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
(µg/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.