Lactofen
CAS No. 77501-63-4
 
 

Return to Lactofen Adverse Effects

ACTIVITY: Herbicide (Diphenyl ether)

CAS Name: 2-ethoxy-1-methyl-2-oxoethyl 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoate

Structure:

Adverse Effects:

Blood
Body Weight Decrease
Bone
Cancer: Probable Human Carcinogen - LIVER
Endocrine: Adrenal
Endocrine: Ovary
Endocrine: Testicular
Endocrine: Thyroid
Endocrine: Thymus
Eye
Kidney

Liver
Reproduction

Spleen

Environmental Effects:

Phototoxic

Fish: Moderately to highly toxic

Regulatory Information
(only comprehensive for the US)
US EPA Registered: Yes 
US EPA PC Code: 128888 
California Chemical Code 3538 
US Tolerances:

CFR 180.432

Note that CFR 180.453 was also given to Lactofen. However, as of February 2005, there is no CFR 180.453 listed at the Code of Federal Regulations website.

FDA LMS Code: A38 
US EPA Permit Date
and Registrant:
1987, PPG 
Registered use in
(includes only a limited list of countries)

India, US, Vietnam 
US Maximum Residue Levels permitted in food commodities

Residue tolerances for Lactofen were amended in Sept 2004. Two of Lactofen's metabolites containing the diphenyl ether linkage were eliminated in the new tolerances. The established tolerances for snap bean and soybean were reduced to 0.01 ppm (from 0.05 ppm) as required by the Lactofen Tolerance Reassessment.

Beans, snap, succulent (excluding limas)
Cotton, gin byproducts
Cotton, undelinted seed
Peanut
Soybean, seed  

Other Information
Molecular Formula: C19H15Cl F3 NO7 
Entry Year: 1980 
Inventing Company: PPG 
Manufacturers: Cyanamid / Valent, Aventis 
Other Names: Cobra
PPG 844
Stellar
 
Of special interest:
PAN BAD ACTOR - Carcinogen 
US Map of Pesticide Use - 1992-1995
2001 - Tolerance Reassessment and Reregistration  
March 12, 2001 - Report of the Mechanism of Toxicity Assessment Review Committee - US EPA 
March 7, 2001 - Phototoxic Pesticides: US EPA Memo Requesting Phototoxicity Study Protocol for Light-Dependent Peroxidizing Herbicides 
October 12, 2000 - Preliminary Human Health Risk Assessment for Tolerance Reassessment incorporating Revised Cancer Unit Risks - US EPA 
July 12, 2000 - Revised Lactofen (Cobra) Quantitative Risk Assessment based on CD-1 Mouse Dietary Study - US EPA 

May 24, 2000 - Cancer Assessment Document. Evaluation of the Carcinogenic Potential of Diclofop-Methyl. (Second Review). Final Report. Cancer Assessment Review Committee, Health Effects Division, US EPA Office of Pesticide Programs. "There are eight diphenyl ethers that are structurally similar to diclofop-methyl. Of the chemicals, fomesafen sodium, haloxyfop-methyl (Verdict), oxyfluorfen, acifluorfen sodium, nitrofen, and lactofen were reviewed in the initial CPRC report. All of these chemicals induced liver adenomas and carcinomas in rats and/or mice..."  
-- organofluorine pesticides highlighted in red

May 4, 2000 - Tolerance Reassessment of Lactofen: Product and Residue Chemistry Considerations - US EPA
March 2, 2000 - Toxicology Evaluation - US EPA
2000 Toxic Release Inventory (TRI): brief summary.
Lactofen: (Cobra Herbicide, PPG-844) Extoxnet Profile  
Classified by the State of California: "Known to Cause Cancer"
April 2000 - Food and Drug Administration Pesticide Residue Monitoring. - Table 3. Pesticides detectable by methods used in 1999 regulatory monitoring.
October 2001 - Glossary of Pesticide Chemials. A listing of pesticides subject to analysis of residues in foods and feeds by the US Food and Drug Administration.

Material Safety Data Sheet for Stellar (R) Herbicide. Active ingredients: Flumiclorac Pentyl (7.6%) and Lactofen (26.6%).  
-- Flumiclorac is an organofluorine


Rationale for US EPA to add Lactofen to the Toxic Release Inventory

Lactofen (5-(2-chloro-4-(trifluoromethyl)phenoxy)-2-nitro-2- ethoxy-1-methyl-2-oxoethyl ester) (CAS No. 077501-63-4) (FIFRA AI) (Ref. 3). Lactofen meets the criteria of an EPA Group B2 compound, i.e., a probable human carcinogen. This conclusion was based on an increased incidence of hepatocellular carcinomas in males and combined incidence of hepatocellular adenomas and carcinomas in both sexes of CD-1 mice following dietary administration of lactofen. In CD rats, there was increased incidence of liver neoplastic nodules in both sexes. Four structurally similar chemicals, acifluorfen, nitrofen, oxyfluorfen, and fomesafen, all produced hepatocellular tumors in rodents.

Results of several subchronic and chronic studies indicated the liver and kidney as target organs for lactofen. Increased absolute and relative liver weight and hepatocytomegaly (the LOEL was 1.5 mg/kg/day; the NOEL was not determined) were observed in male mice fed lactofen for 78 weeks. At 37.5 mg/kg/day, there was also an increased incidence of cataracts and renal pigmentation. Based on the LOEL, an oral RfD of 0.002 mg/kg/day was derived. Renal dysfunction and decreased hemoglobin and hematocrit levels and red blood cell counts (the LOEL was 25/75 mg/ kg/day; the NOEL was 5 mg/kg/day) were observed in a 1-year feeding study in dogs. Increased renal and hepatic pigmentation (the LOEL was 50 mg/kg/day; the NOEL was 25 mg/kg/day) were noted in a 2-year feeding study in rats. In a 90-day mouse study, increased alkaline phosphatase, serum glutamate oxaloacetate transaminase (SGOT), and serum gleutanic pyruvic transaminase (SGPT) activities, increased liver weight, hepatic necrosis, biliary hyperplasia, decreased hematocrit and hemoglobin levels and red blood cell counts, extramedullary hematopoiesis, and kidney nephrosis and fibrosis (the LOEL was 26 mg/kg/day; the NOEL was not determined) were seen. Decreased hemoglobin and hematocrit levels, decreased red blood cell counts, and brown pigment in the kidney and liver (the LOEL was 50 mg/kg/day) were noted in a 90-day feeding study in rats.

EPA believes that there is sufficient evidence for listing lactofen on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available carcinogenicity data and hepatic, renal, and hematological toxicity data for this chemical.

Ref: USEPA/OPP. Support Document for the Addition of Chemicals from Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) Active Ingredients to EPCRA Section 313. U. S. Environmental Protection Agency, Washington, DC (1993).

As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.



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.

Note: "Fate data for lactofen show that it has a high binding potential and that it rapidly is transformed to acifluorfen. It is not clear whether bound lactofen can be degraded and released as aciflorfen..."
Ref: June 8, 2001, US EPA, Reregistration of sodium acifluorifen, p 3

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.


US Federal Register

•• Note: Due to length, the following is a partial list. Click here to see full list of FR entries.

Published Date Docket Identification Number Details

June 20, 2007

 

EPA-HQ-OPP-2006-0178

IR-4. Pesticide Tolerance. FINAL RULE.

Okra 0.02 ppm

Vegetables, fruiting, group 08

This group 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

0.02 ppm

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.

April 13, 2007 EPA-HQ-OPP-2007-0005

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

Registration No. Product Name Registrant
059639 WA-01-0006 Cobra Herbicide Valent U.S.A. Corp.
PO Box 8025
Walnut Creek, CA 94596
February 2, 2007 EPA-HQ-OPP-2005-0287

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.

Document Date Document
Jan 2007 Summary Document.
-- Preliminary Work Plam
-- Fact Sheet
-- Ecological Risk Assessment Problem Formulation
-- Human Health Effects Scoping Document
-- Glossary of Terms and Abbreviations
Docket Number: EPA-HQ-OPP-2005-0287-0002 (45 pages)
Dec 19, 2006 Human Health Assessments. Scoping document to support registration review
Docket Number: EPA-HQ-OPP-2005-0287-0003 (9 pages)
Dec 13, 2006

Problem Formulation for lactofen registration review
-- the methods that will likely be used in the ecological risk assessment of lactofen
-- anticipated LOC exceedances
-- data gaps
-- additional data needs
Docket Number: EPA-HQ-OPP-2005-0287-0004 (26 pages)

Oct 18, 2006 Screening-level usage analysis (SLUA)- Available estimates used on US agricultural crops
Docket Number: EPA-HQ-OPP-2005-0287-0005 (2 pages)
Oct 31, 2005 Appendix A - Food/Feed & Non-Food/Non–Feed Uses Eligible for Registration - Partial Listing.
Docket Number: EPA-HQ-OPP-2005-0287-0006 (2 pages)
Oct 25, 2005 Section 3, IR4 Tolerance petition for the new use of lactofen as Cobra Herbicide 2EC on the fruiting vegetable group and okra.
Docket Number: EPA-HQ-OPP-2005-0287-0007 (9 pages)
Jan 8, 2007 Human Health Risk Assessment for Proposed Uses on Fruiting Vegetables and Okra
Docket Number: EPA-HQ-OPP-2005-0287-0008 (39 pages)
Sept 2003 Lactofen TRED Fact Sheet
Docket Number: EPA-HQ-OPP-2005-0287-0009 (4 pages)
Sept 24, 2003 Report of the Food Quality Protection Act (FQPA) Tolerance Reassessment Progress and Risk Management Decision (TRED) for Lactofen
Docket Number: EPA-HQ-OPP-2005-0287-0010 (9 pages)
Oct 12, 2000 Preliminary Human Health Risk Assessment for Tolerance Reassessment Incorporating Revised Cancer Unit Risks
Docket Number: EPA-HQ-OPP-2005-0287-0011 (30 pages)
May 4, 2000 Tolerance Reassessment of Lactofen: Product and Residue Chemistry Considerations
Docket Number: EPA-HQ-OPP-2005-0287-0012 (38 pages)
Jan 21, 2003 Drinking Water Exposure Assessment for Lactofen, Updated for Prospective Ground Water (PGW) Monitoring Study
Docket Number: EPA-HQ-OPP-2005-0287-0013 (40 pages)
July 14, 2000 Revised Drinking Water Exposure Assessment for Lactofen
Docket Number: EPA-HQ-OPP-2005-0287-0014 (34 pages)
July 22, 2004 Occupational and Residential Risk Assessment for Lactofen on Cotton and Peanuts
Docket Number: EPA-HQ-OPP-2005-0287-0015 (27 pages)
April 12, 2006 EPA-HQ-OPP-2006-0178

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.

Sept 24, 2004 OPP-2004-0293

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:

Commodity Parts per million
Beans, snap, succulent (excluding limas) 0.01
Cotton, gin byproducts 0.02
Cotton, undelinted seed 0.01
Peanut 0.01
Soybean, seed 0.01
Table 2.--Summary of Toxicological Dose and Endpoints for lactofen for Use in Human Risk Assessment
Exposure Scenario Dose Used in Risk
Assessment, Interspecies and Intraspecies and any Traditional UF
Special FQPA SF and Level of Concern for Risk Assessment
Study and Toxicological Effects
Acute Dietary (Females 13-50 years of age) NOAEL = 50 mg/kg/day UF
= 100 Acute RfD = 0.5 mg/kg/day
Special FQPA SF = 3 aPAD = acute RfD/ Special FQPA SF = 0.17 mg/kg/day Rat Developmental Toxicity Study
LOAEL = 150 mg/kg/day based on decreased fetal weight and skeletal abnormalities.
Acute Dietary (General population including infants and children). An endpoint attributable to a single dose (exposure) was not identified from the available studies, including the developmental toxicity studies in rats and rabbits.
Chronic Dietary (All populations) NOAEL = 0.79 mg/kg/day
UF = 100 Chronic RfD = 0.008 mg/kg/day
Special FQPA SF = 1 cPAD = chronic RfD/ Special FQPA SF = 0.008 mg/kg/day Dog chronic toxicity LOAEL = 3.96 mg/kg/day based on increased incidence of
proteinaceous casts in the kidneys, and
statistically significant increases in the absolute weights of the thyroid and adrenal glands in males.
Cancer (Oral, dermal, inhalation) Lactofen acts via a peroxisome proliferation mechanism of action. Likely to be carcinogenic to humans at high enough doses to cause these biochemical and histopathological effects (peroxisome proliferation) in the livers of rodents but unlikely to be carcinogenic at doses below those causing these changes. Lactofen is considered to be a threshold carcinogen. NOAEL = 0.3 mg/kg/day based on increased activities of liver enzymes and increased incidence of liver histopathological findings at the LOAEL of 1.5 mg/kg/day.

•• 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.

Jan 28, 2004 OPP-2003-0294

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)

•• Note: Due to length, the above is a partial list. Click here to see full list of FR entries.

 
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