Malathion (CAS # 121-75-5; C₁₀H₁₂O₆PS₂) is normally a liquid, brown to yellow to clear in color, with a distinctive odor similar to garlic, skunks, or mercaptans (e.g., natural gas). Its molecular weight is 330.4. It sinks in water and is virtually insoluble (145 ppm at 70 F or 0.0015%); the liquid has a vapor pressure of 10^-4 mm mercury indicating a slow natural vaporization. The liquid boils and decomposes at 140 F and freezes at 37 F (NIOSH 1997). It is soluble in organic solvents, including xylene and naphtha (Cornell 2000).

Malathion is an organophosphate insecticide and neurotoxin. A more chemically-descriptive synonym is O,O-dimethyl S-(1,2-dicarbethoxyethyl) phosphorodithioate (NIOSH 1978). A search of an MSDS website with over 250,000 data sheets yielded 55 different formulations using malathion as an active ingredient or co-ingredient (Cornell 2000). The most common use of public health significance for this particular insecticide as opposed to the rest of this class of chemicals is the control of mosquitos and other flying insects, especially during outbreaks of vector-borne diseases (e.g., West Nile encephalitis). This use usually involves formulations that are known as ultra-low velocity (ULV) because of the type of aerosol sprayer used to dispense the agent (EPA 2000a). These formulations are usually in the range of 90 to 95% malathion (Cornell 2000). According to one analysis, the remaining ~5% consists of 15 separate impurities, mostly phosphorus thionates (CalEPA 1993). Other studies report impurities consisting of the thionates and malaoxon, the oxygen analog of malathion. The fogger dilutes the pesticide with air to a concentration of about 1% (EPA 2000a).

Malathion degrades rapidly in the environment, especially in moist soil (EPA 2000a).

In soil, malathion is expected to be highly mobile, but should not volatilize significantly. Biodegradation in soil is rapid, with 80-95% biodegradation occurring in 10 days; it may be much faster, depending on soil content. Its half-life in soil is estimated by various authors at less than one day, to 6 days, depending on the pH and the degradation pathway studied.

If released into water, malathion is not expected to adsorb to suspended solids and sediment in water and should not volatilize from water. Biodegradation may occur in 2 weeks and hydrolysis within 2 to 11 days, according to HSDB (2000). However, NYDOH (2000) states that malathion can persist in water for extended periods, and cites various sources which indicate that malathion has a half life in water of 41 days (aqueous photolysis degradation) to 173 days (in water without sunlight for photolysis). Computer modeling suggests malathion will not bioaccumulate (HSDB 2000).

If released to air, malathion should exist solely as a vapor in the ambient atmosphere and be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be ~5 hours. Malathion may also undergo photolysis.

Essentially, malathion in the open environment undergoes hydrolysis, biodegradation, and photolysis roughly in that order of importance. The rate of transformation is heavily dependent on pH and organic content of the environmental medium. For instance, studies indicate that hydrolysis is not significant in water at pH 5. At pH 7, malathion may completely hydrolyze in 6-7 days, whereas, at pH 9, hydrolysis is complete in less than 12 hours (EPA 2000a). Under least favorable conditions (i.e., low pH and little organic content), malathion may persist with a half-life of months or even years. However, under most conditions, the half-life appears to be roughly 7-14 days (HSDB 2000).

The levels of malathion that have been found in the environment are summarized in Table 1.

* Not Available

Because of the wide use of malathion, food tolerances and residues vary significantly by crop. Many of the current standards may be found on the Internet in the National Library of Medicine's Toxicology Network (ToxNet) at www.toxnet.nlm.nih.gov. Officials should contact the USDA and FDA to verify food tolerances.

Malathion is toxic to aquatic organisms and certain species of birds and mammals at concentrations that may be attained in the open environment (EPA 2000a), especially in waterbodies with limited outflows or slow flowrates. The specific gravity and low solubility of malathion makes it likely to affect aquatic organisms that live or feed at the lower ends of the water column. The effects appear to be acute and other data does not support concerns about any bioconcentration in the food chain (HSDB 2000). Table 2 summarizes the toxicity data of some common or representative species.

Fortunately, malathion has relatively low toxicity for birds and mammals, and low potential for bioaccumulation (EPA 2000b,c; Humphreys 1988; Osweiller 1996; USDOI 1975). The use of malathion is approved for direct application on livestock, cats and dogs to control for fleas and ticks. Fish are particularly susceptible, and care should be taken to prevent contamination of surface waters such as ornamental fish ponds, streams, etc (EPA 2000b,c; Osweiler 1996; Vanschueren 1996). Although malathion is highly toxic to insects, for which it is designed to control, beneficial insects such as honeybees are also susceptible (EPA 2000b,c; Osweiller 1996; USDOI 1980 and 1984).

Summary/Overview

Malathion appears to be readily excreted, based on an oral rat study, where more than 90% of the dose was excreted (mostly in urine) within 72 hours, with most excretion in the first 24 hours. Malathion does not appear to bioaccumulate in organs or tissues. Based on a dermal absorption study in humans, it has been determined that the dermal absorption rate for malathion is about 10%. The major metabolites of malathion are the diacid and monoacid metabolites, namely, malathion dicarboxylic acid (DCA) and malathion monocarboxylic acid (MCA). Malaoxon, the active cholinesterase-inhibiting metabolite of malathion, is a minor metabolite. Malathion's mode of toxic action is the inhibition of cholinesterase which is caused by malaoxon. The toxicity of malathion could be altered by interactions with chemicals that interfere with its detoxication, with chemicals that have the same mechanism of action, or with chemicals that induce hepatic microsomal enzymes.

Absorption, Distribution, and Excretion

In a study in Sprague-Dawley rats (Reddy et al. 1989), single doses of radiolabeled ¹⁴C-malathion (98% purity) were administered by oral gavage to groups of 5 male and 5 female adult rats at dose levels of 40 mg/kg, 800 mg/kg and 40 mg/kg following 15 days of daily oral gavage of non-radio labeled malathion (94.6%) at a dose level of 40 mg/kg/day. More than 90% of the radioactivity in the 40 mg/kg dose was excreted within 72 hours, with most excretion occurring in the first 24 hours. Approximately 80-90% of the administered radioactivity was excreted in the urine. Only minor differences in urine/fecal excretion ratios were observed between animals given 40 mg/kg, 800 mg/kg and 40 mg/kg after 15 previous daily doses of malathion. At 72 hours, the highest concentration of radioactivity was observed in the liver, but less than 0.3% of the administered radioactivity was present in that organ. Radioactivity did not bioaccumulate in any of the tissues analyzed.

Measurement was made of the ether extractable phosphates in the urine of an adult man who was administered a single oral dose of malathion (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 with 97% of this recovered dose excreted in the first 7.5 hours (HSDB 2000).

Autopsy samples from an individual who had ingested a large amount of malathion were analyzed and malathion was present in all samples except the liver. The highest concentrations were found in gastric contents (8621 ppm) and adipose tissue (76.4 ppm). Malaoxon was identified in fat (8.2 ppm) and some other tissues at very low levels. MCA and DCA were found in the bile (221 ppm), kidney (106 ppm) and gastric contents (103 ppm) (HSDB 2000).

In a study to quantify potential human exposure to malathion via dermal contact from ground ULV mosquito sprays, deposition was monitored on body surfaces of 3 human subjects during malathion spraying using a truck-mounted ULV aerosol generator (Moore et al. 1993). Two of the subjects stood at stationary positions for 5 minutes downwind at 7.6 m and 15.2 m, facing the path of the spray vehicle; the other subject jogged in the same direction and immediately downwind at 1.5 m of the vehicle. The amount of time the jogger was exposed was not specified. Deposition of malathion droplets on the skin surfaces was determined from analysis of gauze patches that were placed on various locations. From the results, the investigators determined that total deposition varied from 0.18 mg (0.0026 mg/kg) for a stationary 70-kg man wearing long pants and a long-sleeved shirt to the worst case scenario of 7.8 mg (1.1 mg/kg) for a shirtless 70 kg jogger in short pants. However, these doses represent dermal deposition rather than dermal absorption. In a dermal absorption study in humans (Feldman and Maibach 1970), ¹⁴C-radiolabeled malathion (dissolved in acetone) was applied to a 13 cm² circular area on the ventral surface of the forearms of 7 subjects at a rate of 4 ug/cm². The skin sites were not protected. Dermal penetration of malathion through the skin was estimated by calculating the total amount of radioactivity excreted in the urine in 5 days. A mean of 7.84% ± 2.71% (S.D.) of the applied dose of radioactivity was recovered in the 5-day urine, indicating a dermal absorption rate of approximately 5% to 10% over a 5 day period. Feldman and Maibach concluded that the dermal absorption rate is about 10%.

Metabolism and Metabolites

In the study by Reddy et al. (1989), metabolism of malathion was also studied in the rats. Eight radiolabeled metabolites were observed in urine; however, greater than 80 % of the radioactivity in urine was represented by the diacid (DCA) and monoacid (MCA) metabolites. It was determined that between 4 and 6% of the administered dose was converted to malaoxon, the active cholinesterase inhibiting metabolite of malathion.

Mechanism of Action and Chemical Interactions

As an organophosphate insecticide, malathion's mode of toxic action is the inhibition of cholinesterase. Malathion is metabolically converted to its structurally-similar metabolite, malaoxon, in insects and mammals. Both malathion and malaoxon are detoxified by carboxyesterases leading to polar, water-soluble compounds that are excreted. Mammalian systems show greater carboxyesterase activity compared to insects, so that the toxic agent malaoxon builds up more in insects than in mammals. This accounts for the selective toxicity of malathion towards insects. In humans, the metabolism of malathion results in either detoxification (hydrolysis of malathion to monocarboxylic acids) or the production of malaoxon. In rats, malaoxon exhibits approximately 10 to 30 times greater acute oral toxicity than malathion.

The toxicity of a given dose of malathion could be potentiated by interactions with chemicals that interfere with its detoxication. Potentiation of malathion was seen in rats and dogs given the carboxylesterase inhibitor EPN (ethyl p-nitrophenyl benzenethiophosphonate) (Frawley et al. 1957). Other interactions of concern would be with chemicals that have the same mechanism of action (i.e., organophosphate and carbamate pesticides). Simultaneous exposure to malathion and one of these chemicals could possibly have an additive effect on inhibition of neural acetylcholinesterase. Of five carbamate insecticides tested, only 2-sec-butylphenyl-N-methylcarbamate exhibited marked synergism with malathion when a mixture was tested for combined acute oral toxicity in mice. Also, the toxicity of malathion has shown to be potentiated by some organophosphates (HSDB 2000). In addition, it is also possible that co-exposure to chemicals that are inducers of hepatic microsomal enzymes could affect the toxicity of malathion. In one study, pretreatment with phenobarbital to induce cytochrome P-450 enzymes reduced the lethality of malathion in Holtzman rats and CF₁ mice after intraperitoneal injection; rat LD₅₀ without pre-treatment was 619.4 mg/kg, with phenobarbital pretreatment was 949.9 mg/kg; mice LD₅₀ without pretreatment was 193 mg/kg, with pretreatment was 234 mg/kg (DuBois and Kinoshita 1968). Malathion toxicity was also reduced in rats pretreated with chloramphenicol prior to a single oral LD₅₀ dose of malathion. This protection against malathion-induced inhibition of cholinesterase appears to be attributed to inhibition by chloramphenicol of the metabolic activation of malathion to malaoxon (HSDB 2000).

The data reviewed by ATSDR in the development of this document strongly supports the hypothesis that the health effects associated with malathion are actually due to either the oxygen analog, malaoxon (CAS # 1634-78-2;C₁₀H₁₂O₇PS) or the phosphorus thionate impurities mentioned previously. Malaoxon is both a metabolite and an environmental degradation by-product. The phosphorus thionates are impurities, environmental degradation by-products, and possibly pre-cursors for production. This hypothesis is being investigated at the present time under the authorities of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). In the interim, the chemical similarities of malathion to malaoxon and the thionates justify its use as a surrogate for these potentially more toxic metabolites and degradation products (HSDB 2000; EPA 2000a).

Health Effect in Humans Exposed to Malathion and Other Organophosphates in General

The principal toxicological effect of malathion and other organophosphate insecticides is cholinesterase inhibition. Information on health effects in humans exposed to organophosphate insecticides comes from case reports, case series, statistical surveys, and epidemiological studies. Many of the case reports regard individuals who have accidentally ingested malathion or have attempted suicide by ingestion. Other case reports involve private residents who have improperly applied malathion formulations to their lawns and gardens or were exposed via inadequate packaging or spillage. In many cases, only minor symptoms developed that were related more to the noxious odor than to the cholinergic effects. Most epidemiological studies involve workers who were engaged in manufacturing, formulating, or applying malathion. A few surveys of populations in areas where malathion has been used to control mosquitoes or fruit flies are also available. Many of these studies have been reviewed by Blondell (1998). These studies are generally limited by such factors as inadequate documentation of exposure levels and reporting biases.

• Common early signs or mild symptoms of acute cholinergic poisoning include miosis (pinpoint pupils), headache, nausea/vomiting, dizziness, muscle weakness, drowsiness, lethargy, agitation and anxiety.
• Moderate or severe poisoning can result in chest tightness, difficulty breathing, bradycardia, tachycardia, hypertension, pallor, abdominal pain, diarrhea, anorexia, tremor/ataxia, fasciculation, lacrimation, heavy salivation, profuse sweating, blurred vision, poor concentration, confusion, and memory loss.
• Life-threatening signs and symptoms, such as coma, seizures, incontinence, respiratory arrest, pulmonary edema, loss of reflexes, and flaccid paralysis, can occur at high doses, such as in the cases of attempted suicide.

Malathion may also be slightly irritating to the skin and eyes. In addition to acute poisoning, chronic effects such as peripheral neuropathy, neurobehavioral effects, and the development of allergic sensitivity have been reported in several incident reports, but these effects are not well documented (Blondell 1998).

Health Effects Possibly Related to Municipal Use of Malathion for Mosquito Control

The Florida Department of Health attempted to evaluate adverse health effects potentially related to spraying to control the Mediterranean fruit fly outbreak of 1998 (CDC 1999). The estimated crude rate of malathion-related illnesses associated with the eradication effort was calculated at 9 cases per 10,000 residents in the exposed areas. Of 230 reports of illness received, 34 (15%) were classified as probable, and 89 (39%) were classified as possible. Among these 123 cases, the acute signs and symptoms reported were: respiratory (71%), gastrointestinal (63%), neurologic (60%), dermal (23%), and ocular (19%).

Four human cases were highlighted in the report, two of whom were exposed after spraying:

• one was exposed while removing a pool cover with malathion residue,
• one exposure was from direct contact with pesticide residue on fresh grass trimmings,
• one person worked outside on his roof during aerial spraying, and
• one suffered an acute exacerbation of a chronic asthmatic condition.

The California Department of Health Services conducted indirect assessments and symptom prevalence surveys to determine whether aerial application of malathion bait used to eradicate the Mediterranean fruit fly in Santa Clara County, California posed a health hazard to the public (Kahn et al. 1992). In one indirect assessment, the records of a major hospital emergency department were compared during the first five weeks of spraying, the two weeks before spraying, and a corresponding seven-week period the year before. No significant differences in the number of visits were found, and none of the hospital emergency rooms in the county reported cases of pesticide poisoning. Another assessment of the frequency of ambulance calls in the same periods also showed no significant differences, but this assessment was relatively insensitive. An assessment for an increase in cases of asthma at a medical school hospital showed no increase, but the number of cases in this study were too small for definitive conclusions. In the symptom prevalence surveys, one an on-site home visit study, the other a telephone survey, there was no evidence the aerial spraying of malathion caused any detectable increase in symptoms.

Studies to determine whether an increase in fetal loss, low birth weight, and birth defects occurred in the same malathion program in Santa Clara County, California were negative (Grether et al. 1987; Thomas et al. 1990).

Health Effects in Laboratory Animals

Studies in laboratory animals exposed to malathion orally, by inhalation, or dermally are summarized in Table 3, with NOAEL and LOAEL values indicated. These studies indicate that similar cholinergic effects, along with serious decreases in the plasma, erythrocyte, and brain cholinesterase, occur regardless of route of exposure or duration, depending on the dose. Inhibition of cholinesterase, however, did not necessarily result in overt signs of cholinergic toxicity. The levels of cholinesterase generally return to preexposure levels after exposure ceases. Therefore, decreased levels of the cholinesterases do not necessarily mean that nervous system effects will occur. One study in hens indicated that exposure malathion was not associated with delayed neurotoxicity.

Other effects that have been observed in laboratory animals that have been exposed subchronically by inhalation or chronically to diets containing malathion included irritation of the nasal cavity and lungs, decreases in body weight gain, and possible effects on liver, blood cells, and kidneys.

No increases in fetal anomalies were found when pregnant rats or pregnant rabbits were given oral doses of malathion by gavage, although increased mean resorption sites were found in rabbits at maternally toxic doses. No effects on reproductive ability of male or female rats were found when they were given food containing malathion before, during, and after mating for two generations. However, decreased parental body weight occurred duration gestation and lactation, and decreased pup body weights occurred in the F₁ and F₂ pups during late lactation.

^*EPA 2000d

CEL = Cancer Effect Level

Genetic toxicology studies indicate that malathion did not cause gene mutations in bacteria (Traul 1987) or unscheduled DNA synthesis in cultured rat hepatocytes (Pant 1989). Also, malathion was neither clastogenic nor aneugenic up to doses that showed clear cytotoxicity for the target tissues in vivo (Gudi 1990). Although other studies indicated that malathion was positive in in vivo and in vitro studies (Flessel et al. 1993), the relevance of these findings are not clear since the positive results were seen only at cytotoxic doses or the types of induced aberrations were asymmetric and, therefore, not consistent with cell survival. In addition, the purity of the test substance was an issue (Yang 2000). Weak but positive results were shown for sister chromatid exchange induction at high, cytotoxic doses (Galloway et al. 1987). According to EPA, the weight-of-evidence dose not support a mutagenic hazard or a role of mutagenicity in the carcinogenicity associated with malathion (EPA 2000e).

Evaluation of available data for malaoxon by EPA indicates that malaoxon is not mutagenic in bacteria but is a confirmed positive without S9 activation in the mouse lymphoma forward gene mutation assay (EPA 2000e). Malaoxon was not clastogenic in cultured Chinese hamster ovary cells. However, the findings from the mouse lymphoma assay suggest that malaoxon may induce both gene mutations and chromosome aberrations (Myhr and Caspary 1991). Nevertheless, malaoxon is not carcinogenic in rats (Yang 2000).

The physical and safety hazards of malathion are summarized in Table 5 .

^*Source: HSDB 2000

Regulatory standards and guidance values are summarized in Table 6.

ATSDR has not developed minimal risk levels (MRLs) for malathion, but the EPA (2000d) has proposed several risk assessment values. A proposed acute oral RfD of 0.5 mg/kg for 1-day exposure is based on a dose of 50 mg/kg/day, which resulted in decreased body weight in rabbits that were exposed on gestation days 6 to 18 in the study by Siglin (1985) (see Table 3). Although the 50 mg/kg/day dose was a LOAEL for decreased body weight during the 13 days of exposure, EPA considered this dose to be a NOAEL for decreased body weight for 1 day of exposure and applied an uncertainty factor of 100 (10 for interspecies extrapolation and 10 for human variability). EPA also proposed using an air concentration LOAEL of 100 mg/m³, 6 hours/day, 5 days/week, for 13 weeks in the study by Beattie (1994) (see Table 3), converted to a dose of 25.8 mg/kg/day, for short, intermediate, and long term inhalation risk assessment. The uncertainty factor was 1000 (10 for use of LOAEL, 10 for interspecies extrapolation, and 10 for human variability) to yield a risk assessment value of 0.03 mg/kg/day. A short term and intermediate dermal risk assessment value of 0.5 mg/kg/day was also proposed by EPA, based on a NOAEL of 50 mg/kg/day for cholinesterase inhibition in rabbits exposed dermally for 6 hours/day, 5 days/week for 3 weeks in the study by Moreno (1989) (see Table 3).

Using these proposed values for the risk assessments for public health mosquito uses, EPA (2000d) concluded that adult and the toddler risk estimates for combined dermal and inhalation exposure did not exceed the levels of the EPA's concern for residential bystander inhalation and dermal exposure from truck fogger and aerial ULV mosquito control applications. This assessment included incidental oral ingestion for hand-to-mouth activities. Given the low levels of malathion used for the control of mosquito-borne diseases, ATSDR finds this assessment reasonable.

Malathion is an organophosphate insecticide used since 1956 by public health officials when necessary to control mosquito populations (EPA 2000b,c). When applied in accordance with the rate of application and safety precautions specified on the label, malathion can be used to kill mosquitoes without posing unreasonable risks to human health or the environment. Because of the very small amount of active ingredient released per acre of ground, EPA's scientists found that for all exposure scenarios considered, exposures to malathion were hundreds or even thousands of times below an amount that might pose a health concern (EPA 2000d).

Exposure and Absorption

Because malathion is readily absorbed by inhalation, ingestion, and direct contact with skin and mucous membranes (Ellenhorn 1988), the public should take appropriate precautions to avoid being outside when spraying is occurring in their neighborhoods (EPA 2000b,c; NYDOH 2000). Human exposure can occur during or shortly after an application from inhalation of the spray, as well as from direct contact with skin, eyes, or mucous membranes. Oils and other diluent/ dispersant compounds used may increase the contact time with malathion and result in increased absorption of the compound (Humphreys 1988). Exposure to the active ingredients or their degradation products can also occur through consumption of food (e.g., homegrown vegetables or fruit) and drinking water, contact with surface residues on patio furniture or swingsets, and contact with or ingestion of soil (NYDOH 2000).

If cholinesterase poisoning occurs, medical treatment involves administration of atropine. In seriously ill organophosphate-poisoned patients, treatment with pralidoxime is recommended (MEDITEXT 2000).

Public Health Considerations Before Mosquito-Control Spraying

Municipalities ensure that mosquito control personnel have been trained and are certified to properly apply insecticides, and obtain all permits required for application of insecticides (NYDOH 2000). Pesticide applicators must be provided with all necessary protective equipment required to meet state and federal worker protection requirements (CDC 1999; CDC 2000). Local governments use a variety of means to notify the public of the spraying schedule, and ensure that the public has one central phone number for each municipality where they can call for information.

Considerations for Reducing Exposure During Spraying

1. Pay attention to announced times and dates for spraying.

2. Plan to be indoors when spraying is occurring and prevent exposure to the spray.

• Close windows and turn off window-unit air conditioners when spraying is taking place in the immediate area.
• Keep children away from truck-mounted pesticide applicators when they are in use.
• Cover garden vegetables, bird baths, lawn furniture, swimming pools, etc.
• Provide shelter for pets; bring food and water dishes inside or cover them.

Considerations for Reducing Exposure After Spraying

• Stay indoors for the period of time recommended by local officials.
• Empty and re-fill bird baths and pet water and food containers. Uncover pools, lawn furniture, and childrens' play equipment, taking care not to become contaminated by the items used as covers.
• Wash any potentially contaminated body surfaces promptly with soap and water.

Internet-based Resources Related to Malathion Exposure and Spraying:

• http://www.health.state.ny.us/nysdoh/westnile/final/report.htm
• http://www.epa.gov/pesticides/op/malathion.htm
• http://cdc.gov/ncidod/dvbid/westnile/index.htm
• http://www.mosquito.org/sites.html
• http://www.cdc.gov/nceh/ehserv/EHSA/Vectors/Vectors.htm

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