WHO/FOOD ADD/71.42



    Issued jointly by FAO and WHO

    The content of this document is the result of the deliberations of the
    Joint Meeting of the FAO Working Party of Experts and the WHO Expert
    Group on Pesticide Residues, which met in Rome, 9-16 November, 1970.



    Rome, 1971



    This insecticide was considered at joint Meetings held in 1966, 1967,
    1968 and 1969. In 1969 (FAO/WHO 1970b), the only data considered
    related to use, together with piperonyl butoxide, on fish. This 1970
    meeting confined itself to a consideration of data relating to the
    evaluation of the acceptable daily intake. This consideration is
    summarized in the following addendum.


    In this addendum, the term pyrethrins refers to the mixed active
    ingredients as present in commercially available extracts of
    pyrethrum. Such extracts contain about 30 percent by weight a mixture
    of six components in about the following amounts: pyrethrin I (11.4
    percent), cinerin I (2.2 percent), jasmolin I (1.2 percent), pyrethrin
    II (10.5 percent), cinerin II (3.5 percent) and jasmolin II (1.2
    percent) (Head, 1969).




    Utilizing an in vitro enzyme system from insects in the presence of
    NADPH2, Yamamoto and Casida (1966) showed that pyrethrin I was
    converted to at least ten metabolites. A major metabolite was
    characterized as a product which had undergone oxidation of a methyl
    group in the isobutenyl moiety to the carboxylic acid. In a more
    comprehensive study, these authors conclude that oxidation rather than
    hydrolysis in insects might be the major mode of metabolism of
    pyrethroid chemicals (Yamamoto et al., 1969).

    Pyrethrins I and II have been shown to be oxidatively metabolized in
    rats. Oxidation was found to occur at the trans-methyl group of
    pyrethrin I as well as on the pentadienyl side chain to produce two
    diols. These metabolites were also found in conjugate form (Casida et
    al., 1970).


    Special studies on reproduction


    Two groups of nine rabbits each were administered pyrethrins at 0 and
    90 mg/kg body-weight/day, orally, from day 8-16 of gestation. Pups
    were delivered by normal parturition or by caesarian section on day 30
    of gestation. No apparent effects were noted on the number and weight

    of foetuses, implantation sites or on gross external and internal
    examination. Two control pups and one pup in the group given
    pyrethrins had a club-like deformed front paw, and one pyrethrin pup
    had a missing caudal vertebrae. There appears to be no apparent
    teratogenic effects elicited by pyrethrins in rabbits (Weir, 1966a).

    Special studios on skin sensitization

    Guinea pig

    Two groups of nine male guinea pigs were used to examine the
    sensitizing effect of pyrethrins. The criterion of sensitization was a
    comparison of the response following a challenge dose with the
    response elicited by previous sensitizing doses. A positive control
    (1-chloro-2,4-dinitrobenzene) produced sensitization in all animals of
    one group. No sensitization was obtained with a 1 percent formulation
    of pyrethrins (Weir, 1966b).

    Acute toxicity


                                LD50 (mg/kg
    Species     Route           body-weight)    Reference

    Rat (M)     oral            710             Weir 1966c

    Rat         oral            584-900         Malone & Brown, 1968

                i.p.            167-798         Malone & Brown, 1968

    Mouse       oral            273-796         Malone & Brown, 1968

                i.p.            172-452         Malone & Brown, 1968

    Chick       Perivisceral    240-1262        Malone & Brown, 1968

    The latter five ranges comprise various grades of pyrethrum, including
    crude oleoresins and refined concentrates.

    The acute signs of poisoning in rats include: depression, rapid and/or
    laboured respiration, ataxia, incoordination, convulsions and muscular
    tremors. Necropsy findings include: congestion of the lungs, liver,
    kidneys, adrenals and pancreas and slight gastric inflammation (Weir,
    1966c; Malone and Brown, 1968).

    An acute dermal toxicity test was performed with rabbits using
    pyrethrins in combination with a synergist. Typical sprays made with
    the synergists, tropital or piperonyl butoxide (1 percent) in
    combination with 0.1 percent pyrethrins, exhibited a low order of

    toxicity when tested dermally on 6-12 male rabbits. The acute dermal
    LD50 of both formulations was >10 gm/kg. At 10 gm/kg with tropital,
    three of 12 rabbits died. At 5 and 10 gm/kg, body-weight gain was
    reduced and transient signs of toxicity were evident with both
    synergist combinations. No effects were noted at a concentration of 2
    gm/kg (equivalent to 2 mg/kg pyrethrins and 20 mg/kg synergist)
    (Wisconsin, 1965)

    Short-term studies


    Two groups of rats (ten male and ten female) were exposed to aerosols
    of 1 percent pyrethrins for one hour. The flow was 50 l/min containing
    2 mg/l of air. Gross examination of the lung tissue demonstrated the
    presence of haemorrhagic pin point lesions in nine of ten male and ten
    of ten female rats exposed to pyrethrins (Leong and Martin, 1966).
    Microscopic examination of the lungs indicated that the alterations
    were typical of those found in murine pneumonitis (Weir and Crews,
    1966). No distinguishing pathological observations were reported which
    might be attributed to pyrethrins.


    A group of rabbits (ten male and ten female) and a control group (five
    male and five female) were tested by repeated dermal application to
    either abraded or intact skin with a 1.0 percent formulation of
    pyrethrins at doses of 0 and 10 mg/kg body-weight/day. Treatments of 1
    ml/kg body-weight of the formulation were applied daily (6-8 hour
    exposure per day) five days per week for three weeks. No systemic,
    clinical or necrotic findings were attributed to the test material.
    Repeated dermal applications of a 1 percent formulation of pyrethrins
    was not detrimental to rabbits (Weir, 1966d).

    Long-term studies

    No new information available.


    Two hundred human subjects (177 females, 23 males) were patch tested
    for skin sensitivity and irritation using pyrethrins at 1 percent in
    water simulating formulation levels. Under the conditions of this
    patch test, pyrethrins at the 1 percent formulation level was not a
    primary irritant and was not a sensitizer to human skin (Weir, 1966e).


    Skin sensitization studies using very low levels of pyrethrins have
    been negative. Dermal and inhalation toxicity studies of pyrethrins in
    combination with synergists, using a commercial formulation, exhibited
    a low order of toxicity to rabbits. Further studies of this type,

    using especially the methylenedioxy synergists would, however, appear
    desirable. A rabbit reproduction study indicated that pyrethrins were
    not teratogenic. Some limited information on the mammalian metabolism
    of pyrethrins has recently become available. The short-term studies in
    the dog and other species requested at the 1966 Joint Meeting with a
    view to elucidating the effect on the liver found in a long-term study
    in rats, have not been forthcoming. The Committee therefore decided to
    retain the acceptable daily intake on a temporary basis.


    Level causing no toxicological effect

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


    0-0.04 mg/kg body-weight


    REQUIRED (before June 1973)

    Short-term toxicity studies in several species including a non-rodent
    mammalian species, with special emphasis on the effects on the liver
    and a detailed study of the mammalian metabolism of pyrethrins.


    Further studies to determine if mammalian toxicity to pyrethrins is
    increased when they are used along with synergists, especially with
    methylenedioxy compounds such as piperonyl butoxide.


    Casida, J.E., Kimmel, E.C., Elliot, M. and Janes, N.F. (1970)
    Oxidative metabolism of pyrethrins in mammals. Unpublished report
    submitted to WHO

    FAO/WHO. (1967) Evaluation of some pesticide residues in food. FAO.
    PL:CP/15; WHO/Food Additives/67.32

    Head, S.W. (1969) The composition of pyrethrum extract. Pyrethrum
    Post, 10: 1-5

    Leong, K.J. and Martin, A.R. (1966) Acute inhalation exposures - Rats.
    o/w Emulsion of neopynamin, o/w emulsion of pyrethrin. Unpublished
    report from Hazelton Laboratories, Inc. (31 March 1966) to S.C.
    Johnson and Son, Inc.

    Malone, J.C. and Brown, N.C. (1968) Toxicity of various grades of
    pyrethrum to laboratory animals. Pyrethrum Post, 9: 3-8

    Weir, R.J. (1966a) Reproduction study - rabbits. Neopynamin and
    pyrethrin. Unpublished report (3 August 1966) from Hazelton
    Laboratories, Inc. to S.C. Johnson and Son, Inc.

    Weir, R.J. (1966b) Skin sensitization study - guinea pigs. Neopynamin
    and pyrethrin. Unpublished report (1 June 1966) from Hazelton
    Laboratories, Inc. to S.C. Johnson and Son, Inc.

    Weir, R.J. (1966c) Acute potentiation study - oral administration,
    rats. Neopynamin and pyrethrin. Unpublished report from Hazelton
    Laboratories, Inc. (1 June 1966) to S.C. Johnson and Son, Inc.

    Weir, R.J. (1966d) Repeated dermal application - rabbits. Neopynamin
    and pyrethrin. Unpublished report from Hazelton Laboratories, Inc. (1
    June 1966) to S.C. Johnson and Son, Inc.

    Weir, R.J. (1966) Human patch test. Unpublished report (3 November
    1966) from Hazelton Laboratories, Inc. to S.C. Johnson and Son, Inc.

    Weir, R.J. and Crews, L.M. (1966) Supplement to acute inhalation 
    exposures - rats. Unpublished report from Hazelton Laboratories, Inc.
    (1 June 1966)

    Wisconsin. (1965) Unpublished report (23 September 1965) from the
    Wisconsin Alumni Research Foundation

    Yamamoto, I. and Casida, J.E. (1966) 0-demethylpyrethrin II analogs
    from oxidation of pyrethrin I, allethrin dimethrin and phthalthrin by
    a house fly enzyme system. J. econ. Entomol., 59: 1542-1543

    Yamamoto, I., Kimmell, E.C. and Casida, J.E. (1969) Oxidative
    metabolism of pyrethroids in houseflies. J. Agr. Fd. Chem., 17:

    See Also:
       Toxicological Abbreviations
       Pyrethrins (FAO Meeting Report PL/1965/10/1)
       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 (WHO Pesticide Residues Series 2)
       Pyrethrins (WHO Pesticide Residues Series 4)