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    TRIADIMEFON

    EXPLANATION

         Triadimefon was evaluated for acceptable daily intake (ADI) by
    the Joint Meetings in 1981 and 1983 (Annex 1, FAO/WHO 1982a and 1985).
    A toxicological monograph was prepared by the Joint Meeting in 1981
    (Annex 1, FAO/WHO, 1982b) and a monograph addendum was prepared in
    1983 (Annex 1, FAO/WHO, 1985a). A temporary ADI of 0-0.01 mg/kg b.w.
    was allocated in 1981 and confirmed in 1983. The 1983 Joint Meeting
    required clarification of the toxicological significance of hepatic
    toxicity in rats and mice and of the hyperplastic liver nodules
    observed in chronic mouse feeding studies. Data concerning
    observations in humans were considered desirable.

         Additional information, not all relevant to the above requests,
    was evaluated by the Meeting and is presented in this monograph
    addendum.

    BIOLOGICAL DATA

    Biochemical aspects

    Special study on in vitro metabolism

         l4C-Benzene ring-labelled triadimefon, > 99% radiochemical
    purity, was incubated with 9,000 x G rat liver supernatant for one
    hour with added NADP. After extraction, the radioactivity was
    analysed by thin layer chromatography. It was found that 42%
    of the radioactively-labelled triadimefon had been converted to
    1-(4-chlorophenoxy)-3,3-dimethyl-l(1H-1,2,4-triazol-l-yl)-2-butanol by
    reduction of the keto group of triadimefon. Unreduced triadimefon
    (48%) was also recovered (Puhl & Fredrickson, 1982).

    Special study on reproduction

         Groups of 10 male and 20 female BOR:WISW (SPF/Cpb) rats were fed
    triadimefon in the diet at 0.50 and 1800 ppm. Investigations were made
    of behaviour, body weight, development, mortality, fertility,
    lactation, duration of gestation, male/female sex ratio and pup
    development in two successive generations, each of one litter. Serum
    testosterone and prolactin levels and sperm motility were determined
    in low- and high-dose males surviving at the end of the study. F0 and
    F1 parents and 4 week-old F2 pups were autopsied and their tissues
    examined histopathologically.

         Growth of parents and pups and reproductive performance were not
    affected in any generation at the lower dose. At 1800 ppm general
    appearance and behaviour, parental mortality rate, and length of
    gestation were unaffected by treatment. However, the growth of the F0

    and F1 parents was significantly reduced and pups in the F1 and F2
    litters were smaller and had reduced viability. The male/female sex
    ratio was reduced in the F2-generation pups, but was normal in other
    generations.

         The mating performance (fertility index) of F1 females was only
    about one-third of control and low-dose groups. Similarly, the
    relative number of inseminated F1 females was about half that of
    other groups, indicating reduced mating by Fl males. The number of
    still-births and foetal abnormalities were unaffected by treatment.

         Reduced mating by F1 males treated with 1800 ppm triadimefon was
    confirmed in a supplementary study by mating with (untreated) control
    females. The latter became pregnant less frequently, although their
    insemination index (number pregnant/number inseminated) remained
    within normal limits. Conversely, when F1 females that had been
    treated with 1800 ppm triadimefon were mated with control males they
    became prgenant at normal incidence, indicating that triadimefon
    treatment had no significant effect. The course of resultant
    pregnancies was unremarkable.

         Radioimmunological investigation after 8 months exposure and at
    terminal sacrifice showed that the F1 males treated at 1800 ppm had
    serum testosterone concentrations twice those of untreated males;
    corresponding FSH concentrations were the same.

         At necropsy, sperm taken from 1800 ppm males of the F0, F1 and
    F2 groups showed normal sperm motility and no grossly-apparent sperm
    abnormalities. The F0 rats of the high-dose group had increased liver
    weights (relative and absolute); the livers of high-dose F1 males
    were relatively heavier than the controls while F1 female liver
    weights were lighter than controls. There were no consistent
    variations in organ weights in animals from other generations,
    including reproductive organs (testicle, epididymis and ovary).
    Histopathological examination showed liver hypertrophy in F1b males
    and glycogen accumulation of hepatic vacuoles of F2 pups as the only
    significant findings. There were no microscopic pathological findings
    in the testes of F1 and F2 males. The results of this study confirm
    the previous finding of impaired reproductive performance of rats fed
    1800-ppm - but not 50-ppm - triadimefon in diet (Eiben et al.,
    1984).

    Special study on DNA damage
                                                                        

    Test system                   Concentration   Result   Reference
                                  (g/plate)
                                                                        

    Pol Test

    E. coli (K12) p3478           625;1250        -        Herbold, 1984

    E. coli W3110                 2500;5000;      -
                                  10,000

    Solvent

    Chloramphenicol
    (negative control)            30              -

    Methylmethanesulphonate
    (positive control)            0               +
                                                                        

    COMMENTS

         In chronic feeding studies in the mouse, rat, and dog,
    triadimefon produced a dose-related increase in liver weights
    accompanied by elevation of serum hepatic alkaline phosphatase and
    transaminase activities. The rat was most sensitive, but enzymatic
    induction was readily reversible on cessation of exposure. The
    mouse was the only species tested which exhibited significant
    histopathological changes with hyperplastic liver nodules, but
    only at the highest dose level tested, 1800 ppm (JMPR, 1981).

         In feeding studies, triadimefon increased the liver weights of
    dogs, rats and mice which, in dogs and mice, correlated with
    biochemical evidence of hepatotoxicity at higher doses. In addition,
    reversible induction of hepatic microsomal enzymes of rats and mice
    also occurred. It is known that induction of hepatic microsomal
    activity can be accompanied by compensatory hepatic hypertrophy. These
    related effects were fully reversible in the rat, the species found to
    be most susceptible to microsomal enzyme induction.

         Previous in vitro studies have shown that triadimefon binds to
    hepatic cytochrome P-450 and is a modest inhibitor of microsomal
    enzyme activities. Further studies show that rat liver homogenate
    reduces triadimefon to the corresponding alcohol, triadimenol, and
    that triadimefon does not adversely affect DNA, as indicated by the
    Pol test with E. coli.

         The 1984 Joint Meeting considered the toxicological significance
    of hepatic tumours in the mouse, including those associated with the
    administration of high doses of pesticides able to induce hepatic
    microsomal enzymes. Viewed in that light, the present Meeting
    considered that the toxicological significance of the hyperplastic
    liver nodules observed in chronic mouse feeding studies with
    triadimefon was adequately clarified.

         The Meeting therefore estimated an ADI.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Mouse:    300 ppm in the diet, equivalent to 40 mg/kg b.w.

         Rat:      50 ppm in the diet, equivalent to 2.5 mg/kg b.w.

         Dog:      230 ppm in the diet, equivalent to 8.25 mg/kg b.w.

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0-0.03 mg/kg b.w.

    FURTHER WORK OR INFORMATION DESIRED

         Observations in man.

    REFERENCES

    Eiben, R., Whitney, J.C., & Brown, M.P. MEB 6447 (Triadimefon): Two
    (1984)    generation study with rats (supplementary study).
              Unpublished report No. 12,712 from Institute of Toxicology,
              Bayer AG. Submitted to WHO by Bayer AG.

    Herbold, B. MEB 6447 (c.n. Triadimefon): Pol Test on E. coli to
    (1984)    evaluate for potential DNA damage. Unpublished report No.
              12,780 from Institute of Toxicology, Bayer AG. Submitted to
              WHO by Bayer AG.

    Puhl, R.J. & Fredrickson, D.R. The metabolism of (R)Bayleton-benzene
    (1982)    ring-UL-14C in a rat liver in vitro system. Unpublished
              report No. 82,560 from Agricultural Chem. Div., Mobay
              Chemical Corporation. Submitted to WHO by Bayer AG.
    


    See Also:
       Toxicological Abbreviations
       Triadimefon (Pesticide residues in food: 1979 evaluations)
       Triadimefon (Pesticide residues in food: 1981 evaluations)
       Triadimefon (Pesticide residues in food: 1983 evaluations)
       Triadimefon (Pesticide residues in food: 1984 evaluations)