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PROTOX INHIBITOR HERBICIDES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Protoporphyrinogen oxidase (Protox)-inhibiting herbicides were referred to as "diphenyl ether-type herbicides" prior to knowledge of their molecular target, Protox. Prior to 1989 most of the Protox inhibitors were diphenyl ethers (DPE). Not all diphenyl ethers are Protox inhibitors though, as some have an entirely different molecular site of action. Since 1989 a number of other structural classes of Protox inhibitors have evolved. This group of herbicides controls both monocotyledonous and dicotyledonous weeds. Historically, the Protox inhibitors have been used for broad-spectrum weed control in soybean fields. They are also referred to as photobleaching herbicides.
    B) The Protox inhibitors are divided into the first generation of diphenyl ether or diphenyl ether-like (with p-trifluoromethyl phenyl substitutions) or the second generation of non-diphenyl ether Protox inhibitors, which are non-oxygen-bridged compounds. These latter compounds generally consist of heterobicyclic structures with one phenyl ring attached to a heterocyclic ring.
    C) Protox inhibitors have been shown to have little acute toxicity in mammals.

Specific Substances

    A) DPE AND DPE-LIKE PROTOX INHIBITORS (First Generation)-- ACIFLUORFEN
    1) Benzoic acid,5-(2-chloro-4-(trifluoromethyl)phenoxy)-2-nitro-
    2) Acifluorfene
    DPE AND DPE-LIKE PROTOX INHIBITORS (First Generation)-- BIFENOX
    1) Benzoic acid,5-(2,4-dichlorophenoxy)-2-nitro-,methyl ester
    2) MC-4379
    3) Modown
    DPE AND DPE-LIKE PROTOX INHIBITORS (First Generation)-- CHLOMETHOXYFEN
    1) Ether, (2,4-dichlorophenyl)(3-methoxy-4-nitrophenyl)
    2) Chlomethoxynil
    3) Chloromethoxynil
    4) Diphenex
    5) X-52
    DPE AND DPE-LIKE PROTOX INHIBITORS (First Generation)-- CHLORNITROFEN
    1) Ether, p-nitrophenyl 2,4,6-trichlorophenyl
    2) CNP
    3) MO
    DPE AND DPE-LIKE PROTOX INHIBITORS (First Generation)-- FLUOROGLYCOFEN
    1) Benzoic acid, 5-(2-chloro-4-(trifluoromethyl)phenoxy)-2-nitro-, ester with ethyl glycolate
    2) BAS 9106 H
    3) Compete
    4) Fluoroglycofen-ethyl
    5) RH-0265
    6) Super blazer
    DPE AND DPE-LIKE PROTOX INHIBITORS (First Generation)-- FOMESAFEN
    1) Benzamide, 5-(2-chloro-4-(trifluoromethyl)phenoxy)-N-(methylsulfonyl)-2-nitro-
    2) Flex
    3) Fomesafene
    4) Formesafen
    5) PP021
    6) Reflex
    DPE AND DPE-LIKE PROTOX INHIBITORS (First Generation)-- LACTOFEN
    1) Benzoic acid, 5-(2-chloro-4-(trifluoromethyl)phenoxy)-2-nitro-, 2-ethoxy-1-methyl-2-oxoethyl ester
    2) Cobra
    3) PPG 844
    DPE AND DPE-LIKE PROTOX INHIBITORS (First Generation)-- NITROFEN
    1) Ether, 2,4-dichlorophenyl p-nitrophenyl
    2) FW 925
    3) Mezotox
    4) NCI-C00420
    5) Niclofen
    6) NIP
    7) Nitofen
    8) Nitrafen
    9) Nitraphen
    10) Nitrochlor
    11) Nitrofene
    12) Nitrophen
    13) Nitrophene
    14) TOK
    15) Trizilin
    DPE AND DPE-LIKE PROTOX INHIBITORS (First Generation)-- OXYFLUORFEN
    1) Ether, 2-chloro-alpha,alpha,alpha-trifluoro-p-tolyl 3-ethoxy-4-nitrophenyl
    2) Oxyfluorfene
    3) RH-2915
    NON-OXYGEN-BRIDGED PROTOX INHIBITORS (Second Generation) -- AZAFENIDIN
    1) Azafenidin
    NON-OXYGEN-BRIDGED PROTOX INHIBITORS (Second Generation) -- CARFENTRAZONE
    1) Carfentrazone-ethyl
    NON-OXYGEN-BRIDGED PROTOX INHIBITORS (Second Generation) -- FLUMICLORAC
    1) Flumiclorac-pentyl
    NON-OXYGEN-BRIDGED PROTOX INHIBITORS (Second Generation) -- IR 5790
    1) IR 5790
    NON-OXYGEN-BRIDGED PROTOX INHIBITORS (Second Generation) -- JV-485
    1) JV-485
    NON-OXYGEN-BRIDGED PROTOX INHIBITORS (Second Generation) -- OXADIAZON
    1) delta(sup 2)-1,3,4-Oxadiazolin-5-one, 2-tert-butyl-4-(2,4-dichloro-5-isopropyloxyphenyl)-
    2) RP 17623
    NON-OXYGEN-BRIDGED PROTOX INHIBITORS (Second Generation) -- SULFENTRAZONE
    1) Methanesulfonamide, N-(2,4-dichloro-5-(4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2, 4- triazol-1-yl)phenyl)-
    2) F 6285
    NON-OXYGEN-BRIDGED PROTOX INHIBITORS - BUTAFENACIL
    1) 1,1-dimethyl-2-oxo-2-(2-propenyloxy)ethyl 2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]benzoate
    2) C20H18ClF3N2O6
    3) CAS 134605-64-4
    NON-OXYGEN-BRIDGED PROTOX INHIBITORS - FLUAZOLATE
    1) isopropyl 5-[4-bromo-1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-chloro-4-fluorobenzoate
    2) 1-methylethyl 5-[4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2-chloro-4-fluorobenzoate
    3) C15H12BrClF4N2O2
    NON-OXYGEN-BRIDGED PROTOX INHIBITORS - FLUFENPYR-ETHYL
    1) ethyl 2-chloro-5-[1,6-dihydro-5-methyl-6-oxo-4-(trifluoromethyl)pyridazin-1-yl]-4-fluorophenoxyacetate
    2) ethyl 2-[2-chloro-4-fluoro-5-[5-methyl-6-oxo-4-(trifluoromethyl)-1(6H)-pyridazinyl]phenoxy]acetate
    3) C16H13ClF4N2O4
    NON-OXYGEN-BRIDGED PROTOX INHIBITORS - FLUTHIACET-METHYL
    1) methyl {2-chloro-4-fluoro-5-[(EZ)-5,6,7,8-tetrahydro-3-oxo-1H,3H-[1,3,4]thiadiazolo[3,4-a]pyridazin-1-ylideneamino]phenylthio}acetate
    2) methyl 2-[[2-chloro-4-fluoro-5-[(tetrahydro-3-oxo-1H,3H-[1,3,4]thiadiazolo[3,4-a]pyridazin-1-ylidene)amino]phenyl]thio]acetate
    3) C15H15ClFN3O3S2
    NON-OXYGEN-BRIDGED PROTOX INHIBITORS - PYRAFLUFEN-ETHYL
    1) Ethyl 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-pyrazol- 3-yl)-4-fluorophenoxyacetate
    2) C15H13Cl2F3N2O4
    3) CAS 129630-19-9

    1.2.1) MOLECULAR FORMULA
    1) Acifluorfen: C14-H7-Cl-F3-N-O5
    2) Bifenox: C14-H9-Cl2-N-05
    3) Fluoroglycofen: C18-H13-Cl-F3-N-O7
    4) Fomesafen: C15-H10-Cl-F3-N2-O6-S
    5) Lactofen: C19-H15-Cl-F3-N-07
    6) Nitrofen: C12-H7-Cl2-N-03
    7) Oxyfluorfen: C15-H11-Cl-F3-N-O4
    8) Oxadiazon: C15-H18-Cl2-N2-O3
    9) Sulfentrazone: C11-H10-Cl2-F2-N4-O3-S

Available Forms Sources

    A) FORMS
    1) The first Protox inhibitor, which was introduced for commercial use in 1964, was nitrofen, a diphenyl ether and a relatively weak inhibitor of Protox. Some of the newer diphenyl ether-like herbicides more commonly contain p-trifluoromethyl phenyl substitutions, which are heterocyclic phenyl ethers (Dayan et al, 2001).
    2) The Protox inhibitors are divided into the first generation of diphenyl ether or diphenyl ether-like (with p-trifluoromethyl phenyl substitutions) or the second generation of non-diphenyl ether Protox inhibitors, which are non-oxygen-bridged compounds. These latter compounds generally consist of heterobicyclic structures with one phenyl ring attached to a heterocyclic ring (Dayan et al, 2001).
    B) USES
    1) This group of herbicides is most often applied post-emergence during the early stages of weed development. Most of the older herbicides of this class do not have pre-emergence activity. They have little residual soil activity. Newer Protox inhibitors, such as sulfentrazone, have excellent pre-emergence activity. Some of these herbicides and the crops they are applied to are listed as follows (Dayan et al, 2001):
    HERBICIDEMAIN CROPAPPLICATION
    AcifluorfenSoybean, peanut, ricePost-emergence
    AzafenidinPerennial crops, forestryPre-emergence
    BifenoxSmall grainPre/Postemergence
    CarfentrazoneCereal cropsPost-emergence
    FlumicloracSoybean/MaizePre/Postemergence
    FluoroglycofenCereal cropsPost-emergence
    FomesafenSoybeanPost-emergence
    IR-5790 Pre-emergence
    JV-485Winter wheatPre-emergence
    LactofenSoybeanPost-emergence
    OxadiargylRice/Sugar canePre-emergence
    OxadiazonGrasses/OrnamentalsPost-emergence
    OxyfluorfenVegetable cropsPre/Postemergence
    SulfentrazoneSoybean/Tobacco, Sugar canePre-emergence

    2) Protox inhibitors have been proposed as pharmaceutical agents for use in human tumor phototherapy. Some of these inhibitors may preferentially accumulate in tumors, resulting in adequate differences between tumor protoporphyrinogen accumulation and that in adjacent tissues for use in phototherapy (Dayan et al, 2001; Carre et al, 1999; Fingar et al, 1997).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Protox inhibitor herbicides are used for weed and plant control most often after emergence during the early stages of weed development. PHARMACOLOGY: These herbicides inhibit protophorphyrinogen oxidase (Protox), which causes an unregulated accumulation of protoporphyrinogen (protogen). Protogen is oxidized to protoporphyrin IX (proto); a chlorophyll precursor. Proto, a photodynamic pigment, is energized by light and causes formation of reactive oxygen species, leading to oxidative membrane degradation and plant death. There is a theoretical risk of developing variegate porphyria or transient porphyria cutanea tarda-like syndrome.
    B) TOXICOLOGY: Protox inhibitor herbicides are not considered to pose significant toxicological risk in healthy humans. in patients with long-term chronic exposures or very large acute exposures, there is a theoretical risk of developing variegate porphyria or transient porphyria cutanea tarda-like syndrome. However, this has not been reported. Some herbicidal formulations may contain anionic surfactants, which have severe toxicity, but most protox herbicides are formulated as aqueous dilutions of emulsifiable concentrates without anionic surfactants.
    C) EPIDEMIOLOGY: There are no significant reports of human toxicity. Only a single case report of fatality due to ingestion of an herbicide containing chlornitrofen (as well as butachlor, xylene, and toluene) has been reported; the death was thought due to the butachlor component rather than the chlornitrofen.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Signs and symptoms are typically limited to mild irritation of skin and eyes after prolonged exposure.
    2) SEVERE TOXICITY: Severe toxicity in humans has not been described.
    0.2.20) REPRODUCTIVE
    A) Most of the Protox inhibitor herbicides have not been found to be teratogenic in animals. At the time of this review, no studies have been found regarding human exposure to these herbicides and their effect on teratogeniciy or effects during pregnancy or breast feeding.
    B) Nitrofen has been found to be teratogenic to laboratory animals. Lung hypoplasia, left-sided diaphragmatic hernia, as well as skeletal and cardiac malformations have been seen. It also has been shown to decrease viability and increase the number of stillbirths in rats and mice.
    0.2.21) CARCINOGENICITY
    A) There are no data, either case reports or epidemiological studies, available at the time of this review to assess the carcinogenic effects in humans.

Laboratory Monitoring

    A) Laboratory evaluations are not necessary in most patients unless otherwise clinically indicated.
    B) Serum concentrations are not widely available or clinically useful.
    C) In patients with suspected porphyria due to protox inhibitor herbicide toxicity, CBC, hepatic enzymes, basic metabolic panel, urinalysis, and serum porphyrin levels should be obtained.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Remove contaminated clothing and wash skin with soap and water. Treatment of eye exposure consists of copious irrigation with water or saline.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Severe toxicity in humans has not been described. Treatment is symptomatic and supportive.
    C) DECONTAMINATION
    1) PREHOSPITAL: Remove contaminated clothing and wash skin with soap and water. Irrigate exposed eyes with water or saline. Gastrointestinal decontamination is not recommended.
    2) HOSPITAL: Remove contaminated clothing and wash skin with soap and water. Irrigate exposed eyes with water or saline. There is no indication for gastric decontamination.
    D) AIRWAY MANAGEMENT
    1) There is no known direct toxic effect of protox inhibitor herbicides that would require respiratory support.
    E) ANTIDOTE
    1) There is no specific antidote for protox inhibitor herbicides.
    F) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis would remove protox inhibitor herbicides.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients with inadvertent exposures may be managed safely at home with observation.
    2) OBSERVATION CRITERIA: Patients with deliberate exposures or more than mild symptoms should be referred to a healthcare facility.
    3) ADMISSION CRITERIA: Patients with persistent symptoms, concern for ingestion of an herbicide containing an anionic surfactant, or concern for porphyria due to protox inhibitor herbicide toxicity should be admitted to an inpatient facility.
    4) CONSULT CRITERIA: Contact your local poison center or medical toxicologist for any patient with suspected porphyria due to protox inhibitor herbicide toxicity, or for any patient with severe symptoms suspected due to herbicide toxicity.
    H) PITFALLS
    1) Failure to differentiate exposure to other chemicals that may cause mild irritation.
    I) TOXICOKINETICS
    1) Detailed toxicokinetic data are not available.
    0.4.3) INHALATION EXPOSURE
    A) Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with inhaled beta2 agonist and oral or parenteral corticosteroids.
    0.4.4) EYE EXPOSURE
    A) Irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist, the patient should be seen in a health care facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Remove contaminated clothing and wash exposed area thoroughly with soap and water. A physician may need to examine the area if irritation or pain persists.

Range Of Toxicity

    A) TOXICITY: The toxic dose in humans has not been established. There are no significant reports of human toxicity. Only a single case report of fatality due to ingestion of an herbicide containing chlornitrofen (as well as butachlor, xylene, and toluene) has been reported; the death was thought due to the butachlor component rather than the chlornitrofen.

Clinical Effects

Summary Of Exposure

    A) USES: Protox inhibitor herbicides are used for weed and plant control most often after emergence during the early stages of weed development. PHARMACOLOGY: These herbicides inhibit protophorphyrinogen oxidase (Protox), which causes an unregulated accumulation of protoporphyrinogen (protogen). Protogen is oxidized to protoporphyrin IX (proto); a chlorophyll precursor. Proto, a photodynamic pigment, is energized by light and causes formation of reactive oxygen species, leading to oxidative membrane degradation and plant death. There is a theoretical risk of developing variegate porphyria or transient porphyria cutanea tarda-like syndrome.
    B) TOXICOLOGY: Protox inhibitor herbicides are not considered to pose significant toxicological risk in healthy humans. in patients with long-term chronic exposures or very large acute exposures, there is a theoretical risk of developing variegate porphyria or transient porphyria cutanea tarda-like syndrome. However, this has not been reported. Some herbicidal formulations may contain anionic surfactants, which have severe toxicity, but most protox herbicides are formulated as aqueous dilutions of emulsifiable concentrates without anionic surfactants.
    C) EPIDEMIOLOGY: There are no significant reports of human toxicity. Only a single case report of fatality due to ingestion of an herbicide containing chlornitrofen (as well as butachlor, xylene, and toluene) has been reported; the death was thought due to the butachlor component rather than the chlornitrofen.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Signs and symptoms are typically limited to mild irritation of skin and eyes after prolonged exposure.
    2) SEVERE TOXICITY: Severe toxicity in humans has not been described.

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) IRRITATION: Only mild to moderate, transient eye irritation is expected to occur following ocular exposure (Von Burg, 1992). Irritating effects on the eyes were reported in persons occupationally exposed to nitrofen (Anon, 1983).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SECONDARY PERIPHERAL NEUROPATHY
    1) WITH POISONING/EXPOSURE
    a) It is possible, although not yet substantiated, that a significant ingestion of these herbicides could result in peripheral neuropathy, with extremity pain, in humans due to herbicide-induced porphyria (Krijt et al, 1997; Krijt et al, 1995).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEUROPATHY
    a) Exposure of mice to these herbicides has resulted in porphyric neuropathy with peripheral nerve accumulation of porphyrins. Porphyrin content of the trigeminal nerve was increased after several days of exposure. No decrease in brain protoporphyrinogen oxidase activity was noted in these experiments (Krijt et al, 1997).
    2) SEIZURES
    a) Acute lethal toxicity studies of nitrofen, using the murine model, resulted in progressive depression and difficulty in breathing, often proceeding to tremors and seizures. Death occurred in 2 to 8 days (Hurt et al, 1983).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTRITIS
    1) WITH POISONING/EXPOSURE
    a) Acute abdominal pain, vomiting, and constipation are hallmarks of acute porphyria attacks and may potentially occur following significant herbicide ingestion (Krijt et al, 1997).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) PORPHYRIA DUE TO TOXIC EFFECT OF SUBSTANCE
    1) WITH POISONING/EXPOSURE
    a) Although not reported in human cases, it may be possible, following a significant toxic exposure or long-term exposure to toxic amounts, for humans to develop a toxic porphyria cutanea tarda-like syndrome consistent with a deficiency of uroporphyrin decarboxylase or a variegate porphyria. Porphyrinogen accumulation in the liver may result. Concurrent mild hepatitis may also theoretically develop. It is expected that these effects would be transient. Low-level accumulation of liver uroporphyrin would most likely result from accidental exposure to these herbicides (HSDB , 2002; Krijt et al, 1999; Krijt et al, 1994; Sinclair et al, 1994; Von Burg, 1992).
    1) Presenting clinical manifestations may include cutaneous lesions that may be persistent; fragility of skin in sun-exposed parts of body can be a notable feature. Hypo- or hyperpigmentation of face, hyperpigmentation of periorbital and malar regions, and hypertrichosis of cheeks and lateral aspects of eyebrows may occur. Photo damage of ocular conjunctiva, with pinguecula and pterygium could occur. This is speculative since no human cases have been reported.
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CHEMICAL-INDUCED PORPHYRIA
    a) Chronic high-dose experiments with these herbicides in mouse strains have shown an inhibition of oxidation of protoporphyrinogen as well as inhibition of the conversion of uroporphyrinogen to coproporphyrinogen. A marked increase in the total liver porphyrin content was noted. A porphyria cutanea tarda-like experimental porphyria was induced, which was accelerated with iron treatment. An accumulation of highly carboxylated porphyrins was evident only after prolonged treatment with high doses. Liver preneoplastic changes occurred in the mice (Krijt et al, 1999; Fakan et al, 1998; Krijt et al, 1994; Sinclair et al, 1994; Krijt et al, 1993). Another study demonstrated diminished total hepatic cytochrome P450 content. (Krijt et al, 1997).
    1) An accumulation of uroporphyrin and protoporphyrin in the liver was noted in mice treated with oxadiazon; uroporphyrin and heptacarboxylic porphyrin were noted in livers of mice treated with fomesafen (Krijt et al, 1991).
    2) In mice given oral doses of oxadiazon, a marked accumulation of hepatic porphyrins was noted. Liver heme synthesis was significantly compromised. Also, both the cytochrome P450 levels and activities were decreased (Krijt et al, 1995).
    3) Protox inhibitor herbicides have been shown, in cultured rat hepatocytes, to affect the heme synthetic pathway. Protoporphyrinogen oxidase, the penultimate enzyme of heme biosynthesis, was inhibited by low concentrations of a Protox inhibitor herbicide (Jacobs et al, 1992).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) PORPHYRIA DUE TO TOXIC EFFECT OF SUBSTANCE
    1) WITH POISONING/EXPOSURE
    a) It may be possible, although not yet proven in humans, that ingestion of these herbicides could result in accumulation of porphyrins and porphyrinogens in the kidney, as is the case with variegate porphyria (Krijt et al, 1997).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CHEMICAL-INDUCED PORPHYRIA
    a) Administration of these herbicides to rodent models has resulted in accumulation of porphyrins and porphyrinogens in the kidney as a result of protoporphyrinogen oxidase inhibition. Elevated excretion of urinary porphyrin and precursors, 5-aminolevulinic acid and porphobilinogen, were found (Krijt et al, 1997).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) PORPHYRIA DUE TO TOXIC EFFECT OF SUBSTANCE
    1) WITH POISONING/EXPOSURE
    a) Since human protoporphyrinogen oxidase is involved in hemoglobin synthesis, it has been speculated that exposures to Protox inhibitor herbicides may cause hematologic diseases. Human erythroblastic progenitors were exposed to one of the herbicides in the presence of erythropoietin and the hematoxicity evaluated in vitro. A cytotoxic effect was seen only at very high herbicide concentrations. Hemoglobin synthesis was inhibited by concentrations of the herbicide that have no adverse effect on cellular proliferation. The authors concluded that prolonged exposure to herbicide affects human hemoglobin synthesis in vitro, and may be responsible for unexplained porphyria variegata following chronic exposure (Rio et al, 1997).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANEMIA
    a) In a chronic (2-year) feeding study in rats, hemolytic anemia was reported to occur (Von Burg, 1992).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) PORPHYRIA CUTANEA TARDA
    1) A toxic porphyria cutanea tarda-like syndrome may theoretically result in humans acutely exposed to these herbicides in significant amounts, although this has not yet been reported. Transient symptoms may include cutaneous lesions, photosensitivity, hypo- or hyper-pigmentation of the face, and hyperpigmentation of periorbital and malar regions (Krijt et al, 1999; Krijt et al, 1997; Krijt et al, 1994). Photosensitivity reflects accumulation and excretion of coproporphyrin. It most likely occurs in direct relation to the concentration of plasma porphyrin and may not result in acute problems.
    B) SKIN IRRITATION
    1) Dermal contact may result in mild, transient skin irritation in occupationally exposed individuals (Von Burg, 1992; Anon, 1983; Hurt et al, 1983).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SKIN NECROSIS
    a) Prolonged skin contact with concentrated Nitrofen produced skin necrosis in rabbits(HSDB, 2003).

Reproductive

    3.20.1) SUMMARY
    A) Most of the Protox inhibitor herbicides have not been found to be teratogenic in animals. At the time of this review, no studies have been found regarding human exposure to these herbicides and their effect on teratogeniciy or effects during pregnancy or breast feeding.
    B) Nitrofen has been found to be teratogenic to laboratory animals. Lung hypoplasia, left-sided diaphragmatic hernia, as well as skeletal and cardiac malformations have been seen. It also has been shown to decrease viability and increase the number of stillbirths in rats and mice.
    3.20.2) TERATOGENICITY
    A) SPECIFIC AGENT
    1) NITROFEN - In several murine studies, nitrofen has been shown, in a dose-dependent gestational day-specific manner, to induce lung hypoplasia and left-sided diaphragmatic hernia, as well as skeletal and cardiovascular malformations, in fetuses when administered to pregnant rodents (Leinwand et al, 2002; Greer et al, 2000; Migliazza et al, 1999; Migliazza et al, 1999a; Kim et al, 1999; Cilley et al, 1997; Ostby et al, 1985; Costlow et al, 1983). A high incidence of chromodacryorrhea, thought related to an effect on the Harderian gland, was reported. Hydronephrosis was also noted (Francis, 1986; Ostby et al, 1985; Costlow et al, 1983; Hurt et al, 1983). Prenatal exposure to nitrofen in mice has been shown to induce a Fryns phenotype; it is speculated that nitrofen may target similar molecular mechanisms to those that cause Fryns syndrome (Acosta et al, 2001).
    a) It is speculated that nitrofen causes a teratogenic effect through alterations in thyroid hormone status. Exposure of the embryo to a nitrofen-derived thyromimetic substance is thought to be the cause of incorrect morphogenesis of the heart, lungs, kidneys, and diaphragm (Manson, 1986; Manson et al, 1984). In another study characterizing the distribution and metabolism of nitrofen in the pregnant rat, it was found that the embryo is exposed to the parent compound alone and appears to be a compartment for nitrofen accumulation (Brown & Manson, 1986).
    B) LACK OF EFFECT
    1) ANIMALS - Studies in rats and rabbits have demonstrated a lack of teratogenicity in most of these herbicides (Dayan et al, 2001). Nitrofen, the earliest and now least used herbicide of this group, is known to be teratogenic. Bifenox was not found to be teratogenic in rodent studies (Francis, 1986).
    3.20.3) EFFECTS IN PREGNANCY
    A) ANIMAL STUDIES
    1) SPECIFIC AGENT
    a) During a three generation rat and mouse studey, Nitrofen was found to decrease viability both neonataly and postnataly when given to in very high doses ((IARC, 1998)).
    b) At doses of 10, 20 or 50 mg/kg given by stomach intubation to rats, Nitrofen was found to increase the number of stillbirths and reduce pup viability postnataly at the 20 mg/kg dose. Term fetuses of the dams that were treated with the 50 mg/kg dose were found to have poorly expanded lungs and reduced fetal lung weight ((IARC, 1998)).
    c) Purified nitrofen has caused reduction in pup birthweight and a high mortality postnataly ((IARC, 1998)).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS50594-66-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    B) IARC Carcinogenicity Ratings for CAS42576-02-3 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    C) IARC Carcinogenicity Ratings for CAS32861-85-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    D) IARC Carcinogenicity Ratings for CAS56257-73-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    E) IARC Carcinogenicity Ratings for CAS1836-77-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    F) IARC Carcinogenicity Ratings for CAS87546-18-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    G) IARC Carcinogenicity Ratings for CAS77137-85-0 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    H) IARC Carcinogenicity Ratings for CAS77501-90-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    I) IARC Carcinogenicity Ratings for CAS72178-02-0 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    J) IARC Carcinogenicity Ratings for CAS77501-63-4 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    K) IARC Carcinogenicity Ratings for CAS83513-60-4 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    L) IARC Carcinogenicity Ratings for CAS1836-75-5 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Nitrofen (technical-grade)
    b) Carcinogen Rating: 2B
    1) The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
    M) IARC Carcinogenicity Ratings for CAS51274-07-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    N) IARC Carcinogenicity Ratings for CAS42874-03-3 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    O) IARC Carcinogenicity Ratings for CAS122836-35-5 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) There are no data, either case reports or epidemiological studies, available at the time of this review to assess the carcinogenic effects in humans.
    3.21.4) ANIMAL STUDIES
    A) HEPATIC CARCINOMA
    1) In chronic feeding studies, these herbicides have been shown to be either directly or indirectly associated with biochemical changes that lead to the induction of peroxisomes and subsequent liver tumors. Peroxisome proliferation occurs only in mouse and rat hepatocytes, whereas the guinea pig, marmoset and human do not respond to this mechanism. Thus, it is concluded that man is neither susceptible nor sensitive to this mechanism and these herbicides will most likely NOT cause liver tumors in humans (Fakan et al, 1998; Richert et al, 1996; Von Burg, 1992; Smith & Elcombe, 1989; Quest et al, 1989; Hurt et al, 1983; Butler et al, 1988).
    2) Technical grade Nitrofen significantly increased the incidence of hepatocellular carcinoma in two different rat studies. In another male mouse study, hemangiosarcomas at various sites occurred at a significantly higher incidence when given a higher dose ((IARC, 1998)).
    B) PANCREATIC CANCER
    1) A dose-related (above 65 mg/kg/day) incidence of pancreatic tumors, following chronic administration of nitrofen to rats, was reported in females (Hurt et al, 1983).

Genotoxicity

    A) With the exception of oxyfluorofen and sulfentrazone, Protox inhibitors have not shown genotoxic properties. Oxadiazon has not been found to be mutagenic. Nitrofen, bifenox, chlornitrofen and acifluorfen have been mutagenic in some cultures, but non-mutagenic in others.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Laboratory evaluations are not necessary in most patients unless otherwise clinically indicated.
    B) Serum concentrations are not widely available or clinically useful.
    C) In patients with suspected porphyria due to protox inhibitor herbicide toxicity, CBC, hepatic enzymes, basic metabolic panel, urinalysis, and serum porphyrin levels should be obtained.
    4.1.2) SERUM/BLOOD
    A) Laboratory evaluations are not necessary in most patients unless otherwise clinically indicated.
    B) Serum concentrations are not widely available or clinically useful.
    C) In patients with suspected porphyria due to protox inhibitor herbicide toxicity, CBC, hepatic enzymes, basic metabolic panel, and serum porphyrin levels should be obtained.
    4.1.3) URINE
    A) Obtain urinalysis in patients with suspected porphyria due to protox inhibitor herbicide toxicity.
    B) URINALYSIS
    1) Freshly voided urine may turn dark when exposed to light and air (formation of porphyrin and porphobilin) following a toxic exposure to Protox inhibitors.
    2) Measurement of porphyrin precursors in urine and feces may be recommended following a toxic exposure (Krijt et al, 1997).

Methods

    A) CHROMATOGRAPHY
    1) Determination of oxadiazon residues by headspace solid-phase microextraction and gas chromatography-mass spectrometry has been described for residues in soil samples, human urine, and ground water. Limits of detection were between 0.01 and 0.12 ng/mL (Navalon et al, 2002).
    2) A solid-phase extraction method for acidic herbicides, including benzoic acid related ones like acifluorfen, is described for their removal from aqueous solutions. This is followed by gas chromatographic analysis and high-performance liquid chromatographic analysis (Wells & Yu, 2000).
    3) A liquid chromatograph method with UV detection for the determination of acifluorfen in soil and water has been developed. This method has not been applied to human biological fluids. (Gennari et al, 1990)
    4) A high-performance liquid chromatography method was developed for the quantification of nitrofen and its metabolites in rat tissues. A lower limit of detection was calculated to be 0.2 mcg/mL plasma (Brown & Manson, 1986).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with persistent symptoms, concern for ingestion of an herbicide containing an anionic surfactant, or concern for porphyria due to protox inhibitor herbicide toxicity should be admitted to an inpatient facility.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients with inadvertent exposures may be managed safely at home with observation.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact your local poison center or medical toxicologist for any patient with suspected porphyria due to protox inhibitor herbicide toxicity, or for any patient with severe symptoms suspected due to herbicide toxicity.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate exposures or more than mild symptoms should be referred to a healthcare facility.

Monitoring

    A) Laboratory evaluations are not necessary in most patients unless otherwise clinically indicated.
    B) Serum concentrations are not widely available or clinically useful.
    C) In patients with suspected porphyria due to protox inhibitor herbicide toxicity, CBC, hepatic enzymes, basic metabolic panel, urinalysis, and serum porphyrin levels should be obtained.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Exposure to protox inhibitor herbicides is generally NOT expected to result in significant toxicity. Remove contaminated clothing and wash skin with soap and water. Irrigate exposed eyes with water or saline. Gastrointestinal decontamination is not recommended.
    6.5.2) PREVENTION OF ABSORPTION
    A) There is no indication for gastric decontamination.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Laboratory evaluations are not necessary in most patients unless otherwise clinically indicated.
    2) Serum concentrations are not widely available or clinically useful.
    3) In patients with suspected porphyria due to protox inhibitor herbicide toxicity, CBC, hepatic enzymes, basic metabolic panel, urinalysis, and serum porphyrin levels should be obtained.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) IRRITATION SYMPTOM
    1) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown if hemodialysis would remove protox inhibitor herbicides.

Range Of Toxicity

Summary

    A) TOXICITY: The toxic dose in humans has not been established. There are no significant reports of human toxicity. Only a single case report of fatality due to ingestion of an herbicide containing chlornitrofen (as well as butachlor, xylene, and toluene) has been reported; the death was thought due to the butachlor component rather than the chlornitrofen.

Minimum Lethal Exposure

    A) The minimum lethal human dose for this agent has not been determined.

Maximum Tolerated Exposure

    A) ANIMAL DATA
    1) Little bioaccumulation risk has been reported in animals, even with exaggerated dietary doses (greater than 100 times the recommended field rates) (Dayan et al, 2001).
    B) SPECIFIC SUBSTANCE
    1) ACIFLUORFEN: When human lymphoblasts from normal subjects and those with variegate porphyria, were exposed to acifluorfen, competitive inhibition of protoporphyrinogen oxidase (PPO) was shown for both subject types. The interaction of acifluorfen and PPO from normal human lymphoblasts was similar to that of human liver and placenta (Corrigall et al, 1994).

Workplace Standards

    A) ACGIH TLV Values for CAS50594-66-6 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS42576-02-3 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    C) ACGIH TLV Values for CAS32861-85-1 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    D) ACGIH TLV Values for CAS56257-73-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    E) ACGIH TLV Values for CAS1836-77-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    F) ACGIH TLV Values for CAS87546-18-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    G) ACGIH TLV Values for CAS77137-85-0 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    H) ACGIH TLV Values for CAS77501-90-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    I) ACGIH TLV Values for CAS72178-02-0 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    J) ACGIH TLV Values for CAS77501-63-4 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    K) ACGIH TLV Values for CAS83513-60-4 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    L) ACGIH TLV Values for CAS1836-75-5 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    M) ACGIH TLV Values for CAS51274-07-8 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    N) ACGIH TLV Values for CAS42874-03-3 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    O) ACGIH TLV Values for CAS122836-35-5 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    P) NIOSH REL and IDLH Values for CAS50594-66-6 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    Q) NIOSH REL and IDLH Values for CAS42576-02-3 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    R) NIOSH REL and IDLH Values for CAS32861-85-1 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    S) NIOSH REL and IDLH Values for CAS56257-73-9 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    T) NIOSH REL and IDLH Values for CAS1836-77-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    U) NIOSH REL and IDLH Values for CAS87546-18-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    V) NIOSH REL and IDLH Values for CAS77137-85-0 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    W) NIOSH REL and IDLH Values for CAS77501-90-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    X) NIOSH REL and IDLH Values for CAS72178-02-0 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    Y) NIOSH REL and IDLH Values for CAS77501-63-4 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    Z) NIOSH REL and IDLH Values for CAS83513-60-4 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    AA) NIOSH REL and IDLH Values for CAS1836-75-5 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    AB) NIOSH REL and IDLH Values for CAS51274-07-8 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    AC) NIOSH REL and IDLH Values for CAS42874-03-3 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    AD) NIOSH REL and IDLH Values for CAS122836-35-5 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    AE) Carcinogenicity Ratings for CAS50594-66-6 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    AF) Carcinogenicity Ratings for CAS42576-02-3 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    AG) Carcinogenicity Ratings for CAS32861-85-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    AH) Carcinogenicity Ratings for CAS56257-73-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    AI) Carcinogenicity Ratings for CAS1836-77-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    AJ) Carcinogenicity Ratings for CAS87546-18-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    AK) Carcinogenicity Ratings for CAS77137-85-0 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    AL) Carcinogenicity Ratings for CAS77501-90-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    AM) Carcinogenicity Ratings for CAS72178-02-0 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): C ; Listed as: Fomesafen
    a) C : Possible human carcinogen.
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    AN) Carcinogenicity Ratings for CAS77501-63-4 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: Lactofen
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    AO) Carcinogenicity Ratings for CAS83513-60-4 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    AP) Carcinogenicity Ratings for CAS1836-75-5 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 2B ; Listed as: Nitrofen (technical-grade)
    a) 2B : The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): R ; Listed as: Nitrofen
    a) R : RAHC = Reasonably anticipated to be a human carcinogen

    AQ) Carcinogenicity Ratings for CAS51274-07-8 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    AR) Carcinogenicity Ratings for CAS42874-03-3 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: Oxyfluorfen
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    AS) Carcinogenicity Ratings for CAS122836-35-5 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    AT) OSHA PEL Values for CAS50594-66-6 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    AU) OSHA PEL Values for CAS42576-02-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    AV) OSHA PEL Values for CAS32861-85-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    AW) OSHA PEL Values for CAS56257-73-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    AX) OSHA PEL Values for CAS1836-77-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    AY) OSHA PEL Values for CAS87546-18-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    AZ) OSHA PEL Values for CAS77137-85-0 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    BA) OSHA PEL Values for CAS77501-90-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    BB) OSHA PEL Values for CAS72178-02-0 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    BC) OSHA PEL Values for CAS77501-63-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    BD) OSHA PEL Values for CAS83513-60-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    BE) OSHA PEL Values for CAS1836-75-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    BF) OSHA PEL Values for CAS51274-07-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    BG) OSHA PEL Values for CAS42874-03-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    BH) OSHA PEL Values for CAS122836-35-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)RAT:
    1) 10800 mg/kg (RTECS, 2003)
    B) LD50- (SKIN)RAT:
    1) greater than 10 g/kg (RTECS, 2003)
    C) LD50- (ORAL)MOUSE:
    1) greater than 10 g/kg (RTECS, 2003)
    D) LD50- (SKIN)MOUSE:
    1) greater than 10 g/kg (RTECS, 2003)
    E) ACIFLUORFEN
    1) LD50- (ORAL)MOUSE:
    a) 1370 mg/kg (RTECS, 2003)
    2) LD50- (ORAL)RAT:
    a) 1370 mg/kg (RTECS, 2003)
    F) BIFENOX
    1) LD50- (ORAL)MOUSE:
    a) 4556 mg/kg (RTECS, 2003)
    2) LD50- (ORAL)RAT:
    a) 6400 mg/kg (RTECS, 2003)
    G) CHLOMETHOXYFEN
    1) LD50- (ORAL)MOUSE:
    a) 33 g/kg (RTECS, 2003)
    2) LD50- (SKIN)MOUSE:
    a) greater than 5 g/kg (RTECS, 2003)
    3) LD50- (ORAL)RAT:
    a) 18 g/kg (RTECS, 2003)
    4) LD50- (SKIN)RAT:
    a) greater than 5 mg/kg (RTECS, 2003)
    H) CHLONITROFEN
    I) FLUOROGLYCOFEN
    1) LD50- (ORAL)RAT:
    a) 1480 mg/kg (RTECS, 2003)
    J) FOMESAFEN
    1) LD50- (ORAL)RAT:
    a) 1250 mg/kg (RTECS, 2003)
    K) LACTOFEN
    1) LD50- (ORAL)RAT:
    a) greater than 5 g/kg (RTECS, 2003)
    2) LD50- (SKIN)RAT:
    a) 2 g/kg (RTECS, 2003)
    L) NITROFEN
    1) LD50- (ORAL)MOUSE:
    a) 450 mg/kg (RTECS, 2003)
    2) LD50- (ORAL)RAT:
    a) 740 mg/kg (RTECS, 2003)
    3) LD50- (SKIN)RAT:
    a) 5 g/kg (RTECS, 2003)
    M) OXADIAZON
    1) LD50- (ORAL)MOUSE:
    a) 12 g/kg (RTECS, 2003)
    2) LD50- (ORAL)RAT:
    a) 3500 mg/kg (RTECS, 2003)
    3) LD50- (SKIN)RAT:
    a) 5200 mg/kg (RTECS, 2003)
    N) OXYFLUORFEN
    1) LD50- (ORAL)RAT:
    a) 5 g/kg (RTECS, 2003)
    2) LD50- (SKIN)RAT:
    a) greater than 10 g/kg (RTECS, 2003)
    O) SULFENTRAZONE
    1) LD50- (ORAL)MOUSE:
    a) greater than 700 mg/kg (RTECS, 2003)
    2) LD50- (ORAL)RAT:
    a) greater than 2600 mg/kg (RTECS, 2003)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) PLANTS - Initially, foliar absorption and translocation of the herbicide occurs. Then inhibition of protoporphyrinogen oxidase (Protox), which is located in the outer membrane of chloroplasts, causes an unregulated accumulation of protoporphyrinogen (Protogen). Protogen is oxidized, either enzymatically or chemically, to protoporphyrin IX (Proto), a chlorophyll precursor. Proto, a photodynamic pigment, is energized by light and causes formation of reactive singlet oxygen species, which leads to oxidative membrane degradation (Dayan et al, 2001; Arnould & Camadro, 1998; Watanabe et al, 1998; Matringe et al, 1992; Matringe et al, 1989).

Toxicologic Mechanism

    A) HUMAN/MAMMALS - Protox inhibitor herbicides appear to inhibit mammalian mitochondrial Protox. When ingested in animals, an increase in porphyrin levels occurs. However, due to effective metabolism and/or excretion, porphyrin levels return to normal within a few days. Variegate porphyria is caused by a deficiency of Protox, and variegate porphyria-like symptoms can be generated in mice with high doses. Little bioaccumulation risk occurs in animals, even following exaggerated dietary doses (>100 times recommended field rates). In healthy humans, these herbicides are not considered to pose any significant toxicological risk (Dayan et al, 2001).
    1) In mammalian hepatocyte cultures, exposure to these herbicides has been shown to result in an accumulation of protoporphyrin IX. These herbicides induce porphyrin accumulation in hepatocytes in a concentration-dependent manner (Jinno et al, 1999). Birchfield & Casida (1996) demonstrated rapid, specific, saturable, and reversible binding of a Protox inhibitor radioligand to mouse liver mitochondria.
    2) In contrast, isolated hepatocytes from mice and rats, but not from man, undergo peroxisome proliferation when exposed to these herbicides. Peroxisome-related tumors occur in these rodent hepatocytes, but significantly, not in humans since humans are not susceptible to the peroxisome mechanism (Smith & Elcombe, 1989).

Physicochemical

Molecular Weight

    1) Acifluorfen: 361.67
    2) Bifenox: 342.14
    3) Chlomethoxyfen: 314.80
    4) Chlornitrofen: 318.54
    5) Fluoroglycofen: 447.77
    6) Fomesafen: 438.78
    7) Lactofen: 461.80
    8) Nitrofen: 284.10
    9) Oxadiazon: 345.25
    10) Oxyfluorfen: 361.72
    11) Sulfentrazone: 387.21

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