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PFAS -> PFAS identified in REACH Regulation EC No. 1272/2008

PFAS -> Suspected persistent, mobile, toxic (PMT) PFAS or PFAS-like compounds

Pesticide -> EPA IRIS

Agrochemicals -> Pesticide active substances

Active substance -> EU Pesticides database: Not approved

Pesticides -> Herbicides, Protox-Inhibiting

Pesticide (Lactofen) -> USDA PDB

Pesticide

log Kow = 4.81

4.81

Solubility in isopropanol = 20%; soluble in acetone and xylene

In water, 0.1 mg/L at 25 °C

0.00000007 [mmHg]

7X10-8 mm Hg at 25 °C

Lactofen is a dark brown to tan solid. Insoluble in water. Used as an herbicide.

Tan to dark brown solid; [HSDB] Off-white solid; [MSDSonline]

Warning

H302 (80.9%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P273, P280, P301+P317, P302+P352, P317, P321, P330, P362+P364, P391, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 209 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Hazard Traits - Carcinogenicity

Lactofen is listed in the dataset of EPA Human Health Benchmarks for Pesticides under the Safe Drinking Water Act (40 eCFR 141)

2007/442

Status: Cease Manufacture Update: 13-05-2013 https://echa.europa.eu/registration-dossier/-/registered-dossier/6560

Benzoic acid, 5-2-chloro-4-(trifluoromethyl)phenoxy-2-nitro-, 2-ethoxy-1-methyl-2-oxoethyl ester: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.

The protox inhibitor herbicides (Fomesafen, Oxadiazon, Lactofen, Sulfentrazone, Carfentrazone-ethyl, Oxyfluorofen and Bifenox) can disrupt porphyrin metabolism; It has been speculated that a transient form of porphyria variegate may occur following a massive exposure or long-term exposure to lower doses. A mild skin and moderate eye irritant; [HSDB] Moderate eye irritant; Unlikely to be carcinogenic at low doses; [Reference #1] See Fluthiacet-methyl.

USEPA/Office of Pesticide Programs; Report of the Food Quality Protection Act (FQPA) Tolerance Reassessment Progress and Risk Management Decision (TRED) for Lactofen EPA 738-R-04-002 (September 2003). EPA issues a TRED for a pesticide that requires tolerance reassessment decisions, but does not require a reregistration eligibility decision at present because: the pesticide was initially registered after November 1, 1984, and by law is not included within the scope of the reregistration program; EPA completed a RED for the pesticide before FQPA was enacted on August 3, 1996; or the pesticide is not registered for use in the U.S. but tolerances are established that allow crops treated with the pesticide to be imported from other countries.[Available from, as of February 28, 2007: http://www.epa.gov/pesticides/reregistration/status.htm]

EPA/Prevention, Pesticides and Toxic Substances; Lactofen TRED Facts. 4 p. EPA 738-F-04-002 (September 2003). Available at http://www.epa.gov/oppsrrd1/REDs/factsheets/lactofen_tred_fs.pdf as of February 22, 2007

Tolerances are established for residues of the herbicide lactofen, 1-(carboethoxy)ethyl 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2- nitrobenzoate, in or on the following raw agricultural commodities: [Table#6569]

The Agency has evaluated the dietary risk associated with all currently registered uses of lactofen and has determined that there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure to lactofen when considering dietary exposure and all other non-occupational sources of pesticide exposure for which there is reliable information. Therefore, no mitigation measures are needed, and the two (2) tolerances established for residues of lactofen in/on raw agricultural commodities are now considered reassessed as safe under section 408(q) of the FFDCA.

New Active Ingredients ... includes pesticide active ingredients initially registered after November 1, 1984, that currently have active product registrations. By law, these newer pesticides are not subject to the reregistration program. They must, however, meet the new safety standard of the FQPA, and will be reviewed on a 15-year cycle under the registration review program. ... Active Ingredient Number: 128888; Type of Pesticide: conventional - plant growth regulator; Use Site: food use; Year: 1988.

Do not contaminate water, food or feed by disposal or cleaning of equipment. Open dumping is prohibited. ... If these wastes cannot be disposed of by use according to label instructions, contact your State Pesticide or ENvironmental COntrol Agency, or the Hazardous Waste representative at the nearest EPA Regional Office for guidance.

Do not discharge effluent containing this product into lakes, streams, ponds, estuaries, oceans or other waters unless in accordance with the requirements of a National Pollutant Discharge Elinination System (NPDES) permit and the permitting authority has been notified in writing prior to discharge. Do not discharge effluent containigng this product to sewer systems without previously notifying the local sewage treatment plant authority. For guidance contact your State Water Board or Regional Office of the EPA.

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place.

Avoid contact with eyes, skin or clothing. Avoid breathing vapor or spray mist. Wash thoroughly with soap and water after handling. Wear long sleeved shirt and long pants, socks, shoes, and chemical resistant (such as nitrile or butyl) gloves when handling. Remove contaminated clothing and wash before reuse. /Lactofen technical/

First Aid: If in eyes: hold eye open and rinse slowly and gently with water for 15-20 minutes. Remove contact lenses, if present, after the first 5 minutes, then continue rinsing eye. Call a poison control center or doctor for treatment advice. If on skin or clothing: Take off contaminated clothing. Rinse skin immediately with plenty of water for 15-20 minutes. Call a poison control center or doctor for treatment advice. If swallowed: Call poison control center or doctor immediately for treatment advice. Have person sip a glass of water if able to swallow. Do not induce vomiting unless told to do so by the poison control center or doctor. Do not give anything by mouth to an unconscious person. If inhaled: Move person to fresh air. If person is not breathing, call 911 or an ambulance, then give artificial respiration ... Call a poison control center or doctor for treatment advice. /Lactofen technical/

LC50; Species: Colinus virginianus (Northern bobwhite) diet >5620 ppm/8 days[USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) on 5-

LC50; Species: Anas platyrhynchos (Mallard duck) diet >5620 ppm/8 days[USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) on 5-

LD50; Species: Colinus virginianus (Northern bobwhite, age 5 months) oral >2510 mg/kg[USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) on 5-

LD50; Species: Apis mellifera (Honey bee) topical >160 ug/bee[USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) on 5-

For more Ecotoxicity Values (Complete) data for LACTOFEN (11 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), a Koc value of 10,000(2), indicates that lactofen is expected to be immobile in soil(SRC). Volatilization of lactofen from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.2X10-7 atm-cu m/mole(SRC), calculated from its vapor pressure of 7X10-8 mm Hg(3) and water solubility of 0.1 mg/L(2). Lactofen is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure. The field half-life of lactofen in soil was reported as 3 days(5). Others have reported the half-life of lactofen in soil to range from 1-7 days(6).

AQUATIC FATE: Based on a classification scheme(1), a Koc value of 10,000(2), indicates that lactofen is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 4.2X10-7 atm-cu m/mole(SRC), calculated from its vapor pressure of 7X10-8 mm Hg(4) and water solubility of 0.1 mg/L(2). According to a classification scheme(5), a whole body BCF value of 380 measured in fish(6), suggest bioconcentration in aquatic organism is high(SRC). A base-catalyzed second-order hydrolysis rate constant of 0.21 L/mole-sec(SRC) was estimated using a structure estimation method(7); this corresponds to half-lives of 1 year and 37 days at pH values of 7 and 8, respectively(7). No biodegradation data were located for lactofen in water; however, this compound readily biodegrades in soil with reported half-lives of 1-7 days(8), which suggests that biodegradation in water will also occur(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), lactofen, which has a vapor pressure of7X10-8 mm Hg at 20 °C(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase lactofen is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 5 days(SRC), calculated from its rate constant of 3.2X10-12 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Lactofen absorbs light in the environmental UV spectrum and may undergo photolysis; the photodegradation half-life of lactofen was reported as 24 days(4).

Lactofen

Hepatic

2 x 10 ^-3 mg/kg-day

AEROBIC: The field half-life of lactofen in soil was reported as 3 days(1) and the 50% dissipation time (DT50) has been reported to range from 3-7 days(2). Lactofen is of low persistence in most soil types with reported half-lives of 1-7 days and the predominant degradation pathway being biodegradation(3). The biodegradation half-life of lactofen applied to a silt loam at an application rate of 10 mg/kg and maintained under aerobic conditions was 3 days(4). Acifluorfen (5-(2-chloro-4-trifluoromethyl)phenoxy)-2-nitrobenzoic acid) and 1-(carboxy)ethyl 5-(2-chloro-4-(trifluoromethyl)phenoxy)-2-nitrobenzoate were reported as degradation products(4).

ANAEROBIC: The biodegradation half-life of lactofen applied to a clay loam at an application rate of 5 mg/kg and maintained under anaerobic conditions was 30 days(4).

The BCF value of lactofen was 52, 380, and 830 in the edible, whole body, and viscera of bluegills exposed to 0.01 mg/L of lactofen in a flow through aquarium over the course of a 14 day exposure period(1). According to a classification scheme(2), these BCF data suggest bioconcentration in aquatic organisms is high(SRC).

The Henry's Law constant for lactofen is estimated as 4.2X10-7 atm-cu m/mole(SRC) from its vapor pressure of 7X10-8 mm Hg at 20 °C(1) and water solubility of 0.1 mg/L(2). This Henry's Law constant indicates that lactofen is expected to be essentially nonvolatile from water surfaces(3). Lactofen is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(1).

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ ... Crl:CD-1-mice were administered diets containing 0 or 250 parts per million (ppm) pure lactofen, 2, 10, 50, or 250 ppm technical grade lactofen, or 500 ppm nafenopen for 7 weeks. ... The 250 ppm doses of both pure and technical lactofen significantly increased relative liver weights and hepatic catalase and acyl-CoA-oxidase activities. Similar effects were seen with nafenopen. Lower doses of technical grade lactofen exerted very little or no effect. Liver sections of mice treated with 250 ppm or higher technical grade lactofen, 250 ppm pure lactofen, and nafenopin showed nuclear enlargement, eosinophilia, hepatocyte hypertrophy, and peroxisomal staining.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In a 90-day subchronic toxicity study, mice were fed diets containing 0, 40/2000, 200, 1000, 5000, or 10000 ppm lactofen (calculated doses: 0, 5.7, 29/286, 143, 714 or 1429 mg/kg/day). Further as a result of 100% mortality in 5000 and 10000 ppm males and females, the 40 ppm dose was increased to 2000 ppm at week 5. With the exception of one female, all of the 2000 ppm animals died between 5 and 10 weeks after the increase in the dose. Dose-related increases in serum cholesterol and total protein levels, as well as liver enzymes (ALP, ALT and AST) were observed in 200 and 1000 ppm males and females. Comparable increases in absolute and relative liver weights were seen at 200 ppm (males, 43 - 48%; females, 45 - 53%) and 1000 ppm (males, 198 - 221%; females, 189 - 190%). Gross examination revealed enlarged livers in 200, 1000 and 2000 ppm mice and enlarged spleens in 1000 and 2000 ppm mice. At 2000 and/or 1000 ppm, microscopic examination of the liver showed hepatocytic vacuolization, necrosis of individual hepatocytes, bile retention, coagulative necrosis, hyperplasia of biliary epithelium and increased extramedullary hematopoiesis; the kidney showed nephrosis and cortical fibrosis/scarring.[EPA/OPPTS Health Effects Division; LACTOFEN: Report of the Mechanism of Toxicity Assessment Review Committee. EPA-HQ-OPP-2003-0294-0007 14 p. (March 2001) Available from a query of http://www.regulations.gov/fdmspublic/component/main for EPA documents on lactofen as of March 1, 2007]

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In a 4-week range-finding study, rats were fed diets at 0, 200, 1000, 5000 or 10000 ppm lactofen (76% a.i.). Animals in the high-dose group had 100% mortality by day 7. Increased liver and kidney weights were observed at doses of 1000 ppm and higher

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In a 90-day subchronic toxicity study, rats were fed diets containing 0, 40, 200 or 1000 ppm lactofen (males: 0, 2.9, 14, 74 mg/kg/day; females: 0, 3.5, 17, or 85 mg/kg/day). At the high-dose level, increased relative (to body weight) liver weights in males (3.4%, control 2.8%) and females (3.1%, control 2.7%) and absolute liver weights in males (18.4 g, control 15.0 g) were observed. Gross findings were observed only in high-dose animals and included dark livers in high-dose males (15/19) and females 4/21); darkened renal cortex was also observed in high-dose males (15/19) and females (3/21). Histopathological evaluation of high-dose animals revealed brown pigmentation in hepatocytes and/or Kupffer cells (males, 17/19; females, 7/21; none in controls), and acidophilic hepatocellular degeneration in males (10/19, none in control) and females (1/21, none in controls) and hyperplasia of bile ducts in males (6/19; controls, 1/20). Other microscopic lesions included brown pigment in tubular epithelium in the kidneys of high-dose animals (males, 12/19; females, 3/21; none in controls).

For more Non-Human Toxicity Excerpts (Complete) data for LACTOFEN (12 total), please visit the HSDB record page.

Tolerances are established for residues of the herbicide lactofen, 1-(carboethoxy)ethyl 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2- nitrobenzoate, in or on the following raw agricultural commodities: [Table#6569]

The Agency has evaluated the dietary risk associated with all currently registered uses of lactofen and has determined that there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure to lactofen when considering dietary exposure and all other non-occupational sources of pesticide exposure for which there is reliable information. Therefore, no mitigation measures are needed, and the two (2) tolerances established for residues of lactofen in/on raw agricultural commodities are now considered reassessed as safe under section 408(q) of the FFDCA.

New Active Ingredients ... includes pesticide active ingredients initially registered after November 1, 1984, that currently have active product registrations. By law, these newer pesticides are not subject to the reregistration program. They must, however, meet the new safety standard of the FQPA, and will be reviewed on a 15-year cycle under the registration review program. ... Active Ingredient Number: 128888; Type of Pesticide: conventional - plant growth regulator; Use Site: food use; Year: 1988.

Lactofen belongs to the diphenylether class of herbicides, which targets protoporphyrinogen oxidase, which in turn causes singlet oxygen generation. In tolerant plants like soybean (Glycine max), the chemical nonetheless causes necrotic patches called "bronzing" in contact areas. Here it is shown that such bronzing is accompanied by cell death, which was quantified from digital microscopic images using Assess Software. Cellular autofluorescence accompanied cell death, and a homolog of the cell death marker gene, Hsr203j, was induced by lactofen in treated soybean tissues. Thus, this form of chemically induced cell death shares some hallmarks of certain types of programmed cell death. In addition to the cell death phenotype, lactofen caused enhanced expressions of chalcone synthase and chalcone reductase genes, mainly in the exposed and immediately adjacent (proximal) cells. Furthermore, isoflavone synthase genes, which are wound inducible in soybean, were up-regulated by lactofen in both proximal and distal cell zones in minimally wounded cotyledons and further enhanced in wounded tissues. Moreover, if the wall glucan elicitor from Phytophthora sojae was present during lactofen treatment, the induction of isoflavone synthase was even more rapid. These results are consistent with the fact that lactofen triggers massive isoflavone accumulations and activates the capacity for glyceollin elicitation competency. In addition, lactofen induces late expression of a selective set of pathogenesis-related (PR) protein genes, including PR-1a, PR-5, and PR-10, mainly in treated proximal tissues. These various results are discussed in the context of singlet oxygen-induced responses and lactofen's potential as a disease resistance-inducing agent.

A technical grade of lactofen (1'[carboethoxy]ethyl 5-[2-chloro-4-[trifluoro-methyl] phenoxy]-2-nitrobenzoate) has been shown to induce liver tumors in mice. To determine a possible mechanism of action, the effect of exposure for 7 weeks to dietary concentrations of 2, 10, 50, and 250 ppm technical grade lactofen and 250 ppm of pure lactofen was studied for various liver parameters in groups of male and female CD-1 mice. Liver-weight to body-weight ratio, liver catalase, liver acyl-CoA oxidase, liver cell cytoplasmic eosinophilia, nuclear and cellular size, and peroxisomal staining were increased by the tumorigenic dose of lactofen, i.e., 250 ppm, in a fashion similar to the comparison chemical nafenopin (500 ppm), which is a peroxisome proliferator. Lower doses of lactofen that were reported as nontumorigenic had little or no effect on these parameters.

Based on the weight-of-the-evidence of the toxicity database, there are sufficient data to classify lactofen as a non-genotoxic hepatocarcinogen in rodents with peroxisome proliferation being a plausible mode of action. Studies with transgenic mouse confirmed that essentially all of the of the effects of PPs in rodent liver are mediated by PPAR .

Used as pre- and post-emergence herbicide for control of broad-leaved weeds in snap beans, soybeans, cotton, and forestry; [HSDB] Registered for use on snap beans, soybeans, cotton, kenaf, and forestry; [Reference #1]

Farming (Pesticides) [Category: Industry]

For Lactofen (USEPA/OPP Pesticide Code: 128888) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./

Lactofen is registered for use as an herbicide on snap beans, soybeans, cotton, kenaf, and forestry (non-food use) for both pre- and post-emergent control of broad leaf weeds. Lactofen is not registered for residential use. Although not currently registered, the proposed new food uses of lactofen on peanuts and cotton were included in the risk assessment to support the establishment of new tolerances for these two crops. Lactofen is sold in the United States under the trade names Cobra and Stellar. Lactofen is formulated as technical, manufacturing use product, and emulsifiable concentrate.

Lactofen is not registered for use in residential settings.

Herbicide

Approximately 235,000 pounds of lactofen ai are applied annually to nearly 2.2 million acres. Lactofen's largest markets in terms of total pounds of ai applied annually are soybeans (85%) and cotton (12%). The remaining use is primarily on fresh beans.

(1992) 355,415 pounds

USEPA/OPP Pesticide Code 128888; Trade Names: PPG-844, Cobra herbicide.

COBRA HERBICIDE Active Ingredient 24.0% Lactofen

LACTOFEN MANUFACTURING CONCENTRATE Active Ingredient 60.0% Lactofen

STELLAR HERBICIDE Active Ingredient 7.6% Flumiclorac pentyl ester, 26.6% Lactofen

For more Formulations/Preparations (Complete) data for LACTOFEN (7 total), please visit the HSDB record page.

Lactofen may be applied by aerial and ground application; band treatment, broadcast, directed spray, low volume spray, soil broadcast treatment, and soil incorporation. It is generally applied at a rate of 1 lb active ingredient (ai) per acre (A) or less per application. No more than 1 lb ai/A lactofen may be applied to a site in a single year.

This product is for use in further preparation of herbicide products; for formulation use only. /Lactofen technical/

V-10086 Herbicide is a selective, broad specturm herbicide for preemergence and postemergence control of susceptible broadleaf weeds. V019986 is formulated as an emulsifiable concentrate containing 2 lbs of ai per gallon. ... V-10086 works primarily through contact action.