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HERBICIDES:

Diphenyl Ethers
And
Developmental Toxicity

Diphenyl Ether Dan Toksisitas Perkembangan


DIPHENYL ETHER HERBICIDES
Contact herbicides
Readily absorbed by roots, leaves
Limited translocation
Pre-emergence or early post-emergence
Uses
Control broadleaf weeds, grasses
Soybeans, legumes
Rice
Post-emergence on
Soybeans, wheat, barley, sugar beets

Cl atau substituen lainnya dibutuhkan


Hubungi
herbisida Mudah diserap oleh akar, daun
Translokasi terbatas Pra-Emergence atau awal Post
Emergence
Kegunaan
Kontrol rumput gulma luas, rumput
Kacang kedelai, kacang polong
Nasi
Post Emergence di Kedelai, gandum, jelai, bit gula
Mode of Action

Inhibit photosynthesis
Inhibit electron transport
Inhibit coupled photophosphorylation?
Some auxin-like action
Inhibit protoporphyrinogen oxidase
Last common enzyme in synthesis of chlorophyll
and hemoglobin
(some diphenyl ethers may affect hemoglobin
production , as shown by gray color of treated
mice)
Menghambat fotosintesis

Menghambat transpor elektron


Menghambat ditambah fotofosforilasi?
Beberapa tindakan seperti auksin
Menghambat oksidase protoporfinogen
Enzim umum terakhir dalam sintesis klorofil dan hemoglobin
(beberapa eter difenil dapat mempengaruhi produksi hemoglobin,
seperti yang ditunjukkan oleh warna abu-abu pada tikus yang
diobati)
Acifluorfen

Uses
Water solubility
Persistence
Not very great
Toxicology
LD50 po in rats
EPA: 1,300 mg/kg
UI Extension: 3,300 mg/kg
Kegunaan
Kelarutan air
Kegigihan
Tidak terlalu besar
Toksikologi
LD50 po pada tikus
EPA: 1.300 mg / kg
Ekstensi UI: 3.300 mg / kg
Oxyfluorfen
Water solubility: 0.1 ppm
Bioaccumulation quite probable under normal
use
Herbicidal activity
2-4 months (in medium-textured IL soil)
Pre- and post-emergent herbicide
Broad range of crops
Most uses cancelled in 1982
Kelarutan dalam air: 0,1 ppm
Diperkirakan tidak ada potensi bioakumulasi
Aktivitas herbisida
2-4 bulan (di tanah bertekstur IL sedang)
Herbisida pra-dan pasca-muncul
Luas tanaman
Sebagian besar penggunaan dibatalkan pada tahun 1982
Oxyfluorfen toxicology

Acute
LD50, po, in rats: 5,000 mg/kg
Delayed effects
Probable mutagen
Probable carcinogen
Contaminated with perchloroethylene
Probable hepatotoxicant
Probable thyrotoxicant
Develomental toxicity data inadequate
Akut
LD50, po, dalam tikus: 5.000 mg / kg
Efek tertunda
Kemungkinan mutagen
Kemungkinan karsinogen
Terkontaminasi dengan perchlorethylene
Kemungkinan hepatotoksis
Mungkin tirotoksik
Data toksisitas develomental tidak memadai
Uses:
Bifenox Paddy rice
Pre-emergent
Corn, soybeans
Toxicity
LD50, po, in rats:
UI Extension: 1,630
EPA: 6,400 mg/kg
Delayed toxicities
Carcinogen??
Ecotoxicology
Benign
Kegunaan:
Padi sawah
Pra-muncul
Jagung, kedelai
Toksisitas
LD50, po, pada tikus:
Ekstensi UI: 1,630
EPA: 6,400 mg / kg
Toksisitas tertunda
Karsinogen ??
Ekotoksikologi
Jinak
Bifenox

The 2nd group on the nitrophenyl ring of bifenox acts as a degradophore

Nitrofen

Kelompok ke-2 pada cincin nitrofenil dari bifenox
bertindak sebagai degradophore
Brief History of Nitrofen

1966: First registered in U.S.


1971: Ambrose et al: Neonatal mortality at 100 ppm in
maternal diet
1974: Kimbrough et al, Arch. Environ. Health: Neonatal
mortality confirmed
1981: Costlow and Manson: Heart and lung defects
identified
1981: Withdrawn from all U.S. uses
Sejarah Singkat Nitrofen

1966: Pertama terdaftar di A.S.


1971: Ambrose dkk: Kematian neonatal pada 100 ppm
dalam makanan ibu
1974: Kimbrough et al, Arch. Mengepung. Kesehatan:
Kematian neonatal dikonfirmasi
1981: Costlow dan Manson: Cacat jantung dan paru-paru
diidentifikasi
1981: Ditarik dari semua penggunaan A.S.
Toxicity of Nitrofen in Rats
Adult toxicity
LD50 > 1 g/kg
Adverse effect at LOAEL: liver enlargement
Fetal toxicity
NOAEL: < 0.1 mg/kg/day
Adverse effect at LOAEL: diaphragmatic
hernias
Other: heart, lung, kidney defects; cleft palate.
Toksisitas Nitrofen pada Tikus
Toksisitas orang dewasa
LD50> 1 g / kg
Efek samping pada LOAEL: pembesaran hati
Toksisitas janin
NOAEL: <0,1 mg / kg / hari
Efek samping pada LOAEL: hernia diafragma
Lain-lain: jantung, paru-paru, cacat ginjal; celah langit-
langit
Reproductive Cycle
Human Development: Weeks 3 to 8
3 5
4

6 7 8
Protocol for 2-Generation Assay
F0: parental animals
2nd mating

1st mating F1B

Necropsy parents [F0 and


Select F1 parental animals F1] aftertheir 2nd litter is
Necropsy at weaned.
weaning F1A

Necropsy F2B at
Necropsy at F2B weaning; including
weaning F2A
complete histopathology

Continue feeding chemical to each group at the appropriate dosing level throughout the study (progeny, too!)
Advantages of the 2-Generation Assay
A single assay identifies:
acute or cumulative toxicity leading to
male or female infertility,
pre- and post-natal mortality,
pre- and post-natal growth retardation,
functional deficits in offspring
transplacental carcinogenesis
infertility
behavioral anomalies
The 2-Generation Assay:
Disadvantages
Cost
well over $500,000 per species
but still cheaper than the alternatives
Labor-intensive
Necropsies of all parents
Necropsies of offspring of all litters
Histopathology of offspring from 2nd litters
Identifies the existence of a problem, but not necessarily
its nature
Advantages of the 2-Generation Assay
A single assay identifies:
acute or cumulative toxicity leading to
male or female infertility,
pre- and post-natal mortality,
pre- and post-natal growth retardation,
functional deficits in offspring
transplacental carcinogenesis
infertility
behavioral anomalies
The 2-Generation Assay:
Disadvantages
Cost
well over $500,000 per species
but still cheaper than the alternatives
Labor-intensive
Necropsies of all parents
Necropsies of offspring of all litters
Histopathology of offspring from 2nd litters
Identifies the existence of a problem, but not necessarily
its nature
Chemically induced birth defetcs

Vary with
Chemical
Genotype
Of dam and of embryo
Within and between species
Developmental stage at time of exposure
Dose
Either severity of defects or probability of defect increases with
increasing dose
Karnofskys Law

Any chemical, given at the right time, and at the right dose,
to the right species will cause malformations
The 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.
Developmental Toxicity is a Threshold
Phenomenon
For agents other than mutagens, there is a minimum dose
that will not affect the embryo
because it is metabolized by the dam and does
not reach the embryo, and/or
it does not significantly perturb embryonic
development, and/or
compensatory mechanisms result in repair of
the damage.
Nitrofen

Causes malformations
In both rats and mice
Heart
Kidneys
Diaphragm
Eyes
At a fraction of the adult LD50
NOAEL in rats estimated at 0.03 mg/kg/day

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