Based on mechanistic studies with transgenic mice, lactofen has been classified as a non-genotoxic hepatocarcinogen in rodents with peroxisome proliferation being a plausible mode of action. Lactofen is currently classified as likely to be carcinogenic to humans at high enough doses to cause the biochemical and histopathological changes in the liver of rodents, but unlikely to be carcinogenic to humans below those doses causing these changes.
Ref: Sept 24, 2004, US EPA. Final Rule for Pesticide Tolerances.

Lactofen is a member of the diphenyl ether group of herbicides, which includes acifluorfen (lactofen's major metabolite), nitrofen, oxyfluorfen, and fomefasen. In addition, lactofen degrades to acifluorfen in the environment. The Agency has evidence that these compounds induce similar toxic effects but has not yet determined whether these compounds exhibit a common mechanism of toxicity. The Agency [US EPA] defers the cumulative risk assessment of lactofen and the other diphenyl ethers to a later date.
Ref: Sept 24, 2004, US EPA. Final Rule for Pesticide Tolerances.

June 20, 2007

EPA-HQ-OPP-2006-0178

IR-4. Pesticide Tolerance. FINAL RULE.

DOCUMENTS MADE AVAILABLE WITH THIS FINAL RULE:

• Lactofen: Company Notice of Filing. Docket ID: EPA-HQ-OPP-2006-0178-0002

• Lactofen Acute, Chronic, and Cancer Aggregate Dietary and Drinking Water Exposure and Risk Assessments for the Section 3 Registration Action. Docket ID: EPA-HQ-OPP-2006-0178-0004

• Drinking water and aquatic exposure water assessments for IR4 Tolerance petition for the new use (R17) of lactofen on the fruiting vegetable group and okra. Docket ID: EPA-HQ-OPP-2006-0178-0005

• Lactofen. Addition of New Uses: Fruiting Vegetables (Crop Group 8) and Okra. PRIA R17. Summary of Analytical Chemistry and Residue Data. Docket ID: EPA-HQ-OPP-2006-0178-0006

• Data Evaluation Record. Docket ID: EPA-HQ-OPP-2006-0178-0007

• Lactofen: Revised Human Health Risk Assessment for Proposed Uses on Fruiting Vegetables and Okra. Docket ID: EPA-HQ-OPP-2006-0178-0008

• Cancer. Lactofen has been classified as ``not likely'' to be carcinogenic in humans because of available data on lactofen support activation of the peroxisome proliferator activated receptor alpha (PPARa) as the mode of action which induced liver tumors in rodents. While the proposed mode of action for liver tumors in rodent is qualitatively possible in humans, it is quantitatively implausible and unlikely to take place in humans based on quantitative species toxicodynamic differences in PPARa activation. The quantification of risk is not required.

• Exposure assessment for acifluorfen. Lactofen degrades in the environment to acifluorfen. Sodium acifluorfen is a registered agricultural pesticide. Accordingly, an aggregate assessment for acifluorfen exposure resulting from both use of lactofen and sodium acifluorfen was also conducted.

• EPA determined that an additional safety factor was needed to address the lack of a NOAEL in the rabbit developmental study. Although sufficient reliable information has been submitted on developmental effects of lactofen in rabbits, no NOAEL was identified in one of the two rabbit developmental studies submitted. The endpoints of concern identified in available studies are: Decreased live young/ litter, increased embryonic death/litter, and increased incidence of post-implantation loss. These effects were noted at all dose levels (5, 15, 50 mg/kg/day) thus a NOAEL was not established. Consequently, a LOAEL to NOAEL factor is appropriate and the risk assessment applies a 3X uncertainty factor. A FQPA uncertainty factor of infants and children and will be used for the LOAEL to NOAEL extrapolation. The 3X factor is considered to be protective because the incidence of the effects at the lowest dose tested was only marginally higher than the historical controls.
For sodium acifluorfen, the available toxicology database provides sufficient information for selecting various toxicity endpoints and doses for assessing the risks. The Agency evaluated the hazard and exposure data for sodium acifluorfen and recommended retaining the safety factor at 10X due to the data gap for the developmental neurotoxicity study in rats. In accordance with the current EPA policy, the 10x factor will be applied to all exposure durations.

• The drinking water assessment of lactofen is complicated by the fact that lactofen has a major degradate in common with another registered herbicide, sodium acifluorfen. Lactofen and sodium acifluorfen also have common use sites. The Agency considered the contribution of acifluorfen as an environmental degradate of lactofen and from sodium acifluorfen in the aggregate assessment. The drinking water residues used in the dietary risk assessment were incorporated directly into this dietary exposure from drinking water assessment. Therefore, EPA estimated drinking water concentrations for both lactofen and acifluorfen from lactofen applications.

Notice of Receipt of Requests to Voluntarily Cancel Certain Pesticide Registrations.

Pesticide Registration Review; New Dockets Opened for Review and Comment.
EPA is opening the public comment period for lactofen's registration review. Registration review is EPA's periodic review of pesticide registrations to ensure that each pesticide continues to satisfy the statutory standard for registration, that is, the pesticide can perform its intended function without unreasonable adverse effects on human health or the environment.

IR-4. Pesticide petition; New Tolerance PP 5E6930.
in or on various food commodities
-- vegetable, fruiting, group at 0.01 pp

This group (group 8) includes 17 commodities.
chili, postharvest • eggplant • groundcherry • pepino • pepper • pepper, bell • pepper, nonbell • pepper, nonbell, sweet • tomatillo • tomato • tomato, concentrated products • tomato, dried pomace • tomato, paste • tomato, puree • tomato, wet pomace • vegetable, fruiting • vegetable, fruiting, group

-- okra at 0.01 ppm.

Valent. Pesticide Tolerance. FINAL RULE. The proposed and established tolerances are corrected to conform to the Food and Feed Commodity Vocabulary Database and to lower the established tolerances for snap
bean and soybean to 0.01 ppm as required by the Lactofen Tolerance
Reassessment. Section 180.432 is revised to read as follows:
Sec. 180.432 Lactofen; tolerances for residues.
(a) 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:

•• The toxicology database for lactofen is complete for FQPA purposes except for a developmental toxicity study in rabbits. Based on the quality of the exposure data, EPA determined that the 10X SF to protect infants and children should be reduced to 3X
•• The available rabbit developmental toxicity study was considered unacceptable because dosing was not done at a high enough level to observe significant toxicity.

•• Endpoints for other risk assessments (chronic and cancer) utilize NOAELs significantly lower than 20mg/kg/day; therefore the developmental rabbit study will not affect these assessments. Based on mechanistic studies with transgenic mice, lactofen has been classified as a non-genotoxic hepatocarcinogen in rodents with peroxisome proliferation being a plausible mode of action. Lactofen is currently classified as likely to be carcinogenic to humans at high enough doses to cause the biochemical and histopathological changes in the liver of rodents, but unlikely to be carcinogenic to humans below those doses causing these changes.

Report of the Food Quality Protection Act (FQPA) Tolerance Reassessment and Risk Management Decision (TRED) for Lactofen; Notice of Availability.
• This document announces availability of and starts a 30-day public comment period for the FQPA TRED for Lactofen.
• Tolerances for lactofen in or on raw agricultural commodities for plants are currently established for the combined residues of lactofen and its associated metabolites containing the diphenyl ether linkage, but will be revised to include only lactofen per se. The two existing tolerances for lactofen have been reassessed and will be lowered from 0.05 ppm to 0.01 ppm. There are currently no tolerances for lactofen in processed commodities or animal commodities, and the available residue data indicate that tolerances for these commodities are not necessary.

Documents available:

1. Sept 2003: Lactofen TRED Facts - (4 pages)

2. Sept 24, 2003: Report of the Food Quality Protection Act (FQPA) Tolerance Reassessment Progress and Risk Management Decision (TRED) for Lactofen - (9 pages)

3. Sept 24, 2003: Overview of Lactofen FQPA Risk Assessment for Tolerance Reassessment - (9 pages)

4. Aug 12, 2003: Lactofen. Revisions to HED Tolerance Reassessment Risk Assessment - (3 pages)

5. May 22, 2002: Lactofen - Report of the Cancer Assessment Review Committee - (38 pages)

6. March 12, 2001: LACTOFEN: Report of the Mechanism of Toxicity Assessment Review Committee - (17 pages)

7. Feb 26, 2003: EFED Review of Lactofen Small-Scale Prospective Ground-Water Monitoring Study 166-1 DER MRID #456717-01, 02, and -03. - (40 pages)

8. Jan 21, 2003: DRINKING WATER EXPOSURE ASSESSMENT FOR LACTOFEN, UPDATED FOR
PROSPECTIVE GROUND WATER (PGW) MONITORING STUDY - (40 pages)

9. Sept 15, 2003: Addendum to EFED RED Chapter for sodium acifluorfen. Addendum to TRED for lactofen - (41 pages)

VALENT - Pesticide Petitions to Establish Tolerances in or on the raw agricultural commodities (RACs) cottonseed at 0.01 ppm, cotton gin byproducts at 0.02 ppm, and peanut nutmeats at 0.01 ppm.
-- In the developmental toxicity study in rats, effects were observed at the 150 mg/kg/day dose level consisting of decreases in fetal weight as well as skeletal abnormalities. This dose level also elicited signs of toxicity in the parental group.
-- Chronic toxicity. Lactofen causes adverse health effects when administered to animals for extended periods of time. These effects include proliferative changes in the liver, spleen, and kidney; hematological changes; and blood biochemistry changes.
-- Subchronic toxicity... Mice 3-month. Groups of male and female mice were fed diets containing lactofen technical at concentrations of 0, 40, 200, 1,000, 5,000, and 10,000 for 13 weeks. At week 5, the dosage of the 40 ppm, groups was increased to 2,000 ppm. Treatment related mortality occurred at dosages above 1,000 ppm. The LOAEL was 200 ppm, 28.6 mg/kg/day based on: ¥ Increased WBC; decreased hematocrit, hemoglobin and RBC. ¥ Increased alkaline phosphatase, serum glutamic-oxloacetic transaminase (SGOT), SGPT, cholesterol and total serum protein levels. ¥ Increased weights or enlargement of the spleen, liver, adrenals, heart, and kidney; histopathological changes of the liver, kidney, thymus, spleen, ovaries, and testes.
-- Peroxisome proliferation. Butler et al (1988) studied the effects of lactofen on peroxisome proliferation in mice exposed for 7 weeks to dietary concentrations of 2, 10, 50, and 250 ppm. 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.
-- The Cancer Peer Review Committee (CPRC) evaluated the relevant data on the carcinogenic potential of lactofen in 1987 and classified lactofen as a B2 carcinogen Probable Human Carcinogen. The B2 classification is based on an increase in the combined incidence of liver adenomas and carcinomas in mice and increases in liver neoplastic nodules and foci of cellular alteration (possible precursor of tumors) in rats.
-- EPA has recently determined that lactofen acts via a peroxisome proliferation mechanism and is currently reevaluating its approach to the quantification of the cancer risk for lactofen.
-- Carcinogenicity. As a member of the diphenyl ether chemical family, lactofen is structurally related to four other chemicals that are oncogenic in rodents:
--- Sodium acifluorfen (acifluorfen is a lactofen metabolite), nitrofen, oxyfluorfen, and fomesafen.
--- Sodium acifluorfen produces hepatocellular adenomas and carcinomas in mice but is negative in rats.
--- Nitrofen produces hepatocellular carcinomas in mice and pancreatic carcinomas in rats.
--- Oxyfluorfen produces marginally positive liver tumors in mice but is negative in rats.
--- Fomesafen produces hepatocellular adenomas and carcinomas in mice.

Availability of Risk Assessment. These documents are the human health risk assessment and related documents for lactofen (Cobra). This notice also starts a 60- day public comment period for the risk assessment. copies of the risk assessment and certain related documents for lactofen may also be accessed at http://www.epa.gov/pesticides/reregistration/lactofen/

VALENT - Petition to extend a time-limited tolerance for residues on cottonseed at 0.05 ppm. The tolerance would expire on December 31, 1999. The time limitation on the tolerance would allow Valent to complete, and EPA to evaluate, additional prospective groundwater study data.

VALENT - Petition for Renewal of Time-Limited Tolerance for residues on cottonseed at 0.05 ppm.

IR-4* - Petition for Pesticide Tolerance. - FINAL RULE. This document establishes a tolerance for combined residues of the herbicide lactofen and its metabolites in or on the raw agricultural commodity snap beans of 0.05 ppm.

VALENT - Petition for Pesticide Tolerance. - FINAL RULE. USEPA extends a time-limited tolerance for residues on the raw agricultural commodity cottonseed at 0.05 ppm.

IR-4* - Petition for Proposed Pesticide Tolerance. EPA proposes to establish a tolerance for the combined residues of the herbicide lactofen in or on the raw agricultural commodity snap beans at 0.05 ppm.

VALENT - Petition to renew a time-limited tolerance for residues on cottonseed at 0.05 ppm, The tolerance would establish the maximum permissible level of residues on this commodity.