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.
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)