WORLD HEALTH ORGANIZATION FOOD AND AGRICULTURE
ORGANIZATION
ORGANISATION MONDIALE DE LA SANTE ORGANISATION POUR L'ALIMENTATION
ET L'AGRICULTURE
VBC/DS/77.27
ORIGINAL: ENGLISH
DATA SHEETS ON PESTICIDES No. 27
TRICHLORFON
It must be noted that the issue of a Data Sheet for a
particular pesticide does not imply endorsement of the pesticide by
WHO or FAO for any particular use, or exclude its use for other
purposes not stated. While the information provided is believed to
be accurate according to data available at the time when the sheet
was compiled, neither WHO nor FAO are responsible for any errors or
omissions, or any consequences therefrom.
The issue of this document does Ce document ne constitue pas une
not constitute formal publication. Il ne doit faire
publication. It should not be l'objet d'aucun compte rendu ou
reviewed, abstracted or quoted résumé ni d'aucune citation sans
without the agreement of the l'autorisation de l'Organisation
Food and Agriculture des Nations Unies pour
Organization of the United l'Alimentation et l'Agriculture
Nations or of the World Health ou de l'Organisation Mondiale de
Organization. la Santé.
CLASSIFICATION:
Primary Use: Insecticide
Secondary Uses: Acaricide, Anthelminthic
Chemical Group: Organophosphorous compound
Date issued:
1. GENERAL INFORMATION
1.1 COMMON NAME - Trichlorfon (ISO)
Identity: Dimethyl (2,2,2-trichloro-1-hydroxyethyl)phosphonate
Synonyms: OMS-0800
Dipterex, Dylox, Neguvon
Chlorofos
Bay 15922, Bayer 2349
Tugon, Masoten, Anthon
Dyvon, L 13/59
Metrifonate (when used as a parasiticidal drug)
Local synonyms:
1.2 SYNOPSIS - An organophosphorous compound of
moderate mammalian toxicity, with a wide spectrum of usage. It
is rapidly metabolised in man and animals and does not accumulate
in body tissues.
1.3 SELECTED PROPERTIES
1.3.1 Characteristics - A white crystalline powder of m.p.
83-84°C; the technical material is trichlorfon 98% pure, with a
minimum m.p. of 77°C.
1.3.2 Solubility - Its solubility in water is good.
15.4 g/litre at 25°C. It is also soluble in benzene, ethanol and
most chlorinated hydrocarbons, but insoluble in petroleum oils
and poorly soluble in diethyl ether and carbon tetrachloride.
1.3.3 Stability - It is stable at room temperature
and is converted to dichlorvos in alkaline medium. In acid medium
(pH 1-5) 50% is hydrolysed at 20°C in 526 days.
1.3.4 Vapour pressure (volatility) - 10-5 mbar at 20°C.
1.4 AGRICULTURE, HORTICULTURE AND FORESTRY
1.4.1 Common formulations - Wettable powders 50%; soluble
powders 58, 80 and 95%; soluble concentrate 50%; ULV at
concentrations of 250, 500 and 750 g. A.I. per litre; dusts 5%,
granules 2-1/2 and 5%; Tugon fly mats; cardboard discs
impregnated with 0.1 g A.I.; Nevugon preparations for veterinary
use.
1.4.2 Pests controlled - Lepidopterous larvae,
household pests, DDT resistant flies and chlordane resistant
cockroaches, ectoparasites on domestic animals.
1.4.3 Use pattern - Used in sugar based fly baits; as
dust against insects on vegetables, tobacco, and ornamentals; as
granules for control of stalk borers and leaf eating caterpillars
as maize and sugar cane; by ULV application in forestry, cotton
and cereal crops.
1.4.4 Unintended effects - It should not be applied
to wet cotton plants of sensitive varieties. It should not be
applied on apple trees until 4 weeks after petal fall otherwise
damage to fruit and leaves may be caused.
1.5 PUBLIC HEALTH PROGRAMME
No public health use for insecticide but extensive trials have
been carried out in its use orally as a schistosomicidal drug.
1.6 HOUSEHOLD USE
Marketed as a shampoo and powder formulation for control of fleas
and ticks in dogs and cats, and also for control of stable flies
as "Tugon fly mats".
2. TOXICOLOGY AND RISKS
2.1 TOXICOLOGY - MAMMALS
2.1.1 Absorption route - Trichlorfon can be absorbed from
the gastrointestinal tract by inhalation or through the intact
skin.
2.1.2 Mode of action - Metabolised to dichlorvos
which inhibits cholinesterase.
2.1.3 Excretion products - Although studied
extensively, the metabolism is not fully understood. Trichlorfon
can be rearranged by dehydrochlorination to form dichlorvos,
though only to a very minor extent in mammals. As dichlorvos is
considerably more toxic than trichlorfon, this rearrangement is
important toxicologically. Hydrolysis of the phosphonate bond
can occur as well as hydrolysis of the methoxy moiety.
Trichloroethanol, which is subsequently conjugated, may be
formed. Degradation and excretion is very rapid in mammals.
In rats after an oral dose, 71% of the total was found in the
urine in 16 hours and in cows 66% in 12 hours. Trichlorfon may
be excreted in milk.
2.1.4 Toxicity, single dose
Oral: LD50 Rat (M) 630 mg/kg
Rat (F) 560 mg/kg
Dermal: LD50 Rats (M & F) >2800 mg/kg
Rabbits (M & F) 5000 mg/kg
2.1.5 Toxicity, repeated doses
Oral: Rats were fed diets containings 0, 20, 100 and 300 ppm of
trichlorfon for 16 weeks. Significant cholinesterase inhibition
was observed at 300 ppm. No effects on growth, behaviour, food
consumption or gross and microscopic tissue examination were
observed at 100 ppm. Two dogs were given trichlorfon at 45 mg/kg
orally six days a week for three months. No mortality was
observed. The serum cholinesterase level was 60% of normal at
the conclusion of the experiment.
Inhalation: Inhalation studies in a static chamber exposing rats
and guinea-pigs to concentrations of 22 mg/litre of air, caused
symptoms of cholinergic stimulation but no deaths. At 8
mg/litre, no signs of poisoning were observed.
Cumulation of compound: Trichlorfon is rapidly absorbed,
degraded and excreted. Dermal application of 300 and 100 ml of
labelled trichlorfon to cattle resulted in maximum blood
concentrations 10-16 hours after application, and the levels were
0.45-0.47 ppm with 300 ml and 0.1-0.2 ppm with 100 ml;
respectively. Trace amounts were still detected after 60 hours.
Cumulation of effect: In spite of its low toxicity, continued
ingestion of trichlorfon can be expected to reduce cholinesterase
to hazardous levels. It has been shown that recovery of
cholinesterase activity in man may take 30-40 days after oral
dosage.
2.1.6 Dietary studies
Short-term: Dogs of both sex were fed trichlorfon in the diet at
levels of 0, 50, 250, 500 and 1000 ppm for one year.
Cholinesterase activity was reduced at 500 and 100 ppm and
increased spleen weight with congestion of apparent lymphoid
atrophy was noted. Males at 1000 ppm exhibited a decrease in
spermatogenesis and hyperplastic nodules in the adrenals. No
effects were noted on mortality, growth, food consumption,
behaviour of gross and microscopic tissue examination apart from
those mentioned above.
Long-term: Several long-term studies on the toxicity of
trichlorfon have been carried out, both in rats and dogs.
In rats, survival time was decreased at doses of 1000 ppm in the
diet. Reduction of serum cholinesterase activity have been
observed at dietary levels of 400 ppm and above. Enhanced aging
of the reproductive tissues, aspermogenesis in males and an
absence of primary follicles and primitive ova in females, were
observed in one experiment at dietary levels of 500 and 1000 ppm.
In a second experiment, an increased incidence of cystic granular
ovaries was observed, that appeared to be dose related at dietary
levels of 100, 200 and 400 ppm. A third and larger experiment
failed to confirm these findings on the reproductive tissues.
Decreased cholinesterase (values were observed at 1000 ppm and
increased liver size and SG-OT activity in female rats and SDH
activity in both sexes was observed.
Dogs of both sexes were maintained for four years on diets
containing 0, 50, 200, 800 and 3200 ppm. One out of four male
dogs and two out of four female fed diet at 800 ppm survived the
four year period. Cholinesterase activity was reduced at 200 ppm
and this reduction was greatest at the beginning of the
experiment and tended to decrease as the experiment progressed.
At 3200 ppm, levels of serum transaminases SGOT and SGPT were
increased. At 800 ppm male dogs had enlarged spleens and smaller
adrenals and testis, and females at 3200 ppm had enlarged liver,
spleen and adrenals and reduced ovary size.
2.1.7 Supplementary studies of toxicity
Reproductive study: A three generation rat reproduction study at
levels of 0, 100, 300, 1000 and 3000 ppm in the diet resulted in
adverse effects on reproduction at 1000 ppm and above. At 1000
ppm there was evidence of reduced fertility, smaller litters and
reduced body weight of pups. At 3000 ppm the pregnancy rate was
markedly reduced and the pups were smaller and lighter in weight
with none surviving to weaning. No effects were noted at 300 ppm
or below. Microscopic examination of the F3b generation indicated
no adverse effects.
Carcinogenicity: In two experiments in rats fed diets containing
200 ppm and above, an increased incidence of benign mammary
tumours was observed, which appeared to be dose related. In
another experiment a higher incidence of forestomach papilloma
was observed when mice were administered trichlorfon three times
per week for five months.
Teratogenicity: No foetal abnomalities or embryo-toxic effects
were observed when trichlorfon was administered orally at 100
mg/kg to pregnant rats from day 6 to day 15 of
gestation. However, when pregnant rats were subjected to
continuous inhalation exposure to trichlorfon for 20 days at
0.0005, 0.02 and 9 mg/m3, at all dose levels, there were external
and internal abnormalities in the development of the embryos.
Mutagenicity: Dominant lethal tests run with male mice
injected with a single dose of 0.50 or 100 mg/kg and mated to
untreated females, resulted in no adverse effects on reproduction
or on the young.
Acute oral and subcutaneous dosing of hens at doses of 100 mg/kg
and 90 mg/kg respectively, have not resulted in any delayed
ataxia. Dietary levels of trichlorfon fed to hens at 5000 ppm
for 30 days did not result in ataxia. However, delayed
neurotoxicity has been reported in men exposed to certain
formulations (see 2.2.3 and 2.2.6 below).
Other studies: A single acute oral dose of trichlorfon (500
mg/kg) when given to rats caused immunological depression; the
phagocytic activity of the reticuloendothelial system was
decreased for 60 days. Chronic dosing at 25 mg/kg, insufficient
to produce symptoms of toxicity, caused a similar depression from
the second week of dosing and lasting for two months after the
termination of treatment. The most sensitive parameters appeared
to be the bactericidal activity of the skin, serum lysozyme and
ß-lysine levels, and the phagocytic activity of the
reticuloendothelial system.
2.2 TOXICOLOGY - MAN
2.2.1 Absorption - Trichlorfon may be absorbed from the
gastrointestinal tract, by inhalation, or through the intact
skin.
2.2.2 Dangerous doses
Single: 75 mg/kg caused severe vomiting, colic and weakness for
three days. 35 mg/kg caused vomiting, colic and weakness that
were evident for three hours.
Repeated: 3 doses of 7.5 mg/kg on consecutive days caused a 50%
reduction in plasma cholinesterase. 12 daily doses of 5 mg/kg
caused colic and blurring of vision.
2.2.3 Observations of occupationally exposed workers
- A group of workers were poisoned while working in a field
treated on day previously with chlorofos (trichlorfon). Symptoms
included headaches, dizziness, nausea, weakness, hand tremor and
pain in the limbs, burning sensations in the tongue and eyes and
a feeling of permanent noise in the ears. Two of these workers
lost consciousness and some had psychic disturbances such as
depression and apathy. Peripheral nervous system disturbances
developed 7-10 days following this incident, focused mainly on
the lower limbs.
2.2.4 Observations of the general population -
Trichlorfon is of low persistency; under normal conditions of use
the general population should not be exposed to levels of
toxicological significance. Residues found in food usually
disappear during processing or cooking. The estimate of the
temporary acceptable daily intake for man is from 0-0.01 mg/kg
per day.
2.2.5 Observations of volunteers and people receiving the
compound as antiparasitic drug - Over 12 000 people have
been treated with trichlorfon under the name of metrifonate over
the last few years for various intestinal and body parasites.
The dosage has varied from 5 mg/kg up to 70 mg/kg. Repeated dose
over periods of 12 days have been given, at 5 mg/kg. 7.5 mg/kg
given 2-4 times at two week intervals has caused cholinesterase
inhibition, weakness, nausea, diarrhoea, and abdominal pain.
Higher doses, 24 mg/kg, caused more severe symptoms, including
tachycardia, salivation, colic pain, vomiting, nausea, fatigue
trends and sweating. Spontaneous recovery in all cases was rapid.
2.2.6 Reported mishaps - There have been several
reports of accidental or suicidal poisonings with trichlorfon.
Most of these reports involve the chlorofos formulation of
trichlorfon. A 37-year old man who intentionally ingested 100 ml
of a 30% formulation of chlorofos was admitted to hospital with
miosis, bronchorrhea and bradycardia. Cholinesterase activity
was severely reduced. Acute relapses, including bronchospasm and
cardiac arrest were seen and pneumonia was also evident.
Recovery took 47 days and in the course of treatment 200 ml of
atropine solution and 120 ml of oxime reactivator were used.
Some cases of neurological disorders have resulted from ingestion
of chlorofos, these are typified by the case of a woman who had
drunk about 200 ml of this compound. She was in a comatose state
for 11 hours and subsequently there was exhausting vomiting,
severe headache, stomach pains, frequent liquid stools and
general weakness. She was considerably improved and discharged
after 10 days. Later she noticed increased general
fatiguability, especially "tiredness" of the muscles of the lower
extremities. Seven to 10 days after discharge, paresthesia
appeared in the form of burning and stabbing pains in the region
of the foot. This slowly increased to affect the hands, intense
pain occurred in the arms and legs. There was increased tendency
to sweat and discolouration of the hands and feet appeared. By
this time the patient could no longer walk or hold a spoon. Two
months after the initial poisoning her condition was diagnosed as
toxic polyneuritis with severe motor sensory and vegetative-
trophic disorders. Three months after ingestion the patient
still walked with difficulty because of deep foot paresis, her
Achilles reflexes could not be stimulated.
No cases of this type of syndrome have occurred either in man or
animals with any other formulation of trichlorfon.
2.3 TOXICITY TO NON-MAMMALIAN SPECIES
2.3.1 Fish - Toxic to carp (6 ppm/48 hours)
2.3.2 Birds - Toxic (chickens 110 mgm/kilo)
2.3.3 Other species - Very low order of toxicity to
bees. No danger once spray has dried.
3. FOR REGULATORY AUTHORITIES - RECOMMENDATIONS ON REGULATIONS OF
COMPOUND
3.1 RECOMMENDED RESTRICTIONS ON AVAILABILITY
(for definition of categories, see introduction)
Formulations of 2% and above, category 4.
Formulations below 2%, category 5
3.2 TRANSPORTATION AND STORAGE
Formulations in category 4 - Should be transported or stored in
clearly labelled rigid and leakproof containers under lock and
key, safe from access by unauthorized persons and children. No
food or drink should be stored in the same compartment.
Fomulations in category 5 - Should be stored in clearly labelled
leakproof containers out of reach of children and away from food
and drink.
3.3 HANDLING
Formulations in category 4 - Protective clothing (see 4.1.3 on
part 4) should be provided for all handling of the compound.
Adequate washing facilities should be available at all times
during handling and should be close to the site of handling.
Eating, drinking and smoking should be prohibited during handling
and before washing after handling.
Formulations in category 5 - No facilities other than those
needed for the handling of any chemical need be required.
3.4 DISPOSAL AND/OR DECONTAMINATION OF CONTAINER
All formulations - Container may be decontaminated (for method
see paragraph 4.3, part 4). Decontaminated containers should not
be used for food and drink. Containers that are not
decontaminated should be burned or crushed and buried below the
topsoil and care must be taken to avoid subsequent contamination
of water sources.
3.5 SELECTION, TRAINING AND MEDICAL SUPERVISION OF WORKERS
Formulations in category 4 - Pre-employment medical examination
for workers desirable. Workers suffering from active hepatic or
renal disease should be excluded from contact. Pre-employment
and periodic cholinesterase test for workers desirable. Special
account should be taken of the workers mental ability to
comprehend and follow instructions. Training of workers in
techniques to avoid contact essential.
Formulations in category 5 - Cholinesterase test for workers not
required. Warning of workers to minimize contact essential.
3.6 ADDITIONAL REGULATIONS RECOMMENDED IF DISTRIBUTED BY AIRCRAFT
All formulations - Pilot and loaders should have special training
in application methods and early symptoms of poisoning and must
wear a suitable respirator. Flagmen, if used, should wear
overalls and be located well away from the dropping zone.
3.7 LABELLING
Formulations in category 4 - Minimum cautionary statement
Trichlorfon is an organophosphorus compound that inhibits
cholinesterase. It is poisonous if swallowed or absorbed through
the skin. Avoid skin contact: wear protective gloves and clean
protective clothing while using the material. Wash thoroughly
with soap and water after using. Keep the material out of reach
of children and well away from foodstuffs, animal feed and their
containers. If poisoning occurs, call a physician. Atropine and
pralidoxime are specific antidotes and artificial respiration may
be needed.
Formulations in category 5 - Minimum cautionary statement
This formulation contains trichlorfon, an organophosphorus
compound which inhibits cholinesterase. It is poisonous if
swallowed. Keep the material out of reach of children and well
away from foodstuffs, animal feed and their containers.
3.8 RESIDUES IN FOOD - Maximum residue limits for
trichlorfon have been recommended by the Joint FAO/WHO Meeting on
Pesticide Residues.
4. PREVENTION OF POISONING IN MAN AND EMERGENCY AID
4.1 PRECAUTIONS IN USE
4.1.1 General - Trichlorfon is an organophosphorous
pesticide of moderate toxicity. It is readily absorbed from the
gastrointestinal tract and may also be absorbed by the intact
skin and by inhalation.
4.1.2 Manufacture and formulation - TLV: (ACGIH)
(USSR) 0.5 mg/m3. Closed systems and forced ventilation may be
required to reduce as much as possible the exposure of workers to
the chemical.
4.1.3 Mixers and applicators - When opening the
container and when mixing, protective impermeable boots, clean
overalls, gloves and respirator should be worn. Mixing if not
mechanical, should always be carried out with a paddle of
appropriate length. When spraying tall crops or during aerial
application, a face mask should be worn as well as an impermeable
hood, clothing, boots and gloves. The applicator should avoid
working in spray mists and avoid contact with the mouth.
Particular care is needed when equipment is being washed, after
use. All protective clothing should be washed immediately after
use, including the insides of the gloves. Splashes must be
washed immediately from the skin and eyes, with large quantities
of water. Before eating, drinking or smoking, hands and other
exposed skin should be washed.
4.1.4 Other associated workers (including flamen in aerial
operations) - Persons exposed to trichlorfon and associated
with its application should wear protective clothing and observe
the precautions described above in 4.1.3 under "mixers and
applicators".
4.1.5 Other populations likely to be affected - With
good use, practice subject to 4.2 below, other persons should not
be exposed to hazardous amounts of trichlorfon.
4.2 ENTRY OF PERSONS INTO TREATED AREAS -
Unprotected persons should be kept out of treated areas for two
days.
4.3 DECONTAMINATION OF SPILLAGE AND CONTAINERS -
Residues in containers should be emptied in a diluted form into a
deep pit, taking care to avoid ground waters. The emptied
containers may be decontaminated by rinsing two or three times
with water and scrubbing the sides. An additional rinse should
be carried out with 5% sodium hydroxide solution which should
remain in the container overnight. Impermeable gauntlets should
be worn during this work and a soakage pit should be provided for
the rinsings. Decontaminated containers should not be used for
food and drink.
Spillage of trichlorfon and its formulations should be removed by
washing with 5% sodium hydroxide solution and then rinsing with
large quantities of water.
4.4 EMERGENCY AID
4.4.1 Early symptoms of poisoning - Early symptoms of
poisoning may include excessive sweating, headache, weakness,
giddiness, nausea, vomiting, stomach pains, blurred vision,
slurred speech and muscle twitching. Later there may be
convulsions, coma, loss of reflexes and loss of sphincter
control.
4.4.2 Treatment before person is seen by a physician, if
these symptoms appear following exposure - The person should
stop work immediately, remove contaminated clothing and wash the
affected skin with water and soap, if available, and flush the
area with large quantities of water. If swallowed, vomiting
should be induced if the person is conscious. In the event of
collapse, artificial respiration should be given, bearing in mind
that if mouth to mouth respiration, vomit may contain toxic
amounts of trichlorfon.
5. FOR MEDICAL AND LABORATORY PERSONNEL
5.1 MEDICAL DIAGNOSIS AND TREATMENT IN CASES OF POISONING
5.1.1 General information - Trichlorfon is an
organophosphorus pesticide of moderate toxicity. It is readily
absorbed from the gastrointestinal tract, by inhalation and to
lesser extent by the intact skin. It acts by inhibiting
acetylcholinesterase. It is rapidly degraded and excreted mainly
in the urine.
5.1.2 Symptoms and signs - Symptoms of poisoning are
mainly cholinergic and include headache, excessive sweating,
weakness, giddiness, nausea and vomiting, stomach pains, blurred
vision, slurred speech and muscle twitching. More advanced
symptoms of poisoning may be convulsions, coma, loss of reflexes
and loss of sphincter control. Delayed ataxia has been recorded
in cases involving the chlorofos formulation.
5.1.3 Laboratory - The most important laboratory
finding is reduction in activity of blood cholinesterases.
Urinary levels of phosphate metabolites can also be used to
monitor exposure.
5.1.4 Treatment - If the pesticide has been ingested,
unless the patient is vomiting, rapid gastric lavage should be
performed using 5% sodium bicarbonate, if available. For skin
contact, the skin should be washed with soap and water. If the
compound has entered the eyes, they should be washed with
isotonic saline or water.
Persons without signs of respiratory inefficiency but with
manifest peripheral symptoms should be treated with 2-4 mg of
atropine sulfate and 1000-2000 mg of pralidoxime chloride or 250
mg of toxogonin (adult dose) by slow intravenous injection. More
atropine may be given as needed. Persons with severe
intoxication, with respiratory difficulties, convulsions and
unconsciousness should immediately be given atropine and a
reactivator. In such severe cases 4-6 mg of atropine sulfate
should be given initially followed by repeated doses of 2 mg at
5-10 minute intervals. The patients' condition including
respiration, blood pressure, pulse frequency, salivation and
convulsions should be carefully observed as a guide to further
administration of atropine. If the patient is cyanotic,
artificial respiration should be given at the same time as
sulfate.
The airways should be kept free and artificial respiration should
be applied, if required, preferably by mechanical means. If
necessary, intubation should be performed.
Contraindications are morphine, barbiturates, phenothiazine
tranquillizers and central stimulants of all kinds.
5.1.5 Prognosis - If the acute toxic effect is
survived and adequate artificial respiration has been given, if
needed, the chances of complete recovery are good. However, in
very severe cases, particularly if artificial respiration has
been inadequate, prolonged anoxia may give rise to pemanent brain
damage. There has been report of delayed ataxia with the
chlorofos formulation.
5.1.6 References of previously reported cases
Stutev, A. A. & Varenkina, T. T. (1969) KLINIK Med., 47, 9, 140-
142 abstracted in Health Aspects of Pesticides (1970), 3 (3), 70-
0348
Luzhrikov, Ye. A. & Kosarev, V. A. (1971) TER ARKH, 43, 106-108
abstracted in Health Aspects of Pesticides (1972), 5, (7), 72-
1456.
5.2 SURVEILLANCE TESTS
Test Normal level* Action level* Symptomatic level*
Plasma cholinesterase 100% 50% Variable
Erythrocyte 100% 70% Usually <40%
cholinesterase
*Expressed as a percentage of pre-exposure activity.
Urinary levels of organophosphorus metabolites can also be used
to determine exposure.
5.3 LABORATORY METHODS
5.3.1 Detection and assay of compound - References are
given only.
Trichlorfon can be extracted from animal tissues with
acetonitrile and be determined by gas liquid chromatography
(Anderson et al., 1966) or by thin layer chromatography (Beck
et al., 1968). A colorimetric total phosphorus method is
also applicable for plant material and milk, though non-
specific. The lower limit of determination is 0.1-0.2 ppm.
(Sissons, 1970 and Leaky, 1964).
5.3.2 Other tests in cases of poisoning - Levels of cholinesterase in
the blood, particularly plasma, provide the most useful
diagnosis of poisoning.
Michel, N. O. (1949), J. Lab. Clin. Med., 34, 1564-1568
Ellman, G. L., Courtney, K. D., Andres, Y. jr & Featherstone,
R. M. (1961) Biochem. Pharmacol., I, 88-95