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Carbaryl

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names, main trade names
   1.6 Manufacturers, Importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First-aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Hazardous characteristics
4. USES
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description
   4.2 High risk circumstances of poisoning
   4.3 Occupationally exposed populations
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. TOXICOLOGY
   7.1 Mode of Action
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
      7.2.4 Workplace standards
      7.2.5 Acceptable daily intake (ADI)
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL ANALYSES & BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples & specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples &specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations & their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical investigations
   8.5 Overall Interpretation
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central Nervous System (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      9.4.7 Endocrine & reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ears, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid & electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Others
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATES



    CARBARYL

    International Programme on Chemical Safety
    Poisons Information Monograph 147
    Chemical

    1.  NAME

        1.1  Substance

             Carbaryl

        1.2  Group

             Hydrocarbons, polycyclic, carbamate naphtalene derivative

        1.3  Synonyms

             1-Naphthyl - N - methylcarbamate;
             alpha - Naphthyl N - methylcarbamate;
             1-Napthalenol methyl - carbamate;
             methylcarbamic acid;
             1-naphthyl ester

        1.4  Identification numbers

             1.4.1  CAS number

                    63-25-2

             1.4.2  Other numbers

                    UN Number: 2757
                    RTECS Number: FC5950000

        1.5  Main brand names, main trade names

             Sevin, Arilat, Carbatox, Dicarbam

        1.6  Manufacturers, Importers

    2.  SUMMARY

        2.1  Main risks and target organs

             Carbaryl is a reversible cholinesterase inhibitor.
             Carbaryl is absorbed via inhalation and the oral route, and
             less well absorbed by the dermal route.

        2.2  Summary of clinical effects

             The clinical picture of intoxication is secondary to by
             cholinesterase inhibition. Symptoms may include increased
             bronchial secretion, exessive sweating, salivation, and
             lacrimation, pinpoint pupils, bronchoconstriction, abdominal
             cramps, vomiting, diarrheoa, bradycardia, muscle
             fasciculation, diaphragm and respiratory muscles paralysis,
             tachycardia, headache, dizziness, anxiety, mental confusion,
             convulsion, coma, and depression of  the respiratory
             centre.
             Signs of intoxication develop quickly after absorption.

             In cases of occupational exposure to carbaryl, mild symptoms
             are observed long before a dangerous dose is absorbed.
    
             During agricultural application, dermal exposure may play an
             important role. No local irritation is usually observed,
             however, skin rash after accidental exposure to liquid
             formulations has been described.

        2.3  Diagnosis

             Diagnosis is based on the history of exposure and the
             characteristic presentation of muscarinic, nicotinic, and
             central nervous system effects of an excess of
             acetylcholine.

        2.4  First-aid measures and management principles

             Evaluation and support airway, breathing and
             circulation.
             In the case of ingestion, administer activated charcoal, or,
             if the patient is obtunded within one hour of ingestion,
             gastric lavage with endotracheal intubation may be
             undertaken. Do not induce emesis because of the risk of
             sudden seizures, coma, or respiratory depression. Specific
             treatment is the use of atropine intramuscularly or
             intravenously 0.5 to 2 mg every 15 minutes until the symptoms
             are reversed. It is important to maintain airway potency.
    
             When dermal exposure occurs, decontamination procedures
             include removal of contaminated clothes and copious
             irrigation.
    
             Extensive eye irrigation with water or saline should also be
             performed after acute exposure.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Carbaryl was initially synthesized in 1953, and is a
             synthetic devivative of carbamic acid (H2 N-COOH).

        3.2  Chemical structure

             Structural names:
             1-Naphtalenol methyl carbamate
             methyl carbamic acid 1-naphtylester
    
             Molecular formula: C12H11NO2
             Molecular weight: 201.22

        3.3  Physical properties

             3.3.1  Colour

                    White to greyish

             3.3.2  State/Form

                    Solid-crystals

             3.3.3  Description

                    Boiling Point: Decomposes
                    Melting Point:142 °C
                    Flash Pont: 173 °C
                    Autoignition: 625 °C
                    Vapour Pressure < 4.10-5 mm Hg at 25 °C
                    Solubility in water: Practically insoluble (4mg/100mL
                                         @ 20 °C)
                    Solubility in alcohol: Soluble in ethanol
                    Solubility in ether: Soluble in petroleum ether and
                                         diethylether
    
                    Conversion factor: 1 ppm = 8.22 mg/m3 of air
                    1 mg/m3 = 0.12 ppm

        3.4  Hazardous characteristics

             Stable to heat, light, acids; hydrolyzed in alkalies;
             non corrosive.

    4.  USES

        4.1  Uses

             4.1.1  Uses

                    Pesticide
                    Insecticide

             4.1.2  Description

                    Carbaryl is a contact and stomach insecticide
                    with slight systemic properties, for use against many
                    insect pests of cotton, fruit, vegetables, and other
                    crops. It is available for household lawn and garden
                    pest control, and in veterinary practice carbaryl is
                    used on cattle, poultry and pets especially to control
                    flies, mosquitos, ticks and lice (WHO, 1994).

        4.2  High risk circumstances of poisoning

             Occupational exposure during the manufacture,
             formulation, packing, storage, and transportation.
             Occupational exposure during agricultural application.

        4.3  Occupationally exposed populations

             Farmers and plant workers are at risk for occupational
             hazard of poisoning.
    
             The general population can be exposed to carbaryl during pest
             control operations in both the home and recreational areas.
             Workers can be exposed to carbaryl during its manufacture,
             formulation, packing, transportation, storage, and
             application.  Significant dermal exposure may occur in
             industrial and agricultural workers if protective measures
             are inadequate.

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             Carbaryl is absorbed via the oral route (WHO, 1994)

        5.2  Inhalation

             Carbaryl is easily absorbed via inhalation (WHO, 1994)

        5.3  Dermal

             Carbaryl can be slowly absorbed through the skin (NIOSH,
             1994; WHO, 1994).

        5.4  Eye

             No data

        5.5  Parenteral

             No data.

        5.6  Others

             No data.

    6.  KINETICS

        6.1  Absorption by route of exposure

             In rats, absorption of carbaryl from the
             gastrointestinal tract is rapid (Casper & Pekas, 1971).
    
             When applied to the forearm of humans, C14 labeled carbaryl
             was slowly but almost completely absorbed (Feldman & Maibach,
             1974).

        6.2  Distribution by route of exposure

             Carbaryl is distributed in liver, stomach, intestines,
             kidneys, lungs, bone marrow and brain (WHO, 1994). Animal
             studies showed that placental transfer occurs in the first
             hour after administration. Carbaryl concentration in the eye,
             liver, and brain of the fetus was relatively constant from 8
             to 96 hours(Declume & Derache, 1976, 1977; Declume & Benard,
             1977 a,b, 1978).

        6.3  Biological half-life by route of exposure

             Given intravenously to volunteers, the estimated half-
             life was 9 hours (Feldman & Maibach, 1974).

        6.4  Metabolism

             Metabolic reactions include: hydroxylation, hydrolysis,
             and conjugation. Hydrolysis results in the formation of 1-
             naphtol, carbon dioxide, and methylamine. Metabolites of
             carbaryl were identified in the urine of human volunteers
             after the ingestion of a 2 mg/kg dose. (Andrawes & Myers,
             1976)
             Entero hepatic cycling of carbaryl metabolites is also
             considerable, especially after oral administration.
             Only traces of the unchanged carbaryl could be detected in
             the urine indicating rapid metabolism. The only detectable
             metabolites in urine samples taken from workers exposed to
             carbaryl dust were 1-naphthylglucoronide and sulfate (Knaak
             et al., 1965).
             Carbaryl is metabolized by hepatic microsomal enzymes.

        6.5  Elimination by route of exposure

             The elimination of metabolized carbaryl is rapid.
             Carbaryl is generally excreted entirely within 24 to 96 hours
             after absorption. Elimination takes place via the urine,
             faeces and respiration.  Carbaryl is mainly excreted as its

             product of hydrolysis, 1-naphthol, as a soluble glucuronide
             (Carpenter et al., 1961), and as a sulfate (Whitehurst et
             al., 1963). It is excreted in trace amounts as unchanged
             carbaryl.
             Carbaryl's metabolites are less active than the parent
             compound.

    7.  TOXICOLOGY

        7.1  Mode of Action

             Carbaryl is an inhibitor of cholinesterase enzymes.
             In normal nervous system function, a burst of the
             neurotransmitter acetylcholine is released from a nerve cell
             terminal, diffuses across the synaptic cleft and transmits a
             nerve impulse to a specific cholinergic receptor. To end
             stimulation and restore the sensitivity of the receptor to
             new transmitter, acetylcholine at the receptor must
             continually be eliminated; this function is fulfilled by the
             enzyme acetylcholinesterase, which hydrolyzes acetylcholine
             to choline and acetic acid. By inhibiting
             acetylcholinesterase, anticholinesterase carbamates allow
             acetylcholine to accumulate at cholinergic junctions (Hayes &
             Laws, 1991).
             This effect is dose-related and reversible.
             Chronic exposure may cause a cumulative effect. All
             identified metabolites of carbaryl are less active
             cholinesterase inhibitors than carbaryl itself.

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             Carbaryl was ingested once by
                             individual men at dosages of 0.5, 1.0 and
                             2.0, mg/kg. Neither subjective nor objective
                             effects were noted (Wills et al., 1968). In a
                             further study, five men took a dosage of 0.06
                             mg/kg/day for 6 weeks, and six men took from
                             0.12 to 0.13 mg/kg/day for the same duration.
                             No abnormalties other than a slight,
                             reversible increase in the ratio of amino
                             acid nitrogen to creatinine in the urine were
                             seen (Wills et al., 1968).
    
                             An adult male ingested 250 mg of carbaryl
                             (approx. 2.8 mg/kg). Twenty minutes later he
                             experienced the very sudden onset of violent
                             epigastric pain. A little later he began to
                             sweat profusely. A 1 mg dose of atropine
                             produced little improvement; he gradually

                             developed great lassitude and vomited twice.
                             One hour after taking carbaryl and following
                             a total of 3 mg atropine, he was feeling
                             better (Hayes, 1982).
    
                             An ingestion of 500 mg/kg resulted in the
                             development of a delayed peripheral
                             neuropathy (Dickoff et al., 1987).
    
                             An ingestion of 400 g resulted in severe
                             pulmonary edema and death in a 39 year old
                             male (Farago, 1969).

                    7.2.1.2  Children

                             A nineteen month old infant
                             developed miosis, salivation and muscular
                             inco-ordination despite gastric lavage within
                             half an hour of ingestion of an unknown
                             amount of carbaryl. A single 0.3 mg dose of
                             atropine sulphate was effective and recovery
                             apparently was complete in at hours (Best &
                             Murray, 1962).

             7.2.2  Relevant animal data

                    LD50 (oral, rat): 500 to 600 mg/kg (WHO, 1986);
                    250 mg/kg (Budavari, 1996); 230 to 850 mg/kg (Hayes &
                    Laws, 1991)
                    LD50 (sc, rat) > 4000 mg/kg (Cranmer, 1986)
                    LD50 (sc, rabbit) > 2000 mg/kg (WHO, 1986)
                    LD50 (oral, monkey) > 1000 mg/kg (Cranmer, 1986)
                    LD50 (dermal, rabbit) > 4000 mg/kg (WHO, 1978)
    
                    Toxic to fish, lesser toxicity to most birds, more
                    toxic to bees and crustaceans.
                    Cloudy swelling of cells in the proximal convoluted
                    tubules of the kidneys was noted in rats and dogs fed
                    400 ppm of carbaryl in their diets for several months
                    (Carpenter et al, 1961).
    
                    Eye irritation: rabbit, 45% concentration of carbaryl
                    produced mild irritation with complete recovery
                    (Cranmer, 1986).
    
                    Skin: several studies showed that carbaryl does not
                    produce allergic skin reactions (Cranmer, 1986).
    
                    Immunogenicity: carbaryl inhibited the action of the
                    immune system but severe inhibition occured only at
                    high doses which also produce neurotoxic effects.

                    These effects were completely reversible once the
                    exposure was stopped (Cranmer, 1986). These results
                    have been questioned (WHO, 1994).

             7.2.3  Relevant in vitro data

                    Carbaryl produced a marked concentration
                    dependent inhibition of Inter Leukin 2 driven
                    proliferation of mouse CTLL2 cells (Gasale et al.,
                    1993).

             7.2.4  Workplace standards

                    TWA 5 mg/m3 Australia
                    TWA 5 mg/m3 UK
                    STEL 10 mg/m3 UK
                    TWA 5 mg/m3 USA

             7.2.5  Acceptable daily intake (ADI)

                    The acceptable daily intake is 0.01 mg/kg body
                    weight  per day (WHO, 1994). Food represents the major
                    source of carbaryl intake for the general population.
                    Residues in total dietary samples are relatively low,
                    ranging from trace amounts to 0.05 mg/kg in the
                    USA.

        7.3  Carcinogenicity

             No human information about carbaryl carcinogenicity is
             available. Animal studies show inadequate evidence, although
             N-nitroso carbaryl is carcinogenic when administered in high
             doses but does not represent a significant risk factor
             (Cranmer, 1986; WHO, 1994).

        7.4  Teratogenicity

             Animal studies showed that placental transfer occurs in
             the first hour after administration. Radio active carbon
             concentration in the eye, liver, and brain of the fetus was
             relatively constant from 8 to 96 hours.
             (Declume & Derache, 1976, 1977; Declume & Benard, 1977 a,b,
             1978)
             Monkeys given doses of carbaryl of 0.2, 2, or 20 mg/kg body
             weight from day 18 to day 40 of gestation, did not have any
             teratogenic effects (Dougherty et al, 1971).
             Mammalian studies on the reproductive or developmental
             toxicity of carbaryl clearly show that this compound is
             capable of inducing adverse effects in utero and during the
             reproductive process. These effects are always seen only at
             dose levels at which there is concurrent maternal toxcicity,
             with the possible exception of a few studies on the rat which
             have not been replicated by other workers (WHO, 1994).
             No human information available.

        7.5  Mutagenicity

             The available evidence indicate that Carbaryl does not
             have any DNA-damaging properties. There have been no reports
             of confirmed induction of recombination, gene conversion, and
             UDS in prokaryotes. (H. influenza, B. subtilis) and
             eukaryotes (S.cereviside, A.nidulans, Cultured human
             lymphocytes and rat hepatocytes) in vitro (WHO, 1994).
             However, chromosomal damage with high doses of carbaryl has
             been reported in vitro in human, rats, and hamster, and
             plants (WHO, 1994).
             N-nitrosocarbaryl does bind to DNA and induces mitotic
             recombination and gene conversion (WHO, 1994).

        7.6  Interactions

             Carbaryl is a weak inducer of hepatic microsomal drug
             metabolizing activity. This has been suggested to have
             clinical importance. There is evidence that hepatic enzyme
             inducers may decrease toxicity, and hepatic enzyme inhibitors
             increase toxicity, especially chronic neurotoxicity. Low
             protein diet increases acute toxicity (WHO, 1994).
             Carbaryl metabolism is inhibited by cimetidine in the
             isolated perfused rat liver (Ward et al., 1988).

    8.  TOXICOLOGICAL ANALYSES & BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                             Cholinesterase activity in blood or
                             brain, which has been found to correlate with
                             carbaryl concentration in theses tissues may
                             be determined by colorimetry (Fleisher &
                             Pope, 1954) or by an electrometric method
                             (Michel, 1949), Carbaryl itself has been
                             analysed in biological specimens by a
                             nonspecific colorimetric technique involving
                             diazotisation (Farago, 1969) and by electron
                             capture gas chromatography after
                             derivitization with heptafluorobutyric
                             anhydride (Mount and Oehme, 1980). The
                             measurement of 1-naphthol in urine is
                             generally accomplished by colorimetry (Best &
                             Murray, 1962) or by gas chromatography
                             (Shafik et al., 1971).

                    8.1.1.2  Biomedical analyses

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analyses

                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples & specimens

                    8.1.2.1  Toxicological analyses

                    8.1.2.2  Biomedical analyses

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analyses

                    8.1.2.5  Other (unspecified) analyses

             8.1.3  Transport of laboratory samples &specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analyses

                    8.1.3.5  Other (unspecified) analyses

        8.2  Toxicological Analyses and Their Interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple Qualitative Test(s)

                    8.2.1.2  Advanced Qualitative Confirmation Test(s)

                    8.2.1.3  Simple Quantitative Method(s)

                    8.2.1.4  Advanced Quantitative Method(s)

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple Qualitative Test(s)

                    8.2.2.2  Advanced Qualitative Confirmation Test(s)

                    8.2.2.3  Simple Quantitative Method(s)

                    8.2.2.4  Advanced Quantitative Method(s)

                    8.2.2.5  Other Dedicated Method(s)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations & their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                    8.3.1.2  Urine

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses

             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical investigations

        8.5  Overall Interpretation

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Serious effects occur by ingestion of the
                    substance in high doses.
                    In the early stage, a muscarinic syndrome occurs
                    including nausea, vomiting, abdominal cramps and
                    diarrhea. Symptoms may also include increased
                    bronchial secretion, excessive sweating, salivation,
                    and lacrimation, pinpoint pupils (miosis), and
                    bronchoconstriction. Then a nicotinic syndrome
                    develops with bradycardia, muscle fasciculation,
                    followed by signs of CNS toxicity including:
                    dizziness, anxiety, mental confusion, convulsion and
                    coma, and depression of respiratory centre (WHO,
                    1994).

             9.1.2  Inhalation

                    Carbaryl has a very low tendency to evaporate,
                    and vapour concentrations are normally too low to pose
                    an inhalation hazard. While exposure can occur by
                    inhalation of mist, serious or harmful symptoms have
                    not been reported (CHEMINFO, 1995).

             9.1.3  Skin exposure

                    Dust or liquid can produce mild irritation and
                    a burning sensation (Hayes et al., 1982).
                    Carbaryl can be slowly absorbed through the skin at
                    levels which can result in systemic symptoms (NIOSH,
                    1994).

             9.1.4  Eye contact

                    Liquid or dust can probably produce mild
                    temporary irritation. Splash contact with a liquid
                    containing both carbaryl and dimethoate produced mild
                    temporary swelling of the eyelids and mild irritation
                    of the cornea. Recovery was rapid and complete (Grant
                    et al., 1986).

             9.1.5  Parenteral exposure

                    No data

             9.1.6  Other

                    No data

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Animal models show decreased survival, weight
                    gain, decreased erythrocytes, increased liver weight
                    with chronic high dose exposure (WHO, 1994).
                    It has been reported that the urinary amino acid
                    nitrogen/creatinine ratios were increased in a group
                    of human volunteers who ingested daily doses of
                    carbaryl of 0,12 mg/kg/day for several weeks (Wills et
                    al., 1968).

             9.2.2  Inhalation

                    Long term exposure has occasionaly been
                    reported to decrease cholinesterase activity, which is
                    dependent on the dose and frequency of repeated
                    exposures. These exposures are usually not associated
                    with symptoms (WHO, 1994).

             9.2.3  Skin exposure

                    Long term exposure has occasionaly been
                    reported to decrease cholinesterase activity, which is
                    dependent on the dose and frequency of repeated
                    exposures. These exposures are usually not associated
                    with symptoms (WHO, 1994).


             9.2.4  Eye contact

                    Can result in visual disturbances, miosis, and
                    temporary irritation.

             9.2.5  Parenteral exposure

                    No data available

             9.2.6  Other

                    No data available

        9.3  Course, prognosis, cause of death

             The onset of the symptoms of cholinesterase inhibition
             is usually rapid, with a good prognosis for survival without
             sequelae. Death can occur secondary to respiratory depression
             or pulmonary edema. Long term peripheral neurotoxicity has
             been reported.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Bradycardia, decreased stroke volume, atrio-
                    ventricular block, hypo or hypertension, and QT
                    prolongation have been reported (Leikin & Paloucek,
                    1996).

             9.4.2  Respiratory

                    Respiratory effects include difficulty in
                    breathing, increased bronchial secretion, tachypnoea,
                    pulmonary oedema, diaphragmatic paralysis, and
                    respiratory depression.

             9.4.3  Neurological

                    9.4.3.1  Central Nervous System (CNS)

                             The primary effect of carbaryl on
                             the central nervous system is related to
                             cholinesterase inhibition. Symptoms include
                             dizziness, headache, anxiety, mental
                             confusion, convulsions, coma, and depression
                             of the respiratory centre (WHO,
                             1994).

                    9.4.3.2  Peripheral nervous system

                             Peripheral neuropathy has been
                             reported in one case (Dickoff et al.,
                             1987).

                    9.4.3.3  Autonomic nervous system

                             Increased bronchial secretion,
                             excessive sweating, salivation and
                             lacrimation.
                             Pinpoint pupils, bronchoconstriction,
                             abdominal cramps, and bradycardia (WHO,
                             1994).

                    9.4.3.4  Skeletal and smooth muscle

                             Muscle fasciculation, in severe
                             cases, diaphragm and intracostal muscles may
                             be affected (WHO, 1994).

             9.4.4  Gastrointestinal

                    Symptoms may include abdominal cramps, vomiting
                    and diarrhoea (WHO,1994).

             9.4.5  Hepatic

                    A syndrome similar to acute intermittent
                    porphyria was described 2 to 23 days after ingestion
                    of an unknown amount of carbaryl in one case (Sargin
                    et al., 1992).

             9.4.6  Urinary

                    9.4.6.1  Renal

                             It has been reported that the
                             urinary amino acid nitrogen/creatinine ratios
                             were increased in a group of human volunteers
                             who ingested daily doses of carbaryl of 0.12
                             mg/kg/day for several weeks (Wills et al.,
                             1968).

                    9.4.6.2  Others

                             No data

             9.4.7  Endocrine & reproductive systems

                    With chronic male workplace exposure no
                    reproductive system toxicity was observed (WHO, 1994).
                    In the animal adverse effects on reproduction are seen
                    with severe toxicity (WHO, 1994).

             9.4.8  Dermatological

                    Liquid or dust can produce mild irritation,
                    burning sensation, and a skin rash (Hayes et al.,
                    1982).

             9.4.9  Eye, ears, nose, throat: local effects

                    In some animal tests, carbaryl produced slight
                    temporary eye irritation which cleared in 2 to 3 days
                    (Cranmer, 1986).

             9.4.10 Haematological

                    In in vitro studies, hypo or hyper
                    coagulation were reported (Krug et al., 1988).
                    Carbaryl produces oxidative stress to G-6-PD deficient
                    red blood cells.
                    It produced a decrease in the level of haemoglobin,
                    red blood cells and platelets (Calabrese & Geiger,
                    1986).

             9.4.11 Immunological

                    Carbaryl inhibited the inter leukin 2 mediated
                    proliferation of mouse CTLL2 cells, and resulted in
                    proliferation and enhancement of natural killer cells
                    (Gasale et al., 1993).

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             Carbaryl can produce metabolic
                             acidosis in severe intoxication.

                    9.4.12.2 Fluid & electrolyte disturbances

                             No data

                    9.4.12.3 Others

                             No data available.

             9.4.13 Allergic reactions

                    Generally not associated with skin rashes or
                    allergic skin reactions (WHO, 1994).

             9.4.14 Other clinical effects

                    The intermediate syndrome of delayed
                    peripheral nerve toxicity has been reported similar to
                    organophosphates.

             9.4.15 Special risks

                    No data available.

        9.5  Others

             No data available.

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Specific treatment is the use of atropine
             intramuscularly or intravenously 0.5 to 2 mg every 15 minutes
             (0,01 to 0.05 mg/kg for children) until symptoms are
             reversed. It is important to maintain airways potency.
             Pralidoxime should not be used unless there is evidence of
             nicotinic toxicity without muscarinic effects.
    
             Administer activated charcoal. Do not induce emesis because
             of the risk of sudden seizures, coma, or respiratory
             depression. Gastric lavage is probably not necessary
             following small ingestions if activated charcoal is given
             promptly (Olson, 1994).
    
             Closely observe the patient during the early stages of
             treatment, the principle concerns being those of convulsion,
             coma or respiratory distress.

        10.2 Life supportive procedures

             Airway, breathing, and circulation should be evaluated
             and supported as necessary.
             Artificial ventilation via endotracheal intubation may be
             required for severe respiratory distress (WHO, 1994).

        10.3 Decontamination

             Skin and eyes: remove all contaminated clothing and
             wash exposed skin copiously with soap and water, including
             hair and under nails. Irrigate exposed eyes with copious 
             water or saline (Olson, 1994).
    
             Ingestion: administer activated charcoal. Do not induce
             emesis because of the risk of sudden seizures, coma, or
             respiratory depression. Gastric lavage is probably not
             necessary following small ingestions if activated charcoal is
             given promptly (Olson, 1994).

        10.4 Enhanced elimination

             Dialysis and hemoperfusion are not indicated because
             the duration of toxicity is brief and effective antidotal
             therapy available (Olson, 1994).

        10.5 Antidote treatment

             10.5.1 Adults

                    Atropine is recommended for the treatment of
                    carbaryl poisoning, starting with 0,5 to 2 mg
                    intravenously (IV) repeated every 15 minutes until
                    symptoms (especially pulmonary) resolve, or there is
                    evidence of atropine toxicity (dilated pupils, skin
                    flushing, dry mouth) (WHO, 1994).
    
                    Diazepam has been recommended for treating anxiety,
                    and is suggested to improve other CNS symptoms (WHO,
                    1994).
    
                    Pralidoxime should not be used unless there is
                    isolated evidence of severe nicotinic
                    symptoms.

            10.5.2 Children

                    Atropine dose is 0,01 to 0.05 mg/kg every 15
                    minutes (Olson, 1994).

        10.6 Management discussion

             Not relevant.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             A 23 year old man ingested 500 mg/kg of carbaryl (the
             approximate LD50 in rats) and survived, but developed a
             severe delayed peripheral neuropathy (Dickoff et al.,
             1987).
    
             Death due to respiratory failure was reported after ingestion
             of an unknown amount of carbaryl in an adult (Sargin et al.,
             1992).
    
             A drunken 39 year old man swallowed approximately 500 mL of
             an 80% solution of carbaryl. When he was hospitalized 1.5
             hours later he was confused but still able to answer
             questions. Gastric lavage was performed and drugs to
             stimulate circulation were administered. However, the patient
             became worse; he complained of disturbance of vision and
             developed pulmonary oedema. Atropine was given intravenously
             and intramuscularly at half hours intervals for a total dose
             of 6 mg. A slight amelioration occured, buttere was no sign
             of full atropinization. Three hours after ingestion, 250 mg
             of 2-PAM were administered. Thereafter, pulmonary oedema
             progressed rapidly and the patient died six hours later after
             ingestion (Farago, 1969).
    
             A nineteen months old child developed miosis, salivation and
             muscular incoordination in spite of gastric lavage within
             half an hour after ingestion of carbaryl. The dose was not
             known but the symptoms were promptly relieved by 0.3 mg of
             atropine and recovery apparently was complete in 12 hours
             (Best & Murray, 1962).

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             No data available.

        12.2 Other

             No data available.

    13. REFERENCES

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        information submitted to WHO by Rhone - Poulenc Agro, Lyon).
    

        Best EM Jr & Murray BL (1962). Observations on workers exposed to
        sevin insecticide: a preliminary report. J Occup Med, 4:507-
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        Budavari S ed. (1996) The Merck Index: an encyclopedia of
        chemicals, drugs and biologicals, 12th ed. Rahway, New Jersey,
        Merck and Co., Inc
    
        Calabrese EJ & Geiger CP (1986) Low erythrocyte glucose-6-
        phosphate dehydrogenase activity and susceptibility to carbaryl
        induced methaemoglobin formation and glutathion depletion. Bull
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        Carpenter CP, Weil CS, Palm PE, Woodside MW, Nair JHIII & Smith HF
        Jr. (1961) Mammalian toxicity of 1-naphthyl-N-methyl-carbamate. J
        Agric Food Chem 9:30-39.
    
        Casper HH & Pekas JC (1971). Absorption and excretion of
        radiolabelled 1-naphthyl -N-methylcarbamate) in the rat. N D Acad.
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        analysis. Neurotoxicology 7(I): 247-332.
    
        Declume C & Benard P (1978) Etude de la phamacocin tique du [14C]
        carbaryl chez la souris gestante. Toxicol Eur Res, 1: 174-180.
    
        Declume C & Benard P (1977a) Foetal accumulation of [14C] carbaryl
        in rats and mice autoradiographic study. Toxicology, 8:95-105.
    
        Declume C & Benard P (1977b) Etude autoradiographique de la
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        Gasale GP, Vennerstrum JL, Bavari S & Wang TL (1993) Inhibition of
        interleukin 2 driven proliferation of mouse CTLL2 cells, by
        selected carbamate and organophosphate insecticides and congeners
        of carbaryl. Immunopharmacology & immunotoxicology 15(2-3): 199-
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        in man. J Toxicol Clin Toxicol, 26 (5/6): 269-281.
    
        Wills JH, Jamieson E & Coulston F (1968) Effects of oral doses of
        carbaryl on man. Clin Toxicol 1:265-271.
    
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        Cow. J Agric Food Chem, 11:167-169.
    
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    14. AUTHOR(S), REVIEWER(S), DATES

        Authors: Amal Mutawai
        School of Pharmacy. University of Otago
        Box 913
        Dunedin. New Zealand
    
        Dr Wayne A Temple
        National Toxicology Group. University of Otago
        Box 913
        Dunedin. New Zealand
    
        Phone: 64-3-4797244
        Fax: 64-3-4770509
        E-mail: wtemple@gandalf.otago.ac.nz
    
        Dr Nerida A Smith
        School of Pharmacy. University of Otago
        Box 913
        Dunedin. New Zealand
    
        Phone: 64-3-4797239
        Fax: 64-3-4770509
        E-mail: nerida.smith@stonebow.otago.ac.nz
    

        Date: 11 December 1996
    
        Reviewer: MO Rambourg Schepens
        Centre Anti-Poisons de Champagne Ardenne
        Centre Hospitalier Universitaire
        F-51092 Reims cedex France
    
        E-mail: marie-odile.rambourg@wanadoo.fr
    
        Date: July 1997
    
        Peer review: INTOX-10 Meeting, Rio, Brazil, September, 1997 (Drs
        M Kowalczyk, L Lubomirov, R McKeown, P Rosen, W Watson)
    
        Finalization/Edition: MO Rambourg Schepens. M Ruse (IPCS,
        Geneva)
        Date: October 1997
    



See Also:
        Carbaryl (EHC 153, 1994)
        Carbaryl (IARC Summary & Evaluation, Volume 12, 1976)
        Carbaryl (ICSC)
        Carbaryl (PDS)