Dimefox
Encyclopedia
Dimefox is an organophosphorus
agent and a colourless liquid with a fishy odour. The structure consists of a central phosphate
atom
, which is connected to an oxygen
by a double bond. The phosphor
also binds to a fluor
atom (the leaving group which is most reactive) and two aminodimethyl groups. Dimefox was used as pesticide, but has been deemed obsolete or discontinued for use by the World Health Organisation. However, they do not guarantee that all commercial use of this compound ceased. But in most countries it is no longer registered for use as a pesticide.
Synthesis of organic phosphorus
compounds began around 1820 with the esterifications of alcohol
to form phosphoric acid
. Dimefox was first produced in 1940 by the group of Gerard Schrader in Germany. Schrader is most known for production of several warfare agents like sarin
and tabun
.
Although dimefox is generally considered to be very dangerous, there is little report of any incidents.
Dimefox is a relatively small molecule, with a small polar surface area. Therefore it is likely that the agent can easily pass through membranes. This means it can be absorbed through the skin, as well as it can be inhaled as a fume or an aerosol
. It can also pass through the blood brain barrier and exert it's effect throughout the whole body.
of acetylcholine
to acetic acid
and choline
. Acetylcholine
is a major neurotransmitter
in the central and peripheral nervous system
. It is solely disposed of by AChE, and it is the choline
that is taken back up by the presynaptical membrane.
AChE has in his active site a serine
that binds covalently to acetylcholine
by a nucleophilic attack on the carbonyl
carbon of acetylcholine
. The formed intermediate then releases choline from its active site. The enzyme is regenerated by a hydrolytic attack of water which releases acetic acid
.
Dimefox inhibits the function of AChE because its acts as an acetylcholine analogue, binding the active site serine
, whilst losing its fluoride group. The formation is very fast, but the regeneration of the enzyme by a hydrolytic attack is very slow. It is a matter of hours to days, opposed to that of acetylcholine, which occurs within a second. So the enzyme is rendered inactive, and acetylcholine accumulates at the synapses., However, the phosphotriesterases can, depending on the substrate, catalyse the hydrolysis of organophosphorus compounds.
Another route that can diminish the effect of dimefox is by butyrylcholinesterase
(BChE). This is a B-esterase that is secreted into plasma by the liver
. It can bind Dimefox and so protect AChe against the pesticide. There are many varieties of BChE due to genetic polymorphisms. This is reflected in the strength of their bond to Dimefox. This explains why some people with a less active variety of the enzyme
are more susceptible to Dimefox toxicity.
Furthermore, Dimefox is thought to induce a increased proliferation rate of cells. However, it is not genotoxic.. This suggests that Dimefox has mitogenic activity. Down regulation of the cyclin-dependent kinase inhibitor p21 gene by Dimfox may be connected to the observed mitogenic activity.
1. Acute cholinergic
crisis as a result of AChE inhibition. This inplies hyperstimulation of the muscarinic receptor, nicotinic receptor or both. Hyperstimulation of muscarinic receptor leads to bradycardia
, bronchoconstriction
, bronchorrhoea, hypotension
, increased gastrointestinal motility, abdominal cramps, miosis
and hyper salivation. Hyperstimulation of nicotinic receptors can result in hypertension, tachycardia
, fibrillation, fasciculation
and necrosis
of striated muscles. Hyperstimulation of both receptors can result in tremor, movement in coordination, seizures, central depression of respiration, coma and even death. In most cases death is caused by respiratory failure.
2. Intermediate syndrome (IMS)
3. Organophosphate-induced delayed neuropathy (OPIDN) that has been explained by the inhibition of neuropathy target esterase
.
4. Chronic organophosphate induced neuropsychiatric disorder (results from long-term low-level exposure).
There are a few antidotes against acute organophosphorus pesticides poisoning; the anticholinergic drug atropine
, cholinesterase-reactivating agents, oximes and anticonvulsant drugs benzodiazepines. The delayed neuropathy can unfortunately not be treated.,
Atropine
is the first choice drug in case of an organophosphorus pesticide poisoning. It antagonizes the physiological effects of the acetylcholine accumulation. Atropine is an antimuscarinic drug in the central nervous system
and blocks convulsions.,
Oximes, like trimedoxime (TMB-4), obidoxime
(LüH-6) and pralidoxime (PAM-2) must be administrated quickly after the poisoning and then leads to regeneration of acetylcholinesterase
. Tertiary oximes are able to pass the blood-brain barrier
, reactivate the AChE in the brain, and abolish convulsions. It acts in place of the serine
hydroxyl group in the enzyme and forms a complex with the organophosphorus moiety. The oxime proximally exerts a nucleophilic attack on the phosphorus of the enzyme inhibitor complex. Oxime is a reversible ligand which binds to cholinesterase either at the active site, at an allosteric site, or at both sites. As a result of this reaction, the oxime
binds to the organophosporus moiety, leading to the regeneration of the original acetylcholinesterase.,
Benzodiazepines, like diazepam
, potentiate the action of the inhibitory neurotransmitter γ-aminobutyric acid at its receptors. The main result of this is hyper polarization of neurons is that it makes them less susceptible to cholinergically-induced depolarization. Thereby the propagation of convulsions is stopped. Diazepam in specific reduces anxiety, restlessness and muscle fasciculations, terminating convulsions and reduces mortality when used in combination with atropine
and oxime
. Intoxication effects in general are better treated when the combinations of antidotes are administrated.
Organophosphorus
Organophosphorus compounds are degradable organic compounds containing carbon–phosphorus bonds , used primarily in pest control as an alternative to chlorinated hydrocarbons that persist in the environment...
agent and a colourless liquid with a fishy odour. The structure consists of a central phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
atom
Atom
The atom is a basic unit of matter that consists of a dense central nucleus surrounded by a cloud of negatively charged electrons. The atomic nucleus contains a mix of positively charged protons and electrically neutral neutrons...
, which is connected to an oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
by a double bond. The phosphor
Phosphor
A phosphor, most generally, is a substance that exhibits the phenomenon of luminescence. Somewhat confusingly, this includes both phosphorescent materials, which show a slow decay in brightness , and fluorescent materials, where the emission decay takes place over tens of nanoseconds...
also binds to a fluor
Fluor
Fluor Corporation is a publicly owned engineering, procurement, construction, and maintenance services organization. Fluor is headquartered in the Las Colinas area of Irving, Texas. The company employs more than 41,000 international employees and maintains offices in over 25 countries...
atom (the leaving group which is most reactive) and two aminodimethyl groups. Dimefox was used as pesticide, but has been deemed obsolete or discontinued for use by the World Health Organisation. However, they do not guarantee that all commercial use of this compound ceased. But in most countries it is no longer registered for use as a pesticide.
Discovery
Synthesis of organic phosphorus
Phosphorus
Phosphorus is the chemical element that has the symbol P and atomic number 15. A multivalent nonmetal of the nitrogen group, phosphorus as a mineral is almost always present in its maximally oxidized state, as inorganic phosphate rocks...
compounds began around 1820 with the esterifications of alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
to form phosphoric acid
Phosphoric acid
Phosphoric acid, also known as orthophosphoric acid or phosphoric acid, is a mineral acid having the chemical formula H3PO4. Orthophosphoric acid molecules can combine with themselves to form a variety of compounds which are also referred to as phosphoric acids, but in a more general way...
. Dimefox was first produced in 1940 by the group of Gerard Schrader in Germany. Schrader is most known for production of several warfare agents like sarin
Sarin
Sarin, or GB, is an organophosphorus compound with the formula [2CHO]CH3PF. It is a colorless, odorless liquid, which is used as a chemical weapon. It has been classified as a weapon of mass destruction in UN Resolution 687...
and tabun
Tabun
Tabun may refer to:* Tabun Cave, a cave near Tabun, Israel where remains of Neanderthal Man were found.* A tabun oven, a clay oven used to make tabun bread...
.
Incidents
Although dimefox is generally considered to be very dangerous, there is little report of any incidents.
Absorption into the body
Dimefox is a relatively small molecule, with a small polar surface area. Therefore it is likely that the agent can easily pass through membranes. This means it can be absorbed through the skin, as well as it can be inhaled as a fume or an aerosol
Aerosol
Technically, an aerosol is a suspension of fine solid particles or liquid droplets in a gas. Examples are clouds, and air pollution such as smog and smoke. In general conversation, aerosol usually refers to an aerosol spray can or the output of such a can...
. It can also pass through the blood brain barrier and exert it's effect throughout the whole body.
Toxicodynamics
The primary target of Dimefox is the enzyme acetylcholine esterase(AChE). This enzyme is responsible for the hydrolysisHydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
of acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
to acetic acid
Acetic acid
Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...
and choline
Choline
Choline is a water-soluble essential nutrient. It is usually grouped within the B-complex vitamins. Choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation....
. Acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
is a major neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
in the central and peripheral nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
. It is solely disposed of by AChE, and it is the choline
Choline
Choline is a water-soluble essential nutrient. It is usually grouped within the B-complex vitamins. Choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation....
that is taken back up by the presynaptical membrane.
AChE has in his active site a serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
that binds covalently to acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
by a nucleophilic attack on the carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
carbon of acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
. The formed intermediate then releases choline from its active site. The enzyme is regenerated by a hydrolytic attack of water which releases acetic acid
Acetic acid
Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...
.
Dimefox inhibits the function of AChE because its acts as an acetylcholine analogue, binding the active site serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
, whilst losing its fluoride group. The formation is very fast, but the regeneration of the enzyme by a hydrolytic attack is very slow. It is a matter of hours to days, opposed to that of acetylcholine, which occurs within a second. So the enzyme is rendered inactive, and acetylcholine accumulates at the synapses., However, the phosphotriesterases can, depending on the substrate, catalyse the hydrolysis of organophosphorus compounds.
Another route that can diminish the effect of dimefox is by butyrylcholinesterase
Butyrylcholinesterase
Butyrylcholinesterase is a non-specific cholinesterase enzyme that hydrolyses many different choline esters...
(BChE). This is a B-esterase that is secreted into plasma by the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
. It can bind Dimefox and so protect AChe against the pesticide. There are many varieties of BChE due to genetic polymorphisms. This is reflected in the strength of their bond to Dimefox. This explains why some people with a less active variety of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
are more susceptible to Dimefox toxicity.
Furthermore, Dimefox is thought to induce a increased proliferation rate of cells. However, it is not genotoxic.. This suggests that Dimefox has mitogenic activity. Down regulation of the cyclin-dependent kinase inhibitor p21 gene by Dimfox may be connected to the observed mitogenic activity.
Symptoms
1. Acute cholinergic
Cholinergic
The word choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin...
crisis as a result of AChE inhibition. This inplies hyperstimulation of the muscarinic receptor, nicotinic receptor or both. Hyperstimulation of muscarinic receptor leads to bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
, bronchoconstriction
Bronchoconstriction
Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath. Bronchoconstriction can also be due to an accumulation of thick mucus....
, bronchorrhoea, hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, increased gastrointestinal motility, abdominal cramps, miosis
Miosis
Miosis is the constriction of the pupil of the eye to two millimeters or less...
and hyper salivation. Hyperstimulation of nicotinic receptors can result in hypertension, tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, fibrillation, fasciculation
Fasciculation
A fasciculation , or "muscle twitch", is a small, local, involuntary muscle contraction and relaxation visible under the skin arising from the spontaneous discharge of a bundle of skeletal muscle fibers...
and necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
of striated muscles. Hyperstimulation of both receptors can result in tremor, movement in coordination, seizures, central depression of respiration, coma and even death. In most cases death is caused by respiratory failure.
2. Intermediate syndrome (IMS)
3. Organophosphate-induced delayed neuropathy (OPIDN) that has been explained by the inhibition of neuropathy target esterase
Neuropathy target esterase
Neuropathy target esterase also known as patatin-like phospholipase domain-containing protein 6 is a neuropathy target esterase enzyme that in humans is encoded by the PNPLA6 gene....
.
4. Chronic organophosphate induced neuropsychiatric disorder (results from long-term low-level exposure).
Detoxification and treatment
There are a few antidotes against acute organophosphorus pesticides poisoning; the anticholinergic drug atropine
Atropine
Atropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...
, cholinesterase-reactivating agents, oximes and anticonvulsant drugs benzodiazepines. The delayed neuropathy can unfortunately not be treated.,
Atropine
Atropine
Atropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...
is the first choice drug in case of an organophosphorus pesticide poisoning. It antagonizes the physiological effects of the acetylcholine accumulation. Atropine is an antimuscarinic drug in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
and blocks convulsions.,
Oximes, like trimedoxime (TMB-4), obidoxime
Obidoxime
Obidoxime is a member of the oxime family used to treat nerve gas poisoning. Oximes are drugs known for their ability to reverse the binding of organophosphorus compounds to the enzyme acetylcholinesterase ....
(LüH-6) and pralidoxime (PAM-2) must be administrated quickly after the poisoning and then leads to regeneration of acetylcholinesterase
Acetylcholinesterase
"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...
. Tertiary oximes are able to pass the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
, reactivate the AChE in the brain, and abolish convulsions. It acts in place of the serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
hydroxyl group in the enzyme and forms a complex with the organophosphorus moiety. The oxime proximally exerts a nucleophilic attack on the phosphorus of the enzyme inhibitor complex. Oxime is a reversible ligand which binds to cholinesterase either at the active site, at an allosteric site, or at both sites. As a result of this reaction, the oxime
Oxime
An oxime is a chemical compound belonging to the imines, with the general formula R1R2C=NOH, where R1 is an organic side chain and R2 may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted oximes form a closely related family of compounds...
binds to the organophosporus moiety, leading to the regeneration of the original acetylcholinesterase.,
Benzodiazepines, like diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
, potentiate the action of the inhibitory neurotransmitter γ-aminobutyric acid at its receptors. The main result of this is hyper polarization of neurons is that it makes them less susceptible to cholinergically-induced depolarization. Thereby the propagation of convulsions is stopped. Diazepam in specific reduces anxiety, restlessness and muscle fasciculations, terminating convulsions and reduces mortality when used in combination with atropine
Atropine
Atropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...
and oxime
Oxime
An oxime is a chemical compound belonging to the imines, with the general formula R1R2C=NOH, where R1 is an organic side chain and R2 may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted oximes form a closely related family of compounds...
. Intoxication effects in general are better treated when the combinations of antidotes are administrated.
SAR: Structure Activity Relationship
With the DEREK software, Dimefox is analysed for its toxicity. The agent is tested for both mammalian and bacterial toxicity. In bacteria it isn’t believed to be toxic. On the other hand, cholinesterase inhibition in mammals is plausible. This is because Dimefox is an organophosphorus compound.Toxicity: Dose and response
The severity of the intoxication depends on the dose and the way of exposure. This table shows the critical values and their effects for some organisms.| Organism | Test Type | Route | Reported Dose (Normalized) | Effect | Source |
|---|---|---|---|---|---|
| cat | LD50 | oral | 2 mg/kg | Behavioral: coma, lungs, thorax -Respiration: respiratory stimulation Gastrointestinal: changes in structure or function of salivary glands | National Technical Information Service. Vol. PB158-508 |
| dog | LD50 | intravenous | 5 mg/kg | Behavioral: muscle contraction or spasticity Gastrointestinal: changes in structure or function of salivary glands and other changes | Journal of Pharmacology and Experimental Therapeutics. Vol. 112, Pg. 231-45. 1954. Studies on the toxicity and pharmacological actions of bis (dimethylamido) fluorophosphate (BFP). OKINAKA AJ, DOULL J, COON JM, DUBOIS KP. •• Link to PubMed |
| domestic animals – goat/sheep | LD50 | subcutaneous | 2 mg/kg | Behavioral: coma Gastrointestinal: changes in structure or function of salivary glands, lungs, thorax Respiratory: respiratory stimulation | National Technical Information Service. Vol. PB158-508 |
| frog | LD50 | parenteral | 1410 mg/kg | Peripheral nerve and sensation: flaccid paralysis without anesthesia (usually neuromuscular blockage)Behavioral: altered sleep time (including change in righting reflex, lungs, thorax Respiration: other changes | Archives Internationales de Pharmacodynamie et de Therapie. Vol. 124, Pg. 212-24. 1960. Feb 1. Studies on the effect of organophosphorus insecticides on amphibians. EDERY H, SCHATZBERG-PORATH G. •• Link to PubMed |
| guinea pig | LD50 | intraperitoneal | 2.5 mg/kg | – | Journal of Pharmacology and Experimental Therapeutics. Vol. 112, Pg. 231-45. 1954. Studies on the toxicity and pharmacological actions of bis (dimethylamido) fluorophosphate (BFP). OKINAKA AJ, DOULL J, COON JM, DUBOIS KP. •• Link to PubMed |
| guinea pig | LD50 | oral | 4 mg/kg | Behavioral: coma Gastrointestinal: changes in structure or function of salivary glands, lungs, thorax Respiration: respiratory stimulation | National Technical Information Service. Vol. PB158-508 |
| guinea pig | LD50 | subcutaneous | 2 mg/kg | Behavioral: coma Gastrointestinal: changes in structure or function of salivary glands, lungs, thorax Respiration: respiratory stimulation | National Technical Information Service. Vol. PB158-508 |
| monkey | LD50 | oral | 2 mg/kg | – | National Technical Information Service. Vol. PB158-508 |
| mouse | LD50 | intraperitoneal | 1.35 mg/kg | – | Journal of Agricultural and Food Chemistry. Vol. 13, Pg. 381, 1965. |
| mouse | LD50 | oral | 2 mg/kg | – | Bulletin of the Entomological Society of America. Vol. 12, Pg. 161, 1966 |
| mouse | LD50 | subcutaneous | 1 mg/kg | Behavioral: coma Gastrointestinal: changes in structure or function of salivary glands, lungs, thorax Respiration: respiratory stimulation | National Technical Information Service. Vol. PB158-508 |
| rabbit | LD50 | intravenous | 3 mg/kg | Behavioral: coma Gastronitestinal: changes in structure of salivary glands, lungs, thorax Respiration: respiratory stimulation | National Technical Information Service. Vol. PB158-508 |
| rabbit | LD50 | oral | 3 mg/kg | Behavioral: coma Gastrointestinal: changes in structure of salivary glands, lungs, thorax Respiration: respiratory stimulation | National Technical Information Service. Vol. PB158-508 |
| rabbit | LD50 | subcutaneous | 6 mg/kg | Behavioral: coma Gastrointestinal: changes in structure of salivary glands, lungs, thorax Respiration: respiratory stimulation | National Technical Information Service. Vol. PB158-508 |
| rat | LD50 | intraperitoneal | 5 mg/kg | – | AMA Archives of Industrial Hygiene and Occupational Medicine. Vol. 6, Pg. 9, 1952. |
| rat | LD50 | oral | 1 mg/kg | Behavioral: coma Gastrointestinal: changes in structure of salivary glands, lungs, thorax Respiration: respiratory stimulation | National Technical Information Service. Vol. PB158-508 |
| rat | LD50 | skin | 2 mg/kg | – | World Review of Pest Control. Vol. 9, Pg. 119, 1970. |
| rat | LD50 | subcutaneous | 0.3 mg/kg | – | - |