Abstracts
Fomesafen
- CAS No. 72178-02-0
Fomesafen sodium - CAS No. 108731-70-0

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ACTIVITY: Herbicide (Diphenyl ether)

CAS Name for Fomesafen: 5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzamide

Structure for Fomesafen:

Reports available from
The National Technical Information Service
(NTIS)

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CAS No. Order No. Title Abstract / Keyword
72178-02-0

NTIS/OTS0543933

EPA/OTS; Doc #88-920007002

1992 - INITIAL SUBMISSION: 5-(2-CHLORO-4-
(TRIFLUOROMETHYL)PHENOXY-N-(METHYLSULFONYL)- 2-
NITROBENZAMIDE: SUBACUTE ORAL TOXICITY TO RATS WITH COVER LETTER DATED 08-28-92

IMPERIAL CHEM INDUS LTD

Keywords:
ICI AMERS INC
5-(2-CHLORO-4-(TRIFLUOROMETHYL)PHENOXY-
N-(METHYLSULFONYL)-2*
HEALTH EFFECTS
SUBCHRONIC TOXICITY
MAMMALS
RATS
ORAL
GAVAGE
72178-02-0

NTIS/OTS0545348

EPA/OTS; Doc #88-920006945

1992 - INITIAL SUBMISSION: SUBACUTE ORAL DOSING STUDY WITH PP021 IN DOGS WITH COVER LETTER DATED 08-28-92

IMPERIAL CHEM INDUS LTD

Keywords:
ICI AMERS INC
PP021
HEALTH EFFECTS
SUBCHRONIC TOXICITY
MAMMALS
DOGS
ORAL
GAVAGE
108731-70-0

NTIS/PB87-231692

11p

1987 - Pesticide Fact Sheet Number 132: Sodium Salt of Fomesafen.

Environmental Protection Agency, Washington, DC. Office of Pesticide Programs.

The document contains up-to-date chemical information, including a summary of the Agency's regulatory position and rationale, on a specific pesticide or group of pesticides. A Fact Sheet is issued after one of the following actions has occurred. (1) Issuance or reissuance of a registration standard, (2) Issuance of each special review document, (3) Registration of a significantly changed use pattern, (4) Registration of a new chemical, or (5) An immediate need for information to resolve controversial issues relating to a specific chemical or use pattern.


Toxicology and Applied Pharmacology Volume 189, Issue 1, 15 May 2003, Pages 28-38

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

Jan Krijt (a), Oskar Penák (a), Martin Vokurka (a), Alena Chlumská (b) and Frantiek Fakan (b)

(a) Institute of Pathophysiology, 1st Medical Faculty, Charles University, 128 53, Prague, Czech Republic
(b) ikl’s Department of Pathology, Medical Faculty, Charles University, Pilsen, 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 (~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.

 

From Science Direct

Environmental Pollution, Volume 146, Issue 2, March 2007, Pages 420-427
Lichens in a Changing Pollution Environment

Hemocyte-specific responses to the peroxidizing herbicide fomesafen in the pond snail Lymnaea stagnalis (Gastropoda, Pulmonata)

Jacqueline Russo (a), Luz Lefeuvre-Orfila (b) and Laurent Lagadic (b)
(a) UMR 6553 Écobio CNRS Université de Rennes 1, Campus de Beaulieu, F-35042 Rennes cedex 35042, France
(b) UMR 985 INRA-Agrocampus Écobiologie et Qualité des Hydrosystèmes Continentaux, Équipe Écotoxicologie et Qualité des Milieux aquatiques, 65 rue de Saint-Brieuc CS 84215, F-35042 Rennes cedex 35042, France

Responses of circulating hemocytes were studied in Lymnaea stagnalis exposed to 10, 30, 90, and 270 ?g/L fomesafen for 24 and 504 h. Flow cytometry was used to quantify fomesafen-induced production of reactive oxygen species (ROS), phagocytic activity on Escherichia coli, and oxidative burst when hemocytes were challenged by E. coli or phorbol 12-myristate-13-acetate (PMA). Lysosomal membrane damage was assessed, using the neutral-red retention time (NRRT) assay. Exposure to fomesafen for 24 h resulted in increase in ROS levels and decreases in phagocytosis and the oxidative burst in PMA-stimulated hemocytes. After 504 h, intracellular levels of ROS returned to normal, but phagocytosis of E. coli was still inhibited and the associated oxidative burst significantly reduced. After both durations of exposure, decreases of NRRT indicated that lysosome membrane fragility increased with previous termfomesafennext term concentration. Potential implications for the health and survival of the snails and consequences on populations are discussed.

Excerpt: The snails were individually exposed for 21 days to the nominal fomesafen concentrations of 10, 30, 90 and 270 ?g/L. Semi-static conditions of exposure were obtained by renewing the contaminated water every three days. Acetone was used to solubilize fomesafen. Solvent concentration in the exposure media was below 1 ?l/ml. Such levels do not alter the immunological responses of L. stagnalis (Russo and Lagadic, 2004). Control snails were maintained in either water contaminated with the carrier solvent, or uncontaminated water, that was also renewed every three days.


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12206427&dopt=Abstract

Environ Toxicol Chem 2002 Sep;21(9):1876-88

Nonylphenol polyethoxylate adjuvant mitigates the reproductive toxicity of fomesafen on the freshwater snail Lymnaea stagnalis in outdoor experimental ponds.

Jumel A, Coutellec MA, Cravedi JP, Lagadic L.

UMR 985 INRA-ENSAR Ecobiologie et Qualite des Hydrosystemes Continentaux, Rennes, France.

The influence of nonylphenol polyethoxylates (NPEO), formulated as the adjuvant Agral 90, on the effects of the diphenyl ether herbicide fomesafen in the pond snail Lymnaea stagnalis was investigated, with particular attention to the reproductive performances and underlying energetic and hormonal processes. Separate short-term exposures to low concentrations of fomesafen and fomesafen-Agral mixture were performed in the laboratory. Outdoor experimental ponds (mesocosms) were used for long-term exposures to higher chemical concentrations. At the concentrations used in the studies, NPEO were known as nontoxic in L stagnalis. Fomesafen was mixed with the adjuvant in the 3:7 ratio recommended for agricultural uses (nominal herbicide concentrations of 22 and 40 microg/L in laboratory and mesocosm, respectively). In mesocosms, multiple application of fomesafen, leading to maximal herbicide concentrations of 60.33 +/- 2.68 microg/L in water, resulted in reduced number of egg masses and altered glycogen metabolism in contaminated snails. These changes, as well as affected steroid-like levels in fomesafen-exposed snails, support the hypothesis of impaired neuroendocrine functions. When Agral 90 was added to the herbicide, results obtained in mesocosms showed that the adjuvant softened the impact of fomesafen. In mesocosms treated with the fomesafen-Agral mixture, significantly lower herbicide levels were found in the water (30.33 +/- 14.91 microg/L at the end of the contamination period). Consequently, internal exposure of the snails to fomesafen was reduced when the herbicide was mixed with the adjuvant. Mitigation of the effects of fomesafen by the adjuvant may therefore result from nonionic surfactant activity of NPEO that prevented fomesafen from reaching the snails.

PMID: 12206427 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12216501&dopt=Abstract

Acta Cient Venez 2002;53(1):60-5

[Participation of dexamethasone and E and C vitamins in the modulation of the hepatotoxic effect induced by fomesafen and 2,4-D amino herbicides, in rats ]

[Article in Spanish]

Orfila L, Mendoza S, Rodriguez J, Arvelo F.

Instituto de Investigaciones Farmaceuticas, Unidad de Cultivo Celular-Toxicologia, Facultad de Farmacia Universidad Central de Venezuela, Caracas-Venezuela.

The fomesafen and 2,4-D amine herbicide induce cytotoxic effects at hepatic level in rats, such as: hepatomegaly, hyperplasia and increase in the enzymes activity which participate in the processes of peroxisomal beta-oxidation of fatty acids. In this work, the effect of vitamin E and C was evaluated, as well as, the dexamethasone in the modulation of these hepatotoxic effects. Sprague-Dawley rats were treated with the herbicides and with the agents to be evaluated. The different treatments were given during 15 days orally route. The herbicides combined with the dexamethasone and antioxidant agents were administrated only and simultaneously with the herbicides. Once concluded the different treatment, the rats were weighed and sacrificed. It was evaluated the liver size and liver fragments were obtained to determine the enzymatic activity of Fatty Acyl CoA-oxidase (FACO) and cellular number. The results showed that the hepatomegaly induced by fomesafen was inhibited by the vitamins and by the dexamethasone, while any effect was not observed in the group of rats treated with 2,4-D amine. None of the agents modulated the FACO activity induced by herbicides in treated rats. However, the dexamethasone showed a protective effect in the hyperplasia induced by two herbicides. The hepatotoxic effects induced by the herbicides responded to a different mechanism due to the differences of the effects observed at the antioxidant agents. On the other hand, the inhibition of the cellular proliferation by the dexamethasone does not keep relation with the responsible mechanisms of inducing the oxidant stress into FACO activity. Under experimental conditions of this study, the use of these agents does not guarantee protection against the hepatotoxic effects induced by the herbicides.

PMID: 12216501 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10372757&dopt=Abstract

Hum Exp Toxicol 1999 May;18(5):338-44

Liver preneoplastic changes in mice treated with the herbicide fomesafen.

Krijt J, Stranska P, Sanitrak J, Chlumska A, Fakan F.

Institute of Pathophysiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.

1. Effect of the diphenyl ether herbicide fomesafen on liver preneoplastic changes and porphyrin biosynthesis was examined in male C57BL/6J mice (0.23% in the diet for 14 months) and ICR mice (0.3% in the diet for 50 weeks). Fomesafen treatment resulted in preneoplastic changes (liver nodules and foci of altered hepatocytes) in both strains, uroporphyria developed only in ICR mice.
2. Iron pretreatment (600 mg/kg as a single dose) accelerated the development of fomesafen-induced preneoplastic changes in both mouse strains. The number of foci containing altered hepatocytes, as well as the number and size of liver nodules, were increased in iron-pretreated animals.
3. A single injection of iron induced marked uroporphyria in C57BL/6J mice after 14 months (liver porphyrin content 102 nmol/g). This uroporphyria was further potentiated by fomesafen administration (208 nmol/g).
4. In ICR mice, liver histology was apparently normal after a 3 month recovery from fomesafen treatment (0.32% for 9 months). Liver porphyrin content (260 nmol/g) started to decrease immediately after fomesafen withdrawal, but was still significantly elevated after 3 months (5 nmol/g), as compared to controls (1 nmol/g).
5. It is concluded that the toxicological evaluation of fomesafen should focus on liver porphyrin biosynthesis.

PMID: 10372757 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9624829&dopt=Abstract

Cesk Patol 1998 Apr;34(2):67-71

[Morphologic findings in liver tissue in mice after long-term administration of the herbicide fomesafan]

[Article in Czech]

Chlumska A, Fakan F, Krijt J.

II. patologicko-anatomicky ustav 1. LF UK a VFN, Praha.

Administration of herbicide fomesafen and of fomesafen combined with one dose of iron to 44 mice during 3 to 14 months caused hyperplastic and preneoplastic changes in the liver tissue which had been described in experimental carcinogenesis* small groups of altered hepatocytes storing glycogen or lipids and foci of small basophilic liver cells occurred as early as after 3 months. Altered hepatocytes were found more frequently in mice getting fomesafen and iron. Later nodular hyperplasia of liver cells developed with nodes 3-20 mm in diameter which mostly consisted of altered hepatocytes with plenty of glycogen. After 12 and 14 month-lasting administration of fomesafen and fomesafen with iron, the hepatocellular carcinoma was proved in 5 mice. In 4 mice, the preneoplastic changes in liver tissue were accompanied by micronodular hyperplasia of liver cells which did not participate on the development of big nodes and hepatocellular carcinoma.

PMID: 9624829 [PubMed - indexed for MEDLINE]


From Toxline at Toxnet

TOXICOLOGY AND APPLIED PHARMACOLOGY; 146 (1). 1997. 170-171.

LETTERS TO THE EDITOR AND REPLY

KRIJT J, VOKURKA M, RICHERT L

Abstract: BIOSIS COPYRIGHT: BIOL ABS. RRM LETTER HUMAN TOXICOLOGY FOMESAFEN HERBICIDE FLUAZIFOP OXADIAZON HEPATOCARCINOGEN TUMOR BIOLOGY DIGESTIVE SYSTEM HEPATOCELLULAR CARCINOMA PORPHYRIN NEOPLASTIC DISEASE DIGESTIVE SYSTEM DISEASE


From Toxline at Toxnet

TOXICOLOGY IN VITRO; 11 (1-2). 1997. 99-105.

Quantitative structure-activity relationship (QSAR) analysis for a series of rodent peroxisome proliferators: Interaction with the mouse liver peroxisome proliferator-activated receptor alpha (mPPARalpha).

LEWIS D FV, LAKE BG

Sch. Biol. Sci., Univ. Surrey, Guildford, Surrey GU2 5XH, UK.

BIOSIS COPYRIGHT: BIOL ABS. The results of quantitative structure-activity relationship (QSAR) analysis on a structurally diverse group of peroxisome proliferators are reported. The relative potencies of 11 peroxisome proliferators (with respect to clofibric acid) for induction of palmitoyl-CoA oxidation in rat hepatocyte cultures appear to be determined by a combination of lipophilicity (logP descriptor) and calculated binding affinity (logK) to a model of the mouse liver peroxisome proliferator-activated receptor alpha (mPPARalpha) ligand-binding domain. It is possible that desolvation of the putative binding site and ligand ionization may also play a role in activation of the mPPARalpha.

CAS Registry Numbers:
88107-10-2
72178-02-0 - Fomesafen
50892-23-4
21340-68-1
4376-20-9
3771-19-5
882-09-7
76-03-9


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8993577&dopt=Abstract

Ann N Y Acad Sci 1996 Dec 27;804:628-35

Peroxisome proliferators: species differences in response of primary hepatocyte cultures.

Elcombe CR, Bell DR, Elias E, Hasmall SC, Plant NJ.

Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, U.K.

PMID: 8993577 [PubMed - indexed for MEDLINE]


From Toxline at Toxnet

Source: REDDY, J. K., ET AL. (ED.). ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, VOL. 804. PEROXISOMES: BIOLOGY AND ROLE IN TOXICOLOGY AND DISEASE; INTERNATIONAL SYMPOSIUM, ASPEN, COLORADO, USA, JUNE 28-JULY 2, 1995. XV+801P. NEW YORK ACADEMY OF SCIENCES: NEW YORK, NEW YORK, USA. ISBN 0-89766-968-1(PAPER); ISBN 0-89766-967-3(CLOTH).; 804 (0). 1996. 628-635.

PEROXISOME PROLIFERATORS SPECIES DIFFERENCES IN RESPONSE OF PRIMARY HEPATOCYTE CULTURES

ELCOMBE CR, BELL DR, ELIAS E, HASMALL SC, PLANT NJ

Abstract: BIOSIS COPYRIGHT: BIOL ABS. RRM BOOK CHAPTER MEETING PAPER RAT MOUSE GUINEA-PIG MONKEY HUMAN PEROXISOME PROLIFERATORS CARCINOGENS SPECIES DIFFERENCES PEROXISOME PROLIFERATION CULTURED PRIMARY HEPATOCYTES HEPATOCELLULAR GROWTH RESPONSE CELL BIOLOGY DIGESTIVE SYSTEM TOXICOLOGY DIGESTIVE SYSTEM

CAS Registry Numbers:
72178-02-0 (Fomesafen)
40321-98-0
149-57-5
76-03-9


Toxicology Letters, Volume 78, Supplement 1, August 1995, Page 77

Effect of the peroxisome proliferating diphenyl etther herbicide fomesafen on liver porphyrin biosynthesis and neoplastic transformation—synergism with iron pretreatment 

P. Stránská (1), A. Chlumská (2) , M. Vokurka (1), P. Maruna (1), J. Sanitrik (1), V. Janousek (1) and J. Krijt (1)

(a) Medical Faculty, Charles University, Prague
(b) Second Department of Pathological Anatomy First Medical Faculty, Charles University, Prague

Note from FAN: We copied the following abstract from a poorly legible abstract sheet. Any mistakes in typing are ours. - EC.

Although the diphenyl ether herbicides are in widespread use, their mode of action was elucidated only recently, In addition to their affect of porphyrin metabolism, some of the diphenyl ether herbicides cause hepatocellular carcinoma in rodents. The aim of the presented study was to evaluate the porphyrogenic effects of fomesafen in a long term experiment. 12 male ICR mice were fed 0.3% of the herbicide for 12 months. Another group of 12 mice was pretreated with iron (600 mg/kg) and fed either fomesafen diet, or control diet. After six months of treatment, the liver porphyrin content was 69.9± ug/g in the fomesafen group and :52.2± 52.6 in the fomesafen plus iron group. No increase in porphyrin content was evident in iron pretreated mice. Liver histology showed necrotic foci in fomesafen treated animals. Peroxisomal B-oxidation was increased in both fomesafen treated animals. After 12 months of treatment, liver porphyrin content was 56 ± 18 ug/g in the fomesafen group and 107 ± 36 in the fomesafen plus iron group. No increase in porphyrin content was evident in iron pretreated mice. Liver histology showed necrotic foci in fomesafen treated animals. Peroxisomal B-oxidation was increased in both fomesafen fed group. The porphyrin content of iron pretreated mice was slighly increased to about 250% of control values. On macroscopic examination, livers from the fomesafe nplus iron group showed multiple liver nodules. Histological examination revealed mainly adenomas and one hepatocellular carcinoma. No nodules were observed in mice fed fomesafen only. The results indicate that iron significantly increased the porphyrogenic activity of fomesafen, as well as tyhe tumoroganic activity. These results closely resemble the effects obtained with other porphyrogenic heptacarcinogens, like HCB, TCDD or PCBs. Therefore, the changes inporphyrin metabolism could be an additional factor in fomesafen-induced neoplasia.


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7855041&dopt=Abstract

Pharm Res 1994 Oct;11(10):1396-400

Vehicle effects on in vitro percutaneous absorption through rat and human skin.

Hilton J, Woollen BH, Scott RC, Auton TR, Trebilcock KL, Wilks MF.

Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, England.

We studied the effects of three vehicles (propylene glycol, octanol and ethyl decanoate) with differing polarity on the in vitro percutaneous absorption of three chemicals (fluazifop-butyl, dimethyl phthalate and fomesafen sodium salt) with a range of physico-chemical properties. Absorption rate measurements were made from high vehicle volume (200 microliters/cm2) and low vehicle volume (< 10 microliters/cm2) applications. For the lipophilic fluazifop-butyl absorption rate was highest from the more polar vehicle propylene glycol, but this effect was only significant under high-volume conditions. There was a variable vehicle effect on absorption of the intermediate chemical dimethyl phthalate. The largest vehicle effect was seen for the more hydrophilic fomesafen sodium salt where absorption was fastest from the least polar vehicle ethyl decanoate. These results support the hypothesis that the absorption process can in part be predicted from a knowledge of solute solubility. Vehicle effects were greater from high volume applications than from those more comparable to occupational exposure conditions.

PMID: 7855041 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8045477&dopt=Abstract

Food Chem Toxicol 1994 Jul;32(7):641-50

Effect of the protoporphyrinogen oxidase-inhibiting herbicide fomesafen on liver uroporphyrin and heptacarboxylic porphyrin in two mouse strains.

Krijt J, Vokurka M, Sanitrak J, Janousek V, van Holsteijn I, Blaauboer BJ.

Department of Pathological Physiology, First Medical Faculty, Charles University, Prague, Czech Republic.

The effect of the protoporphyrinogen oxidase-inhibiting herbicide fomesafen on liver porphyrin accumulation was studied in long-term high-dose experiments. Fomesafen caused liver accumulation of uroporphyrin and heptacarboxylic porphyrin when fed at 0.25% in the diet to male ICR mice for 5 months (fomesafen-treated mice: 52 nmol uroporphyrin, 21 nmol heptacarboxylic porphyrin/g liver; control mice: traces of uroporphyrin, heptacarboxylic porphyrin not detected). Uroporphyrinogen decarboxylase activity was depressed to about 25% of control values. Iron treatment accelerated the development of this porphyria cutanea tarda-like experimental porphyria both in ICR and C57B1/6J mice. In contrast to other uroporphyrinogen decarboxylase inhibitors, fomesafen treatment did not increase the cytochrome P450IA-related activities and the amount of P450IA2 protein was shown to be significantly decreased by Western immunoblotting. Thus, fomesafen is a unique chemical that inhibits both the oxidation of protoporphyrinogen as well as the conversion of uroporphyrinogen to coproporphyrinogen. However, the accumulation of highly carboxylated porphyrins is evident only after prolonged treatment with high doses of the herbicide.

PMID: 8045477
[PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7958570&dopt=Abstract

Fundam Appl Toxicol 1994 Jul;23(1):93-100

Effect of dosing vehicle on the dermal absorption of fluazifop-butyl and fomesafen in rats in vivo.

Rawlings JM, Hilton J, Trebilcock KL, Woollen BH, Wilks MF.

Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, England.

One important factor which may influence the extent and rate of percutaneous absorption is the dosing vehicle. The purpose of the experiments described was to compare the effect of dosing vehicles of different polarities on the absorption of two herbicides across rat skin in vivo. Rats were dosed dermally with either fluazifop-butyl (logP(oct) 4.5) or fomesafen sodium salt (logP(oct) -1.2) in propylene glycol (PG), octanol (OCT), or ethyl decanoate (ED), and the amount of radioactivity excreted in urine was determined. Absorption rates were estimated from the urinary excretion data and from blood kinetic data derived from intravenously dosed rats. For fluazifop-butyl the average rate of absorption (x10(-2) micrograms/hr-1 +/- SE) was not greatly influenced by the dosing vehicle (OCT, 2.94 +/- 0.08; ED, 3.66 +/- 0.10; PG, 3.95 +/- 0.32) despite relatively large differences in solubility (PG, 38 mg/ml; OCT, and ED, > 600 mg/ml). These results were consistent with the finding that there was at most only a twofold difference in the epidermal membrane:vehicle partition coefficients (km). In contrast, the absorption rate of fomesafen from PG (1.98 +/- 0.04) was approximately half that of ED (3.98 +/- 0.06) and OCT (4.49 +/- 0.08) for the first 30 hr after application and was in keeping with solubility data (PG, 638 mg/ml; OCT, 12 mg/ml; ED, < 10 mg/ml). At later time points the absorption of fomesafen from PG increased; this is discussed in relation to the penetration-enhancing properties of PG.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 7958570 [PubMed - indexed for MEDLINE]


From Toxline at Toxnet

Rev. Fac. Farm. Univ. Cent. Venez.; VOL 57 ISS 1 1994, P6-11, (REF )

Cytotoxic activity of the herbicide fomesafen in rat hepatocytes treated in vitro

Orfila L, Salazar-Bookaman M

Unidad de Cultivo Celular, Fac. de Farmacia, Univ. Central de Venezuela, Apdo. 40109, Caracas 1040-A, Venezuela

No abstract available

Keywords:
Fomesafen
effects
cytotoxicity
Herbicides
cytotoxic effects

CAS Registry Number:
72178-02-0 - Fomesafen


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8517781&dopt=Abstract

Arch Toxicol 1993;67(4):255-61

Effect of diphenyl ether herbicides and oxadiazon on porphyrin biosynthesis in mouse liver, rat primary hepatocyte culture and HepG2 cells.

Krijt J, van Holsteijn I, Hassing I, Vokurka M, Blaauboer BJ.

Research Institute of Toxicology, University of Utrecht, The Netherlands.

The effects of the herbicides fomesafen, oxyfluorfen, oxadiazon and fluazifop-butyl on porphyrin accumulation in mouse liver, rat primary hepatocyte culture and HepG2 cells were investigated. Ten days of herbicide feeding (0.25% in the diet) increased the liver porphyrins in male C57B1/6J mice from 1.4 +/- 0.6 to 4.8 +/- 2.1 (fomesafen) 16.9 +2- 2.9 (oxyfluorfen) and 25.9 +/- 3.1 (oxadiazon) nmol/g wet weight, respectively. Fluazifop-butyl had no effect on liver porphyrin metabolism. Fomesafen, oxyfluorfen and oxadiazon increased the cellular porphyrin content of rat hepatocytes after 24 h of incubation (control, 3.2 pmol/mg protein, fomesafen, oxyfluorfen and oxadiazon at 0.125 mM concentration 51.5, 54.3 and 44.0 pmol/mg protein, respectively). The porphyrin content of HepG2 cells increased from 1.6 to 18.2, 10.6 and 9.2 pmol/mg protein after 24 h incubation with the three herbicides. Fluazifop-butyl increased hepatic cytochrome P450 levels and ethoxy- and pentoxyresorufin O-dealkylase (EROD and PROD) activity, oxyfluorfen increased PROD activity. Peroxisomal palmitoyl CoA oxidation increased after fomesafen and fluazifop treatment to about 500% of control values both in mouse liver and rat hepatocytes. Both rat hepatocytes and HepG2 cells can be used as a test system for the porphyrogenic potential of photobleaching herbicides.

PMID: 8517781 [PubMed - indexed for MEDLINE]

•• Abstract from Toxline at Toxnet on this paper:

Porphyrin accumulation in mouse liver, rat primary hepatocyte culture and HepG2 cells was investigated after exposure to fomesafen (72178-02-0), oxyfluorfen (42874-03-3), oxadiazon, and fluazifopbutyl (69806-50-4) (fluazifop). Male C57Bl/6J-mice were fed a diet containing 0.25% herbicide, sacrificed after 10 days, and the livers prepared for culture. Hepatocytes were isolated from Wistar-rats and treated with herbicide after being in culture for 24 hours. Fomesafen, oxyfluorfen and oxadiazon significantly increased the porphyrin content of mouse liver, as well as the porphyrin content of rat hepatocytes and HepG2 cells in culture. Fluazifop did not have any effect on porphyrin accumulation. The extent of in-vitro porphyrin accumulation induced by fomesafen, oxyfluorfen and oxadiazon in the rat primary hepatocyte culture was roughly similar. Fomesafen and fluazifop caused a significant increase in the activity of peroxisomal palmitoyl-coenzyme-A oxidation both in rat primary hepatocyte culture and in mouse liver. Hepatic cytochrome levels were increased by fluazifop and there were also increases in ethoxyresorufin-O-dealkylase and pentoxyresorufin-O-dealkylase activities. The authors conclude that both the rat hepatocytes and HepG2 cells can be used to study porphyrogenic activity of protoporphyrinogen-oxidase inhibiting herbicides.


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2689246&dopt=Abstract

Food Addit Contam 1989;6 Suppl 1:S57-65

Mechanistic studies: their role in the toxicological evaluation of pesticides.

Smith LL, Elcombe CR.

Central Toxicology Laboratory, Imperial Chemical Industries plc, Cheshire, UK.

To date, studies on the mechanism of toxicity of pesticides are not yet an integral part of the toxicological evaluation process. However, in recent years mechanistic studies have played an increasing role in the assessment of toxicological hazards to man, and in this paper we have described two examples where an understanding of mechanism has contributed positively to risk assessment or has provided a surer scientific basis for the judgement of whether a potential hazard will be expressed in man. In the first example, an evaluation of the scientific literature leads to the conclusion that hepatic peroxisome proliferation in rats and mice is directly, or indirectly, related to the development of hepatocellular tumours. A wide range of non-mutagenic chemicals elicit peroxisome proliferation in mouse and rat liver, but not the guinea pig or marmoset liver. Using one of the diphenyl ether herbicides, fomesafen, we have shown that isolated hepatocytes from mice and rats, but not those from guinea pigs, marmosets and significantly man, undergo peroxisome proliferation. Therefore, it seems reasonable to conclude that although fomesafen causes peroxisome-related tumours in the mouse, man is neither susceptible nor sensitive to this mechanism. Consequently, we can conclude that fomesafen will not cause liver tumours in humans exposed to this herbicide. The herbicide paraquat, although safe in normal agricultural use, has been responsible for numerous human fatalities, almost exclusively as a result of the intentional ingestion of the concentrated commercial product.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication Types:

  • Review
  • Review, Tutorial

PMID: 2689246 [PubMed - indexed for MEDLINE]


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