And Developmental Toxicity DIPHENYL ETHER HERBICIDES Contact herbicides Readily absorbed by roots leaves Limited translocation Preemergence or early postemergence Uses Control broadleaf weeds grasses ID: 1009247
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1. HERBICIDES:Diphenyl EthersAndDevelopmental Toxicity
2. DIPHENYL ETHER HERBICIDESContact herbicidesReadily absorbed by roots, leavesLimited translocationPre-emergence or early post-emergenceUsesControl broadleaf weeds, grassesSoybeans, legumesRicePost-emergence onSoybeans, wheat, barley, sugar beetsCl or other sub-stituents required
3. Mode of ActionInhibit photosynthesisInhibit electron transport Inhibit coupled photophosphorylation?Some auxin-like actionInhibit protoporphyrinogen oxidaseLast common enzyme in synthesis of chlorophyll and hemoglobin(some diphenyl ethers may affect hemoglobin production , as shown by gray color of treated mice)
4. AcifluorfenUsesWater solubilityPersistenceNot very greatToxicologyLD50 po in ratsEPA: 1,300 mg/kgUI Extension: 3,300 mg/kg
5. OxyfluorfenWater solubility: 0.1 ppmBioaccumulation quite probable under normal useHerbicidal activity2-4 months (in medium-textured IL soil)Pre- and post-emergent herbicideBroad range of cropsMost uses cancelled in 1982
6. Oxyfluorfen toxicologyAcuteLD50, po, in rats: 5,000 mg/kgDelayed effectsProbable mutagenProbable carcinogenContaminated with perchloroethyleneProbable hepatotoxicantProbable thyrotoxicantDevelomental toxicity data inadequate
7. BifenoxUses:Paddy ricePre-emergent Corn, soybeansToxicityLD50, po, in rats:UI Extension: 1,630EPA: 6,400 mg/kgDelayed toxicitiesCarcinogen??EcotoxicologyBenign
8. BifenoxNitrofenThe 2nd group on the nitrophenyl ring of bifenox acts as a degradophore
9. Brief History of Nitrofen1966: First registered in U.S.1971: Ambrose et al: Neonatal mortality at 100 ppm in maternal diet1974: Kimbrough et al, Arch. Environ. Health: Neonatal mortality confirmed1981: Costlow and Manson: Heart and lung defects identified1981: Withdrawn from all U.S. uses
10. Toxicity of Nitrofen in RatsAdult toxicityLD50 > 1 g/kgAdverse effect at LOAEL: liver enlargementFetal toxicityNOAEL: < 0.1 mg/kg/dayAdverse effect at LOAEL: diaphragmatic herniasOther: heart, lung, kidney defects; cleft palate.
11. Reproductive Cycle
12. Human Development: Weeks 3 to 8345678
13. Protocol for 2-Generation AssayF0: parental animals1st matingF1ANecropsy at weaning2nd matingF1BSelect F1 parental animalsF2BF2ANecropsy at weaningNecropsy F2B at weaning; including complete histopathologyContinue feeding chemical to each group at the appropriate dosing level throughout the study (progeny, too!)Necropsy parents [F0 and F1] aftertheir 2nd litter is weaned.
14. Advantages of the 2-Generation AssayA single assay identifies:acute or cumulative toxicity leading tomale or female infertility, pre- and post-natal mortality,pre- and post-natal growth retardation,functional deficits in offspringtransplacental carcinogenesisinfertilitybehavioral anomalies
15. The 2-Generation Assay: DisadvantagesCost well over $500,000 per speciesbut still cheaper than the alternatives…Labor-intensiveNecropsies of all parentsNecropsies of offspring of all littersHistopathology of offspring from 2nd litters Identifies the existence of a problem, but not necessarily its nature
16. Advantages of the 2-Generation AssayA single assay identifies:acute or cumulative toxicity leading tomale or female infertility, pre- and post-natal mortality,pre- and post-natal growth retardation,functional deficits in offspringtransplacental carcinogenesisinfertilitybehavioral anomalies
17. The 2-Generation Assay: DisadvantagesCost well over $500,000 per speciesbut still cheaper than the alternatives…Labor-intensiveNecropsies of all parentsNecropsies of offspring of all littersHistopathology of offspring from 2nd litters Identifies the existence of a problem, but not necessarily its nature
18. Chemically induced birth defetcsVary withChemicalGenotypeOf dam and of embryoWithin and between speciesDevelopmental stage at time of exposureDoseEither severity of defects or probability of defect increases with increasing dose
19. Thalidomide-induced malformations occur 35- 50 days after the last menstrual period
20. “Karnofsky’s Law”Any chemical, given at the right time, and at the right dose, to the right species will cause malformationsThe fact that a pesticide causes malformations in one species - especially at high doses - is not necessarily enough reason to ban it.In the case of nitrofen, malformations occurred in both rats and mice, but not in rabbits.
21. Developmental Toxicity is a Threshold Phenomenon For agents other than mutagens, there is a minimum dose that will not affect the embryobecause it is metabolized by the dam and does not reach the embryo, and/orit does not significantly perturb embryonic development, and/orcompensatory mechanisms result in repair of the damage.
22. NitrofenCauses malformationsIn both rats and miceHeartKidneysDiaphragmEyesAt a fraction of the adult LD50 NOAEL in rats estimated at 0.03 mg/kg/day