Leptophos was reviewed by Meetings in 1974 and 1975 (FAO/WHO,
    1975b, 1976b) and discussed briefly in 1976 (FAO/WHO, 1977a). Some
    guideline levels for residues in food were recorded in 1974 as no
    ADI was allocated. In 1975 a temporary ADI was allocated together
    with an expanded list of temporary MRLs. A number of further
    requirements, by 1978, were recorded. They included expressions of
    need for further information on biochemistry and toxicology, also
    relating to the current usage and the occurrence of residues of the

         The new information received is evaluated in the present
    monograph amendment.




         Results of studies on the metabolic fate of leptophos in the
    rat have confirmed those previously reported. Urinary metabolites
    were identified as demethylation reaction products of leptophos and
    the oxygen analog. There was no mention of the occurrence of the
    desbrominated leptophos metabolite although unidentified
    metabolites, which may include this compound, accounted for a small
    quantity of the excreted product. Leptophos, a lipophilic molecule,
    was observed to concentrate and be released slowly from adipose
    tissue. While the major quantity of leptophos was eliminated in 48
    hours, trace residues in omental and subcutaneous tissues were
    evident for as long as 12 weeks after a single acute oral dose of
    15 mg/kg (Hassan, et al., 1977a). Dietary administration of
    leptophos again resulted in cholinesterase depression pointing to
    the adequacy or the use of this enzyme as an indicator of exposure
    (Hassan, et al., 1977b).

    Effects on enzymes and other biochemical parameters

         El-Sebae, et al., (1978) again confirmed the weak
    anticholinesterase activity of leptophos reporting in vivo PI50
    values of < 4.5 for brain and plasma cholinesterase in mice. In
    vitro bioassays were somewhat more sensitive with PI50 values
    exceeding 5 for brain cholinesterase.

        Acute Toxicity
    Species        Sex1      Route     Formulation     LD50          References
    Mice           N.S.      Oral      Technical       162           El Sebae, et al., 1978
                   N.S.      Oral      30%, E.C.       83            El Sebae et al., 1978
    1 N.S. - not specified
    2 Corn oil solution
    Special studies on neurotoxicity


         Several studies reviewed in draft form by the 1975 Meeting
    have been published in detail attesting to the neurotoxic effects
    of leptophos both chemically and histologically in the hen (Abou
    Donia, 1976b; Abou Donia and Preissig, 1976; Preissig and Abou Donia,
    1976). A conference was held in 1976 to review all known information
    on the subject. The positive neurotoxic results obtained in a variety of
    programs evaluating the effects of leptophos were confirmed (Baron,
    1976). It was reported that a "threshold" effective dose of 1 mg/kg
    was observed over a prolonged period of oral administration of
    leptophos to hens. Clinical signs of ataxia were reported after 62
    days of administration of 1 mg/kg. These signs were not accompanied by
    histological evidence of pathological change (Abou Donia, 1976a).

         In a one year dietary study, groups of hens (35 hens/group were
    fed leptophos in the diet for one year at dosage levels of 0, 0.1,
    0.3, 1.0, 3.0, 10.0, 30.0 and 100.0 ppm. Mortality was observed in all
    groups although there was no relationship of the leptophos dose fed to
    the mortality observed. Growth and food consumption were normal over
    the first 13 weeks of the experiment. Egg production was also normal
    over this period. Clinical signs of ataxia were initially noted at 58
    days in the 100 ppm dose group. All birds in this high dose group
    ultimately showed varying degrees of clinical ataxia. This was not
    observed in any hens of the 30 ppm group. Histological studies were
    incomplete (Fletcher, 1978). (100 ppm in the diet appears to
    correspond to a daily intake of 5.8 mg/kg body weight).


         The neurotoxic effects of prolonged exposure of immature (1 week
    old) mallard ducklings to leptophos was reported by Herin et al.,
    (1978). Within 17 to 23 days after exposure to 260 ppm, ducklings
    showed clinical signs of ataxia that progressed to paralysis.

    Observations in man

         A group of eight of nine occupationally-exposed workers were
    found to have developed a severe neuropathy, which was probably
    associated with their exposure to leptophos in a manufacturing plant
    (Xintaras et al., 1978). In addition to leptophos exposure, these
    workers were also exposed to high levels of n-hexane and toluene,
    both of which have been known to be associated with neuropathies in
    humans. Leptophos exposure was excessive in the occupational setting
    with the workers on occasion reporting general symptoms of
    organophosphorus poisoning. Paraesthesia of the extremities was
    observed in eight workers. Altered pain, vibration and position sense,
    decreased motor function and decreased muscle tone were found in six
    workers. Only one afflicted worker showed a decreased cholinesterase
    value. One of three workers tested displayed a decreased nerve
    conduction. Two of five EEG examinations and one of two EKG
    examinations were abnormal. It was established that the workers were
    occupationally exposed to excessive levels of leptophos in its
    manufacture and this exposure (alone with or complicated by their
    exposure to certain solvents) directly contributed to a neurotoxic
    response similar to that noted in the hen bioassay.

         A group of 32 individuals exposed to leptophos used in an
    agricultural spray program were examined for clinical and his chemical
    indices to evaluate the effect of occupational exposure (Hassan et
    al., 1978). Some of the highly exposed individuals reported typical
    symptoms of cholinesterase depression (which when assayed was
    depressed, suggesting exposure). No other clinical parameter was
    affected. A follow-up examination on 14 weeks did not show signs of
    muscle weakness or paralysis. Recovery of the cholinesterase activity
    was generally slow. In a similar study of 18 occupationally exposed
    agricultural workers, signs and symptoms of cholinesterase depression
    were reported (Hassan, 1978). Recovery or the subjects was noted
    within two weeks and follow-up examinations in 6 to 18 months again
    showed no sign of muscle weakness or paralysis. Two males and one
    female were administered 14c-leptophos to examine the fate in man.
    Cholinesterase was unaffected by the 10 mg oral dose. Elimination was
    slow with 12 to 65% eliminated within 12 days. Hydrolic products were
    the metabolites observed (Hassan, 1978). The metabolic details were
    insufficient to evaluate metabolism in man.


         The toxicological aspects of leptophos have been considered in
    previous Meetings (FAO/WHO, 1976a, 1977a) and based on no-effect
    levels observed in two-year studies in rats and dogs, a temporary ADI
    was allocated. An exceptionally high safety factor was used in this
    evaluation reflecting concerns over the delayed neurotoxicological
    events noted in short term bioassays in hens, a species reflective of
    a similar neurological syndrome observed in man.

         Current studies available to the Meeting confirmed the
    susceptibility of humans to delayed neurotoxicity resulting from
    exposure to high levels of leptophos in an industrial setting. The
    extensive animal toxicological data base available for review and new
    prolonged bioassay neurotoxicity tests in hens further supported the
    existence of a dose-response relationship and a no-effect level.
    Information had come to the attention of the Meeting that leptophos
    was no longer being manufactured and therefore the following
    conclusion was reached.


         The previously allocated temporary ADI should be withdrawn.



         The Meeting was informed that leptophos is not now manufactured,
    although small stocks are being used in various countries until they
    are depleted. In the light of the latter situation and the low
    probability of additional responses to recorded requirements for
    further information becoming available., also in the absence of an
    ADI, it was decided that the recommendations for temporary MRLs should
    be withdrawn.

         Interested parties are referred to FAO/WHO 1978c and to previous
    monographs for guidance on the levels that may follow the use of the
    pesticide on food crops.


    Abou Donia, M.B. Discussion of Research Reported in "Proceedings of
    (1976a)             a Conference Pesticide Induced Delayed
                        Neurotoxicity". Washington, D.C., February 19-20,
                        1976. Environmental Protection Agency,
                        Environmental Health Effects Research Series, EPA-
                        600/1-76-025, July 1976.

    Abou Donia, M.B. Pharmacokinetics of a Neurotoxic Oral Dose of
    (1976b)             Leptophos in Hens. Arch. Toxicol. 36: 103-110.

    Abou Donia, M.B. and S.H. Preissig Delayed Neurotoxicity of
    (1976)              Continuous Low Dose Oral Administration of
                        Leptophos to Hens. Tox. Appl. Pharmacol. 38:

    Baron, R.L. Ed. Pesticide Induced Delayed Neurotoxicity,
    (1976)              Proceedings of a Conference Washington, D.C.,
                        February 19-20, 1976. Environmental Protection
                        Agency, Environmental Health Effects Research
                        Series, EPA-600/1-76-025, July 1976.

    El-Sebae, A.H., N.S. Ahmed and S.A. Soleman Effect of Pre-exposure
    (1978)              on Acute Toxicity of Organophosphorus Insecticides
                        to White Mice. J. Environ. Sci. Health B13 (1):

    Fletcher, D.W. One Year Chronic Oral Neurotoxicity Test with
    (1978)              Technical Reference Standard Phosvel. Unpublished
                        Draft Report from Industrial Biotest Laboratories,
                        Inc. submitted by Velsicol Chemical Co. to the

    Hassan, A., Abdel-Hamid, F.M., Abou-Zeid, A., Mokhtar, O.A.,
    (1978b)             Abdel Razek, A.A. and Ibrahim, M.S. Clinical
                        Observations and Biochemical Studies on Humans
                        exposed to leptophos. Chemosphere 3 283-90.

    Hassan, A., F.M. Abdel-Hamid and S.I. Mohammed Metabolism of
    (1977a)             14C leptophos in the rat. Arch. Env. Contam.
                        Toxicol. 6: 447-454.

    Hassan A. Personal Communication

    Herin, R.A., A.A. Komeil, D.C. Graham, A. Curley and M.B. Abou
    (1978)              Donia Delayed Neurotoxicity Induced by
                        Organophosphorus Compounds in the Wild Mallard
                        Duckling. Env. Path. Tox. 1: 233-240.

    Preissig, S.H. and M.B. Abou Donia The Chronological Effects of
    (1976)              Leptophos on the Spinal Cord and Sciatic Nerve of
                        Hens. J. Neuropathol. Exp. Neurol. 35: 303.

    Xintaras, C., J.R. Burg, S. Tanaka, S.T. Lee, B.L. Johnson, C.A.
    (1978)              Cottrill and J.Bender NIOSH Health Survey of
                        Velsicol Pesticide Workers. NIOSH Technical
                        Report-Publication No. 78-136. U.S. Dept. of
                        Health, Education and Welfare.

    See Also:
       Toxicological Abbreviations
       Leptophos (WHO Pesticide Residues Series 4)
       Leptophos (WHO Pesticide Residues Series 5)