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    FAO Meeting Report No. PL/1965/10/1
    WHO/Food Add./27.65

    EVALUATION OF THE TOXICITY OF PESTICIDE RESIDUES IN FOOD

    The content of this document is the result of the deliberations of the
    Joint Meeting of the FAO Committee on Pesticides in Agriculture and
    the WHO Expert Committee on Pesticide Residues, which met in Rome,
    15-22 March 19651

    Food and Agriculture Organization of the United Nations
    World Health Organization
    1965

                
    1 Report of the second joint meeting of the FAO Committee on
    Pesticides in Agriculture and the WHO Expert Committee on Pesticide
    Residues, FAO Meeting Report No. PL/1965/10; WHO/Food Add./26.65

    CARBARYL

    Chemical names

         1-naphtyl N-methylcarbamate; N-methyl-1-naphtyl carbamate;
    N-methyl-a-naphtyl urethane.

    Synonym

         Sevin

    Empirical formula

         C12H11O2N

    Structural formula

    CHEMICAL STRUCTURE 

    BIOLOGICAL DATA

    Biochemical studies

         A slight rise in free 1-naphthol and a definite rise in
    conjugated 1-naphthol in the urine were observed in the 48 hours
    following ingestion of carbaryl by rats (Carpenter et al., 1961).
    Workers engaged in bagging carbaryl showed excretion of conjugated
    1-naphthol in the urine (Best & Murray, 1962). Metabolism of
    14C-carbaryl by rat-liver microsomes and insects leads to the
    appearance of at least 8 metabolites, 5 of which are carbamates,
    suggesting a non-hydrolytic pathway in the metabolism of carbaryl
    (Dorough et al., 1963; Dorough & Casida, 1964). When 14C-carbaryl was
    administered to a goat in a dose of 1.3 mg/kg, several of these
    metabolites were found in both the milk and the urine. The level of
    total 14C-equivalents of carbaryl reached a peak of 0.93 ppm in the
    milk at 8 hours and decreased to below 0.003 ppm at 60 hours (Dorough
    et al., 1963, Dorough & Casida, 1964). Dairy cattle were fed carbaryl
    for 2 weeks, up to 450 ppm, and carbaryl was searched for in the milk
    by analytical methods. Carbaryl, if present, was below the sensitivity
    of the method (0.01 ppm) (Gyrisco et al., 1960). Similar results were
    obtained with the analysis of tissues (Roberts et al., 1960).

         Some knowledge has recently been obtained on the changes which
    the compound undergoes in plants following injection of 14C-carbaryl
    into the stem of garden snapbeans and cotton seedlings. After 28 days
    55% of the original 14C was still present but only 5.7% of the
    original compound was found. It has been suggested that the
    metabolite(s) are water soluble and quite stable in the plant (Dorough
    et al., 1963; Dorough & Casida, 1964).

         A depression of blood and brain cholinesterase has been reported
    following single large doses of carbaryl (Carpenter et al., 1961;
    Mellon Institute, 1958b). Approximately the same molar concentrations
    are required to produce 50% inhibition in the blood of man, rabbit,
    rat and dog (Mellon Institute, 1958b). As a cholinesterase inhibitor,
    carbaryl is less active than parathion. Pyridine-2-aldoxime
    methiodide, which is a good antidote for organo-phosphorus compounds
    is not effective on cholinesterase inhibition by carbaryl (Mellon
    Institute, 1958b).

    Acute toxicity
                                                                                           
    Animals          Route     Solvent           LD50 (mg/kg)    Reference
                                                                                       

    Mice             I.P.      Corn oil               25         Baron et al., 1964

    Rats, male       P.O.      10% Tween 80           190        Mellon Institute, 1958a

    Rat, male        P.O.      10% Tween 80           310          "       "        "
                               in 0.75% NaCl

    Rat, male
    and female       P.O.      0.25% agar           480-610        "       "        "

    Rat, female      P.O.      Corn oil               560          "       "        "

    Rat, male        P.O.      Corn oil               308          "       "        "

    Rats             I.V.      Propylene glycol       18           "       "        "

    Rats             I.V.      PEG 400                24           "       "        "

    Rats             I.V.      Undiluted              93           "       "        "

    (continued)
                                                                                       
    Animals          Route     Solvent           LD50 (mg/kg)    Reference
                                                                                       

    Guinea-pigs,     P.O.      0.25% agar             280          "       "        "
    male

    Rabbits, male    P.O.      0.25% agar             707          "       "        "

    Dogs             P.O.      Powder              none died       "       "        "
                                                (250-795 mg/kg)
                                                                                       
    
         Chicken. Chickens given 2 g/kg showed leg weakness for 1-2 days
    but recovered. A nephrotoxic action was observed in fowl receiving 2
    g/kg or more. No demyelination was noted (Carpenter et al., 1961).

         Man. A 19-month-old child swallowed an unknown amount of
    carbaryl. The child developed typical early signs of cholinesterase
    inhibition (constricted pupils, salivation, muscular incoordination)
    (Best & Murray, 1962).

    Short-term studies

         Mouse. In one experiment 30 A/Jax and 30 C3H mice at the age of
    3 months were started on a treatment of weekly subcutaneous injections
    of 0.5 mg of carbaryl. Five months later the survivors (26 A/Jax and
    28 C3H) were sacrificed. In neither group did the survival rate and
    the tumour incidence differ from those of untreated animals of the
    same strains (Mellon Institute, 1958a).

         Rat. Groups of 10 rats (5 of each sex) were fed 1500 ppm or
    2250 ppm carbaryl in their diets for 96 days. The 2250 ppm level
    produced a decrease in body-weight of females, an increase in
    liver-weight of males and an increase in kidney-weight of females. At
    the 1500 ppm level the only effect was an increase in kidney-weight in
    females. A minor histopathological change in the form of diffuse
    cloudy swelling of the kidney tubules was noted at the higher
    concentrations (Carpenter et al., 1961).

         Guinea-pig. Four of a group of 16 male guinea-pigs were
    sensitized and after a 3-week incubation period were given a challenge
    dose of carbaryl without the development of sensitization (Carpenter
    et al., 1961).

         Dog. Groups of 3 or 4 dogs distributed randomly by sex and
    litter were given by capsule, 5 days per week, dosage levels of
    carbaryl approximately equivalent to 25, 100 and 400 ppm in the diet
    (0.45, 1.8 and 7.2 mg/kg body-weight) for 1 year. Slight kidney
    damage, consisting of diffuse cloudy swelling of the tubules, was

    noted in the dogs on 400 ppm. One female dog on 25 ppm showed a
    transient hind-leg weakness but no histopathological lesion was noted
    in this animal at autopsy (Carpenter et al., 1961).

    Long-term studies

         Mouse. Groups of 48 male and 48 females Cd-1 mice were given
    400, 100 and 0 ppm of carbaryl in the diet. After 80 weeks 12
    survivors of each sex from each group were sacrificed for histological
    examination. Survival rate, pathology and tumour incidence were
    comparable in all groups (Mellon Institute, 1963).

         Rat. In a 2-year experiment, groups of 40 rats (20 of each sex)
    were given diets containing 50, 100, 200 and 400 ppm carbaryl. After
    periods of 6, 9 and 12 months, 4, 6 or 8 rats of each sex were killed
    in order to make organ weight comparisons and to provide tissues for
    histopathological examinations. The highest dosage level produced
    cloudy swelling in the tubules of the kidneys after 1 year and cloudy
    swelling of the central hepatic cords and a decreased body-weight gain
    (males only) after 2 years. Other dosages showed no effect (Carpenter
    et al., 1961).

    Special studies

         Some studies have been reported describing the effects of a
    single administration of carbaryl on discreet avoidance and food
    reward behavioural tests in rats. In one report (Goldberg et al.,
    1965a) the dose necessary to suppress avoidance response to 50%
    efficiency was slightly lower than the dose required to reduce brain
    cholinesterase to 50% of control value. The effects of carbaryl on
    behaviour are reversed by atropine pre-treatment and the association
    with chlorpromazine leads to more than additive effects.
    -diethylaminoethyl-diphenylpropyl-acetate (SKF-525) increases the
    behavioural effects of carbaryl without enhancement of cholinesterase
    inhibition (Goldberg & Johnson, 1964a; Goldberg & Johnson, 1964b;
    Goldberg et al., 1965a; Goldberg et al., 1965b).

    Comments on the experimental studies reported

         The short-term and long-term studies in the rat showed that 200
    ppm in the diet of the animals did not cause histopathological
    lesions. With higher doses, liver and kidney enlargement and kidney
    lesions were seen. In dogs, the maximum no-effect level is 100 ppm.

         The behavioural studies appear interesting in relation to the
    mode of action and as a potential system for detection of toxicity.
    However, so far no data are available concerning experiments with
    continuous exposure to the compound.

    EVALUATION

    Level causing no significant toxicological effect

         Mouse:  400 ppm in the diet equivalent to 60 mg/kg body-weight
                   per day

         Rat:    200 ppm in the diet equivalent to 10 mg/kg body-weight
                   per day

         Dog:    100 ppm in the diet equivalent to 1.8 mg/kg body-weight
                   per day

    Estimate of acceptable daily intake for man

         0-0.02 mg/kg body-weight per day. (This value is based on
    experiments carried out with carbaryl, and thus does not take account
    of chemical alterations in the pesticide brought about by the plants
    to which it has been applied.)

    Further work desirable

         Determination and evaluation of the toxicity of residues
    occurring in the plants. Biochemical studies.

    REFERENCES

    Baron, R. L., Casterline, J. L. & Fitzhugh, O. G. (1964) Toxicol.
    Appl. Pharmacol., 6, 402

    Best, E. M. jr & Murray, B. L. (1962) J. Occupational Med., 4, 507

    Carpenter, C. P. Weil, C. S., Palm, P. E., Woodside, M. W., Nair, J.
    H. & Smyth, H. F. (1961) J. Agr. Food Chem., 9, 30

    Dorough, H. W., Leeling, N. C. & Casida, J. E. (1963) Science,
    140, 170

    Dorough, H. W. & Casida, J. E. (1964) Agr. Food Chem., 12, 294

    Goldberg, M. E. & Johnson, H. E. (1964a) J. Pharm. Pharmacol., 16,
    60

    Goldberg, M. E. & Johnson, H. E. (1964b) J. Pharmacol. exp. Ther.,
    145, 367

    Goldberg, M. E., Johnson, H. E. & Knaak, J. B. (1965a)
    Psychopharmacologia. (In press)

    Goldberg, M. E., Johnson. H. E. & Knaak. J. B. (1965b) Biochem.
    Pharmacol. (in press)

    Gyrisco, G. G., Lisk, D. J., Fertig, S. N., Huddleston, W. E., Fox, F.
    H., Holland, R. F. & Trimberger, G. W. (1960) J. Agr. Food Chem.,
    8, 409

    Mellon Institute of Industrial Research (1958a) 21-90, Unpublished
    Report

    Mellon Institute of Industrial Research (1958b) 21-94, Unpublished
    Report

    Mellon Institute of Industrial Research (1963) 26-53, Unpublished
    Report

    Roberts, R. H., Jackson, J. B., Westlake, W. E., Ackerman, A. J. &
    Claborn, H. V. (1960) J. Econ. Ent., 53, 326
    


    See Also:
       Toxicological Abbreviations
       Carbaryl (EHC 153, 1994)
       Carbaryl (HSG 78, 1993)
       Carbaryl (ICSC)
       Carbaryl (PIM 147)
       Carbaryl (FAO/PL:CP/15)
       Carbaryl (FAO/PL:1967/M/11/1)
       Carbaryl (FAO/PL:1968/M/9/1)
       Carbaryl (FAO/PL:1969/M/17/1)
       Carbaryl (AGP:1970/M/12/1)
       Carbaryl (WHO Pesticide Residues Series 3)
       Carbaryl (WHO Pesticide Residues Series 5)
       Carbaryl (Pesticide residues in food: 1976 evaluations)
       Carbaryl (Pesticide residues in food: 1977 evaluations)
       Carbaryl (Pesticide residues in food: 1979 evaluations)
       Carbaryl (Pesticide residues in food: 1984 evaluations)
       Carbaryl (Pesticide residues in food: 1996 evaluations Part II Toxicological)
       Carbaryl (JMPR Evaluations 2001 Part II Toxicological)
       Carbaryl (IARC Summary & Evaluation, Volume 12, 1976)