Toxicologic Information About Insecticides
Used for Eradicating Mosquitoes
(West Nile Virus Control)
April 2005
Naled is an organophosphate insecticide registered since 1959 for use in the United States. Naled is used primarily to control adult mosquitoes but also is used on food and feed crops and in greenhouses. The mode of action of naled is as a nonsystemic contact and stomach poison (Hayes and Laws 1990). State and local authorities apply naled by truck-mounted or aircraft-mounted sprayers. Because of the very small quantities of pesticide applied, naled does not pose a moderate or serious health risk if applied according to the guidelines for use (EPA 2002).
Section 1. Environmental Factors
Naled and its degradation products are transformed primarily by abiotic hydrolysis, indirect photolysis in water, and biodegradation (Peckenpaugh et al. 1997). Naled and its degradation products dissipate rapidly under typical terrestrial, aquatic, and forestry field conditions, having halflives of <2 days. Rapid hydrolysis and biodegradation help decrease the concentration of naled that remains in the environment shortly after treatment and thus lower the amount available for runoff (Peckenpaugh et al. 1997).
When naled is present in the atmosphere, it exists primarily in the vapor phase, where it degrades by reacting with hydroxyl radicals (Bidleman 1988; Meylan and Howard 1993). In atmospheric conditions, the estimated half-life of naled is 18 hours (Meylan and Howard 1993).
Naled degrades rapidly in aqueous media. The rate of degradation of naled in water by abiotic hydrolysis depends on pH, with an inverse relation between pH and half-life (Peckenpaugh et al. 1997). Estimated half-lives were 96 hours at pH 5, 15.4 hours at pH 7, and 1.6 hours at pH 9 (Valent USA 1993). Naled is nonvolatile from water, and it persists in water for up to 10 days without accumulation on sediment (Meylan and Howard 1991).
In the presence of a chemical photosensitizer (acetone), indirect photolysis contributed significantly to the photodegradation of naled in aqueous media. The rate of degradation in the presence of a photosensitizer was five times faster than when the photosensitizer was not used. The photodegradation of naled by indirect photolysis under environmental conditions will produce the byproduct dichlorvos (Peckenpaugh et al. 1997).
In soil, the degradation of naled is aided not only by microbial populations, but also by hydrolytic processes. The mobility of naled in soil ranges from medium to high, based on Koc values (Meylan et al. 1992; Lyman et al 1990; Wauchope et al. 1991; Gufstafson 1989). The estimated half-life of naled, based on exponential-decay calculations in soil, is 1 day (Wauchope et al. 1992). A more specific example from a persistence study shows that naled persisted in soil for only 3 days (Jain et al. 1987).
Section 2. Potential for Exposure
Major routes of exposure are by application from fog and mist sprayers. The use of application by aircraft increases the potential for exposure of humans and nontarget organisms to naled. Human exposure to naled during mixing, handling, application, and reentry operations can be minimized by use of approved respirators and other protective clothing. However, data are not available to fully assess such exposures. A reentry level of 24 hours for the use of naled on crops is required (Cornell University 1983).
EPA has estimated the exposure and risks to both adults and children posed by ULV aerial and ground applications of naled. Because of the very small amount of active ingredient released per acre of ground, the estimates found that for all scenarios considered, exposures were hundreds or even thousands of times below an amount that might pose a health concern. These estimates assumed several spraying events over a period of weeks, and they assumed a toddler would ingest some soil and grass in addition to experiencing skin and inhalation exposure (EPA 2002).
Section 3. Health Effects/Toxicity
One of the degradation products of naled is dichlorvos, another registered organophosphate. This is the only degradate of toxicologic concern for naled (food and water). Dichlorvos is included in the naled tolerance expression. Risks from naled-derived dichlorvos should be calculated in an aggregate assessment for dichlorvos. Because of the common metabolite, the risk assessment for naled cannot be considered complete until the assessment for dichlorvos has been considered (EPA 1999b).
Health Effects in Humans Exposed to Naled
The principal toxicologic effect of naled 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 epidemiologic studies. The most common human exposures
to naled occur during mixing, handling, application and reentry
procedures (Purdue University 1987).
Signs and symptoms of acute naled poisoning are as follows
- 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, incontinence, diarrhea, anorexia, tremor/ataxia, fasciculation, lacrimation, heavy salivation, profuse sweating, blurred vision, poor concentration, confusion, and memory loss.
- Life-threatening or very severe signs and symptoms, such as coma, seizures, respiratory arrest, pulmonary edema, loss of reflexes, and flaccid paralysis, can occur at high doses, such as in the cases of attempted suicide.
Human Health Effects Possibly Related to
Municipal Use of Naled for Mosquito Control
When a 1,376 hectare area was sprayed by aircraft with naled and
temephos for mosquito control, the concentration of urinary
metabolites of the compounds in persons who were indoors during
spraying did not increase (Hayes 1982). During loading of an
aircraft for naled spray treatments, naled entered through an
unnoticed hole in the elbow-length gloves worn by a pilot. When
discovered, the formulation was wiped off, not washed. The exposed
area became red, with a burning sensation. When the blisters became
dry, the skin itched. The man continued to work but reduced his
exposure; recovery required 3 weeks (Hayes 1982).
A California study involved 542 agricultural pesticide applicators under medical supervision who had been exposed for >3 hours in a 30-day period to category I and II organophosphate and carbamate pesticides. The pesticides primarily responsible for lowered cholinesterase activity from those not responsible for lowered activity were not possible to distinguish in this study. Of the 26 workers with cholinesterase depression, eight had pesticide-related illness. The frequency of naled inhibition of cholinesterase activity was 0 (<50% of baseline) for plasma and 1 to 2 (<70% and 60%, respectively) for erythrocytes (Ames et al. 1989).
In a study of people working with chrysanthemum plants, 12 women were exposed to a field that had been sprayed with a mixture containing naled at a concentration of 10.8%, captan (6%), and dicofol (2%). Nine of the 12 women complained of burning arms, face, neck, and abdomen. Four who were examined 4 days after the onset of symptoms had contact sensitization dermatitis. The results of a patch test 2 weeks after the exposure was negative. The results of all the tests strongly indicated that naled caused the symptoms (Hayes 1982).
Health Effects in Laboratory Animals
Laboratory animals have been exposed to naled dermally, orally, or
by inhalation (Table 1). At high levels, naled can cause death in
some animals. If the dose is lower, it may have muscarinic effects
(including hypersalivation, lacrimation, sweating, and nasal
discharge); nicotinic effects (fasciculation of muscles, weakness,
and paralysis); and central nervous system effects (nervousness,
apprehension, ataxia, convulsions, and coma). Death can result from
respiratory failure or cardiac arrest (Clarke et al. 1981).
The most common effects at lower levels include decreases in blood, plasma, brain, and erythrocyte cholinesterase; body weight gain decreases; skin irritation; and other clinical signs. These effects occur regardless of route of exposure or duration. The effects are variable, but cholinesterase inhibition is always present if any effect is observed for acute to chronic exposures. Other effects accompany cholinesterase inhibition, but they are not consistent with either species or duration (EPA 1999a).
Serious effects can result from exposure to naled, but in many cases, brain cholinesterase is only slightly to moderately inhibited. No toxic effect was observed in rats that received 100 mg of 99% pure naled/kg for 84 days or in albino rats that received 100 mg of 91% pure naled/kg for 2 years (Worthing and Walker 1983).
Aside from mild cholinergic effects, some evidence indicated maternal and developmental toxicity in reproductive studies. Sprague-Dawley rats showed tremors, hypoactivity, and dyspnea when exposed to 40 mg/kg/day during gestation. Decreased body weight was also observed in pups, as were decreased survival rate and some moderate inhibition of development (Beaudoin and Fisher 1981; EPA 1999a).
The limited effects of naled on test subjects may depend on the route of exposure. Guinea pigs and rats exposed to >42 mg/m3 for 6 hours a day, 5 days a week for 5 weeks showed decreased cholinesterase activity and obvious discomfort and inactivity. In addition, male and female rats exposed to technical-grade naled in aerosol form at concentrations of 3.4–12.1 mg/m3 for 6 hours/day, 5 days/week for 3 weeks showed inhibition of cholinesterase and brain activity (ACGIH 1991).
Table 1. Health Effect Levels of Naled in
Laboratory Animals (PDF Version 70k)
Carcinogenicity
No evidence exists of carcinogenicity in laboratory animals
exposed to technical-grade naled (AMVAC 2002). IARC lists dichlorvos
as possibly carcinogenic to humans, categorizing it in Group 2B, but
states that evidence is inadequate for carcinogenicity (IARC 1991).
IARC (1991) also notes that evidence is sufficient in experimental
animals for the carcinogenicity of dichlorvos. This conclusion is
based on two studies involving mice and three studies involving
rats. Squamous-cell tumors (most often papillomas) were noted in
mice fed dichlorvos. In rats fed dichlorvos, doserelated effects
included mononuclear-cell leukemia and increased pancreatic adenomas
(IARC 1991).
In 1999, at the Cancer Assessment Review Committee meeting for DDVP (dichlorvos), the committee determined that dichlorvos should be classified in category C as a carcinogen with Alow dose risk extrapolation based on the incidence of forestomach tumor (squamous cell papilloma and/or carcinoma) in female mice@ (EPA 2000). In this document, the IARC (1991) review of dichlorvos carcinogenicity is also included.
Genotoxicity
Naled causes mutations in microorganisms, apparently attributable
to alkylation of DNA (Braun 1983). Mutation data exist for two
bacterial species, Bacillus subtilis and Salmonella enterica serovar
Typhimurium. Naled was more genotoxic in the absence of metabolic
activation than in the presence of one, indicating that naled, not
one of its metabolites, is responsible for the genotoxicity in
microorganisms.
Naled can be absorbed into the body by inhalation, dermal contact, and ingesion. It does not accumulate in body tissues, but repeated exposure may have a cumulative effect on cholinesterase levels. Naled is hydrolysed rapidly in the body to produce a number of metabolites, including dichlorvos, dichlorobromoacetaldehyde, dimethyl phosphate, and an amino acid conjugate of degraded naled. In an experiment where 25 mg/kg of radiolabeled naled was fed orally to a cow, 9% was recovered in the urine and 34% was recovered in the fecal matter 1 week after dosing (INCHEM 1978). Residue of naled was not detectable (<0.01 ppm) in milk from Holstein cows that were subject to spray for 14 days with a 7.2-lb/gal EC formulation (HSDB 2002, Purdue University 1987). Because cows are ruminants, oral exposures of cows is not relevant to humans. As noted previously, risks from naled-derived dichlorvos should be calculated in an aggregate assessment for dichlorvos. The toxicity of naled 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.
Section 5. Standards and Guidelines for Protecting Human Health
Regulatory standards and guidance values are summarized in Table 2.
ATSDR has not derived MRLs for naled, and no toxicological profile exists for naled.
EPA has derived an oral RfD based on a chronic study in rats by Chevron Chemical Company. The rats were randomly divided and fed diets by gavage with 0, 0.2, 2, or 10 mg/kg/day. The noted effects were brain cholinesterase inhibition at 24% for the 2-mg/kg/day dosage group and 60% for the 10- mg/kg/day dosage group. Inhibition of erythrocyte cholinesterase at a very low level and moderate inhibition of plasma cholinesterase also were recorded for the dosage group fed 10 mg/kg/day.
Because brain cholinesterase inhibition was the effect used to determine the RfD, an uncertainty factor of 100 was used to account for both interspecies and intraspecies variation (EPA 2003).
Aside from the RfDs, EPA has derived a margin of exposure (MOE) from the dermal no-observedadverse- effect level (NOAEL) of 1 mg/kg/day. Neither short- nor intermediate-term MOEs should be of concern for exposures of adults or children after mosquito applications by ULV spray methods, but applications for blackflies may be reason for concern because they nearly halve the MOE in both child and adult cases (EPA 1999). However, the dermal MOEs may be overestimated because they are based on the dermal NOAEL. This overestimation may result from the large difference between the dermal NOAEL and the LOAEL.
| Table 2. Regulatory Standards and Guidance Values for Naled | ||
| National Institute for Occupational Safety and Health/Centers for Disease Control and Prevention (NIOCH/CDC) Recommended Exposure Limit: (REL) 10-Hour TWA | 3 mg/m³ | NIOSH 1992 |
| Occupational Safety and Health Administration Permissible Exposure Limit (PEL)—8-Hour TWA | 3 mg/m³ | OSHA 2002 |
| American Conference of Governmental Industrial Hygienists Time Limit Value (TLV)—8-Hour TWA (inhalable fraction) (vapor and aerosol) (skin) | 0.1 mg/m³ | ACGIH 2002 |
| NIOSH/CDC Immediately Dangerous to Life or Health | 200 mg/m³ | NIOSH 2002 |
| Reference Dose (RfD) | 0.002 mg/kg/day | EPA 1994 |
| Department of Transportation Reportable Quantity | 10 lbs. (4.54 kg) | DOT 2002 |
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