Organophosphorus pesticides
Organophosphorus Pesticides
International Programme on Chemical Safety
Poisons Information Monograph (Group Monograph) G001
Chemical
1. NAME
1.1 Substance
Organophosphorus pesticides
1.2 Group
The group includes:
Acephate
Azamethiphos
Azinphos ethyl
Azinphos methyl
Bromophos
Bromophos ethyl
Cadusofos
Carbophenythion
Chlormephos
Chlorphoxim
Chlorpyrifos
Chlorpyrifos-methyl
Chlorthiophos
Chlorvinohos
Coumaphos
Crotoxyphos
Crufomate
Cyanofenphos
Cyanophos
Demephron -O and -S
Demeton -O and -S
Demeton-S-methyl
Demeton-S-methylsulphon
Dialifos
Diazinon
Dichlofenthion
Dichlorvos
Dicrotophos
Dimefox
Dimethoate
Dioxabenzophos
Dioxathion
Disulfoton
Ditalmifos
Edifenphos
EPBP
EPN
ESP
Ethion
Ethopropos
Etrimfos
Famphur
Fenamiphos
Fenchlorphos
Fenitrothion
Fensulfothion
Fenthion
Fonofos
Formothion
Fosmethilan
Heptenophos
Isazofos
Isofenphos
Isothioate
Isoxathion
Jodfenphos
Leptophos
Malathion
Menazon
Mephosfolan
Methacrifos
Methamidophos
Methidathion
Mevinphos
Monocrotophos
Naled
Omethoate
Oxydemeton-methyl
Parathion
Parathion-methyl
Phenthoate
Phorate
Phosalone
Phosmet
Phosphamidon
Phospholan
Phoxim
Pirimiphos-ethyl
Pirimiphos-methyl
Profenofos
Propaphos
Propetamphos
Prothiofos
Prothoate
Pyraclofos
Pyridaphenthion
Quinlphos
Schradan
Sulfotep
Sulprofos
Temephos
TEPP
Terbufos
Tetrachlorvinphos
Thiometon
Thionazin
Triazophos
Trichlorfon
Vamidothion
1.3 Synonyms
OP
1.4 Identification numbers
1.4.1 CAS number
Acephate 30560-19-1
1.4.2 Other numbers
Azinphos methyl 86-50-0
Bromophos 2104-96-3
Bromophos ethyl 4824-78-6
Chlorphoxim 14816-20-7
Chlorpyrifos 2921-88-2
Chlorpyrifos-methyl 5598-13-0
Chlorthiophos 60238-56-4
Coumaphos 56-72-4
Crotoxyphos 7700-17-6
Crufomate 299-86-5
Cyanofenphos 13067-93-1
Cyanophos 2636-26-2
Demeton 8065-48-3
Demeton-O 298-03-3
Demeton-S 126-75-0
Demeton-S-methyl 919-86-8
Demeton-S-methylsulphon 17040-19-6
Diazinon 333-41-5
Dichlofenthion 97-17-6
Dichlorvos 62-73-7
Dicrotophos 141-66-2
Dimefox CAS 115-26-4
Dimethoate 60-51-5
Dioxabenzophos 3811-49-2
Dioxathion 78-34-2
Disulfoton 298-04-4
Ditalmifos 5131-24-8
Edifenphos 17109-49-8
EPBP 3792-59-4
EPN 2104-64-5
ESP 2674-91-1
Ethion 563-12-2
Ethopropos 13194-48-4
Etrimfos 38260-54-7
Famphur 52-85-7
Fenamiphos 22224-92-6
Fenchlorphos 299-84-3
Fenitrothion 122-14-5
Fensulfothion 115-90-2
Fenthion 55-38-9
Fonofos 944-22-9
Formothion 2540-82-1
Heptenophos 23560-59-0
Isothioate 36614-38-71
Isoxathion 18854-01-8
Jodfenphos 18181-70-9
Leptophos 21609-90-5
Malathion 121-75-5
Mephosfolan 950-10-7
Methamidophos 10265-92-6
Methidathion 950-37-8
Mevinphos 7786-34-7
Monocrotophos 6923-22-4
Naled 300-76-5
Omethoate 1113-02-6
Oxydemeton-methyl 301-12-2
Parathion 56-38-2
Parathion-methyl 298-00-0
Phenthoate 2597-03-7
Phorate 298-02-2
Phosphamidon amide 16655-69-9
Phospholan 947-02-4
Phoxim 14816-18-3
Pirimiphos-ethyl 23505-41-1
Profenofos 41198-08-7
Propaphos 7292-16-21
Prothiofos 34643-46-4
Quinlphos 13593-03-8
Schradan 152-16-9
Sulfotep 3689-24-51
Sulprofos 35400-43-2
Temephos 3383-96-8
TEPP 107-49-3
Terbufos 13071-79-9
Tetrachlorvinphos 22248-79-9
Thiometon 640-15-3
Thionazin 297-97-2
Triazophos 24017-47-8
Trichlorfon 52-68-6
Vamidothion 2275-23-2
The following UN transportation numbers have
been established for organophosphorus pesticides (UN,
1985):
2783 Organophosphorus pesticides,
solid, toxic, NOS.
2784 Organophosphorus pesticides,
liquid, toxic, flammable, NOS,
freezing point < 61°C, closed cup.
3017 Organophosphorus pesticides,
liquid, toxic, flammable, freezing
point 23°C, closed cup.
3018 Organophosphorus pesticides,
liquid, toxic, NOS.
1.5 Main brand names/main trade names
See individual organophosphorus pesticide
monographs.
1.6 Main manufacturers/main importers
See individual organophosphorus pesticide
monographs.
2. SUMMARY
2.1 Main risks and target organs
Organophosphorus pesticides can be absorbed by all
routes, including inhalation, ingestion, and dermal
absorption. The toxicological effects of the
organophosphorus pesticides are almost entirely due to the
inhibition of acetylcholinesterase in the nervous system,
resulting in respiratory, myocardial and neuromuscular
transmission impairment. A few organophosphorus pesticides
have produced the so-called "Intermediate Syndrome" and
delayed neuropathy, the latter apparently unrelated to
acetylcholinesterase inhibition.
The main target organs are the nervous system, respiratory
tract and cardiovascular system.
Degradation products in the environment are not toxic to any
significant extent. Thermal decomposition products may be
harmful by inhalation and skin contamination. Toxicity may
also be due to the effects of solvent vehicles or other
components of formulated pesticides.
2.2 Summary of clinical effects
The signs and symptoms of acute organophosphate
poisoning are an expression of the effects caused by excess
acetylcholine (cholinergic syndrome); they may occur in
various combinations and can be manifest at different
times.
Signs and symptoms can be divided into three groups:
- muscarinic effect
- nicotinic effect
- central nervous system effect.
According to the degree of the severity of poisoning, the
following signs and symptoms can occur:-
* Mild: anorexia, headache, dizziness, weakness, anxiety,
substernal discomfort, fasciculations of the tongue and
eyelids, miosis, and impairment of visual acuity.
* Moderate: nausea, salivation, bronchorrhoea, lacrimation,
abdominal cramps, diarrhoea, vomiting, sweating,
hypertension or hypotension, and muscular
fasciculations.
* Severe: miosis or mydriasis, non-reactive pupils,
dyspnoea, respiratory depression, pulmonary oedema,
cyanosis, loss of sphincter control, convulsions, coma,
bradycardia or tachycardia, cardiac ischaemia, cardiac
dysrhythmias, hypokalaemia, and hyperglycaemia. Acute
pancreatitis has also occurred. Muscular paralysis may
involve the respiratory muscles.
Some organophosphorus pesticides have caused delayed
peripheral neuropathy.
Intermediate Syndrome: The "Intermediate Syndrome" has been
described. This occurs after initial improvement,
approximately 1 to 8 days after poisoning. Muscle weakness
leading to paralysis and sudden respiratory arrest
occurs.
2.3 Diagnosis
In the absence of a reliable history, the diagnosis of
organophosphorus pesticides poisoning may be initially
clinical, as it is based on the clinical features given in
section 2.2. Foul smell (much like garlic) may be present in
breath, faeces or vomit or in contaminated clothing, if
sulphur-containing insecticides have been ingested.
Favourable response to atropine is a more useful diagnostic
aid than any cholinesterase assay since treatment must often
be initiated before any laboratory results are available.
Other relevant laboratory analysis:
Complete blood cell count, serum electrolyte levels, arterial
pH and blood gases, blood glucose, liver function tests,
urine analysis. Investigations may also include ECG and chest
X-ray.
Cholinesterase levels are helpful in diagnosing
organophosphorus pesticide poisoning, but not in managing the
illness. The red cell (acetyl) cholinesterase level is a
more accurate assessment of poisoning. Blood should be drawn
in a heparinised tube before treatment is begun. In cases of
unknown organophosphorus poisoning, the first aspirate or the
formulation of the pesticide if available, may be used to
identify the type of organophosphorus pesticide.
2.4 First-aid measures and management principles
It is important that the chemical be removed as quickly
as possible, as well as atropine to be administered (see
below). Contaminated clothing and contact lenses should be
removed as quickly as possible to prevent further absorption.
If skin contact occurs, the area should be washed carefully
with soap and water. Wash eyes for 15 to 20 minutes with
running water. First-aid personnel should wear rubber or
plastic gloves to avoid contamination, which should be
changed frequently.
In massive overdoses, acute respiratory failure may occur.
It is important to keep the airway open and to prevent
aspiration if nausea and vomiting occur.
Oxygen should be administered early if necessary. The
patient must be watched constantly and respiratory support
should be instituted if necessary. In the case of ingestion,
gastric aspiration followed by lavage should be preferably
performed within 1 hour of ingestion.
Activated charcoal may be effective for organophosphorus
pesticides.
The patient should be observed carefully during the early
stages of treatment, because the principal concern is severe
respiratory depression. Certain drugs, such as
phenothiazines, methylxanthines, central nervous system
depressants, and parasympathomimetic agents are to be
avoided. Drugs metabolised by plasmacholinesterase are
contraindicated.
When muscarinic signs are present, organophosphate pesticide
poisoning must be treated with atropine. The oximes, such as
pralidoxime or obidoxime may also be indicated. Diazepam is
used to treat seizures.
Atropine: administered intravenously (IV) in doses of 1 to 2
mg (0.05 mg/kg) every five to ten minutes until signs of
atropinisation (dilated and fixed pupils, loss of salivation
and bronchial hypersecretion) or complete reversal of
symptoms occurs. If IV therapy is not possible, atropine may
be given intramuscularly (IM). In severe cases, both
tachycardia and mydriasis may be unreliable features, since
they may result from nicotinic stimulation. In very severe
cases bolus injections of > 10 mg may be necessary. As
such, adequate atropinisation should be assessed by dry mouth
and the effect on bronchial hypersecretion; frequent
auscultation is necessary. Atropine must be continued to
maintain atropinisation until the patient recovers.
Pralidoxime: in doses of 30 mg/kg every four to six hours or,
preferably, by slow intravenous (IV) infusion at a maximum
rate of 8 to 10 mg/kg/h until full recovery occurs, or, 500
mg/h continuously maintained until clinical improvement is
obtained.
Obidoxime: the adult dose is usually 3 mg/kg given by slow
IV; IM dosing is possible when the IV route is inaccessible.
The maintenance dose is 0.4 mg/kg/h.
Diazepam: 5 to 10 mg (0.2 to 0.3 mg/kg) by slow intravenous
(IV) over three minutes which may be repeated every 10 to 15
min (maximum 30 mg) in order to control convulsions.
Some organophosphorus pesticides may cause a delayed
peripheral neuropathy. There is no specific therapy for this
condition except for symptomatic measures; e.g.,
physiotherapy.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of substance
Organophosphate pesticides are synthetic in origin and
are normally esters, amides, or thiol derivatives of
phosphoric, phosphonic, phosphorothioic, or phosphonothioic
acids.
3.2 Chemical structure
Figure 1. General formula for organophosphorus
compounds
R1
\ O (or S)
\ "
P ---X
/
/
R2
3.3 Physical properties
3.3.1 Colour
See individual organophosphorus pesticide
monographs.
3.3.2 State/Form
See individual organophosphorus pesticide
monographs.
3.3.3 Description
Over 100 organophosphorus compounds
representing a variety of chemical, physical, and
biological properties are presently in commercial
use.
Most are only slightly soluble in water and have a
high oil-water partition coefficient and a low vapour
pressure. Most, with the exception of dichlorvos, are
of comparatively low volatility, and are all degraded
by hydrolysis, yielding water-soluble products.
Parathion, for example, is freely soluble in alcohols,
esters, ethers, ketones, and aromatic hydrocarbons,
but is practically insoluble in water (20 ppm) or in
petroleum ether, kerosene, or spray oils (Gallo &
Lawryk, 1991). Parathion is stable at a pH below
7.5.
3.4 Hazardous characteristics
The majority of organophosphorus pesticides are liquid
and have different vapour pressures at room temperature. The
compounds used for agricultural purposes are available mainly
as emulsifiable concentrates or wettable powder formulations
for reconstitution as liquid sprays, but also as granules for
soil applications. A limited number are also available as
fogging formulations, smokes, impregnated resin strips for
use indoors, and as animal or human pharmaceutical
preparations.
Dispersion of spray droplets by wind is possible, but in
general, only small amounts are likely to be dispersed in
this way.
All organophosphorus pesticides are subject to degradation by
hydrolysis, yielding water-soluble products that are believed
to be non-toxic at all practical concentrations. The toxic
hazard is therefore essentially short-term in contrast to
that of the persistent organochlorine pesticides, although
the half-life at neutral pH may vary from a few hours for
dichlorvos to several weeks for parathion. At the pH of
slightly acidic soils (pH 4 to 5), these half-lives will be
extended many times. However, constituents of soil and of
river water may themselves catalyse degradation.
Products of combustion:
Powder, granular, and water-based products will not burn.
Most liquid formulations will burn and are miscible with
water. The products of combustion may be harmful by
inhalation and dermal contamination. Fire Service personnel
should extinguish fires with alcohol-resistant foam, water
spray, or dry powder. Firefighters should wear full
protective clothing including self-contained breathing
apparatus.
Environmental risks:
Three routes of entry into water sources are possible. One
is from industrial waste or effluent discharged directly into
water. A second is by seepage from buried toxic wastes into
water supplies. Neither of these should be tolerated, since
prior treatment of the waste with alkali (or acid in cases
such as diazinon), followed by neutralisation, can destroy
the toxic agents. Thirdly, contamination of running water
directly or from run-off during spraying operations can
occur. No studies on the degradation of organophosphorus
pesticides in running water have been reported. In static
water, in a simulated aquatic environment, there is evidence
that light, suspended particles, and bacteria contribute to
degradation. Thus, the degradation of fenitrothion in lake
water under illumination occurred with a half-life of about 2
days, compared with 50 days in the dark (Greenhalgh et al.,
1980). Furthermore, Drevenkar et al. (1976, as reported in
Gallo & Lawryk, 1991) concluded that although temperature and
pH were major factors controlling the rate of hydrolysis of
dichlorvos in water, large differences in the half-life of
this pesticide in different river waters must be attributed
to microbiological factors.
Degradation in the environment involves both hydrolysis and
oxidation to mono- or di- substituted phosphoric or
phosphonic acids or their thio analogues. There is no
evidence that these products are toxic to any
significantextent (WHO, 1986).
For guidance on safe disposal, see Section 12.2.
4. USES
4.1 Uses
4.1.1 Uses
Pesticide for use on invertebrate
animals
4.1.2 Description
Organophosphorus pesticides are used to control
insect vectors which are found in food and commercial
crops, and infestations in domestic and commercial
buildings, and in man or domestic animals.
Di-isopropanyl fluorophosphate (DFP) is used as an
ophthalmic cholinesterase inhibitor to treat
glaucoma.
4.2 High risk circumstances of poisoning
Accidental poisoning of children can occur when
pesticides are stored improperly in the home or garage.
Occupational exposure among adult farm workers and secondary
accidental exposure to their families can occur.
Suicide attempts probably account for more severe and more
frequent poisonings than accidental or occupational
poisonings in some countries.
Exposure of the general population through the consumption of
foodstuffs treated incorrectly with pesticides or harvested
prematurely before residues have declined to acceptable
levels from contact with treated areas, or from domestic use
has been reported. Accidental poisonings can also occur
through failure to observe the safe re-entry time after
application.
4.3 Occupationally exposed populations
- Factory workers involved in synthesizing
pesticides.
- Workers involved in formulating and dispensing
pesticides.
- Agricultural spray workers.
- Crop harvesters during disease vector control periods.
- Public-health workers involved in vector control.
- Health workers not following the correct procedures when
handling poisoned patients, especially when ventilatory
support is needed.
5. ROUTES OF EXPOSURE
5.1 Oral
- Accidental ingestion, especially by children.
- Ingesting food containing organophoshorus pesticide
residues after incorrect treatment of foodstuffs or
harvested prematurely before residues have declined to
acceptable levels.
- Oral ingestion may also occur through placing contaminated
objects in the mouth during eating, drinking or smoking,
or through violation of proper procedures, e.g., blowing
out clogged spray nozzles by mouth.
- Intentional ingestion is common in suicide attempts (see
section 4.2).
5.2 Inhalation
The majority of organophosphorus pesticides are liquids
that have different vapour pressures at room temperature
(e.g., dichlorvos is much more volatile than parathion);
thus, hazards due to inhalation of vapour vary from compound
to compound. Respiratory exposure is greater when dusts are
applied than when dilute sprays are used. However, aerosols
of concentrated pesticide may be an even greater hazard
(WHO,1986).
5.3 Dermal
Many accidental acute poisonings have occurred after
spillage of a pesticide on skin and clothing. The extent of
uptake will depend on persistence time (related to
volatility, clothing, coverage, and thoroughness of washing
after exposure), and also on the presence of solvents and
emulsifiers that may facilitate uptake. Powder formulations
also have a potential for skin absorption (Wolfe et
al.,1978).
Skin absorption is somewhat greater at high temperatures and
may be much greater in the presence of dermatitis, thus,
leading to serious poisoning after an exposure that would
ordinarily cause no effects (Gallo & Lawryk, 1991).
5.4 Eye
Exposure to vapours, dusts, or aerosols can cause local
effects on the smooth muscles of the eyes. Systemic
poisoning may follow.
5.5 Parenteral
Accidental or intentional (see section 11.2).
5.6 Others
No data available.
6. KINETICS
6.1 Absorption by route of exposure
Organophosphorus pesticides are absorbed by the skin as
well as by the respiratory and gastrointestinal tracts.
Oral exposure:
When 32P-dimethoate was given orally to volunteers, it was
absorbed and excreted rapidly: 76 to 100% of the
radioactivity appeared in the urine in 24 hours (Edson et
al., 1967).
Inhalation exposure:
Exposure by respiratory and dermal routes were compared in
workers spraying parathion, who either breathed a pure air
supply but did not wear protective clothing, or who wore
total protective clothing but did not have any respiratory
protection (Durham et al., 1972). Total urinary output of
4-nitrophenyl as derived from the respiratory source,
compared with that derived from the dermal source, was 1.2%
in one test and 12% in another.
Since the total exposures by the dermal and respiratory
routes were in the proportion of 1000:1 and the efficiency of
dermal absorption was 1 to 2%, it follows that the efficiency
of dermal absorption by the respiratory route was more than
20% and could well have been complete.
Dermal exposure:
Absorption by the skin tends to be slow, but because the
pesticides are difficult to remove, dermal absorption is
frequently prolonged. Uptake of active ingredients through
the skin from powdered and granulated formulations may be
relatively inefficient; the presence of aqueous dispersing
agents or organic solvents in a spray concentrate or
formulation may greatly enhance uptake. On the basis of
radioautographic studies in man and animals, it appears that
skin absorption of parathion is transepidermal (Fredriksson,
1961). The rate of dermal absorption of parathion in the
rabbit is 0.059 mg/min/cm2) (Nabb et al., 1966).
When 14C-malathion was applied to the ventral forearm of 12
volunteers, radioactivity equivalent to a "corrected" average
of 8.2% of the total dose was recovered from urine produced
during the first 5 days (Feldmann & Maibach, 1970). This
percentage is an essentially accurate indication of the
absorption during the period because almost all (90.2%) of
the radioactivity was recovered in the urine after IV
injection of malathion.
6.2 Distribution by route of exposure
The intrinsically reactive chemical nature of
organophosphorus pesticides means that any that enter the
body are immediately liable to a number of biotransformations
and reactions with tissue constituents, so that the tracing
of radiolabelled material alone does not give any clue to the
unchanged parent compound. In view of the inherent
instability of the organophosphorus pesticides, storage in
human tissue is not expected to be prolonged. Experimental
animal studies indicate rapid excretion of these compounds.
However, some organophosphorus pesticides are very lipophilic
and may be taken into, and then released from, fat depots
over a period of many days.
The lipophilic diethyl phosphoryl pesticides:
azinophos-ethyl, bromophos-ethyl, chlorpyrofos, coumaphos,
diazinon, parathion, phosalone and sulfotep may remain in the
body for many days or weeks in severe cases, and may promote
a recurrence of clinical effects after an initial period of
apparent recovery. For example, a case of fenitrothion
poisoning promptly treated by conventional therapy caused a
recurrence of symptoms attributed to mobilisation of the
organophosphate stored in adipose tissue. In contrast,
dichlorvos (a dimethyl phosphate) and omethoate (a dimethyl
phosphorothioate) are rapidly hydrolyzed by plasma and tissue
esterases to inactive products and are unlikely to cause late
clinical effects (Ecobichon et al., 1977; Minton & Murray,
1988).
6.3 Biological half-life by route of exposure
It is possible to determine the rate of disposal of
metabolites and thereby to estimate an approximate half-life
of the pesticide in the body. The half-life of most
organophosphorus pesticides and their inhibitory metabolites
in vivo is comparatively short (WHO, 1986). For example, the
serum half-life of malathion was 2.89 hours in a 24-year-old
white male who, in a suicide attempt, injected approximately
3 mL of 50% malathion intravenously into his right forearm
(Lyon et al., 1987).
A few organophosphorus pesticides, however, are lipophilic
and may remain in the body for many days or weeks (see
section 6.2). For example, leptophos tends to persist in the
fat of hens, and pharmacokinetic studies using radiolabelled
leptophos showed an elimination half-life of 17 days
(Abou-Donia & Graham, 1978).
6.4 Metabolism
Metabolism occurs principally by oxidation, and
hydrolysis by esterases and by reaction with glutathione.
Demethylation and glucuronidation may also occur. Oxidation
of organophosphorus pesticides may result in more or less
toxic products. In general, phosphorothioates are not
directly toxic but require oxidative metabolism to the
proximal toxin. The glutathione transferase reactions
produce products that are, in most cases, of low
toxicity.
Hydrolytic and transferase reactions affect both the thioates
and their oxons. Numerous conjugation reactions follow the
primary metabolic processes, and elimination of the
phosphorus-containing residue may be via the urine or
faeces.
Parathion, for example, must be activated by an oxidative
conversion via liver Cytochrome P450 microsomal enzymes to
paraoxon, a potent cholinesterase inhibitor. Both compounds
are rapidly hydrolyzed by plasma and tissue esterases, to
diethylthiophosphoric acid, diethyl- phosphoric acid, and
p-nitrophenol. These products are excreted mostly in the
urine and represent the majority of a dose of parathion
(Baselt, 1982). Phosphorothioates containing a P = S bond
need to be converted into the analogous oxone before they
acquire substantial anticholinesterase activity.
6.5 Elimination and excretion
There is no evidence of prolonged storage of
organophosphorus pesticides compounds in the body, but the
process of elimination can be subdivided roughly according to
the speed of the reactions involved. Most organophosphorus
pesticides are degraded quickly by the metabolic reactions
described. The elimination of the products, mostly in the
urine with lesser amounts in the faeces and expired air, is
not delayed, so that rates of excretion usually reach a peak
within two days and decline quite rapidly (WHO, 1986).
Experimental animal studies have shown that most of a
radiolabelled dose of organophosphorus pesticides is rapidly
excreted in expired air, urine, and faeces. Thus, it was
reported that from 67 to 100% of the administered
radioactivity was recovered within 1 week in the combined
urine and faeces of cows, rats and a goat that were given
various doses of 32P-dichlorvos (Blair et al., 1975).
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
Organophosphorus pesticides exert their acute effects by
inhibiting acetylcholinesterase in the nervous system with
subsequent accumulation of toxic levels of acetylcholine.
They may also inhibit butylcholinesterases as well as other
esterases. The function of butylcholinesterase is unknown,
but its inhibition can provide an indication of exposure to
an organophosphate.
In many cases, the organophosphorylated enzyme is fairly
stable, so that recovery from intoxication may be slow.
Reactivation of inhibited enzyme may occur spontaneously, the
rates of reactivation depending on the tissue as well as on
the chemical group attached to the enzyme.
Delayed neuropathy is initiated by an attack on a nervous
tissue esterase distinct from acetylcholinesterase. The
target has esterase activity and is called neuropathy target
esterase (NTE) (formerly neurotoxic esterase). The disorder
develops not because of loss of esterase activity, but
because of a change brought about in the protein molecule
that results from the process of ageing of inhibited NTE:
catalytic activity of NTE appears in the nervous tissue, even
during the period of development of neuropathy (WHO,
1986).
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Most organophosphorus pesticides are
highly toxic. The level of toxicity
(described below) ranges from an estimated
human oral LD of < 5 mg/kg to 0.5 to 5
g/kg(Gosselin et al., 1984).
The estimated fatal dose of parathion for an
adult by ingestion or inhalation is 10 to 200
mg (Gosselin et al., 1984).
An oral dose of 7.2 mg parathion, when given
daily to volunteers for six weeks, reduced
cholinesterase activity to levels of 84% of
normal in erythrocytes and 63% in plasma; 28
days after the end of the experiment these
values were only partially restored to
re-experiment control values (Edson,
1964).
The estimated fatal dose of diazinon in
humans is 25 g by oral ingestion (Baselt,
1982).
Oral doses of diazinon given to volunteers
for 37 days at the rate of 0.02 mg/kg per day
reduced plasma cholinesterase levels to 86%
of pre-exposure levels: 0.05 mg/kg per day
for 28 days reduced the levels to 60 to
65%,but neither dosage affected the
erythrocyte cholinesterase levels (Baselt,
1982).
The mean fatal dose of malathion in humans is
estimated to be 60 g (Baselt, 1982). The
mean lethal oral dose of malathion in an
untreated adult may be as low as 250 mg/kg
(Gosselin et al., 1984).
7.2.1.2 Children
Children have died after ingesting
only 2 mg of parathion equal to a dose of
about 0.1 mg/kg. Young animals are more
susceptible than adults of the same species,
and the same may be true of children
(Gosselin et al., 1984). A 34-month-old boy
survived a dose of about 190 mg/kg malathion,
and a boy only 40-days-old survived after a
dose of approximately 1750 mg (about 407
mg/kg) (Gallo & Lawryk, 1991).
7.2.2 Relevant animal data
See Annex.
Animal studies have revealed slight microscopic
changes in the kidney; Renal toxicity has not been
shown to be a feature of acute organophosphorus
insecticide poisoning (Gallo & Lawryk, 1991).
7.2.3 Relevant in vitro data
No general data available.
7.2.4 Workplace standards
COMPOUND TLV TLV (mg/m3)
Azinphos-methyl - 0.2
Chlorpyrifos - 0.2
Crufomate - 5.0
Demeton 0.01 0.1
Diazinon - 0.1
Dichlorvos 0.1 0.9
Dicrotophos - 0.25
Disulfoton - 0.1
Ethion - 0.4
Fenamiphos - 0.1
Fensulfothion - 0.1
Fenthion - 0.2
Fonophos - 0.1
Malathion - 10.0
Methylparathion - 0.2
Mevinphos 0.01 0.092
Monocrotophos - 0.25
Parathion - 0.1
Phorate - 0.05
Temaphos - 10.0
TEPP 0.004 0.05
TLV = Threshold Limit expressed as the time-weighted
average concentration for a normal 8-hour workday and
a 40-hour workweek, to which nearly all workers may be
repeatedly exposed, day after day, without adverse
effect (Reference: ACGIH, 1991)
7.2.5 Acceptable daily intake (ADI)
COMPOUND YEAR OF ADI
JMPR (mg/kg
MEETING bodyweight)
Acephate 1990 0.03
Azinophos-ethyl 1973 No ADI
Azinophos-methyl 1991 0.005
Bromophos 1984 0-0.04
Bromophos-ethyl 1984 0-0.04
Carbophenothion 1983 0-0.0005
Chlorfenvinphos 1971 0-0.002
Chlorpyrifos 1983 0-0.01
Chlorpyrifos-methyl 1992 0.01
Chlorthion 1965 No ADI
Coumaphos 1990 No ADI
Crufomate 1972 0-0.1
Cyanofenphos 1983 ADI withdrawn
Demeton 1984 No ADI
Demeton-S-methyl 1989 0.0003
Demeton-S-methyl
sulfoxide 1984 No ADI
Dialifos 1982 ADI withdrawn
Diazinon 1993 0.002
Dichlorvos 1993 0.004
Dimethoate 1987 0.01
Disulfoton 1991 0.0003
Edifenphos 1981 0-0.003
Ethion 1990 0.002
Ethoprophos 1987 0.0003
Etrimfos 1986 0.003
Fenamiphos 1987 0.0005
Fenclorphos 1983 0-0.01
Fenitrothion 1988 0-0.005
Fensulfothion 1982 0-0.0003
Fenthion 1983 0-0.001
Formothion 1978 0-0.02
Isophenphos 1986 0.001
Leptophos 1978 ADI withdrawn
Malathion 1984 0-0.02
Mecarbam 1986 0.002
Methacrifos 1990 0.006
Methamidophos 1990 0.004
Methidathion 1992 0.001
Mevinphos 1972 0-0.0015
Monocrotophos 1993 0-0.0006
Omethoate 1985 0-0.0003
Oxydemeton-methyl 1989 Evaluated under
Demeton-S
methyl related
compounds
Parathion 1984 0-0.005
Parathion-methyl 1984 0-0.02
Phenthoate 1984 0-0.003
Phorate 1985 0-0.0002
Phosalone 1993 0.001
Phosmet 1979 0-0.02
Phosphamidon 1986 0-0.0005
Phoxim 1984 0-0.001
Pirimiphos-methyl 1992 0.03
Thiometon 1979 0-0.003
Triazophos 1993 0.001
Trichlorfon 1978 0-0.01
Trichloronat 1971 No ADI
Vamidothion 1988 0.008
ADI = Acceptable Daily Intake
JMPR = Joint Meeting on Pesticides Residues
(FAO/WHO)
(reference: IPCS, 1996)
Re-entry Level Pesticide
24 hours Any pesticide with registered
agricultural uses when used on
crops requiring workers to
perform labour-intensive
activities, unless the
pesticide has been granted an
exemption
48 hours azinphos-methyl
carbophenothion
demeton
dicrotophos
disulfoton
endosulfon
endrin
ethion
methidathion
methyl parathion
mevinphos
monocrotophos
oxydemeton-methyl
phorate
phosphamidon
7 days ethyl parathion
(Reference: Ellenhorn et al., 1997)
7.3 Carcinogenicity
Many organophosphorus pesticides have not shown
carcinogenic potential in animal experiments, but some
chemicals (e.g. dichlorvos, tetrachlorvinphos) do induce
tumours in rats and mice. For other chemicals (e.g.
malathion), interpretation of the findings has not found
general agreement (IARC, 1983; Huff et al., 1985; IPCS,
1996).
7.4 Teratogenicity
Teratogenic effects have been reported for trichlorofon
in pigs, but few teratogenic effects have been reported for
other compounds (WHO, 1986). Detailed data on the effects of
organophosphate occupational exposure on pregnant women and
their foetuses are not available, although such information
would be valuable.
In humans only a few cases of acute organophosphorus
insecticide poisoning during pregnancy have been described. A
24-year-old woman in her third month of pregnancy injected
herself malathion in a suicide attempt. A therapeutic
abortion was performed 2 months later. Continuation of the
pregnancy was considered to be dangerous, although the
condition of the foetus was not described (Gadoth & Fisher,
1978).
Two patients in their second and third trimesters of
pregnancy ingested organophosphorus pesticides in suicide
attempts (Karalliedde et al., 1988). On management of the
acute cholinergic and the intermediate phases of poisoning,
recovery was complete and the pregnancies continued to term
unaffected.
Weis et al. (1983) also reported a 21-year-old patient, who
was about 34 to 35 weeks pregnant, who was admitted to
hospital showing signs of severe organophosphorus pesticide
poisoning.However, caesarean section was performed 11 hours
after admission to allow an optimal atropine dosage for the
mother. Acetylcholinesterase levels were less than 2% of
normal in the infant and atropine infusion was given for
eight days.
Both mother and child made uneventful recoveries and were
discharged 30 days post-admission (Weis et al., 1983).
7.5 Mutagenicity
Many organophosphorus pesticides have been tested for
their mutagenic potential. No generalisations can be made
since some compounds exhibit mutagenic activity, whereas
other compounds do not.
7.6 Interactions
Because different classes of enzymes may be inhibited,
the effects of organophosphorus pesticide poisoning may be
complex and potentially at least could involve interactions
with drugs as well as with other pesticides or chemicals.
Potentiation may also involve solvents or other components of
formulated pesticides (Gallo & Lawryk, 1991). Certain drugs
such a phenothiazines, antihistamines, CNS depressants,
barbiturates, xanthines (theophylline), aminoglycosides and
parasympathomimetic agents are to be avoided because of
increased toxicity.
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
The clinical picture of organophosphorus
pesticide poisoning results from accumulation of
acetylcholine at nerve endings. Signs and symptoms can
be divided into three groups: muscarinic,
nicotinic,and central nervous system (CNS) effects
(see table 9.1.1). Some of these effects may be more
prominent than others or may occur first.
Table 9.1.1 Clinical Effects of Organophosphorus
Pesticide Poisoning
MUSCARINIC EFFECTS
- increased bronchial secretion, excessive sweating,
salivation, and lachrymation
- pinpoint pupils, bronchoconstriction, abdominal
cramps (vomiting and diarrhoea)
- bradycardia
NICOTINIC EFFECTS
- fasciculation of muscles. In more severe cases,
paralysis of diaphragm and respiratory muscles
- tachycardia and elevation of blood pressure
CENTRAL NERVOUS SYSTEM EFFECTS
- headache, dizziness, restlessness, and anxiety
- mental confusion, convulsions and coma
- depression of the respiratory centre and vasomotor
centre
(Reference: WHO, 1986)
Systemic effects are, in general, similar,
irrespective of the route of absorption, but the
sequence and times may differ. Respiratory and ocular
symptoms are expected to appear first after exposure
to airborne organophosphates. Gastrointestinal
symptoms and localised sweating are likely to appear
after oral and dermal exposure, respectively.
Following ingestion, the onset of symptoms is usually
rapid, within a few minutes to 1 or 3 hours. Clinical
effects vary according to the amount ingested (see
table 9.1.1). All of the symptoms and signs may occur
in various combinations and can be manifest at
different times, ranging from a few minutes to many
hours, depending on the chemical, dose, and route of
exposure. Mild poisoning may include muscarinic and
nicotinic signs and symptoms only. Severe cases
always show CNS involvement; the clinical picture is
dominated by respiratory failure, sometimes leading to
pulmonary oedema, due to the combination of the
effects of all three groups.
9.1.2 Inhalation
Respiratory and ocular symptoms are expected to
appear first after exposure to airborne
organophosphorus pesticides.
Effects on the respiratory tract include
bronchoconstriction, and increased activity of the
secretory glands and pulmonary oedema.
9.1.3 Skin exposure
Localised sweating and fasciculation at the
site of contact, with systemic effects occurring
following absorption. Secondary exposure of children
through contact with their parents' contaminated
clothing can also occur.
9.1.4 Eye contact
Early miosis and blurred vision may be followed
by cholinergic effects if the substance is appreciably
absorbed.
A 12-month-old boy who had received one drop of 0.1%
Di-isopropyl fluorophosphate (DFP) in each eye daily
for two months experienced two brief apnoeic spells.
Examination revealed miotic, unreactive pupils,
rhinorrhoea, and slight cholinesterase inhibition
(Verhulst & Crotty, 1965, as reported in Gallo &
Lawryk, 1991).
Miosis, caused by direct contact of the eye with
organophosphorus pesticides, may be incorrectly
interpreted as a sign of systemic poisoning.
9.1.5 Parenteral exposure
Intradermal injection of paraoxon or surface
application of maloxon or dichlorvos to human skin
produced a long-lasting, local sweating response in a
few minutes (McLaughlin & Sonneschein, 1960).
Intramuscular administration of DFP to people with
schizophrenia, manic-depressive psychosis, and to
normal controls at a rate of 2 mg/man per day (about
0.028 mg/kg per day) for seven days caused anorexia,
vomiting, and diarrhoea, somewhat more severe in
normal than in psychotic people (Rowntree et al.,
1950).
9.1.6 Other
No data available.
9.2 Chronic poisoning
9.2.1 Ingestion
No data available.
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
No data available.
9.2.6 Other
True chronic poisoning following exposure to
organophosphorus pesticides does not occur.
Organophosphorus pesticides in common use are rapidly
biotransformed and excreted, and sub-acute or chronic
poisoning by virtue of accumulation of the compounds
in the body does not occur. However, acute
intoxications or chronic exposure maylead to
long-term, or delayed, adverse effects. Several of
the organophosphorus pesticides produce slowly
reversible inhibition of cholinesterase, and
accumulation of this effect can occur. Thus an
individual may experience progressive ChE inhibition
but remain asymptomatice. Signs and symptoms of
poisoning that resemble those produced by a single
high dose will occur when the accumulated inhibition
of cholinesterase produced by smaller, repeated doses
reaches a critical level. Cessation of exposure
normally results in complete recovery (Ecobichon,
1996).
The cholinesterase-inhibition from organophosphorus
pesticides sometimes persists for 2 to 6 weeks. Thus,
an exposure that would not produce symptoms in a
person not previously exposed might produce severe
symptoms in a person previously exposed to smaller
amounts. Leptophos (Phosvel), Trichlorphon
(Dipterex), and Dichlorvos (Divipan) are reported to
cause peripheral nerve damage with persistent muscular
weakness (Dreisbach & Robertson, 1987) (see also
section 9.4.3.2).
9.3 Course, prognosis, cause of death
The first four to six hours are the most critical in
acute poisoning. If there is improvement in symptoms after
initial treatment then the patient is very likely to survive
if adequate treatment is continued. Delayed toxicity
represents an onset of effects on the central and peripheral
nervous systems appearing days to weeks after exposure. This
may occur independently of the effects observed in acute
poisoning due to cholinesterase inhibition. Death in cases
of heavy exposure is usually related to respiratory collapse,
reflecting depression of the respiratory centre, weakness of
the muscles of respiration, bronchoconstriction and excessive
pulmonary secretions. Death may also result from cardiac
arrest, due to cardiac dysrhythmias and various degrees of
heartblock.
9.4 Systemic description of clinical effects
9.4.1 Cardiovascular
Cardiac dysrhythmias, various degrees of heart
block, and cardiac arrest may occur. Cardiac rhythm
disturbances have occurred with a frequency of less
than 5%. These are of many types, such as ventricular
rhythm disturbances, alterations of ST segments, T
waves, prolongation of the QT interval, complete heart
block, and asystole. Tachycardia and ST-wave
abnormalities may also be induced by hypoxia (Gallo &
Lawryk, 1991). Patients may have elevated blood
pressure and tachycardia (nicotinic effects), rather
than bradycardia or hypotension (muscarinic effects),
depending on the balance between muscarinic and
nicotinic receptors (Ellenhorn et al., 1997).
9.4.2 Respiratory
Exposure to organophosphorus pesticides by all
routes can exert effects on the smooth muscles of the
respiratory tract resulting in
bronchoconstriction, increased activity of the
secretory glands and pulmonary oedema. The immediate
cause of death in organophosphate poisonings is
asphyxia. Contributing factors are the muscarinic
actions of bronchoconstriction and increased bronchial
secretions, nicotinic action leading to paralysis of
the respiratory muscles and depression of the
respiratory centre.
9.4.3 Neurological
9.4.3.1 Central nervous system
Depression of the respiratory centre
can occur. Accumulation of acetylcholine in
the CNS is believed to be responsible for the
tension, anxiety, restlessness, insomnia,
headache, emotional instability and neurosis,
excessive dreaming and nightmares, apathy,
and confusion that have been described after
organophosphorus pesticide poisoning.
Slurred speech, tremor, generalised weakness,
ataxia, convulsions, and coma are the other
CNS effects (Echobichon, 1996).
Changes have been associated with a
demonstrable depression of plasma or red cell
cholinesterases, and are manifest as
alterations in psychomotor performance,
memory, speech and mood, with features of
depression, anxiety, and irritability. Acute
confusional psychosis of short duration has
occurred following prolonged spraying of
diazinon by a farm worker (Minton & Murray,
1988).
Additional neurological investigations may be
helpful in elucidating cerebral disturbances:
electroencephalographic changes have occurred
in organophosphate poisoning and have been
considered to represent a specific effect on
the mid-brain (Metcalf & Holmes, 1969);
computerized cerebral tomography may be of
use in the diagnosis and follow-up by
cholinesterase inhibitors as generalised
cerebral atrophy has been demonstrated (Pach
et al., 1987).
9.4.3.2 Peripheral nervous system
A few organophosphorus pesticides
(e.g. mipafox, leptophos, merphos,
trichlorphon, chlorpyrifos have produced
delayed and persistent neuropathy, apparently
unrelated to anticholinesterase action (Hayes
& Law, 1991). In man, the delay may be up to
4 weeks after the first exposure. The first
symptoms are often sensory, with tingling and
burning sensation in the limb extremities,
followed by weakness in the lower limbs and
ataxia. This progresses to a paralysis
which, in severe cases, affects the upper
limbs also. Children are less severely
affected than adults. Recovery is slow and
seldom complete in adults. With the passage
of time the clinical picture changes from a
flaccid to a spastic type of paralysis (WHO,
1986). This neuropathy, in the absence of a
history of acute poisoning, may need to be
distinguished from other neuropathies such as
that in the Guillan-Barré syndrome and
sub-acute combined degeneration (see also
section 11.1, merphos case history).
Electromyographic studies may be used to
confirm distal neuropathies and have helped
with the understanding of the functional
basis of this clinical
manifestation.
9.4.3.3 Autonomic nervous system
Both muscarinic and nicotiniceffects
may occur, depending on the severity of
poisoning (see table 9.1.1).
9.4.3.4 Skeletal and smooth muscle
Muscle fasciculations occur and may
be followed by profound weakness and
eventually flaccid paralysis. The cholinergic
nerve endings on smooth muscle and glands are
less susceptible than those on skeletal
muscle to blocking by an excess of
acetylcholine. Therefore, in poisoning,
bronchospasm, cramping of the intestinal
muscles, and excessive secretions often
persist after weakness of the voluntary
muscles have become severe. Contraction of
the smooth muscle of the bladder and tenesmus
may also occur (Gallo & Lawryk, 1991).
Rhabdomyolysis is a well-known complication
of severe poisonings and appears to be also
relatively frequent in severe
organophosphorus pesticide intoxications. In
the acute phase this may cause acute renal
failure and in later stages paresis if not
treated correctly.
9.4.4 Gastrointestinal
Gastrointestinal manifestations are usually the
first to appear after ingestion and some of them maybe
due to local anti cholinesterase action in the
gastrointestinal tract. These symptoms include
increased gastrointestinal tone and peristalsis.
Nausea, vomiting, abdominal cramps, diarrhoea,
tenesmus, and involuntary defecation may
develop.
9.4.5 Hepatic
In poisonings by parathion and by a wide range
of unrelated compounds, serum creatinine, creatinine
phosphokinase, and serum alanine aminotransferase are
frequently elevated. The fact that lactate
dehydrogenase (LDH) and serum aspartate
aminotransferase do not undergo a parallel change, and
that creatinine occurs almost exclusively in the
muscles, suggest that the striated muscles undergo
hypoxic damage during poisoning and exclude
substantial liver involvement. However, temporary
liver damage (increased urinary urobilinogen, or
delayed excretion of bromosulphothalein) may occur
(Gallo & Lawryk, 1991).
9.4.6 Urinary
9.4.6.1 Renal
Acute renal insufficiency has been
described in one patients exposed to
malathion spray (Reynolds, 1996.).
Rhabdomyolysis is a well-known complication
of severe poisonings and appears to be also
relatively frequent in severe
organophosphorus pesticide intoxication,
including diazinon. In the acute phase
thismay cause acute renal failure and in
later stages paresis if not treated correctly
(Abend et al., 1994).
9.4.6.2 Others
Symptoms may include strangury and
also frequent and involuntary urination due
to contraction of the smooth muscle of the
bladder.
9.4.7 Endocrine and reproductive systems
Animal studies have shown that radioactive
parathion passes the placental barrier (Villeneuve et
al., 1972). In animal feeding studies, low dietary
levels of parathion did not affect reproduction;
however, at higher dietary levels approaching those
dangerous to adults, litters are produced but the
young may die (Gallo & Lawryk, 1991). The greater
susceptibility of weanlings is thought to be due to
their poorly developed microsomal enzymes and also to
a great inherent susceptiblity of the young brain
(Benke & Murphy, 1975).
Transient hyperglycaemia and glycosuria are often
found in severe organophosphorus insecticide poisoning
(Namba et al., 1971).
Pancreatitis after ingestion of organophosphorus
pesticides may be painless and terminate fatally,
although all children in one study had a complete
recovery (Ellenhorn et al., 1997).
9.4.8 Dermatological
Local effects of dermal exposure include
localised sweating and contact dermaitis. It may be
associated with fasciculations at the site of contact
(Reichert et al., 1978). (see also Section 9.4.13
Allergic reactions).
9.4.9 Eye, ears, nose, throat: local effects
Exposure to organophosphorus pesticides can
have local effects on the smooth muscles of the eyes
causing early miosis and blurred vision due to spasm
of accommodation, and also conjunctivitis and
keratitis. The secretory glands of the respiratory
tract, as well as the smooth muscles of the eyes may
be affected by minimal inhalational exposure to the
organophosphates leading to watery nasal discharge and
hyperemia. Acute rhinitis and pharyngitis can also
occur (Ecobichon, 1996).
9.4.10 Haematological
Blood coagulation abnormalities have been
described in patients poisoned with parathion (von
Kaulla & Holmes, 1961) including both hypo- or
hyper- coagulability, with prolonged or shortened
prothrombin times respectively. However, because of
the low incidence of these findings (< 1.2%), it is
unlikely that these changes are of clinical
significance.
9.4.11 Immunological
Some deficiency in immune responses has been
reported in animals dosed with quantities of
organophosphorus pesticides that depressed
acetylcholinesterase levels, but not at doses that did
not affect acetylcholinesterase (WHO, 1986).
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
Metabolic disturbances may occur in
more severe cases. Metabolic acidosis may
occur in severe organophosphorus
poisonings.
9.4.12.2 Fluid and electrolyte disturbances
Electrolyte and fluid imbalance may
occur following vomiting and diarrhoea
associated with organophosphorus pesticide
poisoning. Hypokalaemia is common in
organophosphorus poisoning.
9.4.12.3 Others
No data available.
9.4.13 Allergic reactions
Allergic contact sensitivity has been reported
with malathion exposure (Milby & Epstein, 1964). Other
sporadic cases of contact dermatitis with various
organophosphates have also been described; however,
these appear to reflect individual sensitivities and
are not representative of the usual clinical picture
of organophosphorus pesticide exposure (Gallo &
Lawryk, 1991).
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
Animal studies have shown that
organophosphorus pesticides can cross the placental
barrier, thus posing potential risk to the foetus;
weanlings may also be at risk due to their poorly
developed microsomal enzyme systems (Gallo &
Lawryk,1991).
One frequently unrecognised mechanism for the fall in
plasma cholinesterase activity is pregnancy. Studies
in healthy women demonstrated that cholinesterase
levels fall in the first trimester of pregnancy (range
17 to 46%), but they return to normal levels by the
third trimester. No mechanism has been given for this
phenomenon; however, this fact should be considered
when there is an unexplained cholinesterase drop
(Howard et al., 1978).
9.5 Others
Intermediate Syndrome
This occurs occasionally in patients who have not needed
ventilation as well as patients who have been disconnected
from a ventilator early because their condition has appeared
to improve after a period of therapy and artificial
respiration. It is expressed as a sudden loss of respiratory
ability associated with profound weakness of certain
respiratory and neck muscles. The syndrome was originally
seen following the ingestion of highly lipophilic
organophosphorus pesticide-compounds, such as fenthion, but
it is not confined to a few distinct compounds (De Bleecker
et al., 1993). If not immediately fatal, the condition
usually regresses within a few days of re-intubation
(Senanayake and Karalliedde, 1987; 1992). The effect may be
an outcome of prolonged nicotinic cholinergic stimulation
causing functional paralysis of neuromuscular transmission
(Besser et al, 1989) followed by local necrotic damage at the
motor endplate (Dettbarn, 1984) and skeletal muscle (Bright
et al, 1991; Karalliedde & Henry, 1993).
9.6 Summary
10. MANAGEMENT
10.1 General principles
Treatment of organophosphorus pesticide poisoning
should begin with decontamination and resuscitation if
needed. Decontamination is vital in reducing the dose of the
pesticide absorbed, but care must be taken not to contaminate
others, such as medical and paramedical workers. In the case
of ingestion, lavage can be performed, and activated charcoal
administered. The patient should be observed carefully
during the early stages of treatment because respiratory
arrest may occur.
Phenothiazines, parasympathomimetics and antihistamines are
contraindicated since they have anticholinesterase activity
and may potentiate organophosphorus pesticide toxicity.
Without possibility for artificial ventilation, central
nervous system depressants (e.g., opiates) should be avoided
since they may increase the likelihood of respiratory arrest
(Ellenhorn et al., 1997).
Solvent vehicles and other components of the formulated
organophosphorus pesticide may complicate the clinical
picture and should be taken into consideration.
10.2 Life-supportive procedures and symptomatic/specific
treatment
Supportive measures should be directed towards the
cardiorespiratory system with particular emphasis on
maintenance of ventilation, cardiac rhythm and blood
pressure; the removal by suction of respiratory and oral
secretions which may cause respiratory distress; and the
oxygenation of the patient. Respiratory arrest may be a
feature of organophosphate poisoning (Minton & Murray, 1988).
When assisted ventilation is required and a neuro-muscular
blocker is needed, the ganglion blocker, suxamethonium, is to
be avoided because undue sensitivity to this agent may lead
to prolonged respiratory paralysis (Seldon & Curry, 1987).
Suxamethonium is normally metabolised rapidly by
pseudocholinesterase (Gilman et al., 1985); hence, an
alternative neuromuscular blocking agent should be used (e.g.
pancuronium bromide).
Organophophorus pesticide poisoning can be treated with
atropine and oximes (see section 10.6).
Severely poisoned patients disconnected from the ventilator
when the general condition improves, must be carefully
watched for rapid deterioration and development of the
Intermediate Syndrome (see section 9.5) during the following
few days in the Intensive Care Unit.
Seizures should be treated with diazepam as follows:
Adults: 5 to 10 mg intravenously (IV) slowly over three
minutes which may be repeated every 10 to 15 minutes (maximum
30 mg).
Children: 0.2 to 0.3 mg/kg intravenously (IV) slowly over
three minutes (maximum 5 mg in children between one month and
five years old; maximum 10 mg in children five years old and
over).
Some organophosphorus pesticides may cause a delayed
peripheral neuropathy. There is no specific therapy for this
condition except for symptomatic measures; e.g.,
physiotherapy.
10.3 Decontamination
Ingested organophosphates should be removed by early
gastric aspiration and then lavage, with protection of the
airway because they are mostly dissolved in aromatic
hydrocarbons; this may be the best remedy in unconscious
patients. Gastric lavage is most effective within 30 minutes
of ingestion (but might be still effective up to 4 hours post
ingestion) as organophosphates are rapidly absorbed from the
gastrointestinal tract. Do not induce vomiting. In the
case of ingestion, gastric aspiration followed by lavage
should be performed, preferably within 1 hour.-
Administration of oral activated charcoal, in conventional
doses, may also be considered for reducing further absorption
of some organophosphorus pesticides (Haddad & Winchester,
1983; WHO, 1986). If poisoning has occurred by inhalation,
the patient should be removed from the source of exposure and
given oxygen; the rescuer should first take adequate
precautions.
Dermal exposure may be managed by removing and discarding
contaminated clothing (particularly leather which absorbs
pesticides) into sealed bags and repeated vigorous washing of
exposed skin with soap and plenty of warm water. Delayed
inadequate washing with ordinary soap and water removed only
50 to 70% of the radiolabelled parathion (Fredrikkson, 1961).
Special attention should be given to washing in skin creases,
around the ears, and the external auditory canals, around the
umbilicus and genitalia and under the nails (AAP, 1983).
Ocular contamination should be managed by continuous
irrigation of the affected eye with clean water for 15 to 20
minutes. Contact lenses should be removed and irrigated with
soap and water.
10.4 Enhanced Elimination
Elimination techniques have not been effective in the
treatment of organophosphorus pesticide poisoning.
10.5 Antidote treatment
10.5.1 Adults
Depending on the severity, organophosphorus
pesticide poisoning can be treated with:
(a) atropine, which is the antidote of choice and is
useful in reversing the muscarinic features;
(b) oximes, which reactivate cholinesterases inhibited
by organophosphorus pesticides.
Atropine acts as a physiological antidote by
competitively blocking the action of acetylcholine at
muscarinic receptors, and will reverse the excessive
parasympathetic stimulation which results from
acetylcholinesterase inhibition. A trial dose of
atropine should be instituted on clinical grounds when
one suspects organophosphate insecticide poisoning.
The fact that large doses of atropine can be given
without observable adverse effects is diagnostic of
organophosphorus pesticide poisoning.
Oxime reactivators (e.g., pralidoxime, obidoxime)
specifically restore cholinesterase activity. The
treatment should be administered within 24 to 48 hours
of poisoning since it is ineffective as an antidote
once "ageing" of phosphorylated cholinesterase
enzymes, with irreversible loss of function, has
occurred. The timing of administration, however, is
controversial (see section 10.7).
If absorption, distribution, and metabolism are
thought to be delayed for any reasons, oximes can be
administered for several days after poisoning.
Effective treatment with oximes reduced the required
dose of atropine.
Atropine
An initial trial dose of atropine, 1 to 2 mg (0.05
mg/kg) intravenously (IV), should be given, and then
repeated every five to ten minutes if there is no
observable adverse effect. Atropine may then be
repeated or increased in increments at 15 to 30 minute
intervals until the patient demonstrates signs of
atropinisation. Atropine in doses of 0.5 mg/kg per
hour may be necessary in extreme cases, sometimes by
continuous infusion; total daily doses up to several
hundred milligrams may be necessary during the first
few days of treatment.
The dose and the frequency of atropine varies with
each patient, but the patient should remain fully
atropinised (signs include dilated pupils, dry mouth,
skin flushing). Repeated evaluations of the quantity
of the secretions through regular auscultation of the
lungs is the only adequate measure of atropinization
in the severely poisoned patient.
Precautions: cyanotic patients should be oxygenated
and, if necessary, intubated at the same time that
atropine is administered to avoid ventricular
tachyarrhythmias. Patients should be weaned slowly
from atropine, particularly if they have had atropine
for several days.
Adverse effects: possible hypersensitivity to
cholinergic stimulation (tremors, rigidity) after
prolonged atropine therapy.
Oximes
Pralidoxime chloride, methylsuphate or mesylate should
be administered in a dose of 500 mg/h, continuously
maintained until clinical improvement is obtained, or
30 mg/kg body weight bolus intravenously (IV) over 4
to 6 hours or 8 to 10 mg/kg/h intravenously (IV) until
full recovery occurs (Ellenhorn et al., 1997).
Precautions and contraindications: the iodide salt of
pralidoxime should no longer be used because of the
risk of cardiac arrest. Pralidoxime iodide also
causes iodism.
Obidoxime: the adult dose is usually 250 mg given by
slow intravenous(IV)injection followed by continuous
infusion of 750 mg/24h (0.4mg/kg/h) to reach plasma
concentrations of 10-20 Fmol/l. intramuscular (IM)
dosing is possible when the IV route is inaccessible.
Concerning the dosage of oxime, it is essential to
adjust the appropriate plasma concentration, i.e. for
pralidoxime 20 to 40 mg/L and for obidoxime about 4
mg/L. This concentration is usually attained by a
daily dose of 10 to 15 g P2S or PAMCl and 0.75 to 1.0g
obidoxime, respectively, either given divided in 4 to
6 single bolus doses or, preferably, by continuous
intravenous infusion, following the first loading dose
(2 g pralidoxime and 0.25g obidoxime, respectively).
It is essential for the oxime treatment to be
continued until full clinical recovery (usually 2 to 4
days). There are no published data concerning the
duration and safety of uses. The administering
physician is advised to monitor closely the liver
function, with a view to better understanding possible
hepatoxicity, particularly with obidoxime.
10.5.2 Children
Atropine
For diagnosis, use an intravenous (IV) dose of 0.015
mg/kg and watch for signs of atropinisation (dilated
pupils, dry or red skin, confusion, tachycardia,
fever, ileus) (Ellenhorn et al., 1997).
For a therapeutic intravenous (IV) dose in symptomatic
patients, use 0.015 to 0.05 mg/kg every 15 minutes as
needed (Ellenhorn et al., 1997).
Oximes
The dose of Obidoxime is 3 to 6 mg/kg slowly
administered intravenously (IV) over at least 5
minutes.
Pralidoxime chloride, methylsuphate or mesylate should
be administered in a dose of 25 mg/kg IV for 15 to 30
minutes, folowed by a continuous infusion of 10 to 20
mg/kg/h. The therapy can continue for 18 hours or
longer, depending on the clinical status (Ellenhorn et
al., 1997).
10.6 Management discussion
Main alternatives or controversies
The usefulness of gastric lavage after four hours of
ingestion and the effectiveness of activated charcoal for gut
decontamination remain to be demonstrated conclusively. The
use of emetics may be dangerous due to possible aspiration of
the solvent. Whole bowel irrigation has not been
demonstrated to be of value and may not be practicable for
severely poisoned patients in coma or on a ventilator.
Haemoperfusion is not considered to be generally effective in
the management of organophosphorus poisonings.
Atropine is the therapeutic agent of choice for controlling
the muscarinic features of organophosphorus pesticide
poisoning and should be carefully dosed, according to
bronchial and other hypersecretions as well as heart rate to
maintain mild atropinisation Although there are no
controlled clinical trials, oxime therapy is considered
beneficial, in combination with atropine and other supportive
treatment. Oximes are ineffective if the OP-AchE complex is
aged. Therefore, in poisoning with OP where ageing occurs
relatively rapidly, e.g. dimethyl compounds (halftime of
ageing 3-4 h) oxime treatment has to be started not later
then 12 hours after exposure to be effective. High
persisting concentrations of the poison in the body prevent
net reactivation by reinhibition of the reactivated enzyme.
Nonetheless in the poisoning with OP with slow ageing
potential as diethyl OP (halftime of ageing about 30 h) rapid
initiation of oxime therapy and continous infusion is
indicated even at persisting poison in the body and initially
lacking reactivation. After the concentration of the poison
decreases in these cases, net reactivation can be expected
even 1 week after poisoning.
Differences between countries
While health care in developing countries may be accessible
to organophosphorus pesticide poisoned patients, intensive
care medical treatment facilities may not be. In these
latter circumstances, especially where the exposure is not
massive, antidotal therapy is particularly useful, in
addition to decontamination and supportive care and
appropriate management of organophosphorus pesticide-induced
convulsions, e.g. with benzodiazepines.
Identification of research needs
There appears to be a relationship between enzyme
reactivation and the disappearance of the muscarinic and
nicotinic features, i.e. improvement in the clinical
condition of the patient, provided that there are no
complications. A reliable, simple and cheap method should be
established for measuring AChE activity in red blood cells.
Such a method, using non sophisticated equipment would be
useful for all countries.
Although clinical observations indicate a possible value of
bicarbonate in organophosphorus pesticide poisoning
treatment, this needs further investigation both in animal
experiments and clinical studies.
Further research is required concerning the therapeutic and
adverse effects of the oximes in organophosphorus pesticide
poisonings.
There is a clear need for systematic collection of harmonised
data on organophosphorus pesticide poisoning cases, including
long-term follow-up, with a view to comparing cases,
situations and treatment regimens, and also to pool data on
exposure to a particular substance. There is also a need for
a universally agreed severity grading system for reporting
cases. It would also be useful to consider developing
criteria for predicting outcome which takes into
consideration the organophosphorus pesticide, the dose, and
clinical features, with a view to identifying the optimum
treatment procedure for a particular case. This work is
being undertaken by the IPCS and its partners in developing a
severity grading, and case data harmonisation and collection
system, which should be further promoted.
Further research is needed to better understand the
Intermediate Syndrome, as well as the longer-term
neurological and other sequelae, and to relate these to the
biochemical and physiological evolution of organophosphorus
pesticide poisoning.
It is recommended that the health sector in each country make
appropriate plans for undertaking studies in follow-up of
major incidents involving exposure by organophosphorus
pesticides to population groups. International guidelines
for data collection should be developed in order to promote
comparability of data.
11. ILLUSTRATIVE CASES
11.1 Case reports from the literature
Child
Worrell (1975) as reported in Gallo & Lawryk (1991)
successfully treated a 2-year-old boy who weighed 13.6 kg,
poisoned by diazinon, with a total of 707.2 mg
atropineadministered over a period of 19 days. The boy
received 32.5 mg during the first 12 hours; the largest
single dose was 15 mg.
Adults, animals, oral ingestion
Flour contaminated with carbophenthion was used to make
tortillas which were subsequently eaten by seven members of a
family. Four to six hours after ingestion symptoms appeared,
ranging from nausea and vomiting in one patient who did not
need to be admitted, to 4 patients who became comatose and
were hospitalised; one severely poisoned patient remained
critically ill for 4 days, even though he received 66 mg
atropine and 8 g pralidoxime before he regained
consciousness; all patients fully recovered within 6 days.
The family pets fed leftover tortillas fared worse; eight
chickens, one dog and one cat died (Older & Hatcher,
1969).
Adult dermal exposure
A 19-year old man accidentally splashed about 570 mL liquid
emulsion concentrate of monocrotophos on to his bare chest
and arms during a transfer operation. He tried to
decontaminate himself by washing the exposed area, but he did
not remove any clothing. Twenty-eight hours after exposure,
he had muscle weakness and blurred vision, followed by chest
pains and "blackouts". He was hospitalised 38 hours
postexposure; on admission he was vomiting, pale,
perspiring, confused, and miotic. Treatment with atropine and
pralidoxime led to a marked recovery within 48 hours and he
was essentially symptom-free on the third day. However, as a
precaution, pralidoxime was continued through day 8. He was
discharged on day 10 but continued to have headaches and some
numbness of the head and arms. Red cell cholinesterase
activity took 8 weeks to return to the normal range (Simson
et al., 1969). This case demonstrates the need for thorough
decontamination (the report gives no indication of later
attempts to decontaminate either pre- or post- admission).
The long delay between exposure and the onset of serious
symptoms may be been due to factors such as slow dermal
absorption and poor decontamination.
Adult, dermal exposure
A similar exposure involved a 28-year-old man accidentally
exposed to a 72% formulation of liquid merphos. Not only did
he fail to adequately decontaminate himself, but he had
further exposures over the next 2 days. Four days
postexposure he noted weakness in his upper limbs which
gradually progressed to paralysis of the limbs, and 2 days
later he presented to hospital. He did not have the
classical signs of anticholinergic poisoning. Substantial
doses of atropine and pralidoxime chloride were given, but
there was no improvement on side effects. Although vital
capacity, arterial blood gases, plasma cholinesterase level,
and other measured laboratory findings were normal, he was
totally unable to move his extremities but retained cutaneous
sensation. Electromyography showed decreased voltage of
muscle action, potentials, delayed conduction capacity in
motor nerve fibres, increased insertional activity, and
denervation potentials. He received supportive care and
intense physiotherapy. Six weeks postexposure, he was
discharged but had residual weakness and required a walking
aid; 14 weeks after discharge he had recovered completely
(Fisher, 1977). This case is typical of delayed neuropathy
following exposure to some organophosphates including merphos
(see section 9.4.3.2). It has been claimed that EMG studies
give sensitive indications of exposure to organophosphorus
pesticides, even in situations where blood cholinesterase
activity has returned to normal levels; however, there is
still considerable doubt about the validity of some published
studies (WHO, 1986).
Adult, oral ingestion
A 26-year-old farmer was found 2 hours after swallowing
methidathion. Seven hours post-ingestion, gastric lavage was
performed and he was treated with substantial doses of
atropine and obidoxime over several days. Artificial
respiration was required until day 15. Deep coma was a
feature of the early illness, as well as high fever, and
jaundice (no cause assigned) which occurred from days 4 to 8.
Obidoxime treatment was stopped after day 3 "due to its known
hepatotoxicity" but reinstituted on days 7 to 8, during which
time serum bilirubin increased. Follow-up examinations
several months after discharge revealed no delayed neuropathy
or other abnormality (Teitelman et al., 1975). It is
interesting to note that De Kort et al. (1988) have reported
that after prolonged use of obidoxime, transaminase values
may increase. This is apparently reversible, and whether it
indicates actual liver damage is uncertain. Thus, the
prolonged use of high-dose obidoxime in organophosphorus
insecticide treatment should be accompanied by regular
monitoring of liver function.
Adult, parenteral exposure
A 24-year old white male injected approximately 3 mL of 50%
malathion (1.8 g) intravenously into his right forearm
approximately 1 hour prior to seeking medical attention. He
had pinpoint pupils and muscular fasciculations and was given
atropine 5 mg. He was admitted to hospital 2 hour
postexposure and complained of headache, nausea, and
increased urination. No respiratory difficulty was observed.
There were bowel sounds and he was having hallucinations and
delusions. During the course of his 2-day stay, pralidoxime
1 g and atropine 7 mg, were administered. He was transferred
to a psychiatric hospital (Lyon et al., 1987).
12. ADDITIONAL INFORMATION
12.1 Specific preventive measures
It is essential that persons intending to use
organophosphorus pesticides are provided with adequate health
precautions and other safety instructions prior to usage.
This information should be provided by the manufacturer in
the form of either an information leaflet or a label attached
to the pesticide container.
Protective clothing is important. Organophosphorus
pesticides can be dermally absorbed, resulting in poisoning.
The risk is greatest in hot weather when the user is
sweating. Protective measures may include a long-sleeved
shirt, long trousers or overalls, and a hat of some sort. The
more toxic organophosphorus pesticides will require gloves,
waterproof outerwear (preferably made of heavy PVC), and
rubber boots. The label should list these details.
Clothing worn during spraying should be washed daily after
use. Contaminated clothing should be washed separately from
the general wash to avoid cross-contamination. When working
with liquid concentrates, there is often a danger that they
will splash the eyes. This not only can damage the eyes, but
also can allow a significant amount of the chemical to be
absorbed into the bloodstream. Simple goggles or a face
shield will protect against this danger. Eye protection is
most important if contact lenses are worn, because the
chemical may seep in behind the lenses. The lenses must be
removed before the eyes are washed, and in the time it takes
to remove them, serious damage can occur. With some
pesticides, a respirator may be required. The label will
specify when this is necessary. The correct canister or
cartridge must be used.
Greater precautions are necessary when mixing the
concentrated material than when spraying. Measurements
should be accurate and spillages should be cleaned up
promptly. Mix the chemicals carefully, using a stick or
paddle. Ensure that there is minimal skin exposure by
wearing gloves. If any concentrate is spilled on the skin,
wash it off as soon as possible.
The hazards of spraying increase dramatically on windy days
because there is an increased risk of inhaling spray drift or
contaminating the skin. Also, the risk of drift on to other
properties or crops is increased.
Always wash hands before eating, drinking or smoking. After
spraying, shower and change clothing.
By preference, all chemicals should be stored in a locked
shed, out of the reach of children and animals. Chemicals
should also be kept away from work areas and separate from
other stored materials such as animal foods. Always leave
chemicals in their original containers. If they must be
transferred to another container, ensure that it is one not
normally used for food or drink. This secondary container
should be labelled properly and be of a variety that is not
likely to leak.
Following spillage, empty any of the product remaining in
damaged/leaking container(s) into a clean empty container(s),
which should then be tightly closed and suitably labelled.
If it is a liquid product, prevent it from spreading or
contaminating other products, vegetation, or waterways by
building a barrier of the most suitable available material,
e.g., earth or sand. Sweep up the spillage with sawdust,
sand, or earth (moisten the powders), and place it in a
suitable container for disposal. Decontamination and
clean-up procedures utilise the instability of
organophosphorus pesticide products with alkali. The
following procedure has been developed for decontaminating
spills of organophosphorus pesticides (Shell, 1982):
Apply a 10% sodium carbonate (washing soda solution) to the
contaminated area, brush well in, and leave for at least 8
hours.
Absorb into sawdust, sand, or earth and then rinse.
Contaminated sawdust, sand, earth, and containers should be
burnt in a proper incinerator. When no incinerator is
available, bury in an approved dump or in an area where there
is no risk of contamination of surface water. Before
burying, mix liberally in sodium carbonate (washing soda)
crystals to hydrolyse the product.
It is essential that any personnel involved in these
procedures be adequately protected before beginning clean-up
operations.
Empty containers must be disposed of carefully, so as to
ensure that rivers, streams, and other water sources are not
polluted, and that people or animals are not exposed to
residues of concentrate. Crushing or burning, followed by
burial, is generally the best method.
Workers involved in harvesting crops must adhere carefully to
re-entry standards which have been set in order to prevent
the asymptomatic depression of cholinesterase and the
possibility of the development of an insidious, but low-level
chronic intoxication syndrome.
For workers who are exposed on a regular basis to
organophosphorus pesticides, it is advisable for them to have
a pre-employment examination to determine their baseline
cholinesterase levels. These tests should be undertaken on a
regular basis to determine whether exposure is occurring with
sub-clinical findings. When the red blood cell or plasma
cholinesterase falls below 25% of baseline levels, workers
should be taken off the job and should not return to work
until their cholinesterase levels return to normal.
12.2 Other
No data available.
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14. AUTHOR(S), REVIEWER(S), ADDRESS(ES), DATE (INCLUDING EACH UPDATE)
Authors: Dr W.A. Temple
National Toxicology Group
Otago University
Medical School
P.O.Box 913
Dunedin
New Zealand
Dr N.A. Smith
Pharmacy School
Otago University
P.O.Box 913
Dunedin
New Zealand
Tel: 64-3-4797244
Fax: 64-3-4770509
e-mail: wtemple@gandalf.otago.ac.nz
Date: 19 July 1989
Reviewer: London Poisons Unit
New Cross Hospital
Avonley Road
London SE14 5ER
United Kingdom
Tel: 44-71-9555095
Fax: 44-71-6392101
Date: 1989
Peer Review: Hamilton, Canada, 1989
Review:
Post JMPR, Working Group on Review PIMs on Pesticides,
Geneva, Switzerland, 26 September 1991
Update: Geneva, July 1994
Brazil, September 1994
Geneva, August 1996, AHP van Heijst
Cardiff, September 1996
Brazil, September 1997
Brazil, October 1999 (INTOX 11: Drs Dr L.
Szinicz, L. Karalliedde, Y. Ostapenko, Dr W.
Jonitz, M. Balali-Mood, A. Wong, J. Socrates
Lima)
Editor: Dr M.Ruse, March 1998
ANNEX
Organophosphorus Pesticides: Relevant Animal Data (LD50 for the
rat mg/kg bodyweight)
"Extremely Hazardous"
ORAL DERMAL
SOLIDS (S) LIQUIDS (L) SOLIDS (S) LIQUIDS (L)
5 mg/kg 20 mg/kg 10 mg/kg 40 mg/kg
Chlorvinohos (L) 10 mg/kg
Chlormephos (L) 7 mg/kg
Chlorthiophos (L) 9.1 mg/kg
Coumaphos (L) 7.1 mg/kg
Demephron -O and -S (L) 15 mg/kg
Demeton -O and -S (L) 2.5 mg/kg
EPN (S) 14 mg/kg
Ethopropos (L) 26 mg/kg
Fenamiphos (L) 15 mg/kg
Fensulfothion (L) 3.5 mg/kg
Fonofos (L) c 8 mg/kg
Leptophos (S) 50 mg/kg
Mephosfolan (L) 9 mg/kg
Mevinphos (L) 4 mg/kg
Parathion (L) 13 mg/kg
Parathion-methyl (L) 14 mg/kg
Phorate (L) 2 mg/kg
Phospholan (L) 9 mg/kg
Phosphamidon (L) 7 mg/kg
Prothoate (L) 8 mg/kg
Schradan (L) 9 mg/kg
Sulfotep (L) 5 mg/kg
TEPP (L) 1.1 mg/kg
Terbufos (L) c 2 mg/kg
Thionazin (L) 11 mg/kg
Organophosphorus Pesticides: Relevant Animal Data (LD50 for the
rat mg/kg bodyweight)
"Highly Hazardous"
ORAL
SOLIDS (S) LIQUIDS (L)
5 - 50 mg/kg 20 - 200 mg/kg
Azinphos ethyl (S)12 mg/kg
Azinphos methyl (S)16 mg/kg
Bromophos ethyl (L)71 mg/kg
Cadusofos (L)37 mg/kg
Carbophenythion (L)32 mg/kg
Crotoxyphos (L)74 mg/kg
Demeton-S-methyl (L)40 mg/kg
Demeton-S-methylsulphon (S) 37 mg/kg
Dichlorvos (L)56 mg/kg
Dicrotophos (L)22 mg/kg
Dioxathion (L)23 mg/kg
Edifenphos (L)150 mg/kg
ESP (L)105 mg/kg
Famphur (S)48 mg/kg
Fosmethilan (S)49 mg/kg
Heptenophos (L)96 mg/kg
Isazofos (L)60 mg/kg
Isofenphos (OIL) 28 mg/kg
Isothioate (L) 150 mg/kg
Isoxathion (L)112 mg/kg
Methamidophos (L)50 mg/kg
Oxydemeton-methyl (L)103 mg/kg
Pirimiphos-ethyl (L) 140 mg/kg
Propaphos (L) 70 mg/kg
Propetamphos (L) 106 mg/kg
Thiometon (OIL) 120 mg/kg
Triazophos (L) 82 mg/kg
Vamidothion (L) 103 mg/kg
Organophosphorus Pesticides: Relevant Animal Data
(LD50 for the rat mg/kg bodyweight)
"Moderately Hazardous"
ORAL
SOLIDS (S) LIQUIDS (L)
50 - 500 mg/kg 200 - 2000 mg/kg
Chlorpyrifos (S) 135 mg/kg
Cyanofenphos (S) 89 mg/kg
Cyanophos (L) 610 mg/kg
Dialifos (S) 145 mg/kg
Diazinon (L) 300 mg/kg
Dichlofenthion (L) 270 mg/kg
Dimethoate (S) c 150 mg/kg
Dioxabenzophos (S) 125 mg/kg
EPBP (OIL) 275 mg/kg
Ethion (L) 208 mg/kg
Etrimfos (L) 1,800 mg/kg
Fenchlorphos (L) 1,740 mg/kg
Fenitrothion (L) 503 mg/kg
Fenthion (L) 586 mg/kg
Formothion (L) 365 mg/kg
Methacrifos (L) 678 mg/kg
Naled (L) 430 mg/kg
Phenthoate (L) c 400 mg/kg
Phosalone (L) 120 mg/kg
Phosmet (S) 230 mg/kg
Phoxim (L) 1,975 mg/kg
Profenofos (L) 358 mg/kg
Prothiofos (L) 925 mg/kg
Pyraclofos (L) 237 mg/kg
Quinlphos (S) 62 mg/kg
Sulprofos (OIL) 130 mg/kg
Organophosphorus Pesticides: Relevant Animal Data
(LD50 for the rat mg/kg bodyweight)
"Slightly Hazardous"
ORAL
SOLIDS (S) LIQUIDS (L)
More than 500 mg/kg More than 2000 mg/kg
Acephate (S) 945 mg/kg
Azamethiphos (S) 1,010 mg/kg
Bromophos (S) c 1,600 mg/kg
Crufomate (S) 770 mg/kg
Malathion (L) c 2,100 mg/kg
Menazon (S) 1,950 mg/kg
Pirimiphos-methyl (L) 2,018 mg/kg
Pyridaphenthion (S) 769 mg/kg
Trichlorfon (S) 560 mg/kg
Organophosphorus Pesticides: Relevant Animal Data
(LD50 for the rat mg/kg bodyweight)
"Unlikely to Present an Acute Hazard"
SOLIDS (S) LIQUIDS (L)
Chlorphoxim (S) + 2,500 mg/kg
Chlorpyrifos-methyl (L) + 3,000 mg/kg
Ditalmifos (S) 5,660 mg/kg
Jodfenphos (S) 2,100 mg/kg
Temephos (L) 8,600 mg/kg
Tetrachlorvinphos (S) 4,000 mg/kg
Organophophorus insecticides: a general introduction
(EHC 63, 1986)