Vitamin A (Systemic). Drug information for the health care
professional. 10th Edition, USA, 2415-2417.

Vanderveen E (1980) Vitamins and other nutrients. In: Osol
Arthur, Remington's Pharmaceutical Sciences. Mack Publishing
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14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Dr O.J. Kasilo
Drug and Toxicology Information Service
Department of Pharmacy
University of Zimbabwe Medical School
P.O.Box A178
Avondale
Harare,
Zimbabwe

Dr C.F.B. Nhachi
Department of Clinical Pharmacology and Toxicology
University of Zimbabwe Medical School
(address as above).

Tel: 263-4-790233 or 791631, Ext. 117/172
Telex: 2526801 UNIVZ ZW
Fax: 263-4-303 292

Date: December 1989.

    See Also:
       Toxicological Abbreviations