A) The following are signs and symptoms from organophosphates in general, which are due to the anticholinesterase activity of this class of compounds. All of these effects may not be documented for azinophos-methyl, but could potentially occur in individual cases.
B) USES: Azinophos-methyl, an organophosphate insecticide, is registered for use in the United States, and may be available in other countries.
C) TOXICOLOGY: Organophosphates competitively inhibit pseudocholinesterase and acetylcholinesterase, preventing hydrolysis and inactivation of acetylcholine. Acetylcholine accumulates at nerve junctions, causing malfunction of the sympathetic, parasympathetic, and peripheral nervous systems and some of the CNS. Clinical signs of cholinergic excess develop.
D) EPIDEMIOLOGY: Exposure to organophosphates is common, but serious toxicity is unusual in the US. Common source of severe poisoning in developing countries.
E) WITH POISONING/EXPOSURE
1) MILD TO MODERATE POISONING: MUSCARINIC EFFECTS: Can include bradycardia, salivation, lacrimation, diaphoresis, vomiting, diarrhea, urination, and miosis. NICOTINIC EFFECTS: Tachycardia, hypertension, mydriasis, and muscle cramps.
2) SEVERE POISONING: MUSCARINIC EFFECTS: Bronchorrhea, bronchospasm, and acute lung injury. NICOTINIC EFFECTS: Muscle fasciculations, weakness, and respiratory failure. CENTRAL EFFECTS: CNS depression, agitation, confusion, delirium, coma, seizures. Hypotension, ventricular dysrhythmias, metabolic acidosis, pancreatitis, and hyperglycemia can also develop.
3) DELAYED EFFECTS: Intermediate syndrome is characterized by paralysis of respiratory, cranial motor, neck flexor, and proximal limb muscles 1 to 4 days after apparent recovery from cholinergic toxicity, and prior to the development of delayed peripheral neuropathy. Manifestations can include inability to lift the neck or sit up, ophthalmoparesis, slow eye movements, facial weakness, difficulty swallowing, limb weakness (primarily proximal), areflexia, and respiratory paralysis. Recovery begins 5 to 15 days after onset. Distal sensory-motor polyneuropathy may rarely develop 6 to 21 days following exposure to some organophosphate compounds, however, it has not yet been reported in humans after exposure to azinphos-methyl. Characterized by burning or tingling followed by weakness beginning in the legs which then spreads proximally. In severe cases, it may result in spasticity or flaccidity. Recovery requires months and may not be complete.
4) CHILDREN: May have different predominant signs and symptoms than adults (more likely CNS depression, stupor, coma, flaccidity, dyspnea, and seizures). Children may also have fewer muscarinic and nicotinic signs of intoxication (ie, secretions, bradycardia, fasciculations and miosis) as compared to adults.
5) INHALATION EXPOSURE: Organophosphate vapors rapidly produce mucous membrane and upper airway irritation and bronchospasm, followed by systemic muscarinic, nicotinic and central effects if exposed to significant concentrations.
0.2.3 VITAL SIGNS
0.2.3.1 ACUTE EXPOSURE
A) Fever, bradycardia and hypotension, or tachycardia and hypertension may occur.
0.2.4 HEENT
0.2.4.1 ACUTE EXPOSURE
A) Miosis, lacrimation, and blurred vision are common; mydriasis may occur in severe poisonings. Opsoclonus has been reported in one case. Salivation commonly occurs.
0.2.4.2 CHRONIC EXPOSURE
A) Decreased visual acuity and persistent photophobia may be seen.
0.2.5 CARDIOVASCULAR
0.2.5.1 ACUTE EXPOSURE
A) Bradycardia, hypotension, and chest pain may occur. Tachycardia and hypertension may also be noted. Dysrhythmias and conduction defects may occur in severe poisonings. Myocarditis may develop.
0.2.6 RESPIRATORY
0.2.6.1 ACUTE EXPOSURE
A) Dyspnea, rales, bronchorrhea, bronchospasm, or tachypnea may be noted.Noncardiogenic pulmonary edema may occur in severe cases. Chemical pneumonitis may be seen.
B) Bronchospasm may occur in previously sensitized asthmatics or as a pharmacological muscarinic effect.
C) Acute respiratory insufficiency is the main cause of death in acute poisonings.
D) Most organophosphate compounds can release toxic and irritating fumes on thermal decomposition. Exposure to such fumes could cause chemical pneumonitis, bronchospasm, or noncardiogenic pulmonary edema.
0.2.7 NEUROLOGIC
0.2.7.1 ACUTE EXPOSURE
A) Headache, dizziness, muscle spasms and profound weakness are common. Alterations of level of consciousness, anxiety, paralysis, seizures and coma may occur. Seizures may be more common in children.
B) Peripheral neuropathy of the mixed sensory-motor type may be delayed by 6 to 21 days following exposure to some organophosphates. Recovery may be slow or incomplete.
1) Azinphos-methyl did NOT produce delayed peripheral neuropathy in the standard hen test.
C) Dyskinesias may develop. Abnormal neuropsychiatric tests and EEGs may persist for months after acute exposure.
0.2.8 GASTROINTESTINAL
0.2.8.1 ACUTE EXPOSURE
A) Vomiting, hypersalivation, diarrhea, fecal incontinence and abdominal pain may occur.
B) Intussusception has been reported in a single pediatric organophosphate poisoning case.
0.2.10 GENITOURINARY
0.2.10.1 ACUTE EXPOSURE
A) Increased urinary frequency or, in severe cases, urinary incontinence has occurred.
B) Immune-complex nephropathy with proteinuria and/or amorphous crystalluria may be possible.
0.2.11 ACID-BASE
0.2.11.1 ACUTE EXPOSURE
A) Metabolic acidosis has occurred in several severe poisonings.
0.2.13 HEMATOLOGIC
0.2.13.1 ACUTE EXPOSURE
A) Alteration in prothrombin time and/or tendency to bleeding may occur. Clinically significant bleeding or hypercoagulability are rare.
B) The hallmark of organophosphate poisoning is the inhibition of plasma pseudocholinesterase or erythrocyte acetylcholinesterase, or both.
0.2.14 DERMATOLOGIC
0.2.14.1 ACUTE EXPOSURE
A) Sweating is a consistent but not universal sign.
0.2.14.2 CHRONIC EXPOSURE
A) Dermal sensitization may occur.
1) One case of generalized dermatosis has been reported.
0.2.15 MUSCULOSKELETAL
0.2.15.1 ACUTE EXPOSURE
A) Muscle weakness, fatigability and fasciculations are common findings and may be delayed by several days. Paralysis may supervene.
0.2.16 ENDOCRINE
0.2.16.1 ACUTE EXPOSURE
A) Hyperglycemia and glycosuria without ketosis may be present.
0.2.17 METABOLISM
0.2.17.1 ACUTE EXPOSURE
A) Hyperglycemia and glycosuria without ketosis may occur in severe poisoning.
0.2.18 PSYCHIATRIC
0.2.18.1 ACUTE EXPOSURE
A) Decreased vigilance, defects in expressive language and cognitive function, impaired memory, depression, anxiety or irritability and psychosis have been reported, more commonly in persons having other clinical signs of organophosphate poisoning or pre-existing psychological conditions.
B) Psychosis may be noted following acute poisoning.
C) Abnormal neuropsychiatric tests and EEGs may persist for months after acute exposure.
0.2.19 IMMUNOLOGIC
0.2.19.2 CHRONIC EXPOSURE
A) Chronic skin exposure to some organophosphates may lead to dermal sensitization.
0.2.20 REPRODUCTIVE HAZARDS
A) At the time of this review, no studies were found on the possible reproductive effects of azinphos-methyl in humans.
B) Newborn toxic effects have been observed in rat studies, including changes in weaning and viability indices, central nervous system developmental abnormalities and changes in growth statistics. In mice, musculoskeletal system developmental abnormalities, reduced fetal weight, and fetotoxicity have also been observed. However, azinphos-methyl was not teratogenic in mice and rats.
C) No increased chromosome damage was seen in the spermatogonia or primary spermatocytes of mice given two injections of azinphos-methyl.
0.2.21 CARCINOGENICITY
0.2.21.1 IARC CATEGORY
A) IARC Carcinogenicity Ratings for CAS86-50-0 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
1) Not Listed
0.2.21.2 HUMAN OVERVIEW
A) At the time of this review, no studies were found on the potential carcinogenic activity of azinphos-methyl in humans.
0.2.21.3 ANIMAL OVERVIEW
A) Designated an equivocal tumorigenic agent by RTECS criteria with observed gastrointestinal and thyroid tumors in rat studies.
B) NCI Carcinogenesis Bioassay
1) EQUIVOCAL EVIDENCE in rat systems (Feed)
2) NO EVIDENCE in mouse systems (Feed)
C) No EVIDENCE of an increased incidence of tumors was noted in a mouse oncogenicity study.
D) More recent long-term studies showed no carcinogenic potential in mice and rats.
0.2.22 GENOTOXICITY
A) Azinphos-methyl induced unscheduled DNA synthesis in human fibroblasts. No increased chromosome damage was seen in the bone marrow cells, spermatogonia, or primary spermatocytes of mice given one or two injections of azinphos-methyl. Mutations were induced in S. typhimurium (Ames Test), S. pombe, mouse lymphocytes, human fibroblasts and hamster ovary cells.
B) Azinphos-methyl induced chromosome aberrations were observed by cytogenetic analysis in human lung cells and hamster ovary cells. In hamster V79 cells and one species of fish, azinphos-methyl did not cause and increased frequency of sister chromatid exchanges (SCEs).
C) In the EPA Genetox Program, azinphos-methyl was found to be positive for S. cerevisiae-homozygosis, inconclusive in the B subtilis rec assay, E coli polA without S9, histidine reversion-Ames test, and D. melanogaster sex-linked lethal and negative for in vitro UDS-human fibroblast and TRP reversion.
D) Cytogenetic studies of organophosphate-exposed workers have suggested possible increases in frequencies of chromosome aberrations, but the evidence is not compelling.
E) Two generations of an Israeli family who had been chronically exposed to organophosphates had 100-fold amplification of the "silent" allele of the CHE gene on chromosome 3; the absence of amplification of other genes on chromosome 3 suggests that the amplification of the CHE gene was a specific response to exposure to the organophosphate.
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