Toxicological Properties

Mechanism of Action
Toxicology Testing
Human Toxicity

Mechanism of Action

Chlorpyrifos is one of the many organophosphate insecticides. Like other organophosphates, chlorpyrifos' insecticidal activity is caused by the inhibition of the enzyme acetylcholinesterase which results in the accumulation of the neurotransmitter, acetylcholine, at the nerve endings. This results in excessive transmission of nerve impulses, which causes mortality in the target pest. This reaction is also the mechanism by which high levels of organophosphate insecticides can produce toxic effects in mammals.

In mammals, acetylcholinesterase can be found in both nervous tissue and in red blood cells. However, the red blood cell enzyme is not associated with nerve conduction, and its depression alone is not associated with toxicity.

Mammals possess yet another enzyme known as plasma butyryl-chlolinesterase, or pseudocholinesterase, which is also inhibited by organophosphate insecticides. It is an entirely different enzyme compared with the acetylcholinesterase found in nervous tissue and red blood cells. Pseudocholinesterase has no known function and its activity can be depressed without adverse effect.

Of the three cholinesterase enzymes, the plasma-derived pseudocholinesterase is generally the most sensitive to inhibition by commonly used organophosphate insecticides. This is especially true for chlorpyrifos-induced inhibition. The acetylcholinesterase enzymes found in red blood cells and nervous tissue also show large differences in sensitivity to chlorpyrifos; with the enzyme found in red blood cells being much more sensitive. Consequently, significant depression of both pseudocholinesterase and red blood cell acetylcholinesterase can occur without evidence of toxicity.

Furthermore, animal studies demonstrate that modest reductions in brain acetylcholinesterase activity in response to the administration of chlorpyrifos fail to elicit toxic effects. In these studies, observable signs of toxicity required a greater than 60 percent reduction in brain acetylcholinesterase activity. These data provide strong evidence that, with respect to chlorpyrifos, significant depression of brain acetylcholinesterase is required to cause toxicity in mammals.

Toxicology Testing

The potential for technical chlorpyrifos and chlorpyrifos-containing formulations to cause adverse health effects has been extensively examined in approved regulatory studies using laboratory animals. This information is supplemented by results of well-controlled, voluntary clinical studies.

Toxicity testing in animals is performed with the active ingredient and with formulations. Animal studies often involve use of exaggerated doses to fully explore toxic potential.

Acute Toxicity
Short-term (acute) exposure studies are mainly intended to determine the harmful effects that could occur due to an accident, misuse or deliberate ingestion of a large quantity of the product (e.g., suicide attempt). They may also attempt to predict the likelihood of skin and eye irritation and skin sensitization.

Oral and Dermal Toxicity
Chlorpyrifos is of only moderate toxicity by the acute oral and dermal routes of exposure in numerous animal studies.

The acute toxicity of formulated chlorpyrifos is generally less than that of technical chlorpyrifos. Toxicity also varies with formulation. Microencapsulated formulations and granules are less toxic than emulsifiable concentrates (EC).

Skin and Eye Irritation
Skin and eye irritation studies evaluate possible irritant or corrosive effects of a compound. These studies are also considered in classifying the acute toxicity of a compound. Skin and eye irritation studies are graded along certain norms:

non-irritating
positive indicates irritation, but no degree of severity
slight, moderate, severe and corrosive indicate degrees of irritation
reversible indicates initial irritation, the effects of which were reversed after a specific period of time.

Chlorpyrifos is not considered a skin irritant or skin sensitizer. However, prolonged or repeated exposure to emulsifiable concentrate (EC) formulations may cause skin burns. Granular (G), wettable powder (WP), microencapsulated and finished dilutions (e.g., ready to use) formulations are not likely to cause significant skin irritation.

Chlorpyrifos is poorly absorbed through the human skin, with dermal penetration measured at 1 to 3 percent. A single prolonged exposure of an EC concentrate might result in the material being absorbed in harmful amounts. A single prolonged exposure to G, WP and microencapsulated concentrates or finished dilutions of 1 percent or less are not likely to result in the material being absorbed through skin in harmful amounts.

Inhalation Toxicity
Due to the low vapor pressure of chlorpyrifos, acutely toxic levels of vapors cannot be attained at room temperature. A repeated inhalation study was conducted in which rats received nose-only exposures to chlorpyrifos vapors 6 hours/day, 5 days/week for 13 weeks, at concentrations of 0, 75, 147 or 296 µg/m3 of air (0, 5, 10 or 21 ppb, respectively). No signs of toxicity were observed in any animals throughout the test. No effects were observed on plasma, red blood cell or brain cholinesterase, or on any other parameters evaluated. The experimental level of 296 µg/m3 was a level that approached complete saturation of the air, a nearly impossible condition except under controlled laboratory conditions.

Chronic Toxicity
Repeated oral studies of chlorpyrifos have shown the only effects to be those associated with the inhibition of cholinesterase enzymes. No effects were observed on any organs or tissues. Chlorpyrifos is not carcinogenic in lifetime animal studies. A long-term dietary study in rats showed the No Observable Effect Level (NOEL) to be 0.1 mg/kg body weight/day. No significant depression of plasma or red blood cell cholinesterase occurred at this dosage. Even in rats receiving 3.0 mg/kg/day of chlorpyrifos, no adverse effects were observed during the two-year test period.

Carcinogenicity
Chlorpyrifos was not carcinogenic in two-year dietary studies done with both rats and mice.

Mutagenicity
A number of mutagenicity tests have been conducted on chlorpyrifos - both in vivo (whole animal) and in vitro (test tube). The results indicate that chlorpyrifos has minimal mutagenic potential.

Teratogenicity
Chlorpyrifos is not considered teratogenic.

Human Toxicity

Voluntary Clinical Studies
Chlorpyrifos is rather unique in that, in addition to the wealth of animal testing data, information from voluntary clinical studies is also available. Human volunteers ingesting either a single dose or daily repeated doses of chlorpyrifos showed that plasma butyryl-cholinesterase levels may be depressed by over 60 percent with no effect on red blood cell acetylcholinesterase levels. Moreover, in these same studies, no signs or symptoms of toxicity were observed. The test material was rapidly metabolized, with excretion of the principal metabolite (TCP) in the urine. The half-life for elimination of the principal metabolite from the body was 27 hours, which means that essentially all (>90 percent) of an oral dose of the chemical would be eliminated in 4 days. In the same study, chlorpyrifos, applied to the forearm of volunteers was shown to be absorbed through the skin in only limited amounts (1 to 3 percent of that applied).

Symptoms of Intoxication
Signs and symptoms of organophosphate insecticide poisoning in humans may be headache, dizziness, loss of coordination, muscle twitching, tremors, nausea, abdominal cramps, diarrhea, sweating, pinpoint pupils, blurred vision, salivation, tearing, excessive urination and tightness in the chest. Obviously, many of these symptoms are nonspecific and are not unique to organophosphate poisoning. Measurement of plasma butyryl-cholinesterase enzyme via a simple blood test may differentiate exposure to organophosphate insecticides from other potential sources of aforementioned symptoms.

Immediate medical treatment should be sought if any of the above-mentioned signs become apparent after exposure is known to have occurred. If you have additional health or safety questions regarding this molecule, consult your country's Material Data Safety Sheet (MSDS) as it will have local numbers and information. Within the United States, please call the US Emergency Response line at 1-800-992-5994.

Because chlorpyrifos acts on the enzymes in the blood, an antidote is available in cases of accidental or intentional overexposure. A health care professional should determine serum and/or red blood cell cholinesterase levels prior to administration of the antidote. Atropine by injection is the preferable antidote. Oximes, such as 2-PAM/protopam, may be therapeutic if used early. However, oximes should be used only in conjunction with atropine. Treatment is based on the judgment of the physician in response to actions of the patient. In all but exceptional cases, persons seriously poisoned with chlorpyrifos recover rapidly with appropriate treatment leaving no long-term effects. In case studies, persons showing mild symptoms of poisoning show a rapid and complete recovery even if antidote therapy is not used.

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