CAS No. 62476-59-9
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Adverse Effects

ACTIVITY: Herbicide (diphenyl ether)

Also known as:
• 5-(2-chloro-4- (triflouromethyl)phenoxy)-2-nitro-benzoic acid, sodium salt

Structure for Acifluorfen:

Reports available from
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Order No. Title Abstract / Keywords



1988 - Health Advisories for 50 Pesticides (Including Acifluorfen, Ametryn, Ammonium Sulfamate, Atrazine, Baygon, Bentazon, Bromacil, Butylate, Carbaryl, Carboxin, Chloramben, Chlorothalonil, Cyanazine, Dalapon, Dacthal, Diazinon, Dicamba, 1,3-Dichloropropene, Dieldrin, Dimethrin, Dinoseb, Diphenamid, Disu

Environmental Protection Agency, Washington, DC. Office of Drinking Water.

The documents summarize the health effects of 50 pesticides including: acifluorfen, ametryn, ammonium sulfamate, atrazine, baygon, bentazon, bromacil, butylate, carbaryl, carboxin, chloramben, chlorothalonil, cyanazine, dalapon, dacthal, diazinon, dicamba, 1,3-dichloropropene, dieldrin, dimethrin, dinoseb, diphenamid, disulfoton, diuron, endothall, ethylene thiourea, fenamiphos, fluometuron, fonofos, glyphosate, hexazinone, maleic hydrazide, MCPA, methomyl, methyl parathion, metalachlor, metribuzin, paraquat, picloram, prometon, pronamid, propachlor, propazine, propham, simazine, 2,4,5-T, tebuthiuron, terbacil, terbufos, and trifluralin. Topics discussed include: General Information and Properties, Pharmokinetics, Health Effects in Humans and Animals, Quantification of Toxicological Effects, Other Criteria and Standards, Analytical Methods, and Treatment Technologies. Supersedes PB88-113543.



1987 - Health Advisories for 50 Pesticides (Including Acifluorfen, Ametryn, Ammonium Sulfamate, Atrazine, Baygon, Bentazon, Bromacil, Butylate, Carbaryl, Carboxin, Chloramben, Chlorothalonil, Cyanazine, Dalapon, Dacthal, Diazinon, Dicamba, 1,3-Dichloropropene, Dieldrin, Dimethrin, Dinoseb, Diphenamid, Disu

Environmental Protection Agency, Washington, DC. Office of Drinking Water.

These documents summarize the health effects of 50 pesticides including: acifluorfen, ametryn, ammonium sulfamate, atrazine, baygon, bentazon, bromacil, butylate, carbaryl, carboxin, chloramben, chlorothalonil, cyanazine, dalapon, dacthal, diazinon, dicamba, 1,3-dichloropropene, dieldrin, dimethrin, dinoseb, diphenamid, disulfoton, diuron, endothall, ethylene thiourea, fenamiphos, fluometuron, fonofos, glyphosate, hexazinone, maleic hydrazide, MCPA, methomyl, methyl parathion, metolachlor, metribuzin, paraquat, picloram, prometon, pronamid, propachlor, propazine, propham, simazine, 2,4,5-T, tebuthiuron, terbacil, terbufos, and trifluralin. Topics discussed include: General Information and Properties, Pharmacokinetics, Health Effects in Humans and Animals, Quantification of Toxicological Effects, Other Criteria Guidance and Standards, Analytical Methods, and Treatment Technologies. Draft rept. See also PB86-118338.



1985 - Analyses of Groundwater for Trace Levels of Pesticides,

Authors: Lavy TL, Mattice JD, Cavalier TC

Arkansas Water Resources Research Center, Fayetteville.
Arkansas Univ., Fayetteville. Dept. of Agronomy.

Prepared in cooperation with Arkansas Univ., Fayetteville. Dept. of Agronomy. Sponsored by Geological Survey, Reston, VA. Water Resources Div.

Agricultural production is a major source of revenue in Arkansas. In order to increase productivity, it has been necessary to rely increasingly on the use of pesticides and irrigation water. In the last 15 years several states have reported finding pesticides in groundwater as a result of normal agricultural practices. Multiresidue analytical techniques were developed for the analysis of acifluorfen, alachlor, atrazine, cyanazine, diuron, fluormeturon, linuron, metolachlor and propanil from groundwater. Analytical sensitivities ranged from 1 to 10 ppb. The major objective of the study was to collect groundwater samples from irrigation wells in areas of southeastern Arkansas where pesticides are intensively used and to analyze these samples for trace levels of pesticides that are commonly used in these areas.



1980 - The Activity and Post-Emergency Selectivity of Some Recently Developed Herbicides: R 40244, DPX 4189, Acifluorfen, ARD 34/02 (NP 55) and PP 009

Authors: Richardson WG, West TM, Parker C

Agricultural Research Council, Oxford (England). Weed Research Organization.

The present report gives indications of the post-emergence selectivity of five new herbicides. Results of activity experiments are also included for DPX 4189, ARD 34/02 (NP 55) and PP 009 to provide information on levels of phytotoxicity, type and route of action. Technical rept. Also pub. as ISSN-0511-4136.




1979 - The Activity and Pre-Emergence Selectivity of Some Recently Developed Herbicides: R 40244, AC 206784, Pendimethalin, Butralin, Acifluorfen and FMC 39821

Authors: Richardson WG, West TM, Parker C

Agricultural Research Council, Oxford (England). Weed Research Organization.

The present report gives pre-emergence selectivity data on R 40244, AC 206784, pendimethalin, butralin, acifluorfen and FMC 39821. Results of activity experiments are also included for five of these to provide information on levels of phytotoxicity, type and route of action. Technical rept. Also pub. as ISSN-0511-4236.



Environ Mol Mutagen. 1995;25(2):148-53.

Mutagenicity testing of nine herbicides and pesticides currently used in agriculture.

Kale PG, Petty BT Jr, Walker S, Ford JB, Dehkordi N, Tarasia S, Tasie BO, Kale R, Sohni YR.

Department of Biology, Alabama A. & M. University, Normal 35762, USA.

Nine herbicides and pesticides were tested for their mutagenicity using the Drosophila sex-linked recessive lethal mutation assay. These are Ambush, Treflan, Blazer, Roundup, 2,4-D Amine, Crossbow, Galecron, Pramitol, and Pondmaster. All of these are in wide use at present. Unlike adult feeding and injection assays, the larvae were allowed to grow in medium with the test chemical, thereby providing long and chronic exposure to the sensitive and dividing diploid cells, i.e., mitotically active spermatogonia and sensitive spermatocytes. All chemicals induced significant numbers of mutations in at least one of the cell types tested. Some of these compounds were found to be negative in earlier studies. An explanation for the difference in results is provided. It is probable that different germ cell stages and treatment regimens are suitable for different types of chemicals. larval treatment may still be valuable and can complement adult treatment in environmental mutagen testing.

PMID: 7698107 [PubMed - indexed for MEDLINE]


Regul Toxicol Pharmacol. 1989 Oct;10(2):149-59.

Evaluation of the carcinogenic potential of pesticides. 1. Acifluorfen.

Quest JA, Phang W, Hamernik KL, van Gemert M, Fisher B, Levy R, Farber TM, Burnam WL, Engler R.

Health Effects Division, U.S. Environmental Protection Agency, Washington, D.C. 20460.

The Health Effects Division of the Office of Pesticide Programs evaluates the carcinogenic properties of pesticides by a consensus peer review process in which all available biological information on a compound is evaluated according to EPA's guidelines for cancer risk assessment. In many cases, pesticides are also evaluated by an external group of accomplished scientists who comprise the Agency's Scientific Advisory Panel. The herbicide acifluorfen was evaluated by these processes and was classified as a Category B2 (probable human) carcinogen based upon evidence of an increased incidence of malignant, or combined benign and malignant, tumors in multiple experiments involving two different strains of mice. The compound produced benign and malignant liver tumors in male and female B6C3F1 mice and in female CD1 mice. Stomach papillomas were also observed in male and female B6C3F1 mice. Acifluorfen was mutagenic in bacteria and yeast, but not in mammalian cell systems. In addition, acifluorfen is structurally related to eight other diphenyl ether pesticides, all of which evoke liver tumours in mice or rats. The data were found to be sufficient to quantify human risk to acifluorfen.

PMID: 2813868 [PubMed - indexed for MEDLINE]

PESTIC SCI; 31 (1). 1991. 9-24.

Photodynamic herbicides: VIII. Mandatory requirement of light for the induction of protoporphyrin IX accumulation in acifluorfen-treated cucumber.


202 ABL, 1302 W. Pennsylvania Ave., Univ. Ill., Urbana, Ill. 61801, USA.

BIOSIS COPYRIGHT: BIOL ABS. It is shown that continuous illumination is mandatory for the induction of tetrapyrrole accumulation in acifluorfen-sodium-treated plants and for the photosensitization of tetrapyrrole-dependent photodynamic damage. At low concentrations of acifluorfen-sodium (up to 20 muM), photoporphyrin IX appears to be the major light-induced tetrapyrrole that accumulates in the treated plants. At higher concentrations of acifluorfen-sodium, monovinyl chlorophyllide a accumulates in addition to protoporphyrin IX. In the light, the development of photodynamic injury appears to be directly related to the accumulation of the light-induced tetrapyrroles. For example when acifluorfen-sodium-treated plants the returned to darkness, or are treated with tetrapyrrole biosynthesis inhibitors, tetrapyrrole accumulation and photodynamic injury come to a halt. In-vivo and in-organello studies failed, however, to support the commonly held hypothesis that the induction of tetrapyrrole [abstract truncated]



J Agric Food Chem. 2003 Jul 16;51(15):4331-7.
Soil photolysis of herbicides in a moisture- and temperature-controlled environment.

Graebing P, Frank MP, Chib JS.

Pittsburgh Environmental Research Laboratory, Inc., 3210 William Pitt Way, Pittsburgh, Pennsylvania 15238, USA.

The problem of maintaining the moisture content of samples throughout the course of a soil photolysis study is addressed. The photolytic degradations of asulam, triclopyr, acifluorfen, and atrazine were independently compared in air-dried soils and in moist (75% field moisture capacity at 0.33 bar) soils maintained at initial conditions through the use of a specially designed soil photolysis apparatus. Each pesticide was applied at 5 microg/g. The exposure phase extended from 144 to 360 h, depending on the half-life of the compound. A dark control study, also using moist and air-dried soils, was performed concurrently at 25 degrees C. The results showed significant differences in half-life. The dissipations generally demonstrated a strong dependence on moisture. In most cases, photolytic degradation on air-dried soil was longer than in the moist dark control soils. Half-lives in dry soil were 2-7 times longer, and in the case of atrazine, the absence of moisture precluded significant degradation. Moist soil experiments also tended to correlate more strongly with linear first-order degradations. The dark control experiments also demonstrated shorter half-lives in moist soil. Moisture was also observed to affect the amount of degradate formed in the soils.

PMID: 12848506 [PubMed - indexed for MEDLINE]


Toxicol Appl Pharmacol. 2003 May 15;189(1):28-38.

Experimental hepatic uroporphyria induced by the diphenyl-ether herbicide fomesafen in male DBA/2 mice.

Krijt J, Psenak O, Vokurka M, Chlumska A, Fakan F.

Institute of Pathophysiology, 1st Medical Faculty, Charles University, 128 53, Prague, Czech Republic

Hepatic uroporphyria can be readily induced by a variety of treatments in mice of the C57BL strains, whereas DBA/2 mice are almost completely resistant. However, feeding of the protoporphyrinogen oxidase-inhibiting herbicide fomesafen (0.25% in the diet for 18 weeks) induced hepatic uroporphyria in male DBA/2N mice (liver porphyrin content up to 150 nmol/g, control animals 1 nmol/g), whereas fomesafen-treated male C57BL/6N mice displayed only a slight elevation of liver porphyrins ( approximately 5 nmol/g). The profile of accumulated hepatic porphyrins in fomesafen-treated DBA/2N mice resembled the well-characterised uroporphyria induced by polyhalogenated aromatic hydrocarbons, while histological examination confirmed the presence of uroporphyria-specific cytoplasmic inclusions in the hepatocytes. Uroporphyrinogen decarboxylase activity decreased to about 30% of control values in fomesafen-treated DBA/2N mice; microsomal methoxyresorufin O-dealkylase activity was slightly reduced. The amount of CYP1A1 and CYP1A2 mRNA, as determined by real-time PCR, was not significantly changed; mRNA encoding the housekeeping 5-aminolevulinic acid synthase was elevated 10-fold. Total liver iron was slightly increased. A similar uroporphyria was induced by the herbicide formulation Blazer, containing a structurally related herbicide acifluorfen, when fed to DBA/2N mice at a dose corresponding to 0.25% of acifluorfen in the diet. Since DBA/2 mice are almost completely resistant to all well-characterised porphyrogenic chemicals, the results suggest the possible existence of a yet unknown mechanism of uroporphyria induction, to which the DBA/2 mouse strain is more sensitive than the C57BL strain.

PMID: 12758057 [PubMed - in process]


J Environ Qual. 2002 Jan-Feb;31(1):268-74.

Photochemistry and photoinduced toxicity of acifluorfen, a diphenyl-ether herbicide.

Scrano L, Bufo SA, D'Auria M, Meallier P, Behechti A, Shramm KW.

Dipartimento di Produzione Vegetale, Universita della Basilicata, Potenza, Italy.

Photochemistry studies can be helpful in assessing the environmental fate of chemicals. Photochemical reactions lead to the formation of by-products that can exhibit different toxicological properties from the original compound. For this reason the photochemical behavior of the herbicide acifluorfen (5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoic acid) in the presence of different solvents was studied. Photochemical reactions were carried out using a high-pressure mercury arc and a solar simulator. Kinetic parameters and quantum yields were determined. The identification of photoproducts was performed by mass spectrometry and [1H] nuclear magnetic resonance (NMR). Nitrofluorfen, hydroxy-nitrofluorfen, 2-chloro-4-(trifluoromethyl)phenol, 5-trifluoromethyl-5'-nitrodibenzofuran, and other derivatives were identified. The photochemical reactions were also carried out in the presence of either a singlet or a triplet quencher, and in the presence of either a radical initiator or a radical inhibitor. Substances used as inhibitors of the excited levels T1 and S1 showed that photodegradation of acifluorfen begins from a singlet state S1 through a pi,pi* transition. The role of free radicals in the photodegradation of acifluorfen was determined and a radical mechanism was proposed. Toxicity tests against Daphnia magna Strauss showed that acifluorfen was not toxic at a concentration of 0.1 mM; however, photoproducts formed after 36 h of UV exposure of the herbicide induced a remarkable toxicity to the test organism.

PMID: 11837431 [PubMed - indexed for MEDLINE]


Pest Manag Sci. 2001 Apr;57(4):372-9.

Photochemical transformation of acifluorfen under laboratory and natural conditions.

Vialation D, Baglio D, Paya-Perez A, Richard C.

Laboratoire de Photochimie Moleculaire et Macromoleculaire, UMR CNRS No. 6505, F-63177 Aubiere, France.

Acifluorfen was irradiated in pure water at various excitation wavelengths and pH values. Numerous photoproducts were obtained which were identified by [1H]NMR and/or HPLC-MS/MS. The main reaction pathways were photo-decarboxylation, photo-cleavage of the ether bonding with formation of phenolic compounds, photo-dechlorination and photo-Claisen type rearrangement. Decarboxylation was observed in acidic and neutral media whereas cleavage of the ether bonding dominated in basic media. The photo-Claisen type rearrangement only occurred on excitation at short wavelengths. The quantum yield of photolysis was significantly lower at 313 nm (6.1 x 10(-5)) than at 254 nm (2.0 x 10(-3)). The photoreactivity of acifluorfen was then studied in conditions approaching environmental conditions. Acifluorfen was dissolved in pure water, in water containing humic substances or in a natural water, and exposed to solar light in June at Clermont-Ferrand (latitude 46 degrees N). In pure water, the half-life was estimated at 10 days and photo-decarboxylation accounted for 30% of the conversion. The presence of humic substances (10 mg litre-1) did not affect the rate of photo-transformation. However, the half-life of acifluorfen dissolved in the natural water was only 6.8 days.

PMID: 11455817 [PubMed - indexed for MEDLINE]


Indian J Biochem Biophys. 2000 Dec;37(6):498-505.

Oxidative stress in cucumber (Cucumis sativus L) seedlings treated with acifluorfen.

Gupta I, Tripathy BC.

School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.

Treatment of diphenyl ether herbicide acifluorfen-Na (AF-Na) to intact cucumber (Cucumis sativus L cv Poinsette) seedlings induced overaccumulation of protoporphyrin IX in light (75 mumole m-2 s-1). The extra-plastidic protoporphyrin IX accumulated during the light exposure disappeared within two hours of transfer of acifluorofen-treated seedlings to darkness. The dark disappearance was due to re-entry of migrated protoporphyrin IX into the plastid and its subsequent conversion to protochlorophyllide. In light, protoporphyrin IX acted as a photosensitizer and caused generation of active oxygen species. The latter caused damage to the cellular membranes by peroxidation of membrane lipids that resulted in production of malondialdehyde. Damage to the plastidic membranes resulted in damage to photosystem I and photosystem II reactions. Dark-incubation of herbicide-sprayed plants before their exposure to light enhanced photodynamic damage due to diffusion of the herbicide to the site of action. Compared to control, in treated samples the cation-induced increases in variable fluorescence/maximum fluorescence ratio and increase in photosystem II activity was lower due to reduced grana stacking in herbicide-treated and light-exposed plants.

PMID: 11355639 [PubMed - indexed for MEDLINE]


Eur J Pharmacol. 2000 Oct 13;406(2):171-80.

A key role for the mitochondrial benzodiazepine receptor in cellular photosensitisation with delta-aminolaevulinic acid.

Mesenholler M, Matthews EK.

Department of Pharmacology, University of Cambridge, Tennis Court Road, CB2 1QJ, Cambridge, UK.

The aim of this study was to determine the part played by the mitochondrial benzodiazepine receptor in cellular photosensitisation with the protoporphyrin IX precursor, delta-aminolaevulinic acid. Evaluation of the delta-aminolaevulinic acid-concentration dependence and kinetics of fluorescent protoporphyrin IX accumulation in monolayers of rat AR4 2J pancreatoma cells established a basis for assessing pharmacological modulation of the biosynthetic pathways for protoporphyrin IX production and photocytotoxicity. Iron chelation enhanced the accumulation of photo-active protoporphyrin IX whereas 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxam ide (PK11195), dipyridamole, or 7-(dimethylcarbamoloxy)-6-phenylpyrrolo-[2,1-d]benzothiazepi ne (DPB), competitive ligands of the mitochondrial benzodiazepine receptor, all diminished protoporphyrin IX accumulation, as did acifluorfen, a mitochondrial protoporphyrinogen oxidase inhibitor. In addition to protoporphyrin IX (Em(max): 630 nm), delta-aminolaevulinic acid-treated cells also generated a fluorophore of Em(max) 580 nm; this compound was identified as Zn-protoporphyrin IX. Mitochondrial benzodiazepine receptor ligands increased the formation of the zinc porphyrin whilst decreasing that of protoporphyrin IX. The involvement of the mitochondrial benzodiazepine receptor in the translocation of porphyrins and the formation of Zn-protoporphyrin IX have wide implications for the use of delta-aminolaevulinic acid in photodynamic therapy.

PMID: 11020479 [PubMed - indexed for MEDLINE]

Trends in Plant Science Volume 5, Issue 7 , 1 July 2000, Page 277

Resistance to the herbicide acifluorfen

G. E. de Vries

Available online 7 July 2000.

The first wave of herbicide resistant crops included those with resistance to glyphosate, glufosinate and bromoxynil, representing three different modes of action: disrupting aromatic amino acid biosynthesis, ammonium assimilation and photosynthesis. Acifluorfen inhibits protoporphyrinogen IX oxidase (PPOX), an enzyme that catalyzes a step in the common tetrapyrrole pathway leading to the synthesis of chlorophyll, and has a rapid action because of the destruction of cell membranes by oxygen radicals. Recent work has demonstrated that resistance to the herbicide acifluorfen can be achieved by overexpression of the target enzyme. Plant Physiol. (2000) 122, 75–83.


Biochemistry. 1998 May 12;37(19):6905-10.

Human protoporphyrinogen oxidase: relation between the herbicide binding site and the flavin cofactor.

Birchfield NB, Latli B, Casida JE.

Department of Environmental Science, University of California, Berkeley 94720-3112, USA.

Protoporphyrinogen IX oxidase (protox) catalyzes the oxidation of protoporphyrinogen IX to protoporphyrin IX in the penultimate step of heme and chlorophyll biosynthesis in animals and plants. Protox is the target of light-dependent peroxidizing herbicides and is inhibited at nanomolar levels by several chemical classes including tetrahydrophthalimides (discussed below) and diphenyl ethers (e.g., acifluorfen) usually with little selectivity between the mammalian and plant enzymes. The herbicide binding site is examined here with a photoaffinity radioligand optimized on the basis of structure-activity relationships. A radiosynthetic procedure is described for this new herbicidal probe, N-(5-azido-4-chloro-2-fluorophenyl)-3,4,5, 6-[3H]tetrahydrophthalimide ([3H]AzTHP), resulting in high specific activity (2.6 TBq/mmol). Human protox expressed in Escherichia coli and purified by affinity chromatography is used with [3H]AzTHP to characterize the herbicide/substrate binding site. Specific binding of [3H]AzTHP to human protox is rapid, completely reversible in the absence of light with a Kd of 93 nM, and competitively inhibited by the 5-propargyloxy analogue and by acifluorfen, which are known to bind at the substrate (protoporphyrinogen) site. The Bmax establishes one [3H]AzTHP binding site per FAD. Diphenyleneiodonium, proposed to inhibit protox by interaction with the FAD cofactor, inhibits enzyme activity by 48% at 100 micro M without affecting [3H]AzTHP binding in the presence or absence of substrate, suggesting that the herbicide binding site may not be proximal to FAD. The first step has been taken in photoaffinity labeling the herbicide/substrate site with [3H]AzTHP resulting in apparent covalent derivatization of 13% of the herbicide binding site.

PMID: 9578577 [PubMed - indexed for MEDLINE]

Toxicology Letters Volume 95, Supplement 1 , July 1998, Pages 142-143

Effects of diphenyl-ether herbicides on human erythropoiesis in vitro

B. Rio (a), J. Guinard-Flament (a), A. Boucher (a) and D. Parent-Massin (a)

a Laboratoire de Microbiologie et Sécurité Alimentaire, ESMISAB/ISAMOR, Technopôle Brest-Iroise 29280 Plouzanë France

Oxyfluorfen and acifluorfen, two diphenyl-ether herbicides, exert their phytotoxic activity preventing chlorophyll synthesis in plants. They inhibit protoporphyrinogen oxidase, the last enzyme of the common pathway for chlorophyll and heme synthesis. The aim of this work was to determine if these herbicides could inhibit human protoporphyrinogen oxidase during porphyrin and heme synthesis taking part in hemoglobin formation. Thus, they could induced metabolic diseases such as Porphyria, characterized by porphyrin accumulation.
The in vitro evaluation of hematotoxicity due to diphenyl-ether herbicides was performed on human cells, using an erythroblastic progenitor culture model. BFU-E/CFU-E are erythroblastic progenitors able to proliferate and differentiate in vitro to form colonies of hemoglobinized erythroblasts, under growth factor influence. Progenitors from human umbilical cord blood obtained from placentas after normal deliveries, were cultured in semi-solid medium, in the presence of increasing concentrations of acifluorfen or oxyfluorfen. BFU-E/CFU-E development was appreciated by morphological analysis of cell colonies obtained after 14 days of incubation in the presence of acifluorfen or oxyfluorfen. Spectrophotometric and chromatographic techniques were used to evaluate cells abilities to synthetize proteins, porphyrins and hemoglobin, in the presence of diphenyl-ethers.
Results showed that two molecules in the same class of herbicides, acting by the same mode of action, but differing only by the presence of a carboxyl group in acifluorfen and an ethoxy group in oxyfluorfen, did not develop the same effect in human. Even though the two molecules were cytotoxic for human BFU-E/CFU-E proliferation, for the same concentration (10-3 M), they did not exhibit the same effect on differentiation. In contrast to acifluorfen, oxyfluorfen was able to inhibit hemoglobin synthesis, in vitro. Thin layer chromatography revealed an absence of heme and the presence of porphyrins in cells exposed to 10-4 M of oxyfluorfen. Porphyrins were separated and identified: 10-4 M of oxyfluorfen induced porphyrin accumulation in erythroblastic progenitors. Oxyfluorfen could act on hemoglobin synthesis as diphenyl-ethers act chlorophyll synthesis in plant, by inhibition of protoporphyrinogen oxidase.


Naunyn Schmiedebergs Arch Pharmacol. 1997 Jan;355(1):8-13.

Regulation of CYP 2 A 5 induction by porphyrinogenic agents in mouse primary hepatocytes.

Salonpaa P, Kottari S, Pelkonen O, Raunio H.

Department of Pharmacology and Toxicology, University of Oulu, Finland.

All cytochrome P450 (CYP) enzymes contain heme as a prosthetic group. In contrast to other CYP enzymes, murine CYP 2 A 5 is upregulated in vivo by several agents that disturb cellular heme balance. To test the hypothesis that porphyrinogenic agents have the common feature of being able to increase CYP 2 A 5 expression, mouse liver primary hepatocytes were exposed to various porphyrinogenic chemicals and changes in CYP 2 A 5 catalytic activity and levels of mRNA were monitored. Phenobarbital increased hepatic CYP 2 A 5-mediated coumarin 7-hydroxylase (COH) activity (13.2-fold) and the amount of CYP 2 A 5 steady-state mRNA (10.6-fold). Hepatocyte COH activity was increased also by the ferrochelatase inhibitor griseofulvin and the protoporphyrinogen oxidase inhibitor acifluorfen (about 9-fold induction). Of these inducers, only phenobarbital affected CYP 1 A 12 and CYP 2 B 10 expression. In contrast, many other porphyrinogenic agents such as cobalt, 2,2,4-trimethyl-1,2-dihydroquinoline (TMDQ), 1-[4-(3-acetyl-2,4,6-trimethylphenyl)-2,6-cyclohexanedionyl]-O-eth yl propionaldehyde oxime (ATMP), aminotriazole, and thioacetamide either decreased or had no effect on CYP 2 A 5. The increases in COH activity and CYP 2 A 5 mRNA were unaffected by combined treatment with the inducers and heme arginate, suggesting that heme is not a regulator of CYP 2 A 5 induction. Treatment with actinomycin D totally abolished both constitutive CYP 2 A 5 expression and its inducibility, suggesting that a transcriptional component is involved. These data suggest that, in mouse primary hepatocytes, CYP 2 A 5 induction is not a universal response to disturbed cellular heme biosynthesis.

PMID: 9007836 [PubMed - indexed for MEDLINE]

From Toxline at Toxnet

ENVIRONMENTAL SCIENCE & TECHNOLOGY; 31 (9). 1997. 2445-2454.

Fluorinated organics in the biosphere.


Dep. Civil Environ. Eng., Mich. State Univ., East Lansing, MI 48824, USA.

BIOSIS COPYRIGHT: BIOL ABS. The use of organofluorine compounds has increased throughout this century, and they are now ubiquitous environmental contaminants. Although generally viewed as recalcitrant because of their lack of chemical reactivity, many fluorinated organics are biologically active. Several questions surround their distribution, fate, and effects. Of particular interest is the fate of perfluoroalkyl substituents, such as the trifluoromethyl group. Most evidence to date suggest that such groups resist defluorination, yet they can confer significant biological activity. Certain volatile fluorinated compounds can be oxidized in the troposphere yielding nonvolatile compounds, such as trifluoroacetic acid. In addition, certain nonvolatile fluorinated compounds can be transformed in the biosphere to volatile compounds. Research is needed to assess the fate and effects of nonvolatile fluorinated organics, the fluorinated impurities present in commercial formulations, and the transformation

CAS Registry Numbers:
137938-95-5 - na
112839-33-5 - chlorazifop [C14H11Cl2NO4]
112839-32-4 - chlorazifop [ C14H11Cl2NO4]
106917-52-6 - flusulfamide [C13H7Cl2F3N2O4S]
104040-78-0 - flazasulfuron [C13H12F3N5O5S]
102130-93-8 - 4-Fluorothreonine [ C4-H8-F-N-O3 ]
101463-69-8 - flufenoxuron [C21H11ClF6N2O3]
101007-06-1 - acrinathrin [C26H21F6NO5]
97886-45-8 - dithiopyr [C15H16F5NO2S2]
96525-23-4 - flurtamone [C18H14F3NO2]
90035-08-8 - flocoumafen [C33H25F3O4]
88485-37-4 - fluxofenim [C12H11ClF3NO3]
85758-71-0 - 1-Decanol, 1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heneicosafluoro- [ C10-H-F21-O ]
83164-33-4 - diflufenican [C19H11F5N2O2]
82657-04-3 - bifenthrin [C23H22ClF3O2]
81613-59-4 - flupropadine [C20H23F6N]

80164-94-9 - Methanone, phenyl((trifluoromethyl)phenyl)-, dichloro deriv. [ C14-H7-Cl2-F3-O ]
80020-41-3 - furyloxyfen [C17H13ClF3NO5]
79622-59-6 - fluazinam [C13H4Cl2F6N4O4]
79538-32-2 - tefluthrin [C17H14ClF7O2]
77501-63-4 - lactofen [C19H15ClF3NO7]
77501-60-1 - fluoroglycofen [C16H9ClF3NO7]
76674-21-0 - flutriafol [C16H13F2N3O]
72850-64-7 - flurazole [C12H7ClF3NO2S]
72178-02-0 - fomesafen [C15H10ClF3N2O6S]
71422-67-8 - chlorfluazuron [C20H9Cl3F5N3O3]

69806-34-4 - Haloxyfop
69335-91-7 - fluazifop [C15H12F3NO4]
68694-11-1 - Triflumizole [ C15-H15-Cl-F3-N3-O ]
68085-85-8 - cyhalothrin [C23H19ClF3NO3]
67485-29-4 - hydramethylnon [C25H24F6N4]
66332-96-5 - flutolanil [C17H16F3NO2]
64628-44-0 - triflumuron [C15H10ClF3N2O3]
63333-35-7 - bromethalin [C14H7Br3F3N3O4]
62924-70-3 - flumetralin [C16H12ClF4N3O4]
61213-25-0 - flurochloridone [C12H10Cl2F3NO]
59756-60-4 - fluridone [C19H14F3NO]

57041-67-5 - Desflurane [ C3-H2-F6-O ]
56425-91-3 - flurprimidol [C15H15F3N2O2]
55283-68-6 - ethalfluralin [C13H14F3N3O4]
53780-34-0 - mefluidide [C11H13F3N2O3S]

50594-66-6 - acifluorfen [C14H7ClF3NO5]
42874-03-3 - oxyfluorfen [C15H11ClF3NO4]
40856-07-3 - Difluoromethanesulphonic acid [ C-H2-F2-O3-S ]
37924-13-3 - perfluidone [C14H12F3NO4S2]
35367-38-5 - diflubenzuron [C14H9ClF2N2O2]
33245-39-5 - fluchloralin [C12H13ClF3N3O4]
31251-03-3 - fluotrimazole [C22H16F3N3]
29091-21-2 - prodiamine [C13H17F3N4O4]
29091-05-2 - dinitramine [C11H13F3N4O4]

28606-06-6 - na
28523-86-6 - Sevoflurane [ C4-H3-F7-O ]
27314-13-2 - norflurazon [C12H9ClF3N3O]
26675-46-7 - Isoflurane [ C3-H2-Cl-F5-O ]
26399-36-0 - profluralin [C14H16F3N3O4]
25366-23-8 - thiazafluron [C6H7F3N4OS]

24751-69-7 - Nucleocidin [ C10-H13-F-N6-O6-S ]
14477-72-6 - Acetic acid, trifluoro-, ion(1-) [ C2-F3-O2 ]
9002-84-0 - Polytetrafluoroethylene (Teflon) ( (C2-F4)mult- or (C2-F4)x-)
2837-89-0 - 1,1,1,2-Tetrafluoro-2-chloroethane (Freon 124) [ C2-H-Cl-F4 ]

2164-17-2 - fluometuron [C10H11F3N2O]
1861-40-1 - benfluralin [C13H16F3N3O4]
1827-97-0 - 2,2,2-Trifluoroethanesulfonic acid [ C2-H3-F3-O3-S ]
1763-23-1 - Perfluorooctane sulfonic acid [ C8-H-F17-O3-S ]
1717-00-6 - 1,1-Dichloro-1-fluoroethane [ C2-H3-Cl2-F ]

1582-09-8 - trifluralin [C13H16F3N3O4]
1493-13-6 - Trifluoromethanesulfonic acid [ C-H-F3-O3-S ]
811-97-2 - 1,1,1,2-Tetrafluoroethane (Norflurane) [ C2-H2-F4 ]
754-91-6 - Perfluorooctanesulfonamide [ C8-H2-F17-N-O2-S ]

640-19-7 - fluoroacetamide [C2H4FNO]
513-62-2 - Fluoroacetate [ C2-H2-F-O2 ]
453-13-4 - 1,3-Difluoro-2-propanol [ C3-H6-F2-O ]
420-46-2 - 1,1,1-Trifluoroethane [ C2-H3-F3 ]
406-90-6 - Fluroxene (Ethene, (2,2,2-trifluoroethoxy)-) [ C4-H5-F3-O ]

370-50-3 - flucofuron [C15H8Cl2F6N2O]
335-76-2 - Perfluorodecanoic acid [ C10-H-F19-O2 ]
335-67-1 - Perfluorooctanoic acid (PFOA) [ C8-H-F15-O2 ]
311-89-7 - Perfluorotributylamine [ C12-F27-N ]
306-83-2 - 2,2-Dichloro-1,1,1-trifluoroethane [Freon 123) [ C2-H-Cl2-F3 ]
151-67-7 - 2-Bromo-2-chloro-1,1,1-trifluoroethane (HALOTHANE) [ C2-H-Br-Cl-F3 ]
144-49-0 - Fluoroacetic acid [ C2-H3-F-O2 ]

116-14-3 - Tetrafluoroethylene [ C2-F4 ]
98-56-6 - 1-Chloro-4-(trifluoromethyl)benzene [ C7-H4-Cl-F3 ]
88-30-2 - TFM (3-Trifluoromethyl-4-nitrophenol)[ C7-H4-F3-N-O3 ]
79-38-9 - Chlorotrifluoroethylene [ C2-Cl-F3 ]
76-38-0 - Methoxyflurane [ C3-H4-Cl2-F2-O ]
76-15-3 - Chloropentafluoroethane (Freon 115 )[C2-Cl-F5 ]
76-14-2 - Dichlorotetrafluoroethane (Freon 114 )[ C2-Cl2-F4 ]
76-13-1 - 1,1,2-Trichloro-1,2,2-trifluoroethane (Freon 113 ) [C2-Cl3-F3 ]
76-05-1 - Trifluoroacetic acid [ C2-H-F3-O2]
75-71-8 - Dichlorodifluoromethane (Freon 12) [ C-Cl2-F2]

75-69-4 - Trichloromonofluoromethane ( Freon 11, 11A, 11B) [C-Cl3-F]
75-68-3 - 1-Chloro-1,1-difluoroethane (Freon 142, Freon 142b) [ C2-H3-Cl-F2]
75-45-6 - Chlorodifluoromethane (Freon 21) [ C-H-Cl-F2]

75-43-4 - Dichlorofluoromethane (Freon 21) [C-H-Cl2-F]


Res Microbiol. 1996 Mar-Apr;147(3):193-9.

Identification of spore-forming strains involved in biodegradation of acifluorfen.

Fortina MG, Acquati A, Ambrosoli R.

Dipartimento di Scienze e Tecnologie Alimentari e Microbiologiche, Universita degli Studi di Milano, Italy.

We isolated and identified four spore-forming bacteria from activated sludges and soil, three of which were able to degrade acifluorfen. Biochemical characteristics, DNA base composition and DNA-DNA homology indicated that the degrading strains belonged to the species Bacillus thuringiensis, Clostridium perfringens and Clostridium sphenoides. The fourth strain, identified as C. sphenoides and showing the same characteristics of the corresponding degrading strain, was unable to metabolize acifluorfen. Thus, the plasmid content of these strains was analysed to study the possible correlation between the presence of extrachromosomal elements and the ability to degrade this herbicide.

PMID: 8761738 [PubMed - indexed for MEDLINE]

Full free text available at http://www.jbc.org/cgi/reprint/269/51/32085.pdf

J Biol Chem. 1994 Dec 23;269(51):32085-91.

Purification and properties of protoporphyrinogen oxidase from the yeast Saccharomyces cerevisiae. Mitochondrial location and evidence for a precursor form of the protein.

Camadro JM, Thome F, Brouillet N, Labbe P.

Departement de Microbiologie, Institut Jacques Monod, Paris, France.

Protoporphyrinogen oxidase, the molecular target of diphenylether-type herbicides, was purified to homogeneity from yeast mitochondrial membranes and found to be a 55-kDa polypeptide with a pI of 8.5 and a specific activity of 40,000 nmol of protoporphyrin/h/mg of protein at 30 degrees C. The Michaelis constant (Km) for protoporphyrinogen IX was 0.1 microM. Due to the high affinity of the enzyme toward oxygen, the Km for oxygen could only be approximated to 0.5-1.5 microM. The purified enzyme contained a flavin as cofactor. Studies with rabbit antibodies to yeast protoporphyrinogen oxidase showed that the enzyme is synthesized as a high molecular weight precursor (58 kDa) that is rapidly converted in vivo to the mature (55 kDa) membrane-bound form. Protoporphyrinogen oxidase activity was found only in purified yeast mitochondrial inner membrane (not in the outer membrane). Acifluorfen-methyl, a potent diphenylether-type herbicide, competitively inhibited the purified enzyme (Ki = 10 nM). The mixed inhibition by acifluorfen-methyl previously reported for the membrane-bound protoporphyrinogen oxidase (Camadro, J.M., Matringe, M., Scalla, R., and Labbe, P. (1991) Biochem. J. 277, 17-21) was shown to be related to partial proteolysis of the enzyme.

PMID: 7798202 [PubMed - indexed for MEDLINE]


Biochem Mol Biol Int. 1994 Dec;34(6):1283-9.

Inhibition of mammalian protoporphyrinogen oxidase by acifluorfen.

Corrigall AV, Hift RJ, Adams PA, Kirsch RE.

UCT/MRC Liver Research Centre, Department of Medicine, South Africa.

We have studied the kinetics of the inhibition of mitochondrial protoporphyrinogen oxidase (PPO) from liver and placenta of 3 mammalian species by the diphenyl ether herbicide acifluorfen (AF). AF competitively inhibited PPO from human liver and placenta, mouse liver and pig placenta with respect to its substrate protoporphyrinogen. In contrast, mixed-type inhibition was shown for pig liver. The differing results shown in pig liver may point to structural differences in PPO derived from different species and tissues. We have also compared the effects of AF on the function of PPO in human lymphoblasts from normal subjects and those with variegate porphyria, an inherited disorder of PPO. Competitive inhibition was shown for both and there were no significant differences in the values of Ks or Ki.

PMID: 7697001 [PubMed - indexed for MEDLINE]


Zentralbl Mikrobiol. 1993 Jan;148(1):16-23.

Microbial biomass-persistence relationships of acifluorfen in a clay-loam soil.

Perucci P, Scarponi L.

Istituto Chimica Agraria, Universita di Perugia, Italy.

The interference of the effect of the herbicide acifluorfen on microbial biomass and on hydrolytic capacity, and its persistence in a clay-loam soil before and after enrichment with glucose, were investigated. The experiment was carried out under laboratory conditions for 120 days. Acifluorfen was added to the soil at two different application rates corresponding to 1X and 10X the recommended field rate. Biomass-C was significantly higher in the enriched soil during the first 35 days; subsequently there was a tendency to return to the original value of the unenriched soil. The herbicidal treatments depressed the biomass-C level, particularly at the higher rate. The hydrolytic capacity, measured as FDA-hydrolase activity, was significantly higher in the enriched soil than in the unenriched soil. This was enhanced by acifluorfen treatment, chiefly at the higher rate. The degradation trend of acifluorfen was not significantly different at the two rates, but was significantly faster in the enriched soil. Half-life values of 28 and 40 days were found in the enriched and unenriched soil, respectively.

PMID: 8451878 [PubMed - indexed for MEDLINE]

PESTIC BIOCHEM PHYSIOL; 42 (3). 1992. 271-278.

Effects of light and ethylene on the herbicidal action of acifluorfen.

Acifluorfen CAS No. 50594-66-6


Ain Shams Univ., Cairo, Egypt.

BIOSIS COPYRIGHT: BIOL ABS. Fully expanded cotyledons from 7-day-old cucumber (Cucumis sativis L. cv Ashy) seedlings were used to study the interaction of light and ethylene on the herbicidal action of acifluorfen (5-(2-chloro-4-(trifluoromethyl)phenoxy)-2-nitrobenzoic acid). Acifluorfen alone increased the level of ethylene production from cucumber cotyledons. The stimulation was most pronounced after 12 hr in the light as compared to continuous dark. The evolution of ethylene induced by acifluorfen was complete by 48 hr after treatment. Symptoms resulting from acifluorfen treatment developed rapidly in light, while no visible symptoms developed in the dark treatment. Cotyledons treated with acifluorfen showed a corresponding increase in carbon dioxide production. An ethylene inhibitor, alpha-aminooxyacetic acid (AOA), inhibited ethylene production in acifluorfen-treated cucumber cotyledons. In addition it reduced the visual injury induced by this herbicide. Cucumber cotyledons treated with AOA a [abstract truncated]


J Biochem Toxicol. 1992 Summer;7(2):87-95.

Effects of diphenyl ether herbicides on porphyrin accumulation by cultured hepatocytes.

Jacobs JM, Sinclair PR, Gorman N, Jacobs NJ, Sinclair JF, Bement WJ, Walton H.

Department of Microbiology, Dartmouth Medical School, Hanover, New Hampshire 03756.

Several diphenyl ether herbicides, such as acifluorfen methyl, have been previously shown to cause large accumulations of the heme and chlorophyll precursor, protoporphyrin, in plants. Light-induced herbicidal damage is mediated by the photoactive porphyrin. Here we investigate whether diphenyl ether herbicides can affect porphyrin synthesis in rat and chick hepatocytes. In rat hepatocyte cultures, protoporphyrin, as well as coproporphyrin, accumulated after treatment with acifluorfen or acifluorfen methyl. Combination of acifluorfen methyl with an esterase inhibitor to prevent the conversion of acifluorfen methyl to acifluorfen resulted in a greater accumulation of porphyrins than caused by acifluorfen methyl or acifluorfen alone. In vitro enzyme studies of hepatic mitochondria isolated from rat and chick embryos demonstrated that protoporphyrinogen oxidase, the penultimate enzyme of heme biosynthesis, was inhibited by low concentrations of acifluorfen, nitrofen, or acifluorfen methyl with the latter being the most potent inhibitor. These findings indicate that diphenyl ether treatment can cause protoporphyrin accumulation in rat hepatocyte cultures and suggest that this accumulation was associated with the inhibition of protoporphyrinogen oxidase. In cultured chick embryo hepatocytes, treatment with acifluorfen methyl plus an esterase inhibitor caused massive accumulation of uroporphyrin rather than protoporphyrin or coproporphyrin. Specific isozymes of cytochrome P450 were also induced in chick embryo hepatocytes. These effects were not observed in the absence of an esterase inhibitor. These results suggest that diphenyl ether herbicides can cause uroporphyrin accumulation similar to that induced by other cytochrome P450-inducing chemicals such as polyhalogenated aromatic hydrocarbons in the chick hepatocyte system.

PMID: 1404247 [PubMed - indexed for MEDLINE]




Taxonomic Name: HOMO SAPIENS
Tissue Cultured: LYMPHOCYTES
Experimental Conditions: IN VITRO

Name of Agent (CAS RN):
NITROFEN ( 1836-75-5 )
BIFENOX ( 42576-02-3 )
OXYFLUORFEN ( 42874-03-3 )
ACIFLUORFEN ( 50594-66-6 )
SODIUM FLUORIDE ( 7681-49-4 )

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