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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

    PYRETHRINS

    Chemical name

           Pyrethrin I: Pyrethrolone ester of chrysanthemummonocarboxylic
    acid.

           Pyrethrin II: Pyrethrolone ester of chrysanthemumdicarboxylic
    acid monomethyl ester.

           Cinerin I: 3-(2-Butenyl)-4-methyl-2-oxo-3-cyclopenten-1-yl 
    ester of chrysanthemummonocarboxylic acid.

           Cinerin II: 3-(2-Butenyl)-4-methyl-2-oxo-3-cyclopenten-1-yl 
    ester of chrysanthemumdicarboxylic acid monomethyl ester.

    Synonyms

           The active ingredients in pyrethrum extract consist of a 
    mixture of four compounds in approximately the following percentage: 
    pyrethrin I, 40%; pyrethrin II, 36%; cinerin I, 12%; and cinerin II, 
    12%. The current commercial product is a more or less purified form of
    the mixture. Highly purified separate isomers although available for
    research purposes are too expensive for practical use.

    Empirical formula

    Pyrethrin I          C21H28O3 (mol. wt. 328.43)

    Pyrethrin II         C22H28O5 (mol. wt. 372.44)

    Cinerin I            C20H28O3 (mol. wt. 316.42)

    Cinerin II           C21H28O5 (mol. wt. 360.43)

    Structural formula

    CHEMICAL STRUCTURE 

                                                                        

    Compound               R                        R'
                                                                        

    Pyrethrin I          - CH3              - CH2 - CH===CH - CH===CH2

    Pyrethrin II         - COOCH3           Same

    Cinerin I            - CH3              - CH2 - CH===CH - CH3

    Cinerin II           - COOCH3           Same
                                                                        

    Relevant physical and chemical properties

           These compounds are virtually insoluble in water, but are 
    soluble in many organic solvents, e.g. kerosene, carbon tetrachloride,
    alcohol, petroleum, ether, etc. They are decomposed by exposure to
    light with loss of insecticidal activity. They are also rapidly
    oxidized and inactivated in air. Antioxidants used to protect
    insecticidal residues of pyrethrins include pyrocatechol, pyrogallol,
    hydroquinone, benzene-320-napthol is used to protect against effects
    of sunlight. A more complete description of their physical and
    chemical properties is contained in Negherbon (1959).

    Uses

           Very few uses remain for formulations of the pyrethrins alone.
    Some "pyrethrins dusts" are still in use for control of a variety of
    insects damaging horticultural crops. These dusts usually contain from
    0.3% to 0.5% pyrethrins and are used at the rate of 25 to 50 pounds
    per acre. No restrictions have been placed on frequency or timing of
    use. Poultry are treated for flea and lice control with 0.5% dusts.
    Household and stored product uses of pyrethrin solutions alone (at
    0.25%) are for space sprays or direct contact spray. Since these
    formulations have little residual effectiveness they are being
    superceded by synergized formulations.

    Residues

           Since there have been no restrictions on use of pyrethrin
    formulations alone, very little data are available on resulting
    residues. With tolerance established in some countries for residues of
    synergized formulations, residues of these formulations are currently
    being studied anew.

    Effect on treated crop

           There are no known recent studies on the effect of pyrethrins 
    on the treated crop.

    BIOLOGICAL DATA

    Biochemical aspects

           Following ingestion, the pyrethrins are hydrolysed by various
    digestive enzymes in the gastro-intestinal tract. However, a small
    portion of the insecticidally active compounds or their derivatives
    are absorbed as shown by their toxicity and their effect on the liver.
    The pyrethrins or their metabolites are not known to be stored in the
    body or to be excreted in the milk, but no study of the matter has
    employed modern methods. Absorption does result in urinary excretion
    of chrysanthemummonocarboxylic acid (Audiffren, 1934). It is said that
    the diarrhoea produced by pyrethrin results from central vagal
    stimulation (Leonard, 1942).

    Acute toxicity
                                                                                 
    Animal         Route          LD50 mg/kg           References
                                  body-weight
                                                                             

    Rat            Oral               820              Carpenter et al., 1950
                              pyrethrum oleoresin
                                   purified

    Rat            Oral              1870              Carpenter et al., 1950
                              purified pyrethrum
                           extract in petroleum oil

    Rat            Oral               200              Lehman, 1951

    Rat            Oral            > 2600              Ambrose & Robbins, 1951

    Guinea-pig     Oral              1500              Shimkin & Anderson, 1936

    Dog            i.v.              6-8*              Chevalier, 1930
                                                                             
    
    * "Lethal dose"
                The relatively high inherent toxicity of pyrethrum should be
    noted. The very marked difference in the oral and intravenous
    toxicities indicates a low rate of absorption from the
    gastro-intestinal tract, very efficient destruction by the liver, or a
    combination of the two.

           The acute effects resemble veratrine intoxication, proceeding
    from excitation to convulsions to tetanic convulsions, except that
    pyrethrins also cause muscular fibrillation. Death is caused by
    respiratory failure (Leonard, 1942; Chevalier & Ripert, 1927).
    Persistent tremor is occasionally seen in animals that recover from a
    single large dose (Leonard, 1942).

    Short-term studies

           No data available.

    Long-term studies

           Rat. Groups of 12 male and 12 female rats were fed pyrethrin in
    soybean oil at dietary levels of 0, 200, 1000 and 5000 ppm for 2
    years. The daily dosage was, therefore, approximately 0, 10, 50 and
    250 mg/kg respectively. Even the highest level had no significant
    effect on growth or survival. Slight, though definite, liver damage
    characterized by bile duct proliferation and focal necrosis was found
    at the two highest dosage levels (Lehman, 1965).

           Man. Injury to man from pyrethrum has most frequently resulted
    from the allergenic properties of the material rather than its direct
    toxicity. Although the allergy has been associated with occupational
    or therapeutic contact, it is impossible to exclude any importance of
    it in connexion with food residues.

           Pyrethrum sensitivity may manifest itself in several forms in
    man. Contact dermatitis is by far the most common. The usual picture
    is a mild erythematous, vesicular dermatitis with papules in moist
    areas, and intense pruritis (McCord et al., 1921; Sequeira, 1936). In
    a few cases bullae appear (McCord et al., 1921, Sequeira, 1936;
    Tonking, 1936). Oedema and cracking develop in severe cases (Sequeira,
    1936; Tonking, 1936; Martin & Hester, 1941). Pyrethrum dermatitis may
    be made worse by exposure to the sun (Tonking, 1936).

           Some individuals show manifestations of pyrethrum sensitivity
    similar to those seen in pollinosis, including sneezing, serous nasal
    discharge and nasal "stuffiness" (Feinberg, 1934; Ramirez, 1930). A
    few cases of extrinsic asthma due to pyrethrum mixtures have been
    reported (Ramirez, 1930; Garratt & Bigger, 1923). Some of the
    individuals involved had a previous history of asthma with a very
    broad allergic background. Several cases have shown what McCord et
    al., 1921, called "dermal anaphylaxis" characterized by dermatitis and
    sudden severe swelling of the face and lips (McCord et al., 1921;
    Ramirez, 1930). A mild form was produced in the course of experiments
    (Martin & Hester, 1941). A severe anaphylactic reaction, including
    peripheral vascular collapse is rare but can occur (Bosredon, 1897).

           Pyrethrum flowers and certain extracts from them are much more
    allergenic than the more or less purified pyrethrins now marketed as
    insecticides (Martin & Hester, 1941; Lord & Johnson, 1947).* Thus
    many reports of pyrethrum dermatitis involve contact with flowers in
    connexion with harvesting, weighing or grinding (McCord et al., 1921;
    Tonking, 1936). However, dermatitis (Schwartz, 1934), and especially

    allergy of the respiratory tract may result from exposure to pyrethrum
    formulations intended for use in the home (Feinberg, 1934; Ramirez,
    1930). Sensitivity as judged by skin tests occurs in over 45% of
    persons who are sensitive to ragweed (Feinberg, 1934) and was produced
    by repeated application of pyrethrum ointment in 10% and 26% of
    unselected test populations (Lord & Johnson, 1947). On the other hand,
    the insecticide has been considered so innocuous that an ointment
    containing 0.75% of pyrethrin was recommended for treatment of
    scabies, and such use led to only a few cases of dermatitis, some of
    doubtful relation to the treatment (Sweitzer & Tedder, 1935; Sweitzer,
    1936). Pyrethrins have been used extensively for the control of human
    body lice. The formulation used early during World War II was called
    MYL powder; its use was discontinued only after the more effective and
    long-lasting DDT louse powder became available (Simmons, 1959).

           Pyrethrins have also been given by mouth to combat intestinal
    worms. It is possible to use pyrethrins for short periods in this way
    because a considerable period, even two or three years, may be
    required for susceptibility to appear (Sequeira, 1936; Tonking, 1936;
    Martin & Hester, 1941; Schwartz, 1934). Onset may be delayed even when
    exposure is to a purified ointment (Lord & Johnson, 1947; Sweitzer,
    1936). This argues against the unsupported contention (Sequeira, 1936)
    that the dermatitis is usually the result of irritation rather than
    allergy. It is generally recognized that susceptibility is increased
    during summer months or periods of excessive perspiration (McCord et
    al., 1921; Sequeira, 1956; Tonking, 1936; Martin & Hester, 1941). The
    fact that pyrethrum insecticides can be tolerated for brief periods is
    not a justification for recommending frequent, repeated exposure to
    them over a period of years.


                 
    * Investigations have shown that the allergenic agent or agents in
    pyrethrum are extractable by solvents such as petroleum ether (Martin
    & Hester, 1941; Lord & Johnson, 1947); they can be absorbed on
    adsorbents such as fullers earth (Lord & Johnson, 1947) and they are
    probably volatile with steam (Martin & Hester, 1941, Frank &
    McGeachin, 1949). Acetic acid has been identified as being present in
    pyrethrum extracts and is claimed (Frank & McGeachin, 1949) to be a
    contributory irritating factor although it is not in itself
    allergenic.

    Comment on experimental work reported and evaluation

           Because of the long experience in using pyrethrum without
    observed injury, except allergy in those with occupational and
    therapeutic contact, there is no reason to question the customary uses
    of the material. The rapid metabolism and apparent lack of storage are
    also reassuring. On the other hand, no long-term study has been made
    of the synergized formulations now in current use. At the present time
    an acceptable daily intake for man cannot be suggested.

    Further work required

           Long-term studies should be made in at least one more species
    with special emphasis on the effect on the liver. Effects on the rat
    liver should be re-evaluated. The tests should include chemically
    identified commercial pyrethrin concentrates alone and combined with
    major synergists. The metabolism of pyrethrins should be explored in
    greater detail.

    REFERENCES

    Ambrose, A. M. & Robbins, D. (1951) Fed. Proc., 10, 276

    Audiffren, M. (1934) J. Pharm. Chim., 19, 535

    Bosredon, Dr (1897) Bull. gen. therapeutique, medicale, chirurgical,
    obstetrical et pharmaceutique, 132, 275

    Carpenter, C. P. Weil, C. S., Pozzani, U. C. & Smith, H. F. (1950)
    Arch. industr. Hyg. Occup. Med., 2, 420

    Chevalier, J. (1930) Bull. d. sci. pharmacol., 37, 154

    Chevalier, J. & Ripert, J. (1927) Compt. rend. Accad. d. sc., 184,
    776

    Feinberg, S. M. (1934) J. Amer. med. Ass., 102, 1557

    Frank, R. L. & McGeachin, R. L. (1949) J. Amer. Pharm. Ass. sci.
    Ed., 38, 297

    Garratt, J. R. & Bigger, J. W. (1923) Brit. med. J., 2, 764

    Lehman, A. J. (1951) Quart. Bull. Assoc. Food and Drug Officials
    U.S., 15, 122

    Lehman, A. J. (1965) Summaries of pesticide toxicity (in press)

    Leonard, C. S. (1942) J. econ. Ent., 35, 261

    Lord, J. T. & Johnson, C. G. (1947) Brit. J. Dermatol., 59, 367

    Martin, J. T. & Hester, K. H. C. (1941) Brit. J. Dermatol., 53,
    127

    McCord, C. P. Kilker, C. H. & Minster, D. K. (1921) J. Amer. med.
    Ass., 77, 448

    Negherbon, W. (1959) Insecticides, Handbook of Toxicology W. B.
    Saunders, Philadelphia, Vol. 3, pp. 1-854

    Ramirez, M. A. (1930) J. Allergy, 1, 149

    Schwartz, L. (1934) Publ. Hlth Bull., 215, 51

    Sequeira, J. H. (1936) Brit. J. Dermatol., 43, 473

    Shimkin, N. B. & Anderson, H. H. (1936) Proc. Soc. exp. Biol.
    (N.Y.), 34, 135

    Simmons, S. W. (1959) DDT, the insecticide dichlorodiphenyl-
    trichloroethane and its significance, Paul Mull, Ed., Birkhauser
    Verlag Basel, Vol. II, pp. 251-502

    Sweitzer, S. E. & Tedder, J. W. (1935) Minnesota Med., 18, 793

    Sweitzer, S. E. (1936) Journal-Lancet, 56, 467

    Tonking, H. D. (1936) E. Afr. med. J., 13, 7
    


    See Also:
       Toxicological Abbreviations
       Pyrethrins (FAO/PL:CP/15)
       Pyrethrins (JMPR Evaluations 2003 Part II Toxicological)
       Pyrethrins (FAO/PL:1967/M/11/1)
       Pyrethrins (FAO/PL:1968/M/9/1)
       Pyrethrins (FAO/PL:1969/M/17/1)
       Pyrethrins (AGP:1970/M/12/1)
       Pyrethrins (WHO Pesticide Residues Series 2)
       Pyrethrins (WHO Pesticide Residues Series 4)