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    VAMIDOTHION

    EXPLANATION

         Vamidothion was evaluated by the Joint Meetings in 1973, 1982 and
    1985 (Annex I, FAO/WHO 1974b, 1985b, 1986b). A temporary ADI was
    allocated in 1981. A toxicological monograph was prepared by the Joint
    Meeting in 1973 and monograph addenda were prepared in 1982 and 1985.

         Additional studies required by 1988 to complete the toxicological
    data base were a multi-generation reproduction study and a one-year
    dog study. These data have now been received and are reviewed in this
    monograph addendum.

    EVALUATION FOR ACCEPTABLE INTAKE

    Toxicological studies

    Special studies on reproduction

    Rats

         In a 2-litter, 2-generation reproduction study, groups of male
    and female Sprague-Dawley CD rats (30/sex/group in the F0 generation
    and 24/sex/group in the F1 generation) were administered by oral
    gavage 0, 0.05, 0.5 or 5.0 mg vamidothion (purity:technical)/kg bw as
    an aqueous solution. The F0 generation, as well as the F1
    generation, received 14 weeks' treatment before pairing to produce
    F1 and F2 litters, respectively (dosing of the F1 animals
    commenced at weaning and continued until termination after the
    breeding phase). All adult animals were subjected to a detailed
    necropsy procedure and the reproductive organs were weighed and
    retained; histological examination was performed on tissues from the
    control and high-dose group animals. Parental animals were observed
    for clinical signs, mortality, body weight and food consumption.
    Offspring was observed for number of live and dead foetuses, pup
    weight and sex, clinical signs, mortality and litter size. Those F1
    weanlings not selected for continuation of the study and F2
    weanlings were examined for macroscopic abnormalities. Plasma,
    erythrocyte and brain cholinesterase determinations were conducted at
    final sacrifice of F0 and F1 adults (10/sex) at the termination of
    each generation and of F1 and F2 offspring (5/sex) one week after
    weaning and at weaning, respectively.

         No effects were observed on reproduction parameters. The only
    effect observed was inhibition of cholinesterase. Parental
    cholinesterase activity was reduced at 5.0 and 0.5 mg/kg bw.
    Erythrocyte cholinesterase inhibition was about 90% and 50%,
    respectively, and plasma cholinesterase about 70% and 40%,
    respectively. In F0 and F1 parents, brain cholinesterase activity
    was decreased about 30% (20-39%) at 5.0 mg/kg bw. At 0.5 mg/kg bw only
    a slight but statistically significant inhibition of 5-8.5% was
    observed in F0 and F1 parents. This is not considered as
    toxicologically relevant. At 0.05 mg/kg bw erythrocyte cholinesterase
    was slightly inhibited (about 5-20%) in F0 parents only. In F1
    parents, only plasma cholinesterase was slightly inhibited (about
    15%). Only high-dose weanlings of the F1 generation had depression
    of erythrocyte and plasma cholinesterase activity, but it was to a
    lesser extent than parents. Based on the effects on cholinesterase in
    brain, the NOAEL is 0.5 mg/kg bw. (Willoughby et al., 1988).

    Short-term toxicity

    Dogs

         Groups of 21-23 week old beagle dogs (6/sex/group) were orally
    administered 0, 0.05, 0.5 or 5.0 mg vamidothion/kg/day for 52 weeks. A
    vamidothion/methylethylketone mixture (500 g/l) was dissolved in
    polypropylene glycol and incorporated into gelatin capsules (freshly
    prepared weekly) for administration. Observations included clinical
    signs, mortality, food and water consumption, body weight,
    ophthalmoscopy, haematology, clinical chemistry, urinalysis, plasma,
    erythrocyte and brain cholinesterase, macroscopy, organ weight and
    histopathology. Samples of liver, kidney cortex and kidney medulla
    from control and high-dosed animals were examined by transmission
    electron microscopy.

         No effects were seen on most parameters. Diarrhoea was observed
    in high-dosed males and stiff gait of the hind legs was occasionally
    observed in 5/6 male and 5/6 female dogs during the first 10 weeks of
    the experiment. SAP, ALAT and to a lesser extent ASAT activity were
    increased in males at 5.0 mg vamidothion/kg bw. Plasma and erythrocyte
    cholinesterase activity were significantly inhibited at 5.0 and
    0.5 mg/kg bw (plasma: about 50 and 30%, respectively; erythrocytes:
    about 90 and 40%, respectively). Plasma cholinesterase was also
    decreased in males (5-10%) at 0.05 mg/kg but this is not considered
    toxicologically relevant. Brain cholinesterase activity was
    significantly reduced at the highest dose only (20-30%). The NOAEL in
    this study was 0.5 mg vamidothion/kg bw based on the effect on brain
    cholinesterase (West et al, 1988a; 1988b).

    Observations in man

         Groups of 6-11 normal healthy volunteers of both sexes were
    administered 9.6 or 37.2 g vamidothion/kg/day orally in aqueous
    solution on five days each week for three weeks. Other groups received
    78.8 or 122.8 g vamidothion/kg/day in aqueous solution for five
    weeks. A control group was studied for 25 weeks. No clinical signs or
    symptoms were found which could be attributed to treatment. Plasma
    cholinesterase, estimated weekly, showed no consistent depression in
    any group but erythrocyte cholinesterase was depressed in three of six
    volunteers receiving 122.8 g/kg/day. The no-effect level was
    considered to be 78.8 g/kg/day (calculated to be equivalent to
    56.3 g/kg/day if vamidothion was administered every day without a
    break) (Noel et al., 1970). (From 1973 JMPR Evaluations.)

    COMMENTS

         In a 2-generation reproduction study in rats, vamidothion had no
    effect on reproductive performance, survival, growth or development.
    In this study treatment-related decreases in plasma cholinesterase and
    erythrocyte acetylcholinesterase activities were observed in parental
    rats at 5.0 and 0.5 g/kg bw. F1 weanlings showed these effects at
    5.0 mg/kg bw. Inhibition of brain acetylcholinesterase was observed at
    5.0 mg/kg bw in the parent animals.

         In a one-year toxicity study in dogs, inhibition of brain
    acetylcholinestarase was found at 5.0 mg/kg bw/day. Plasma
    cholinesterase and erythrocyte acetylcholinesterase were inhibited at
    5.0 and 0.5 mg/kg bw.

         The 1973 JMPR reviewed a study in human volunteers. In this study
    inhibition of erythrocyte acetylcholinesterase was observed at a dose
    level of 0.123 mg/kg bw/day, given 5 days per week for 5 weeks. An ADI
    based on the human data was estimated.

    TOXICOLOGICAL EVALUATION

    CAUSING NO TOXICOLOGICAL EFFECT

         Mouse:    1 ppm in the diet, equal to 0.137 mg/kg bw
         Rat:      1 ppm in the diet, equal to 0.054 mg/kg bw
         Dog:      0.5 mg/kg bw
         Man:      0.08 mg/kg bw/day

    ESTIMATE FOR ACCEPTABLE DAILY INTAKE FOR MAN

         0-0.008 mg/kg bw

    STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE IN THE CONTINUED
    EVALUATION OF THE COMPOUND

         Further observations in man.

    REFERENCES

    Noel, P.R.B., Hayes, G. & Street, A.E. 1970. Vamidothion:
    Determination of no-effect level in human volunteers. Unpublished
    report of Huntingdon Research Centre, submitted by Rhne-Poulenc to
    the JMPR in 1973.

    West, H., Virgo, D.M., Wooley, A.P.A.H., Lee, P., Fowler, J.S.L. &
    Brown, P.M. 1988a. Vamidothion: toxicity study by oral (capsule)
    administration to beagle dogs for 52 weeks. Unpublished report
    No. 87/RHA074/94 d.d. 8 March 1988 from Life Science Research, Eye,
    Suffolk IP23 7PX, England. Submitted to WHO by Rhne-Poulenc
    Agrochemie, Boite Postale 9163, F-69263 Lyon Cedex 09, France.

    West, H., Wallace, W., Sykes, A.K. & Fowler, J.S.L. 1988b.
    Vamidothion: toxicity study by oral (capsule) administration to beagle
    dogs for 52 weeks. First supplement to LSR report No. 87/RHA074/904,
    electron microscopy report. Unpublished report No. 88/RHA074/137 d.d.
    30 March 1988 from Life Science Research, Eye, Suffolk IP23 7PX,
    England. Submitted to WHO by Rhne-Poulenc Agrochemie, Boite Postale
    9163, F-69263 Lyon Cedex 09, France.

    Willoughby, C.R., Tesh, J.M., Enticott, J. & Fowler, J.S.L. 1988.
    Vamidothion: effects upon reproductive performance of rats treated
    continuously throughout two successive generations. Vol. I, II and
    III. Unpublished report No. 88/RHA098/144 d.d. 4 May 1988 from Life
    Science Research, Eye, Suffolk IP23 7PX, England. Submitted to WHO by
    Rhne-Poulenc Agrochemie, Boite Postale 9163, F-69263 Lyon Cedex 09,
    France.
    


    See Also:
       Toxicological Abbreviations
       Vamidothion (ICSC)
       Vamidothion (WHO Pesticide Residues Series 3)
       Vamidothion (Pesticide residues in food: 1982 evaluations)
       Vamidothion (Pesticide residues in food: 1985 evaluations Part II Toxicology)