National Toxicology Program

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. ¹

Names (NTP)

• Malathion
• ((DIMETHOXYPHOSPHINOTHIOYL)THIO)-BUTANEDIOIC ACID (9CI)

Human Toxicity Excerpts

• Harmful by inhalation, in contact with skin & if swallowed. [Commission of the European Communities. Legislation on Dangerous Substances - Classification and Labelling in the European Communities. Vol. II. London and Trotman Ltd., 1989., p. 99]**PEER REVIEWED**
  
• IN EXPTL STUDY, MALATHION WAS FOUND TO BE A WEAK CONTACT SENSITIZER, INDUCING MILD CUTANEOUS REACTION IN HIGH PROPORTION OF SUBJECTS. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-298]**PEER REVIEWED**
  
• A RELATIVELY LOW ACUTE TOXICITY OF MALATHION TO HUMANS IS INDICATED BY THE FACT THAT A DAILY ORAL DOSAGE OF 24 MG GIVEN FOR MORE THAN 14 DAYS WAS NECESSARY TO LOWER BLOOD CHOLINESTERASE ACTIVITIES IN ADULT VOLUNTEERS. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 118 (1983)]**PEER REVIEWED**
  
• MALATHION POISONING IN FATAL CASES SHOWS DAMAGE TO MYOCARDIUM WITH DILATION OF THE PERICARDIAL BLOOD VESSELS & MARKED HEMORRHAGE IN THE SURROUNDING TISSUES, INTERSTITIAL EDEMA, INFLAMMATORY CELLS, HEMOSIDERIN-LADEN MACROPHAGES, & FATTY INFILTRATION OF THE MYOCARDIUM. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 872]**PEER REVIEWED**
  
• In a human experiment in which four men were exposed 1 hr daily for 42 days to 84.8 mg/cu m, there was moderate irritation of the nose and conjunctiva but there were no cholinergic signs or symptoms. [Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981., p. 2]**PEER REVIEWED**
  
• Estimated fatal oral dose for ortho-Malathion 50 Insect Spray is 60.0 g/70 kg. /From table/ [Haddad, L.M. and Winchester, J.F. Clinical Management of Poisoning and Drug Overdosage. Philadelphia, PA: W.B. Saunders Co., 1983., p. 705]**PEER REVIEWED**
  
• Very large exposures are required to cause symptoms. After inhalation of malathion, breathing and eye effects are the first to appear. These include tightness of the chest, wheezing, a bluish discoloration of the skin, small pupils, aching in and behind the eyes, blurring of the vision, tearing, runny nose, headache, and watering of the mouth. After swallowing malathion, loss of appetite, nausea, vomiting, abdominal cramps and diarrhea may appear within two hr. After skin absorption, sweating and twitching in the area of absorption may occur, usually within 15 minutes to four hr. With severe intoxication by all routes, in addition to the above symptoms, weakness, generalized twitching and paralysis may occur and breathing may stop. In addition, dizziness, confusion, staggering, slurred speech, generalized sweating, irregular or slow heartbeat, convulsions, and coma may occur. [Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981., p. 1]**PEER REVIEWED**
  
• Immune complex nephropathy with renal dysfunction & massive proteinuria occurred several wk after a malathion exposure. /Complement 3 factor/ levels were marginally reduced & the renal dysfunction resolved spontaneously after 1 mo. [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 1073]**PEER REVIEWED**
  
• The major signs and symptoms of malathion poisoning are attributable to the potentiation of responses to acetylcholine released from preganglionic, postganglionic cholinergic, and somatic motor nerve endings whenever nerve volleys reach the periphery. In milder cases, the postganglionic stimulation may predominate. ... Signs and symptoms include nausea, vomiting, diarrhea, excessive sweating, salivation, miosis, increased bronchial secretion, bronchial constriction, and the appearance of generalized muscular fasciculations followed by weakness. Central nervous system effects may include anxiety, restlessness, headache, and in more serious cases, tremors, confusion, drowsiness, slurred speech, coma, loss of reflexes, and convulsions. [NIOSH; Criteria Document: Malathion p.35 (1976) DHEW Pub. NIOSH 76-205]**PEER REVIEWED**
  
• Alterations of the activities of serum butyrylcholinesterase (BuChE), serum glutamic-oxalacetic transaminase, serum glutamic-pyruvic transaminase and serum aldolase, and the concn of serum albumin in twelve agricultural workers exposed to malathion over a period of six months were examined. Two groups of controls were used, consisting of 30 blood samples each, the first from randomly selected healthy blood donors, and the second from healthy blood donors engaged in manual labor. The mean butyrylcholinesterase activity of the agricultural workers at the end of the exposure period was not significantly different from that of either group of controls. However, ... the enzyme activity of any single subject changed significantly after exposure. A reduction in butyrylcholinesterase activity was noted in 11 of 12 agricultural workers, and six showed a sustained fall until the end of the study. Two showed slight increases over their pre-exposure activities at the end. ... The largest percent changes in the mean values of the agricultural workers during exposure to malathion were decreases in the activities of serum aldolase, serum glutamic-oxalacetic transaminase and serum glutamic-pyruvic transaminase, with that of butyrylcholinesterase changing the least of the four serum enzymes studied. No significant differences were observed in serum albumin concentrations. This study indicates that butyrylcholinesterase depression secondary to malathion exposure under field conditions does occur. [Grech JL; Br J Ind Med 22: 67-71 (1965) as cited in NIOSH; Criteria Document: Malathion p.50 (1976) DHEW Pub. NIOSH 76-205]**PEER REVIEWED**
  
• ... A 42 year old woman ingested a minimum of 120 ml of 50% malathion garden spray. She was admitted to a hospital 30 minutes later, at which time she was comatose, markedly cyanotic, flaccid, devoid of tendon reflexes, and markedly miotic. ... The patient was discharged 5 weeks after admission. Laboratory investigations during the patient's hospital course included determinations of plasma and erythrocyte cholinesterase activities. Serum cholinesterase activity was less than 22% of laboratory normal for the first nine days. Thereafter, the level gradually rose to 100% by the 31st day. The erythrocyte cholinesterase activity was first measured on the 12th day, when it was found to be 10% of normal. It remained between 10 and 25% of normal until the 45th day after hospital admission and then gradually rose to 100% by 130 days after admission. By this time, the patient had been discharged. Hematocrit measurement showed a small drop after admission, from 43 to 37%, and the reticulocyte count never rose above 2%. ... Blood urea levels rose to 77 mg/100 ml of blood during the first 5 days, thereafter returning to normal as the non renal uremia due to diarrhea and hypersecretion was controlled. Electrocardiograms taken immediately after admission and daily thereafter showed a prolongation of the P-R interval that persisted for 5 days, as well as changes in the S-T segment which was reported as consistent with panmyocardial ischemia. These latter changes disappeared gradually as the patient's respiratory function improved. [Goldin AR et al; N Engl J Med 271: 1289-93 (1964) as cited in NIOSH; Criteria Document: Malathion p.23 (1976) DHEW Pub. NIOSH 76-205]**PEER REVIEWED**
  
• To assess effects attributed to malathion which escaped from an overheated tank at a chemical plant in Linden, New Jersey, researchers surveyed seamen subjects (n= 22) on board a nearby tanker and seamen control subjects (n= 22). Self report measurement strategies included a medical review of body systems, the "demoralization" scale reflecting psychological symptoms of distress, demographics, and factors that may buffer stress, specifically, social support and knowledge regarding toxic chemicals. Self reported postincident physical health differences between the two groups of seamen were noted. There were no differences between subjects and control subjects on demoralization levels. Further analysis indicated higher levels of demoralization among less knowledgeable seamen subjects. [Markowitz JS et al; J Occup Med 28 (5): 377-83 (1986)]**PEER REVIEWED**
  
• Concn of up to 400 ug/ml of 95% malathion failed to incr chromosomal aberrations in human hematopoietic B411-4, RPMI-1788 & RPMI-7191 cell cultures; however, /others/ ... reported a positive, although not dose related, result in human lymphocytes with 99% pure malathion. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 117 (1983)]**PEER REVIEWED**
  
• A significant increase in chromosomal aberrations was found in the lymphocytes of a group of 14 people intoxicated with a commercial formulation of malathion (Fosfotion), as compared with that in healthy controls. Aberrations observed included chromatid breaks, chromatid isobreaks, chromatid exchanges and unstable chromosomal & structural aberrations. No dose effect relationship was evident, since high frequencies of aberrations were also detected in cases of mild intoxication. (The small number of subjects involved & the inappropriateness of the control group used does not permit the association to be established as causal.) [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 119 (1983)]**PEER REVIEWED**
  
• Malathion is less toxic to humans than most anticholinesterase agents because it is metabolized in the liver to an inactive form. [Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981., p. 2]**PEER REVIEWED**
  
• To evaluate the latent neurological effects of organophosphate pesticide poisoning, 100 matched pairs (1 black, 14 Mexican American, and 85 Anglo/Caucasian; 99 pairs were male) of individuals with previous acute organophosphate pesticide poisoning (malathion, 6 cases; results are not given for individual chemicals) and nonpoison controls were examined. No significant difference between the groups was found on audiometric tests, ophthalmic tests, electroencephalograms, or the clinical serum and blood chemistry evaluations. From the neurological examination, abnormalities were demonstrated among the cases only on measures of memory, abstraction, and mood, and on one test of motor reflexes. Differences between the cohorts were more apparent in the neuropsychological tests, and occurred on tests of widely varying abilities, including intellectual functioning, academic skills, abstraction and flexibility of thinking, and simple motor skills. Twice as many cases as controls had Halstead Reitan Battery summary scores in the range characteristic of cerebral damage of dysfunction. Greater distress and complaints of disability for the poisoned subjects were indicated by the Minnesota Multiphasic Personality Inventory and the Patient's and Relative's Assessment of Patient Functioning Inventories. [Savage EP et al; Arch Environ Health 43 (1): 38-45 (1988)]**PEER REVIEWED**
  
• The cytotoxic, cytostatic, and cytogenetic effects of 14 organophosphate pesticides, one of which was malathion, on human lymphoid cells in vitro were studied. Cultures of human lymphoid LAZ-007 cells were exposed to the test compounds at concentrations of 0.02, 0.2, 2.0, or 20 ug/ml for 48 hr with or without metabolic activation by rat liver microsomal S9 product. At concentration of 0.2 ug/ml malathion caused a significant increase in the sister chromatid exchanges (SCE) which was elevated by exposure to 20 ug/ml. Addition of S9 mix did not significantly increase sister chromatid exchanges frequency. Treatment of cultures with 20 ug/ml decr the viable cell count to 53% of control. [Sobti RC et al; Mutat Res 102 (1): 89-102 (1982)]**PEER REVIEWED**
  
• California collects data on most occupational and many non-occupational illnesses and injuries related to pesticide exposure. Most of the occupational incidents are investigated by local agencies. A thorough investigation is conducted on all pesticide-related cases that meet "priority" guidelines: death; hospitalization of 1 or more persons for more than 24 hours with treatment; or 5 or more people with symptoms seeking medical care as a result of the same incident. This report summarizes the priority cases determined to be related to pesticide exposure during 1986. Of the 67 described incidents, involving 583 people ill, 26 (38%) were related to exposure to pesticides applied indoors (residences, offices), either by commerical pest control companies, employees or homeowners. Nearly 200 people (33%) became ill and more than 200 people were evacuated as a result of these types of applications. Most of these incidents were a result of careless application techniques and not following label instructions. Four other incidents, with 33 people ill, were the result of spills in retail stores. In all 4 cases, store employees tried to clean the spill without wearing protective clothing. Two other cases involved exposure via a pesticide being put in a food container. Nineteen of these type of incidents involved a pesticide product containing an organophosphate; most often chlorpyrifos (8 incidents), diazinon (3 incidents), and malathion (5 incidents). There were also 10 cases that resulted from suicide; eight different pesticides were involved. Five incidents involving agricultural workers, as well as 4 incidents involving non-agricultural workers, were primarily the result of allowing pesticides to drift from the target field. [Maddy KT, Edminton S; Vet Hum Toxicol 30 (3); 246-54 (1988)]**PEER REVIEWED**
  
• A 100-fold DNA amplification in the CHE gene, coding for serum butyrylcholinesterase, was found in a farmer expressing the "silent" CHE phenotype. Individuals homozygous for this gene display a defective serum butyrylcholinesterase and are particularly vulnerable to poisoning by agricultural organophosphorous insecticides, to which all members of this family had long been exposed. DNA blot hybridization with regional butyrylcholinesterase cDNA probes suggested that the amplification was most intense in regions encoding central sequences within butyrylcholinesterase cDNA, whereas distal sequences were amplified to a much lower extent. This is in agreement with the "onion skin" model, based on amplification of genes in cultured cells and primary tumors. The amplification was absent in the grandparents but present at the same extent in one of their sons and in a grandson, with similar DNA blot hybridization patterns. In situ hybridization experiments localized the amplified sequences to the long arm of chromosome 3, close to the site where we previously mapped the CHE gene. Altogether, these observations suggest that the initial amplification event occurred early in embryogenesis, spermatogenesis, or oogenesis, where the CHE gene is intensely active and where cholinergic functioning was indicated to be physiologically necessary. /Such/ findings demonstrate a de novo amplification in apparently healthy individuals within an autosomal gene producing a target protein to an inhibitor. Its occurrence in two generations from a family under prolonged exposure to parathion indicates that organophosphorous poisons may be implicated in previously unforeseen long-term ecological effects. [Prody CA et al; Proc Nat Acad Sci 86 (2): 690-4 (1989)]**PEER REVIEWED**
  
• The lethal dose in mammals is about 1 g/kg. [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 167]**PEER REVIEWED**
  
• Nearly all reported fatalities from malathion have been through ingestion. [Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994, p. 627]**PEER REVIEWED**
  
• There is a single report of an association between brief anecdotal exposure to malathion and subsequent fatal aplastic anemia. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 118 (1983)]**PEER REVIEWED**
  
• All the organophosphorus insecticides have a cumulative effect by progressive inhibition of cholinesterase ... /Organophosphorus insecticides/ [Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981., p. 148]**PEER REVIEWED**
  
• The symptoms of chronic poisoning due to organophosphorus pesticides include headache, weakness, feeling of heaviness in head, decline of memory, quick onset of fatigue, disturbed sleep, loss of appetite, & loss of orientation. Psychic disorders, nystagmus, trembling of the hands & other nervous system disorders can be observed in certain cases. Sometimes neuritis, paresis & paralysis develop. /Organophosphorus pesticides/ [International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour Office, 1983., p. 1639]**PEER REVIEWED**
  
• Organophosphate insecticides ... are potent cholinesterase enzyme inhibitors that act by interfering with the metabolism of acetylcholine, resulting in the accumulation of acetylcholine at neuroreceptor transmission sites. Exposure produces a broad spectrum of clinical effects that are indicative of massive overstimulation of the cholinergic system, including muscarinic effects (parasympathetic), nicotinic effects (sympathetic and motor), and CNS effects. These effects present clinically as feelings of headache, weakness, dizziness, blurred vision, psychosis, respiratory difficulty, paralysis, convulsions, and coma. Typical findings are given by the mnemonic SLUD (salivation, lacrimation, urination, and defecation). A small percentage of patients may fail to demonstrate miosis, a classic diagnostic hallmark. The onset of the clinical manifestation of organophosphate poisoning usually occurs within 12 hr of exposure. /Organophosphate insecticides/ [Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995., p. 979]**PEER REVIEWED**
  
• A woman at 34 to 35 weeks' gestation presented in acute respiratory distress with cyanosis and tachypnea and bilateral rhonchi and crepitation. Her heart rate was 78 beats per min and her blood pressure 120/80 mm Hg, with a fetal heart rate of 140 beats per min. The mother was salivating markedly and her pupils were reduced to "pinpoint size." An uncorrected metabolic acidosis was diagnosed. Serum and erythrocyte acetylcholinesterase determinations were near zero. Cholinesterase inhibitor poisoning was felt to be the likely cause of her disorders. Administration of atropine 2.4 mg iv bolus with infusion of 0.02 mg/kg/hr lead to unacceptable fetal tachycardia. The woman had shown increased cooperativeness and secretion control until the atropine had to be stopped. A cesarean section was performed for delivery of a hypotonic infant with a 1 min Apgar score of 3. The baby was mechanically ventilated for 2 days and required atropine therapy at 0.1 mg/kg/hr for 8 days. The mother required 8 days of mechanical ventilation and 11 days of atropine therapy. In this case, the infant appeared relatively less poisoned than the mother by a presumed organophosphate exposure. /Organophosphate poisoning/ [Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 430]**PEER REVIEWED**
  
• A follow-up study of 232 people three years after a history of organophosphorus pesticide poisoning disclosed only one person with slight residual blurring of vision that might have been related to the earlier poisoning, though at the time of poisoning over one third of the people had blurring, which lasted only a day or two after exposure was discontinued. The possile exceptional case had findings suggestive of basilar artery insufficiency, rather than effects of poisoning. /Organophosphorus pesticide poisoning/ [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 679]**PEER REVIEWED**
  
• The effects of acute intoxication by anti-cholinesterase agents are manifested by muscarinic and nicotinic signs and symptoms and, except for compounds of extremely low lipid solubility, by signs referable to the CNS. Local effects are due to the action of vapors or aerosols at their site of contact with the eyes or respiratory tract, or due to the local absorption after liquid contamination of the skin or mucous membranes, including those of the gastrointestinal tract. Systemic effects appear within minutes after inhalation of vapors or aerosols. In contrast, the onset of symptoms is delayed after gastrointestinal and percutaneous absorption. The duration of effects is determined largely by the properties of the compound: its lipid solubility, whether it must be activated, the stability of the organophosphorus-AChE bond, and whether "aging" of the phosphorylated enzyme has occurred. /Anticholinesterase agents/ [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 169]**PEER REVIEWED**
  
• Ocular effects include marked miosis, ocular pain, conjunctival congestion, diminished vision, ciliary spasm, and brow ache. With acute systemic absorption, miosis may not be evident due to sympathetic discharge in response to the hypotension. /Anticholinesterase agents/ [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 170]**PEER REVIEWED**
  
• In addition to rhinorrhea and hyperemia of the upper respiratory tract, respiratory effects consist of "tightness" in the chest and wheezing respiration, caused by the combination of bronchoconstriction and increased bronchial secretion. /Anticholinesterase agents/ [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 170]**PEER REVIEWED**
  
• Gastrointestinal symptoms occur earliest after ingestion, and include anorexia, nausea and vomiting, abdominal cramps, and diarrhea. /Anticholinesterase agents/ [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 170]**PEER REVIEWED**
  
• With percutaneous absorption of liquid, localized sweating and muscular fasciculation in the immediate vicinity are generally the earliest manifestations. /Anticholinesterase agents/ [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 170]**PEER REVIEWED**
  
• ... Severe intoxication is manifested by extreme salivation, involuntary defecation and urination, sweating, lacrimation, penile erection, bradycardia, and hypotension. /Anticholinesterase agents/ [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 170]**PEER REVIEWED**
  
• The time of death after a single acute exposure may range from less than 5 minutes to nearly 24 hours, depending upon the dose, route, agent, and other factors. The cause of death is primarily respiratory failure, usually accompanied by a secondary cardiovascular component. Muscarinic, nicotinic, and central actions all contribute to respiratory embarrassment; effects include laryngospasm, bronchoconstriction, increased tracheobronchial and salivary secretion, compromised voluntary control of the diaphragm and intercostal muscles, and central respiratory depression. Blood pressure may fall to alarmingly low levels and cardiac irregularities intervene. These effects usually result from hypoxemia; they often are reversed by assisted pulmonary ventilation. /Anticholinesterase agents/ [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 170]**PEER REVIEWED**
  
• ACCUMULATION OF ACETYLCHOLINE IN CNS IS BELIEVED TO BE RESPONSIBLE FOR TENSION, ANXIETY, RESTLESSNESS, INSOMNIA, HEADACHE, EMOTIONAL INSTABILITY, & NEUROSIS, EXCESSIVE DREAMING & NIGHTMARES, APATHY, & CONFUSION ... DESCRIBED AFTER ORGANOPHOSPHATE POISONING. /ORGANOPHOSPHATE INSECTICIDES/ [Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986., p. 528]**PEER REVIEWED**
  
• Three clinical syndromes of organophosphate toxicity have been described: immediate, intermediate (1 to 4 days), and delayed (8 to 14 days) after exposure. /Organophosphates and related compounds/ [Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994., p. 260]**PEER REVIEWED**
  
• Immediate or delayed ascending paralysis (dying back axonopathy) starting in the lower extremities may occur. This may be confused with Guillain-Barre syndrome. /Organophosphates and related compounds/ [Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994., p. 260]**PEER REVIEWED**
  
• The usual symptoms include headache, giddiness, nervousness, blurred vision, weakness, nausea, cramps, diarrhea, and discomfort in the chest. Signs include sweating, miosis, tearing, salivation and other excessive respiratory tract secretion, vomiting, cyanosis, papilledema, uncontrollable muscle twitches followed by muscular weakness, convulsions, coma, loss of reflexes, and loss of sphincter control. The last four signs are seen only in severe cases but do not preclude a favorable outcome if treatment is prompt and energetic. Cardiac arrhythmias, various degrees of heart block, and cardiac arrest may occur ... /Organic phosphorus pesticides/ [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 938]**PEER REVIEWED**
  
• Acute emphysema, pulmonary edema, pink froth in the trachea and bronchi, and considerable congestion of the organs are found at autopsy. Slight microscopic changes may occur in the liver and kidneys ... Petechial hemorrhages in the organs may be present, especially if convulsions occurred during life. The findings are not diagnostic. In a few cases in which death occurred unexpectedly after several days of survival, multiple pericapillary and periprecapillary hemorrhages were noted in the myocardium and medulla oblongata ... /Organic phosphorous pesticides/ [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 950]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• DIPPING 4 TIMES AT 4 DAY INTERVALS IN A 2% SOLUTION OF 57% 'EMULSIFIABLE SOLUTION' OF MALATHION HAD NO EFFECT UPON DOGS. [Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981., p. 151]**PEER REVIEWED**
  
• AT 100 PPM /IN RATS/, NO EFFECTS WERE OBSERVED, EVEN ON RED CELL CHOLINESTERASE ACTIVITY. IN TWO STUDIES, 500 PPM FOR 8 WK ALSO PRODUCED NO ADVERSE EFFECT ON WHOLE BLOOD CHOLINESTERASE ACTIVITY. AT 1000 PPM & HIGHER, HOWEVER, RED CELL CHOLINESTERASE ACTIVITY WAS SIGNIFICANTLY DECR. IP INJECTION ... FOR 60 DAYS RESULTED IN A NO ADVERSE EFFECT LEVELS OF 100 MG/KG WITHOUT MORTALITY, BUT DOSAGES OF 200 & 300 MG/KG/DAY RESULTED IN MORTALITY RATES OF 60 & 100%, RESPECTIVELY. [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 623]**PEER REVIEWED**
  
• NO TERATOGENIC EFFECTS WERE OBSERVED WHEN RATS WERE TREATED IP WITH MALATHION AT 900 MG/KG. ... ON DAY 11 AFTER INSEMINATION, PREGNANT RATS WERE GIVEN SINGLE IP INJECTION OF MALATHION. NO SIGNIFICANT DIFFERENCE BETWEEN TREATED FEMALES & CONTROLS RELATIVE TO DEAD FETUSES/LITTER, RESORPTIONS, AVG WT OF FETUSES, AVG WT OF PLACENTA, OR FETAL MALFORMATIONS WERE OBSERVED. [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 625]**PEER REVIEWED**
  
• WHEN ACUTE TOXICITY OF A NUMBER OF ORGANOPHOSPHATE INSECTICIDES IN 23 DAY OLD WEANLING MALE RATS WAS COMPARED WITH THAT IN ADULTS. WEANLINGS WERE FOUND TO BE APPROX TWICE AS SUSCEPTIBLE TO ... MALATHION ... [The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 678]**PEER REVIEWED**
  
• UNDILUTED TECHNICAL LIQ MALATHION DROPPED ON RABBIT'S EYE CAUSED SLIGHT IMMEDIATE IRRITATION WITH CONJUNCTIVAL HYPEREMIA & EDEMA OF LIDS ... [Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974., p. 640]**PEER REVIEWED**
  
• THE ORAL TOXIC DOSE TO CALVES ... IS 10-20 MG/KG & TO ADULT CATTLE & SHEEP, 50-100 MG/KG. THE LETHAL DOSE IN GIVEN AS 200 MG/KG IN CATTLE & 150 MG/KG IN SHEEP. SPRAYS CONTAINING 1% MALATHION WERE LETHAL TO CALVES. [Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981., p. 151]**PEER REVIEWED**
  
• PERSISTENT MUSCLE WEAKNESS HAS BEEN DESCRIBED IN CHICKENS FOLLOWING SINGLE DOSES OF 100 MG/KG. ... USED IN CONCN OF 1.25% AS SPRAY OR 4% AS DUSTING POWDER, MALATHION APPEARS TO BE HARMLESS TO POULTRY. ... 100 PPM MALATHION IN DIET OF CHICKENS DOES NOT AFFECT THEIR GROWTH OR FEED CONVERSION. UP TO 15 PPM DOES NOT AFFECT HATCHABILITY OF PULLETS' EGGS. DOSES OF 400 MG/KG GIVEN TO FOWLS CAUSED A PRONOUNCED RISE IN THE BLOOD GLUCOSE LEVELS. [Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981., p. 151]**PEER REVIEWED**
  
• BLOOD CHOLINESTERASE LEVELS IN CALVES GIVEN 2 MG/KG OF MALATHION DAILY FOR UP TO 13 DAYS FELL TO 50%, BUT PROMPTLY RETURNED TO NORMAL WHEN ADMIN CEASED. [Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981., p. 151]**PEER REVIEWED**
  
• ... TREATMENT WITH 15% SOLN /MALATHION/ ... CAUSED DEATHS OF 16 DOGS. IN SOME CASES CLINICAL SIGNS (MALAISE, SALIVATION, ANOREXIA, & VOMITING) DID NOT START UNTIL 12TH DAY; DEATH CONTINUED FOR UP TO 12 WK. [Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981., p. 151]**PEER REVIEWED**
  
• WHEN MALATHION WAS: ... GIVEN TO RATS IN AMT OF 240 MG/KG, NO TERATOGENIC ACTIVITY WAS DETECTED. THERE WAS ... INCR IN MORTALITY RATE OF NEWBORNS FROM TREATED MOTHERS. ... /IN ANOTHER EXPT/ ... PREGNANT RATS /WERE FED BY GAVAGE/ ... 300 MG/KG ON DAYS 6 THROUGH 15 & ... NO TERATOGENICITY /FOUND/. [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 353]**PEER REVIEWED**
  
• Six pesticides, one of which was malathion, induced a significant increase of sister chromatid exchange frequencies in a dose dependent fashion in cultured Chinese hamster cell line V79. The six in decreasing order of sister chromatid exchanges induction are methyl parathion, demeton, trichlorfon, dimethoate, malathion, & methidathion. Cells were exposed to malathion for 28 hr at concn of 10, 20, 40, ug/ml, respectively. All test cmpd caused a delay in cell cycle. [Chen HH et al; Mutat Res 88 (3): 307-16 (1981)]**PEER REVIEWED**
  
• PURE MALATHION WAS TESTED FOR DNA DAMAGING & MUTAGENIC ACTIVITY IN BACILLUS SUBTILIS & SALMONELLA TYPHIMURIUM TESTER STRAINS & WAS WAS FOUND TO BE MODERATELY MUTAGENIC WITHOUT METABOLIC ACTIVATION. [SHIAU SY ET AL; MUTAT RES 71 (2): 169-79 (1980)]**PEER REVIEWED**
  
• GROUPS OF 50 MALE AND 50 FEMALE WEANLING CHARLES RIVER B6C3F1 MICE WERE FED DIETS CONTAINING 8000 OR 16000 MG/KG MALATHION (PURITY 95%, IMPURITIES UNSPECIFIED) FOR 80 WK AND OBSERVED FOR 14-15 WK. A MATCHED CONTROL GROUP COMPRISING 10 ANIMALS OF EACH SEX WAS OBSERVED FOR 95 WK ... AN ADDITIONAL POOLED CONTROL GROUP OF 50 ANIMALS OF EACH SEX WAS USED ... IN HIGH DOSE GROUP, WHICH RECEIVED A MAX TOLERATED DOSE, 94% OF THE MALES & 88% OF THE FEMALES WERE STILL ALIVE AT END OF THE EXPT; SURVIVAL WAS ... LOWER IN LOW DOSE & CONTROL ... IN FEMALE MICE, NO STATISTICALLY SIGNIFICANT INCR IN TUMOR INCIDENCE WAS FOUND. IN MALE MICE THE INCIDENCES OF HEPATOCELLULAR CARCINOMAS PLUS NEOPLASTIC NODULES WERE: 2/10 IN MATCHED CONTROLS, 8/49 IN POOLED CONTROLS, 7/48 IN THE LOW DOSE GROUP AND 17/49 IN THE HIGH DOSE GROUP (COCHRAN ARMITAGE TEST FOR POS TREND, P= 0.041 (USING MATCHED CONTROLS) OR P= 0.019 (USING POOLED CONTROLS); FISHER EXACT TEST, HIGH-DOSE VERSUS POOLED CONTROLS, P= 0.031). WHEN A TIME ADJUSTED ANALYSIS WAS PERFORMED, ELIMINATING ... MALE MICE THAT DIED BEFORE WK 52 OF STUDY, THE FOLLOWING INCIDENCES RESULTED: MATCHED CONTROLS, 2/9; POOLED CONTROLS, 8/48; LOW-DOSE, 7/47; & HIGH-DOSE 17/49. ... /TESTS DID NOT SHOW/ THESE INCIDENCES TO BE SIGNIFICANT ... . [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 113 (1983)]**PEER REVIEWED**
  
• MALATHION WAS INEFFECTIVE IN INDUCING SEX LINKED RECESSIVE LETHAL MUTATIONS IN DROSOPHILA MELANOGASTER FED SOLN CONTAINING 0.25 OR 0.5 MG/L OF THE CMPD. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 117 (1983)]**PEER REVIEWED**
  
• The clastogenic effect of malathion was studied in mice given ip injections of 115, 230, or 460 mg/kg. Results in mice injected with 115 mg/kg of malathion were not different from controls. At 230 mg/kg, increasing the frequencies of abnormal metaphases and chromosomal aberrations were noted in animals killed 6 or 24 hr after injection. Mice injected with 460 mg/kg, exhibited significant increments of abnormal metaphases, gaps, breaks, and chromatid exchanges in relation to controls. [Dulout FN et al; Mutat Res 122 (2): 163-7 (1983)]**PEER REVIEWED**
  
• Oral single & repeated doses of malathion affected the activities of serum glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, acid phosphatase, & cholinesterase in rats, depending on sex and duration of exposure. The first three enzymes were much more sensitive than cholinesterase. The serum cholesterol & bilirubin contents of female rats were more susceptible to these insecticides than those of males. [Enan EE; Int Pest Control 25 (2): 42-4 (1983)]**PEER REVIEWED**
  
• THREE GROUPS OF 50 MALE AND 50 FEMALE FISCHER 344 RATS, SIX WK OLD, WERE FED DIETS CONTAINING MALATHION (PURITY, 95%; IMPURITIES UNSPECIFIED) AT CONCN OF 0, 2000, OR 4000 MG/KG FOR 103 WK. THEY WERE OBSERVED FOR A FURTHER 2 TO 3 WK & THEN KILLED; SURVIVING RATS IN THE MATCHED CONTROL GROUP WERE KILLED AFTER 105-106 WK OF STUDY. OF THE MALE RATS, 88% OF THE CONTROL GROUP, 86% OF THE LOW DOSE GROUP & 80% OF THE HIGH DOSE GROUP SURVIVED THE EXPERIMENTAL PERIOD; WHILE OF THE FEMALES, 94% OF THE CONTROL GROUP, 98% OF THE LOW DOSE GROUP & 90% OF THE HIGH DOSE GROUP WERE STILL ALIVE AT TERMINATION OF THE EXPT. FEMALES MAY NOT HAVE RECEIVED A MAX TOLERATED DOSE, AS INDICATED BY GAIN IN BODY WT. NO STATISTICALLY SIGNIFICANT INCR IN TUMOR INCIDENCE WAS FOUND IN FEMALE RATS. IN MALE RATS, THE INCIDENCE OF ADRENAL PHEOCHROMOCYTOMAS APPEARED TO INCR IN THE LOW DOSE GROUP (11/48) COMPARED WITH THE CONTROL GROUP (2/49, P= 0.006), WHEREAS IN THE HIGH DOSE GROUP ONLY 6/49 PHEOCHROMOCYTOMAS WERE SEEN. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 114 (1983)]**PEER REVIEWED**
  
• To determine the effects of low dosage administration on exercise in a hot environment, malathion (7.5 mg/day, 4 days) was administered ip to rats, and affected a 35% reduction in plasma cholinesterase /activities/. Treadmill endurance was unaffected when the animals were exercised to hyperthermic exhaustion (rectal temp approx 45 deg). While rates of heat gain were similar, malathion treated rats displayed higher tail skin temp at a number of sampling times during the treadmill run. [Francesconi R et al; Pharmacol Biochem Behav 19 (6): 1031-5 (1983)]**PEER REVIEWED**
  
• Female Sprague Dawley rats were placed on a drinking soln of 1 ppm malathion dissolved in water for 6 mo. Hepatic morphology, basically hepatocyte degeneration, was altered. Prolonged prothrombin time and partial thromboplastin time were the only changes in clotting activity. [Lox CD, Davis JR; Ecotoxicol Environ Safety 7 (6): 546-51 (1983)]**PEER REVIEWED**
  
• The Tradescantia micronucleus (Trad-MCN) bioassay was utilized to determine the genotoxicity of malathion. Results of sixteen experiments indicated that malathion vapors at 0.15-0.25% induced significantly higher (0.05) micronucleus frequencies above the controls and altered the nuclear structure to form unequal sized nuclei and multiple breaks in each of the 4 cells of a tetrad. It also caused degeneration of nuclei, protrusions on nuclei, and inhibition of cell growth. Higher doses (greater than 0.25%) were toxic. [Ma TH et al; Environ Mutagen 5 (2): 127-37 (1983)]**PEER REVIEWED**
  
• Malathion at 10 and 20% LD50 doses, ip, impaired learning and memory retrieval of rats. [Uppal RP et al; Indian J Exp Biol 21 (11): 617-9 (1983)]**PEER REVIEWED**
  
• IgE antibody mediated and cell mediated hypersensitivity to malathion was evaluated in BALB/c mice. To elicit malathion specific antibodies of the IgE class, a conjugate of the anhydride of the diacid metabolite of malathion with keyhole limpet hemocyanin was administered ip with aluminum hydroxide as adjuvant. Serums collected following 3 sequential sensitizations were tested for specific IgE with the passive cutaneous anaphylaxis (PCA) test in rats. Anhydride coupled to bovine serum albumin was used as the challenge antigen. Specific IgE was produced following the second and third sensitization in the mice receiving 1 ug of conjugate. Malathion applied epicutaneously for 2 days or over 4 wk failed to elicit delayed type hypersensitivity. Anhydride specific IgE antibodies were not detected by the passive cutaneous anaphylaxis test in the serum of mice treated epicutaneously for 4 wk. [Cushman JR, Street JC; Toxicol Appl Pharmacol 70 (1): 29-42 (1983)]**PEER REVIEWED**
  
• Malathion was injected at concn of 3.99 or 6.42 mg/egg into the yolk sacs of 50 hen eggs incubated for 5 days. Twenty five control eggs were used. The eggs injected with malathion produced chicks exhibiting sparse plumage, micromelia, overall growth retardation, and beak defects. [Greenberg J, Laham QN; Can J Zool 47: 539-42 (1969) as cited in NIOSH; Criteria Document: Malathion p.74 (1976) DHEW Pub. NIOSH 76-205]**PEER REVIEWED**
  
• Malathion in concn greater than 1 ug/ml was toxic to primary cultures of chick embryo fibroblasts. [Wilson BW, Walker NE; Proc Soc Exp Biol Med 121: 1260-4 (1966) as cited in NIOSH; Criteria Document: Malathion p.76 (1976) DHEW Pub. NIOSH 76-205]**PEER REVIEWED**
  
• ... It is concluded that under the conditions of this bioassay, there was no clear evidence of the association of the tumor incidence with the administration of malathion to Osborne Mendel rats. Levels of Evidence for Carcinogenicity: Male Rats: Negative; Female Rats: Negative. [Bioassay of Malathion for Possible Carcinogenicity (1978) Technical Rpt Series No. 24 DHEW Pub No. (NIH) 78-824, U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014]**PEER REVIEWED**
  
• A daily dose of 46 mg/kg malathion ip for fifteen days affected the activity of the adrenal gland & liver glycogen in rats. The decr in the level of adrenaline, noradrenaline, and dopamine indicate that malathion causes incr adrenal medullary function without affecting the cortical activity. The incr glycogen levels in the liver of malathion exposed animals could be attributed to the release of adrenal catecholamines. [Gowda H et al; Indian J Med Res 77 (Dec): 847-51 (1983)]**PEER REVIEWED**
  
• Daily administration of malathion (46 mg/kg, ip) to female rats for 15 days prior to mating caused a significant reduction in the litter size and survival of pups. Though different traits of reproduction were not affected significantly, a slight effect was observed in viability index and lactation index in malathion treated animals. [Kumar R, Uppal RP; J Environ Biol 7 (1): 35-9 (1986)]**PEER REVIEWED**
  
• The effect of in vivo administration of malathion on cellular, humoral, and mitogenic responses was examined. Acute (50% LD50) or subacute (10% LD50/day for 14 days) treatment with malathion in vivo did not affect the in vivo generation of specific antibody secreting cells to sheep red blood cells or cytotoxic T-lymphocytes to allogeneic tumor. Acute treatment with 50% LD50 purified malathion did not affect body weight, splenic cell number, or thymus size. However, mitogenic responses to concanavalin A and lipopolysaccharide was significantly enhanced on all days tested following acute administration of malathion. In contrast, subacute treatment with malathion did not affect mitogenic response to concanvalin A or lipopolysaccharide, but led to a significant decrease in thymic cell number. [Rodgers KE et al; Pest Biochem Physiol 25 (3): 358-65 (1986)]**PEER REVIEWED**
  
• Malathion admin orally at 20-40 mg/kg for 2-19 days to juvenile rats caused a reduction of spermatogenic cells and Leydig cells. /From table; purity not given/ [National Research Council. Drinking Water and Health, Volume 6. Washington, D.C.: National Academy Press, 1986., p. 75]**PEER REVIEWED**
  
• Embryos of the sheepshead minnow, exposed to 10 mg/l malathion, developed skeletal deformities that rendered them incapable of normal swimming. Fry also manifested convulsive, uncoordinated movements, characteristic of the exposed embryos. Such fry, though sometimes normal looking, usually developed a bent appearance akin to scoliosis (lateral curvature of the spine). [Murty, A.S. Toxicity of Pesticides to Fish. Volumes I, II. Boca Raton, FL: CRC Press Inc., 1986., p. V2 56]**PEER REVIEWED**
  
• Exposure to malathion caused little alteration of hepatic protein in Clarias batrachus, but there was marked incr in the free amino acid level, with the incorporation of lysine into the protein of liver being drastically reduced. [Murty, A.S. Toxicity of Pesticides to Fish. Volumes I, II. Boca Raton, FL: CRC Press Inc., 1986., p. V2 72]**PEER REVIEWED**
  
• A single treatment of the Atlantic silverside with ... malathion or carbaryl induced optical malformations, although not dose related. In treated groups the axis formation & heartbeat initiation were impaired. Microphthalmia (reduced size of eyes), unilateral or bilaterial anophthalmia (absence of eyes), & cyclopia (median eye) were some of the observed deformities. After hatching, lordotic fry were seen in the 10 ug/l carbaryl or malathion ... groups. The ... insecticides reduced the survival time of the embryos. ... Carbaryl and malathion ... caused abnormalities in the circulatory system of the embryos of medaka. [Murty, A.S. Toxicity of Pesticides to Fish. Volumes I, II. Boca Raton, FL: CRC Press Inc., 1986., p. V2 82]**PEER REVIEWED**
  
• Growth of oyster, Crassostrea virginica, was reduced 32% by 96 hr exposure to 1 mg/l. [Butler PA; US Fish Wildlife Serv Circ 167 (1963) as cited in USEPA/OWRS; Quality Criteria for Water: Malathion (1986) EPA 440/5-86-001]**PEER REVIEWED**
  
• ... Inhibition of acetylcholinesterase (AChE) and mortality were noted in pinfish 24, 48, and 72 hours at measured concentrations of 142, 92, and 58 ug/l, respectively. A concentration of 31 ug/l caused 34 percent acetylcholinesterase inhibition in pinfish but no deaths in 72 hours. [Coppage DL et al; Pest Biochem Phys (1975) as cited in USEPA/OWRS; Quality Criteria for Water: Malathion (1986) EPA 440/5-86-001]**PEER REVIEWED**
  
• ... Moribund mullet, Mugil cephalus, in an estuary sprayed with malathion (3 oz/acre) during a large scale mosquito control operation had about 98% inhibition of brain acetylcholinesterase (AChE). [USEPA/OWRS; Quality Criteria for Water: Malathion (1986) EPA 440/5-86-001]**PEER REVIEWED**
  
• FOLLOWING THE ADMIN OF (3)H-O,O,S-TRIMETHYL PHOSPHOROTHIOATE (OOS-TMP), AN IMPURITY OF MALATHION, TO RATS, SUBSTANTIAL AMT OF RADIOLABELED MATERIAL WERE COVALENTLY BOUND TO LUNG WITH A CONCOMITANT DEPLETION OF GLUTATHIONE (GSH). OTHER ORGANS SHOWING SIGNIFICANT RADIOACTIVITY WERE LIVER, KIDNEYS, & ILEUM. THE MAX ACCUM OCCURRED IN THE TISSUES WITHIN 6 HR, & REACHED A PLATEAU BETWEEN 6-12 HR. THE COVALENT BINDING WAS POSSIBLY DUE TO A METABOLITE(S) OF (3)H-O,O,S-TRIMETHYL PHOSPHOROTHIOATE AND THE METABOLITE(S) WAS INVOLVED IN THE MECHANISM OF TOXICITY OF (3)H-O,O,S-TRIMETHYL PHOSPHOROTHIOATE. PULMONARY GLUTATHIONE MAY HAVE PLAYED A PROTECTIVE ROLE AGAINST (3)H-O,O,S-TRIMETHYL PHOSPHOROTHIOATE INDUCED LUNG TOXICITY. /(3)H-O,O,S-TRIMETHYL PHOSPHOROTHIOATE/ [IMAMURA T, HASEGAWA L; TOXICOL APPL PHARMACOL 72 (3): 476-83 (1984)]**PEER REVIEWED**
  
• White leghorn cockerels were fed a diet containing 0, 400, 800, and 1600 ppm of malathion for 90 days. Malathion at 800 and 1600 ppm caused a significant decrease in body weights. There was a significant increase in liver/body weight ratio. A marked inhibition of aniline hydroxylation and demethylation of p-chloro N-methylaniline was observed in the S9 fraction of the liver. Protein contents of liver supernatant of the treated group were significantly lower than control. Plasma half lives of antipyrine in cockerels receiving malathion at 800 and 1600 ppm were increased. Pentobarbital sleeping time was longer in malathion treated cockerels. [Varshneya C et al; Toxicol Lett 31 (2): 107-11 (1986)]**PEER REVIEWED**
  
• The effect of O,O,S-trimethyl phosphorothioate (OOS-TMP), an impurity in malathion, on immune responses such as antigen presentation, antibody production, and cytotoxic T-lymphocyte (CTL) function was examined in vitro. The roles of non enzymatic and enzymatic glutathione (GSH) conjugation of O,O,S-trimethyl phosphorothioate in these responses were studied. Antibody responses to T-dependent and T-independent antigens were evaluated after (i) direct culture with spleen or B cells; (ii) cocultivation of B cells with T cells with and without preincubation of O,O,S-trimethyl phosphorothioate with glutathione fortified cytosol. Antigen presentation by macrophages was also assessed after such treatment as compared to untreated controls. O,O,S-trimethyl phosphorothioate preincubated with glutathione had an inhibitory effect on the cytotoxic T lymphocyte and the direct hemolytic plaque forming cell responses. This was found to be mediated by a direct inhibitory effect on macrophages, T and B cells of the immune system and not through the generation of regulatory suppressor T cells. Thus, the mode of suppressive action of O,O,S-trimethyl phosphorothioate in vitro is due to inhibition of lymphocytic proliferation. This is only possible in the presence of glutathione which was determined to be a prerequisite for the induction of O,O,S-trimethyl phosphorothioate suppressive effect. [Thomas IK, Imamura T; Toxicol Appl Pharmacol 83 (3): 456-64 (1986)]**PEER REVIEWED**
  
• WITH IMPROVED SYNTHETIC METHODS PURITY OF THIS CMPD NOW EXCEEDS 99%. INCR IN PURITY HAS RESULTED IN CORRESPONDING DECR IN ACUTE TOXICITY SO THAT RECENT ORAL AE (A underlined) LD50'S FOR RATS TEND TO CLUSTER AROUND 2500 MG/KG ... [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-298]**PEER REVIEWED**
  
• beta- Glucuronidase activity increased in the liver of adult male rats in a dose dependent manner with malathion treatment (orally, for 3 wk). Low protein diets, however, appeared to reduce the enzyme activity. In protein deprived rats, there was initially a decrease in the activity of the enzyme which was greater after pesticide treatment. [Bulusu S, Chakravarty I; Bull Environ Contam Toxicol 36 (1): 73-80 (1986)]**PEER REVIEWED**
  
• There has been much debate concerning the teratogenic potential of the organophosphate pesticides, including malathion, although few experimental studies have been performed on mammals. This study was designed to expand the range of animal species used in the testing of malathion and to further evalutate malathion's teratogenic potential. A 100 mg/kg dose regimen from /days/ 7 to 12 of gestation was administered to New Zealand white rabbits. This produced no detectable differences in the number of resorptions, fetal size, and external or visceral anomalies between the treated and control groups. This suggests, as has been previously reported, that malathion has little or no teratogenic potential in the mammal. [Machin MG, McBride WG; J Toxicol Environ Health 26 (3): 249-53 (1989)]**PEER REVIEWED**
  
• The time course of immune modulation induced by acute treatment with O,S,S-trimethyl phosphorodithioate, an impurity in techincal formulations of malathion, was examined in female C57BL/6 mice. The immune parameters studied included the generation of cytotoxic T lymphocytes to alloantigen (H-2 incompatible) and antibody secreting cells to sheep red blood cells, proliferative response to the mitogens, and interleukin-2 production. Acute administration of the non-toxic doses of O,S,S-trimethyl phosphorodithioate, ie 20 or 40 mg/kg, led to an elevation in the generation of a cytotoxic T lymphocyte response on day 1 or 7, respectively. At 20 mg/kg O,S,S-trimethyl phosphorodithioate, the antibody response was elevated at day 3. However, at a dose of 40 mg/kg O,S,S-trimethyl phosphorodithioate, the antibody response was suppressed at day 1 following treatment. Following acute administration of 60 or 80 mg/kg O,S,S-trimethyl phosphorodithioate, the generation of an antibody and cytotoxic T lymphocytes responses was suppressed at all time points tested with 1 exception. One day following treatment at a dose of 60 mg/kg O,S,S-trimethyl phosphorodithioate, there was no change in the cytotoxic T lymphocytes response. At day 7 following treatment, the mitogenic responses to lipopolysacharide and phytchemagglutinin were elevated at administered. ... The proliferative response to concanavalin A was elevated in a dose dependent manner. Interleukin-2 production was suppressed following acute administration of 60 or 80 mg/kg O,S,S-trimethyl phosphorodithioate all doses of O,S,S-trimethyl phosphorodithioate at all time points tested and at all doses tested on day 5 following treatment. [Rogers KE, et al; Toxicology 51 (2-3): 241-54 (1988)]**PEER REVIEWED**
  
• The glutathione dependent degradation of salithion, which is one of the effective insecticide against organophosphate-resistant housefly (Musca domestica L.) and that of the ineffective insecticcides, fenitrothion and malathion, was studied. The most degradable insecticide was malathion (22% and 97% with susceptible SRS and organophosphate-resistant 3-Y homogenates, respectively), then fenitrothion (9% and 26%), and the least was salithion (3% and 9%). Ethacrynic acid inhibited the in vitro degradation of all three organophosphate-insecticides by both LSRS and 3-Y homogenates, and lowered the degradation level to the same as that existing under conditions without the addition of glutathione. [Shiotsuki T et al; Agric Biol Chem 51 (7): 1851-58 (1987)]**PEER REVIEWED**
  
• Results from the testing of 108 coded chemicals in Chinese hamster ovary cells for the induction of chromosome aberrations and sister chromatid exchanges are presented. All chemicals were tested with and without exogenous metabolic activation, using protocols designed to allow testing up to toxic doses. Cell harvest times could also be extended if chemical-induced cell cycle delay was seen. Chromosome aberrations were induced by 43 of the chemicals, and 66 induced sister chromatid exchanges; 37 of the chemicals were positive for both endpoints. [Cannon C et al; Environ Mol Mutagen 10 (Suppl 10) P1-175 1987]**PEER REVIEWED**
  
• Exposure to 0.5 of the 96 hr median lethal concentrations of endrin and malathion formulations retarded the gonadotrophin secretion in Heteropneustes fossilis & this led to a reduced ovarian (32)P uptake. The fish had reduced thyroid activity. After 4 wk of exposure to a concn of endrin or malathion that had no effect in 96 hr, the thyroid (131)I uptake and the conversion ratio of protein bound (131)I in blood serum, in relation to total serum were significantly reduced. At half the 96 hr median lethal concn both cmpd reduced the pituitary and serum thyroid stimulating hormone content. ... After 4 wk of exposure to half the 96 hr median lethal concn ... ovarian (32)P uptake was reduced in preparatory, prespawning, & spawning phases. ... These two pesticides seem to interfere with gonadotrophin secretion. [Murty, A.S. Toxicity of Pesticides to Fish. Volumes I, II. Boca Raton, FL: CRC Press Inc., 1986., p. V2 74]**PEER REVIEWED**
  
• ... It was concluded that under the conditions of this bioassay, malathion was not carcinogenic in male or female rats, but the females may not have received a maximum tolerated dose. ... Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative. [Bioassay of Malathion for Possible Carcinogenicity (1978) Technical Rpt Series No. 192 U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014]**PEER REVIEWED**
  
• Storage of technical malathion for 3-6 months at 40 deg C resulted in materials that were noticeably more toxic to mice. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 979]**PEER REVIEWED**
  
• The lethal dose in mammals is about 1 g/kg. [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 167]**PEER REVIEWED**
  
• Malathion: can be detoxified by hydrolysis of the carboxyl ester linkage by plasma carboxylesterases, and plasma carboxylesterase activity dictates species resistance to malathion. The detoxification reaction is much more rapid in mammals and birds than in insects. [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 167]**PEER REVIEWED**
  
• Malathion (technical grade, 95% pure) was fed to rats at a dietary concentration of 4000 mg/kg (approximate daily intake, 240 mg/kg bw) for two generations. Males and females 70-100 days of age were bred after 10 weeks on test; survival of the progeny of days 7 and 21 after birth was found to be reduced, and the surviving offspring showed growth retardation and an increased incidence of ring-tail disease. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 115 (1983)]**PEER REVIEWED**
  
• The clinical signs associated with organophosphorus cmpd poisoning are due to accumulation of acetylcholine & hence over-stimulation of the parasympathetic nervous system. It is usual to divide them under 3 categories, namely, muscarinic, nicotinic & central effects. Muscarinic signs ... consist of hypersalivation, lacrimation, sweating & nasal discharge. Miosis, dyspnea, vomiting, diarrhea & frequent urination also occur. The nicotinic effects consist of fasciculation of the muscles, weakness & paralysis. The central effects include nervousness, apprehension, ataxia, convulsions & coma. Death is due to resp failure, or sometimes cardiac arrest. There is little difference between the signs produced by the different organophosphorus compounds, but the route of absorption may influence one system more than another. /Organophosphorus insecticides/ [Humphreys, D.J. Veterinary Toxicology. 3rd ed. London, England: Bailliere Tindell, 1988., p. 157]**PEER REVIEWED**
  
• In adult cattle the minimum toxic oral dose of organophosphate pesticides varies from 1 to 125 mg/kg; the minimum toxic dermal concentration varies from 0.5 to 3%, but these figures are not sacred. The literature is not complete with regard to animal toxicity of organophosphates; even if it were, toxicity values would not be reliable because of the number of factors that influence toxicity of these chemicals under different conditions of use. /Organophosphorus pesticides/ [Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982., p. 985]**PEER REVIEWED**
  
• Biologic factors also influence toxicity of organophosphates. Species is very important here. ... Age of the animal is another biologic factor that alters toxicity of organophosphate pesticides. Compounds that do not require enzymatic activation are more toxic in very young animals in which the enzymes of pesticide degradation are deficient. Compounds that require enzymatic activation are not so toxic for very young animals because the enzymes of activation are deficient during the early weeks of life. Sex of the animals can also alter toxicity of organophosphates ... . /Organophosphate pesticides/ [Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982., p. 986]**PEER REVIEWED**
  
• Some anticholinesterase organic phosphorous compounds interfere with temperature control and make the body temperature of rats and mice abnormally dependent on the environmental temperature ... No such effect was observed in guinea pigs or rabbits. The effect in rats .. and in mice ... was partially prevented by atropine, suggesting that it is related to cholinesterase inhibition. /Organic phosphorous pesticides/ [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 929]**PEER REVIEWED**
  
• The cause of death in poisoning by organic phosphorous compounds is usually respiratory failure and consequent anoxia but may be cardiovascular in origin. Four factors (excessive secretion of the respiratory tract, bronchoconstriction, weakness of the muscles of respiration, and failure of the respiratory center) may contribute to respiratory failure. ... In a few instances, death has followed profound brain damage that occurred, usually early in the course of poisoning, as a result of severe anoxia ... . /Organic phosphorous pesticides/ [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 930]**PEER REVIEWED**
  
• Some organic phosphorous compounds produce an immediate /CNS depressant/ effect, ranging from incoordination to deep anesthesia following iv injection. At the same time respiration may be affected. A large dosage is required for all compounds for which the effect has been demonstrate and, by necessity, all of them are of low toxicity. /Organic phosphorous pesticides/ [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 971]**PEER REVIEWED**
  
• Although some anticholinergic compounds are teratogenic, most are not. /Organic phosphorous pesticides/ [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 971]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• LD50 Rat (male) oral 5,843 mg/g [Hazelton, Holland; Arch Ind Hyg Occup Med 8: 399-405 (1953)]**PEER REVIEWED**
  
• LD50 Mice (male) oral 4,059 mg/mg [Hazelton, Holland; Arch Ind Hyg Occup Med 8: 399-405 (1953)]**PEER REVIEWED**
  
• LD50 Rat male oral 1375 mg/kg /purity of cmpd not stated/ [Farm Chemicals Handbook 1989. Willoughby, OH: Meister Publishing Co., 1989., p. C-180]**PEER REVIEWED**
  
• LD50 Rat (female) oral 1000 mg/kg /purity of cmpd not stated/ [Farm Chemicals Handbook 1989. Willoughby, OH: Meister Publishing Co., 1989., p. C-180]**PEER REVIEWED**
  
• LD50 Dog intraperitoneal 1.51 ml/kg (19% soln) [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 623]**PEER REVIEWED**
  
• LD50 Rabbit percutaneous 4100 mg/kg /purity of cmpd not stated/ [Farm Chemicals Handbook 1989. Willoughby, OH: Meister Publishing Co., 1989., p. C-180]**PEER REVIEWED**
  
• LD50 Rat intraperitoneal 750 mg/kg /purity of cmpd not stated/ [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 623]**PEER REVIEWED**
  
• LD50 Mouse intraperitoneal 420-474 mg/kg /purity not stated/ [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 623]**PEER REVIEWED**
  
• LD50 Chicken subcutaneous 1400 mg/kg /purity of cmpd not stated/ [ITII. Toxic and Hazarous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1982., p. 308]**PEER REVIEWED**
  
• LD50 Guinea pig oral 570 mg/kg /purity not stated/ [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 623]**PEER REVIEWED**
  
• LD50 Rat subcutaneous 1000 mg/kg /purity not stated/ [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 623]**PEER REVIEWED**
  
• LD50 Rat percutaneous > 4444 mg/kg /purity not stated/ [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 623]**PEER REVIEWED**
  
• LD50 Rat oral 290 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2083]**PEER REVIEWED**
  
• LC50 Rat ihl 43,790 ug/cu m/4 hr [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2083]**PEER REVIEWED**
  
• LD50 Rat ip 250 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2083]**PEER REVIEWED**
  
• LD50 Rat iv 50 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2083]**PEER REVIEWED**
  
• LD50 Mouse oral 190 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2083]**PEER REVIEWED**
  
• LD50 Mouse skin 2330 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2083]**PEER REVIEWED**
  
• LD50 Mouse ip 193 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2083]**PEER REVIEWED**
  
• LD50 Mouse sc 221 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2083]**PEER REVIEWED**
  
• LD50 Mouse iv 184 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2084]**PEER REVIEWED**
  
• LD50 Dog ip 1857 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2084]**PEER REVIEWED**
  
• LD50 Rabbit oral 250 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2084]**PEER REVIEWED**
  
• LD50 Rabbit skin 4100 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 2084]**PEER REVIEWED**
  
• LD50 Rat (female) oral 1400 mg/kg [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 736]**PEER REVIEWED**
  
• LD50 Rabbit dermal 2460 to 6150 mg/kg [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 736]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• THE LESS VOLATILE AGENTS THAT ARE COMMONLY USED AS AGRICULTURAL INSECTICIDES (EG PARATHION, FENTHION, DIAZINON, MALATHION) ARE GENERALLY DISPERSED AS AEROSOLS OR AS DUSTS CONSISTING OF THE ORGANOPHOSPHORUS COMPOUND ADSORBED TO AN INERT, FINELY PARTICULATE MATERIAL. CONSEQUENTLY, THE COMPOUNDS ARE ABSORBED RAPIDLY AND EFFECTIVELY BY PRACTICALLY ALL ROUTES, INCLUDING THE GASTROINTESTINAL TRACT, AS WELL AS THROUGH THE SKIN AND MUCOUS MEMBRANES FOLLOWING CONTACT WITH MOISTURE, AND BY THE LUNG AFTER INHALATION. [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 169]**PEER REVIEWED**
  
• ... WHEN (14)C-MALATHION ... WAS APPLIED /TO HUMAN SKIN/ 7, 9, & 23% WERE ABSORBED THROUGH FOREARM, ABDOMEN, & FOREHEAD, RESPECTIVELY. [The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972., p. 144]**PEER REVIEWED**
  
• THE INSECTICIDE (14)C-MALATHION WAS ABSORBED & RAPIDLY EXCRETED IN RATS. 8 HR AFTER ORAL DOSE, 44% OF (14)C HAD BEEN EXCRETED IN URINE & 47% STILL REMAINED IN GI TRACT, WHEREAS AFTER 24 HR, 83% HAD BEEN EXCRETED IN URINE, 6% IN FECES, 3% IN EXPIRED AIR, & 8% REMAINED IN GI TRACT. EXCRETION OF (32)P AFTER AN ORAL DOSE OF (32)P-MALATHION TO LACTATING COW WAS LESS RAPID. 69% WAS EXCRETED IN 4 DAY URINE, 8% IN FECES, & 0.2% IN MILK. SINCE EXCRETION OF (32)P WAS VERY SLOW AFTER THAT TIME, ITS INCORPORATION INTO BODY TISSUES HAD PROBABLY OCCURRED, & ITS RELEASE WAS DEPENDENT ON TURNOVER RATES OF THOSE TISSUES. [The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970., p. 78]**PEER REVIEWED**
  
• Percutaneous absorption of chronically applied malathion was determined in man and chronic absorption was compared to single dose absorption. (14)C-Malathion was applied topically to the ventral forearm of human male volunteers. This procedure was followed by repeated administration of non radioactive malathion to the same site. (14)C-Malathion was reapplied on day 8 when urinary excretion of radioactivity from the first application reached minimum detectable levels. Percutaneous absorption from the first admin was 4.48% of the applied dose. Absorption from the second administration was 3.53%. Therefore, the single dose application data are relevant for predicting toxic potential for long term exposure. [Wester RC et al; Toxicol Appl Pharmacol 68 (1): 116-9 (1983)]**PEER REVIEWED**
  
• EIGHT AUTOPSY SAMPLES FROM AN INDIVIDUAL WHO HAD INGESTED A LARGE AMT OF MALATHION WERE ANALYZED. MALATHION WAS PRESENT IN ALL SAMPLES EXCEPT LIVER. THE HIGHEST CONCN WERE FOUND IN GASTRIC CONTENTS (8621 PPM) & ADIPOSE TISSUE (76.4 PPM). MALAOXON WAS IDENTIFIED IN SOME TISSUES AT VERY LOW LEVELS; A SIGNIFICANT AMT WAS FOUND ONLY IN FAT (8.2 PPM). MALATHION MONOCARBOXYLIC ACID & MALATHION DICARBOXYLIC ACID WERE FOUND IN GREATER ABUNDANCE: 221 PPM IN BILE, 106 PPM IN KIDNEY, & 103 PPM IN THE GASTRIC CONTENTS. [MORGADE C, BARQUET A; J TOXICOL ENVIRON HEALTH 10 (2): 321-5 (1982)]**PEER REVIEWED**
  
• Measurement was made of: the ether extractable phosphates in the urine of an adult man who had been administered malathion in a single oral dose of 58 mg (0.84 mg/kg). A total of 23% of the ingested dose was recovered in the ether extractable, urinary phosphate fraction of the urine during the first 16.3 hours. 97% of this recovered dose was excreted in the first 7.5 hours. ... Based on experiments in rats injected ip or fed (32)P-labeled malathion, /it was/ found that an average of 69 and 36%, respectively, of the malathion excreted in the urine to be recoverable in the ether extractable fraction. [Mattson AM, Sedlak VA; J Agric Food Chem 8: 107-10 (1960) as cited in NIOSH; Criteria Document: Malathion p.40 (1976) DHEW Pub. NIOSH 76-205]**PEER REVIEWED**
  
• ... 7% OF TOTAL METABOLITES IN FECES /FROM COW GIVEN MALATHION ORALLY/ WAS CHLOROFORM SOLUBLE, OF WHICH 85% WAS MALATHION & 12% MALAOXON. THE MILK CONTAINED A SMALL AMOUNT OF MALATHION METABOLITES (9.2% OF TOTAL DOSE AFTER 7 DAYS); OF THIS, ONLY 29% WAS EXTRACTABLE OUT OF MILK AND PARTITIONED IN FAVOR OF WATER OVER BENZENE, INDICATING THE ABSENCE OF EITHER MALATHION OR MALAOXON. [White-Stevens, R. (ed.). Pesticides in the Environment: Volume 1, Part 1, Part 2. New York: Marcel Dekker, Inc., 1971., p. 166]**PEER REVIEWED**
  
• No malathion residues were found 24 hr after the exposure of pinfish to 75 ug/l; only malathion monoacid was detected in the gut. [Murty, A.S. Toxicity of Pesticides to Fish. Volumes I, II. Boca Raton, FL: CRC Press Inc., 1986., p. V1 91]**PEER REVIEWED**
  
• The American cockroach was treated by topical application of (14)C-malathion. The distribution of the label within the body tissues was found to be both rapid and extensive. As much as 40% of the applied label was still present superficially in the cuticle even 24 hr post-application. The overall tissue ranking order for (14)C label was found to be: foregut > digestive tract contents > skeletal muscle > fat body > hidout > midgut > nerve cord > brain > malpighian tubules. Malathion, malaoxon and malathion monoacids were detected in the nerve cord plus brain, the digestive tract, skeletal muscle and fat body at 1, 2 and 24 hr after topical application of the insecticide. At 24 hr post-application a significant proportion of malathion remained unmetabolized in all tissues examined. The highest levels of metabolic transformation were found in the digestive tract and fat body. Insects were prostrate 24 hr after topical application of (14)C-malathion. In these insects the greatest concentration of malathion and monoacids (expressed in relation to unit tissue wt) was found in the digestive tract. On the other hand, the nerve cord and brain contained the greatest concentration of malaoxon. About 18% of applied (14)C-malathion label partitioned into the tissue aqueous phase up to 24 hr after topical application but very little applied label was expired as (14)CO2 or excreted. Although a neurotoxic action may be the cause of prostration and death, the extensive dissemination of malathion and its products belies the concept of any tissue specificity. The haemolymph, after an initial sharp rise in malathion content, maintained a steady malathion level over the 24 hr experimental periods suggesting that the hemolymph is the main distributor of the insecticide to the various body tissues. [Dales MJ et al; Comp Biochem Physiol C Comp Pharmacol Toxicol 92 (1): 155-62 (1989)]**PEER REVIEWED**
  
• Most organophosphate compounds are ... absorbed from skin, conjunctiva, gastrointestinal tract, & lung. /Organophosphate compounds/ [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 1071]**PEER REVIEWED**
  
• The rate of dermal absorption /of organophosphorus pesticides/ may be ... influenced by the solvent used. /Organophosphorus insecticides/ [Humphreys, D.J. Veterinary Toxicology. 3rd ed. London, England: Bailliere Tindell, 1988., p. 157]**PEER REVIEWED**
  
• Many of /the organophosphorus insecticides/ are excreted in the milk ... /Organophosphorus insecticides/ [Humphreys, D.J. Veterinary Toxicology. 3rd ed. London, England: Bailliere Tindell, 1988., p. 157]**PEER REVIEWED**
  
• Following their absorption, most organophosphorus cmpd are excreted almost entirely as hydrolysis products in the urine. /Anticholinesterase agents/ [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 169]**PEER REVIEWED**
  
• TOXICANTS CAN BE ABSORBED BY INHALATION, INGESTION, AND SKIN PENETRATION. ... ALL UNDERGO HYDROLYTIC DEGRADATION IN LIVER AND OTHER TISSUES, USUALLY WITHIN HR OF ABSORPTION. DEGRADATION PRODUCTS ARE OF LOW TOXICITY, AND ARE EXCRETED IN URINE AND FECES. /ORGANOPHOSPHATE CHOLINESTERASE-INHIBITING PESTICIDES/ [Morgan, D.P. Recognition and Management of Pesticide Poisonings. EPA 540/9-80-005. Washington, DC: U.S. Government Printing Office, Jan. 1982., p. 2]**PEER REVIEWED**
  
• THEY: ... ARE RAPIDLY ABSORBED THROUGH MUCOUS MEMBRANE OF DIGESTIVE SYSTEM, RESPIRATORY SYSTEM & THE SKIN, & CONVEYED BY THE BLOOD TO VARIOUS BODY TISSUES. ... THE MAIN ROUTE OF ELIMINATION ... /IS/ THE KIDNEYS. /ORGANOPHOSPHORUS PESTICIDES/ [International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour Office, 1983., p. 1638]**PEER REVIEWED**
  
• Organic phosphorous insecticides are absorbed by the skin, as well as by the respiratory and GI tracts. Absorption by the skin tends to be slow, but, because the insecticides are difficult to remove, such absorption is frequently prolonged. Skin absorption is somewhat greater at higher temperatures and may be much greater in the presence of dermatitis. /Organic phosphorous pesticides/ [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 937]**PEER REVIEWED**
  

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Metabolism/Metabolites

• SELECTIVE TOXICITY TO INSECTS HAS BEEN ACCOUNTED FOR BY DIFFERENCES IN METABOLISM. (32)P-MALATHION IS RAPIDLY METABOLIZED IN MICE, RATS, & DOGS, PRINCIPALLY BY HYDROLYSIS OF THE ETHYL ESTER BONDS TO GIVE MALATHION MONOESTER & MALATHION DIACID, WHEREAS IN INSECTS OXIDN TO MALAOXON & CLEAVAGE OF THE PHOSPHATE THIOESTER BOND TO GIVE O,O-DIMETHYL-PHOSPHORODITHIONATE & -PHOSPHOROTHIONATE ARE THE PRINCIPAL ROUTES OF METAB. THE TOXICITY OF MALATHION IS PROBABLY DUE TO ITS OXIDATION TO MALAOXON, WHICH IS SOME 1000 TIMES MORE ACTIVE THAN MALATHION AS AN ANTI CHOLINESTERASE. [Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968., p. 204]**PEER REVIEWED**
  
• MALATHION ... REQUIRES ACTIVATION TO /MALAOXON/ ... TO BECOME AN ACTIVE ANTICHOLINESTERASE AGENT. ... THE CONVERSION OF MALATHION TO MALAOXON IS A REACTION CARRIED OUT BY THE LIVER MICROSOMAL MONOOXYGENASE SYSTEM. COMPETING WITH THE ACTIVATION OF MALATHION ARE ENZYMES RESPONSIBLE FOR ITS DEGRADATION TO NON-TOXIC METABOLITES. THESE ARE ... CHARACTERIZED AS PHOSPHATASES AND CARBOXYLESTERASES OR ALIESTERASES. PRODUCTS OF REACTIONS CATALYZED BY THESE ENZYMES ARE MALATHION MONOESTER, VARIOUS PHOSPHORIC ACIDS & DEMETHYLATED PRODUCT. ... THE DEGRADATION RATE OF MALAOXON EXCEEDS THE ACTIVATION RATE OF MALATHION, SO THERE IS ... LITTLE ACCUMULATION OF THE TOXIC ACTIVATION PRODUCT IN MAMMALIAN SYSTEMS. [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 622]**PEER REVIEWED**
  
• STUDIES /SHOWED/ ARTHROBACTER SP ... WAS CAPABLE OF DEGRADING MALATHION. LAB STUDIES IDENTIFIED METABOLITES AS MALATHION HALF ESTER, DICARBOXYLIC ACID, DIMETHYL PHOSPHORODITHIOATE, & DIMETHYL PHOSPHOROTHIOATE. [Menzie, C.M. Metabolism of Pesticides, Update II. U.S. Department of the Interior, Fish Wildlife Service, Special Scientific Report - Wildlife No. 2l2. Washington, DC: U.S. Government Printing Office, 1978., p. 165]**PEER REVIEWED**
  
• WHEN LARVAL HOMOGENATES OF MALATHION-RESISTANT & ... SUSCEPTIBLE STRAIN OF INDIAN MEAL MOTH (PLODIA INTERPUNCTELLA HUBNER) WERE TESTED FOR ESTERASE ACTIVITY, RESISTANT STRAIN HAD GREATER ALPHA-NAPHTHYL ACETATE ESTERASE THAN SUSCEPTIBLE STRAIN; LESS CARBOXYLESTERASE & BUTYRYLCHOLINESTERASE; & SIMILAR ACETYLCHOLINESTERASE ACTIVITY. [Menzie, C.M. Metabolism of Pesticides, Update II. U.S. Department of the Interior, Fish Wildlife Service, Special Scientific Report - Wildlife No. 2l2. Washington, DC: U.S. Government Printing Office, 1978., p. 165]**PEER REVIEWED**
  
• Metabolite of malathion found in cow feces: dimethyl phosphate. /From table/ [DeRoetth A Jr, Am J Ophthalmol 59: 586-92 (1965) as cited in NIOSH; Criteria Document: Malathion p.168 (1976) DHEW Pub. NIOSH 76-205]**PEER REVIEWED**
  
• Metabolites of malathion in cow, rat, and dog urine and serum are desmethyl malathion and malathion diacid. /From table/ [O'Brien RD; Insecticides - Action and Metabolism p.32-107 (1967) as cited in NIOSH; Criteria Document: Malathion p.168 (1976) DHEW Pub. NIOSH 76-205]**PEER REVIEWED**
  
• A metabolite of malathion in mouse urine and serum is desmethyl malathion. /From table/ [NIOSH; Criteria Document: Malathion p.168 (1976) DHEW Pub. NIOSH 76-205]**PEER REVIEWED**
  
• In plants ... /the/ malathion carboxylic acids /malathion mono & dicarboxylic acids/ are ... formed. [Matsumura, F. Toxicology of Insecticides. 2nd ed. New York, NY: Plenum Press, 1985., p. 267]**PEER REVIEWED**
  
• Malathion ... is broken down by the mammalian liver. ... Malathion`s selectivity is due to the presence of the carboxyl groups, which are susceptible to mammalian hydrolysis. [Matsumura, F. Toxicology of Insecticides. 2nd ed. New York, NY: Plenum Press, 1985., p. 77]**PEER REVIEWED**
  
• Two organophosphorus impurities of technical malathion (insecticide), isomalathion and O,S,S-trimethyl phosphorodithioate, were examined for their effects on the in vivo metabolism of malathion in rats. Both impurities were confirmed to be potent in vivo inhibitors of plasma, liver, and kidney malathion carboxylesterases at relatively low doses. Pretreatment of rats with these impurities followed by administration of (14)C malathion resulted in changes in the quantities of certain malathion metabolites excreted in the urine. Compared to the corn oil pretreated controls, the most notable change in the impurity pretreated animals was in the decrease in the amount of malathion diacid excreted along with a commensurate increase in the amount of excreted malathion alpha monoacid. An increase in malaoxon metabolites in the urine of impurity pretreated rats was indicated, suggesting that more malaoxon was originally produced in these animals. [Ryan DL, Fukuto TR; Pest Biochem Physiol 21 (3): 349-57 (1984)]**PEER REVIEWED**
  
• BY USING HIGH SPECIFIC ACTIVITY MALATHION & ION EXCHANGE CHROMATOGRAPHY, A TOTAL OF 11 METABOLITES WERE ISOLATED FROM THE GERMAN COCKROACH, AMERICAN COCKROACH, & THE COMMON HOUSEFLY, & SEVEN METABOLITES FROM THE WHITE MOUSE. THE PRINCIPAL METABOLITES ISOLATED FROM THE MOUSE WERE MONOETHYL ESTER OF MALATHION (86%), DIMETHYL PHOSPHOROTHIOIC ACID (13%), DIMETHYL PHOSPHORODITHIOIC ACID (5%), 10% OF AN UNKNOWN METABOLITE. RELATIVE AMT OF VARIOUS METABOLITES OBTAINED WERE SIMILAR BETWEEN ROACHES, WHICH IN TURN WERE SLIGHTLY DIFFERENT FROM FLIES. ... LEVEL OF MALAOXON WAS ... GREATER IN COCKROACH THAN IN MOUSE @ ANY TIME AFTER INJECTION, EG, @ 1 HR AFTER INJECTION /OF MALATHION/ THERE WAS 10 TIMES MORE MALAOXON PER G OF ANIMAL. RELATIVE PROP OF METABOLITES INDICATES GREATER PS TO PO ACTIVATION IN INSECTS COMPARED TO MAMMALS ... [White-Stevens, R. (ed.). Pesticides in the Environment: Volume 1, Part 1, Part 2. New York: Marcel Dekker, Inc., 1971., p. 165]**PEER REVIEWED**
  
• The conversion of many organophosphates with a P=S group to P=O is another instance of activation by MFO /mixed function oxidase/ resulting in an incr in toxicity. This process explains the greater toxicity of metabolites like paraoxon, malaoxon, fenitrooxon, etc than that of their parent compounds. [Murty, A.S. Toxicity of Pesticides to Fish. Volumes I, II. Boca Raton, FL: CRC Press Inc., 1986., p. V1 94]**PEER REVIEWED**
  
• The hydrolysis of malathion by rabbit liver oligomeric and monomeric carboxylesterase results in the formation of a mixture of an alpha and beta monoacid. The oligomeric carboxylesterase produced an alpha/beta ratio of monoacids of 4.55, and the monomeric carboxylesterase produced an alpha/beta ratio of monoacids of 2.33. Kinetic studies demonstrated that the Km values were the same for the corresponding reactions which produced alpha monoacid, or beta monoacid with the same enzyme. Since both carboxylesterases are electrophoretically pure, the kinetic data strongly supports the theory that the reactions which produced alpha and beta monoacids are catalyzed by the same active site. [Lin PT et al; Pest Biochem Physiol 20 (2): 232-7 (1983)]**PEER REVIEWED**
  
• In man, malathion is metabolized by (1) hydrolytic cleavage of ethyl groups from the succinic acid moiety of the molecule by carboxylesterase enzymes; and (2) hydrolysis of the succinate moiety from the dialkyl thiophosphate. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 119 (1983)]**PEER REVIEWED**
  
• Plasma and tissue enzymes are responsible for hydrolysis /of organophosphorus compounds/ to the corresponding phosphoric and phosphonic acids. However, oxidative enzymes are also involved in the metabolism of some organophosphorus compounds. /Anticholinesterase agents/ [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 169]**PEER REVIEWED**
  
• The organophosphorus anticholinesterase agents are hydrolyzed in the body by a group of enzymes known as A-esterases or paraoxonases. These enzymes are found in the plasma and liver and hydrolyze a large number of organophosphorus compounds ... by cleaving the phosphoester, anhydride, P-F, or P-CN bonds. /Anticholinesterase agents/ [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 169]**PEER REVIEWED**
  

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TSCA Test Submissions

• Malathion (CAS # 121-75-5) was evaluated for cytotoxicity in study to evaluate the validity of in vitro testing for direct reuse water toxicity in mammalian systems. As a quick, inexpensive, reproducible, and sensitive means of detection, if this test is also a valid reflection of toxicity in mammals, it would be highly beneficial in assessing the potability of direct reuse water and in prescribing mode of water treatment. Continuous L-cell cultures (mouse or rat, 26 cultures/assay, >200,000 cells/culture) in minimal medium with 1% fetal bovine serum were exposed to 12 graded doses (unspecified) in ethanol solution for 72 to 96 hours. A reflection of effects on growth and reproduction of the indicator cells, the change in protein synthesis as determined by calorimetric Lowry method was chosen to quantify the cytotoxicity in 6 cultures/assay at 24, 48, 72 and 96 hours after initiation of study. A concentration of 32 mg/L was toxic to L-cells. Levels greater than 1 mg/L inhibited protein production in a time-dependent manner; cells exposed in vitro to 18 mg/L demonstrated static protein synthesis by the third day, with protein loss evident at Day 4. The effect was less pronounced in response to a 10 mg/L malathion exposure, although this level halved protein synthesis (LC50). An LC10 was 2.0 mg/L. The authors suggested that the timed response might be due to altered cellular metabolism or intracellular accumulation of malathion. The LC50 (10 mg/L) was both significantly lower than the NOEL in chronic animal studies (100-1000 and 100 ppm in rats and dogs, respectively) and higher than WHO/FAO's maximum daily intake standard (0.02 mg/kg/day). However, a positive relationship was established in both instances by a two-way ANOVA statistical method, indicating a relevant toxicological result with the cell culture bioassay. Malathion, a non-persistent (biodegradable) and poorly soluble insecticide of low relative mammalian toxicity that is rarely found in drinking water, bears no EPA-derived drinking water standard limit. Using an EPA convention for calculation of drinking water maximum limits and either the same historical minimal effect level or WHO/FAO data, the resultant standard (0.03 or 0.15 mg/L respectively) would be undetectable with the tissue culture bioassay.[U S Dept of the Army; The Development of a Test for the Potability of Water Treated by Direct Reuse System (Contract No. DADA-17-73-C-3013) (Final Report); 04/21/80; EPA Document No. 40-8069226; Fiche No. OTS0517889]**UNREVIEWED**
  
• Malathion (CAS # 121-75-5) was evaluated for acute oral toxicity in study of strain-specific differences in Fischer 344-derived (CDF) and Sprague-Dawley (SPB) rats (5/sex/strain/group) administered single oral doses of 252 to 3980 mg/kg by oral gavage. Groups of female rats of both strains received doses of 252, 500, 1000, 2000, and 3980 mg/kg, while groups of male rats also received doses of 2520 mg/kg. Additional groups of Sprague-Dawley males only received doses of 2100 and 2250 mg/kg. Single-dose oral LD50's, based on a moving average method, were 2101 and 2102 mg/kg for SPB males and females and 1875 and 1898 mg/kg for CDF male and female rats, respectively. Clinical signs of toxicity, associated with doses of 500 and above throughout 14-day post-gavage observation, included lethargy, total body tremors, bluish face (1000-3980 mg/kg, SPB females only), piloerection, heightened tail color (2000 mg/kg, 5/5 SPB males only), gasping, and convulsions. No significant treatment-related changes in bodyweight were noted in either strain. Upon necropsy of both surviving and decedent rats, gross lesions were limited to focal corneal cloudiness, which was more prevalent in the CDF males. The authors concluded, however, that the overall response between these strains of rat were comparable.[Dow Chem Co; A Comparison of Single-Dose Oral LD50's for SPB; 05/01/92; EPA Document No. 88-920002473; Fiche No. OTS0537283]**UNREVIEWED**
  

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Footnotes

¹ Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.