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    PESTICIDE RESIDUES IN FOOD - 1997


    Sponsored jointly by FAO and WHO
    with the support of the International Programme
    on Chemical Safety (IPCS)




    TOXICOLOGICAL AND ENVIRONMENTAL
    EVALUATIONS 1994




    Joint meeting of the
    FAO Panel of Experts on Pesticide Residues
    in Food and the Environment
    and the
    WHO Core Assessment Group 

    Lyon 22 September - 1 October 1997



    The summaries and evaluations contained in this book are, in most
    cases, based on unpublished proprietary data submitted for the purpose
    of the JMPR assessment. A registration authority should not grant a
    registration on the basis of an evaluation unless it has first
    received authorization for such use from the owner who submitted the
    data for JMPR review or has received the data on which the summaries
    are based, either from the owner of the data or from a second party
    that has obtained permission from the owner of the data for this
    purpose.



    FENTHION (addendum)

    First draft prepared by
    A. Moretto
    Istituto di Medicina del Lavoro
    UniversitÓ degli Studi di Padova, Padua, Italy

         Explanation
         Evaluation for acute reference dose
              Acute toxicity
         Comments
         Toxicological evaluation relevant for establishing an acute
         reference dose
         Reference

    Explanation

    Fenthion was reviewed most recently by the 1995 JMPR (Annex 1,
    reference 74), which established an ADI of 0-0.007 mg/kg bw on the
    basis of an NOAEL of 0.07 mg/kg bw per day (the highest dose tested)
    for inhibition of erythrocyte acetylcholinesterase activity in a
    25-day study in volunteers. The available data did not permit the
    Meeting to establish an acute reference dose different from the ADI. A
    study of neurotoxicity in rats given a single dose was available to
    the present Meeting to assist in reviewing the acute reference dose.

    Evaluation for acute reference dose

    Acute toxicity

     Rats

    Technical-grade fenthion (purity, 94.6%) dissolved in corn oil was
    administered by gavage at a volume of 5 ml/kg bw to groups of 18 male
    and 18 female fasted adult Wistar rats at doses of 0 (vehicle), 1, 50,
    or 125 mg/kg bw for males and 0, 1, 75, or 225 mg/kg bw for females.
    Twelve animals in each group were observed for clinical signs, death,
    and body weight and underwent a functional observational battery of
    tests and automated measurements of activity (figure-eight maze);
    after death, the brains were weighed and a gross necropsy was
    performed. Skeletal muscle, peripheral nerves, eyes with optic nerves,
    and tissues from the central nervous system were examined
    microscopically. After a preliminary experiment, behavioural testing
    was started on the day of treatment (day 0), at the beginning of the
    peak effect, a minimum of 5 h after application. The activities of
    plasma, erythrocyte, and brain cholinesterases were determined about
    5.5 hours after treatment (i.e. at the peak of clinical
    manifestations) in the remaining six animals in each group.

    Four females at the high dose died within three days of treatment, and
    dose-related cholinergic signs were seen in animals at the
    intermediate and high doses. The clinical signs persisted up to five
    days after treatment. Body weight was decreased in males at the high
    dose on day 7, and recovery was not complete by day 14. Females at the
    high dose had marginally decreased body weights at day 7 only. The
    functional observational battery of tests revealed dose-related
    effects on the day of treatment in males and females at the two higher
    doses. These effects were associated with signs of acute cholinergic
    toxicity, most of which were reversed by day 14. Decreased motor and
    locomotor activity in the figure-eight maze were also seen in animals
    at these doses on day 0, with almost complete recovery by day 14. At
    the time of functional and motor activity testing on day 0, plasma and
    erythrocyte cholinesterase activities were inhibited in males and
    females at the intermediate dose (by 89-95%) and high dose (by
    90-96%); females at the low dose showed marginal inhibition of plasma
    (by 23%) and erythrocyte cholinesterase activity (by 22%). Brain
    acetylcholinesterase activity was inhibited by 76% in animals at the
    intermediate dose and by 86% in those at the high dose; in rats at the
    low dose, it was inhibited by 4% in males and 9% in females, the
    latter being statistically significant. The only treatment-related
    gross lesion was emaciation in the four females at the high dose that
    died before terminal sacrifice. Terminal brain weight was not
    affected. There were no treatment-related microscopic lesions in
    skeletal muscle or neural tissues. The NOAEL for both inhibition of
    brain acetylcholinesterase activity and neurobehavioural effects was
    1 mg/kg bw (Dreist & Popp, 1997).

    Comments

    In rats treated by gavage with single doses of 0, 1, 50 (males), 75
    (females), 150 (males), or 225 (females) mg/kg bw of technical-grade
    fenthion, the NOAEL for inhibition of brain acetylcholinesterase
    activity and for neurobehavioural effects was 1 mg/kg bw.

    In a study that was reviewed by the 1995 JMPR, administration of 0.07
    mg/kg bw to volunteers daily for about 25 days did not inhibit
    erythrocyte acetylcholinesterase activity.

    The Meeting concluded that an acute reference dose of 0.01 mg/kg bw
    could be allocated by taking into account the NOAEL of 1 mg/kg bw in
    rats and applying a safety factor of 100.

    Toxicological evaluation relevant for establishing an acute
    reference dose

     Levels that cause no toxic effect

         Rat:      1 mg/kg bw (single oral administration, inhibition of
                   brain acetylcholinesterase activity)

         Human:    0.07 mg/kg bw per day (four-week study in volunteers,
                   highest dose tested)

     Estimated acute reference dose for humans

         0.01 mg/kg bw

    Reference

    Dreist, M. & Popp, A. (1997) E 1752 (common name: fenthion). Acute
    oral neurotoxicity screening in Wistar rats. Unpublished report No.
    26113 from Bayer AG, Toxicology, Wuppertal, Germany. Submitted to WHO
    by Bayer AG, Leverkusen, Germany.
    


    See Also:
       Toxicological Abbreviations
       Fenthion (ICSC)
       Fenthion (WHO Pesticide Residues Series 1)
       Fenthion (WHO Pesticide Residues Series 5)
       Fenthion (Pesticide residues in food: 1977 evaluations)
       Fenthion (Pesticide residues in food: 1978 evaluations)
       Fenthion (Pesticide residues in food: 1979 evaluations)
       Fenthion (Pesticide residues in food: 1980 evaluations)
       Fenthion (Pesticide residues in food: 1983 evaluations)
       Fenthion (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)
       Fenthion (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)