Adverse Effects
Lactofen
CAS No.
77501-63-4
 
 

Return to Lactofen Index Page

Activity: Herbicide (Diphenyl ether)
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

As of February 15, 2005, this herbicide is permitted in or on 5 food commodities in the United States. 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. The 5 food commodities are:

Beans, snap, succulent (excluding limas) - 0. 01 ppm
Cotton, gin byproducts
- 0. 02 ppm
Cotton, undelinted seed
- 0. 01 ppm
Peanut - 0. 01 ppm
Soybean, seed
- 0. 01 ppm

- see tolerances at http://www.fluorideaction.org/pesticides/mrl.lactofen.htm

Blood (click on for all fluorinated pesticides)

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.

Body Weight Decrease (click on for all fluorinated pesticides)

Prenatal developmental-- rodents (rat)
Maternal NOAEL = 50 mg/kg/day. Maternal LOAEL = 150 mg/kg/day based on signs of toxicity (excessive salivation, lethargy, dried red material around the nares and inguinal regions) and statistically significant decreases in body weight gain.
Developmental NOAEL = 50 mg/kg/day.
Developmental LOAEL = 150 mg/kg/day based on decreased fetal weight and skeletal abnormalities (increased incidence of bent ribs and/or limb bones) and reduced ossification of vertebral arches.

Ref: Sept 24, 2004. Lactofen. Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluorideaction.org/pesticides/lactofen.fr.sept.24.2004.htm

Bone (click on for all fluorinated pesticides)

-- Prenatal developmental-- rodents (rat). Developmental NOAEL = 50 mg/kg/day.
Developmental LOAEL = 150 mg/kg/day based on decreased fetal weight and skeletal abnormalities (increased incidence of bent ribs and/or limb bones) and reduced ossification of vertebral arches.
-- Rat Developmental Toxicity Study. LOAEL = 150 mg/kg/day based on decreased fetal weight and skeletal abnormalities.
Ref: Sept 24, 2004. Lactofen. Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluorideaction.org/pesticides/lactofen.fr.sept.24.2004.htm

Developmental toxicity-- Rats. Pregnant rats were administered oral doses of 0, 15, 50 and 150 mg/kg/day Lactofen Technical on days 6- 19 of gestation. Maternal toxicity (death, abortion and reduced body weight gain) was observed at 150 mg/kg/day. Developmental toxicity (reduced fetal weight, slightly reduced ossification, bent ribs and bent limb bones) was also observed at 150 mg/kg/day. The NOEL for this study was 50 mg/kg/day."
Ref: Federal Register, February 25, 1998. [PF-789; FRL-5767-5]

http://www.fluoridealert.org/pesticides/Lactofen.FR.Feb.1998.htm

Cancer: Probable Human Carcinogen - LIVER (click on for all fluorinated pesticides)

Likely to be Carcinogenic to Humans at High Doses. Not Likely to be Carcinogenic to Humans at Low Doses. Hepatocellular carcinomas (M); Hepatocellular adenomas & carcinomas (M & F); CD-mice. Liver neoplastic nodules; Sprague-Dawley rats (M & F). MOE approach should be used for estimating human cancer risk, using a NOAEL of 2 ppm (0.3 mg/kg/day)
Ref:
April 26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the Office of Pesticide Programs. From: Jess Rowland, Chief Science Information Management Branch Health Effect Division (7509C) Office of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf

Group B2--Probable Human Carcinogen. Reviewed 4/ 8/ 87.
Ref: List of Chemicals Evaluated for Carcinogenic Potential. Science Information Management Branch, Health Effects Division, Office of Pesticide Programs, U. S. Environmental Protection Agency. March 15, 2002.
http://www.biomuncie.org/chemicals_evaluated_for_carcinog.htm

-- 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.
-- Cancer (Oral, dermal, inhalation). 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.
Ref: Sept 24, 2004. Lactofen. Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluorideaction.org/pesticides/lactofen.fr.sept.24.2004.htm

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.

Chronic/carcinogenicity feeding study-- Mouse-- 24-month. In a dietary 18-month oncogenicity study in mice at dosages of 10, 50 and 250 ppm Lactofen Technical, an increase in liver adenomas and carcinomas, cataracts and liver pigmentation was observed at 250 ppm. The lowest dose, 10 ppm, was the LOEL based on increased liver weight and hepatocytomegaly.
-- Chronic/carcinogenicity feeding study-- Rat-- 24-month. In a 2- year chronic feeding/oncogenicity study of Lactofen Technical in rats at dosages of 0, 500, 1,000 and 2,000 ppm in the diet, an increase in liver neoplastic nodules and foci of cellular alteration was observed in both sexes at 2,000 ppm. The NOEL for systemic toxicity is 500 ppm based on kidney and liver pigmentation.
-- Carcinogenicity. The Toxicology Branch Peer Review Committee has determined that lactofen meets the criterion for a B2 (possible human) carcinogen since it caused an increase in liver tumors (adenomas and/or carcinomas) in two species. Based on the mouse oncogenicity study, a human upper-bound potency estimate (Q1*) was calculated as 0.17 (mg/kg/day).
-- More importantly, evidence summarized above suggest that carcinogenic effects observed in rodent liver related to long term lactofen consumption are attributable to peroxisomal proliferation as opposed to a direct genotoxic effect. This mechanism of action would more appropriately be regulated as a threshold effect (similar to RfD comparisons) as opposed to a non-threshold effect with a quantitative potency factor derived from low dose extrapolations. This change in the hazard assessment process for lactofen would have a profound effect on the exposure and risk assessments for this chemical.
Ref: Federal Register: February 25, 1998 [Page 9532-9540]. Notice of Filing of Pesticide Petition.
http://www.fluoridealert.org/pesticides/Lactofen.FR.Feb.1998.htm

"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..."
Ref: 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.
http://www.fluoridealert.org/pesticides/Cancer.EPA.Assess.May.2000.pdf

• Note from FAN:
Except for Nitrofen, all the pesticides cited above are fluorinated.

Endocrine: Adrenal (click on for all fluorinated pesticides)

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.
Ref: Sept 24, 2004. Lactofen. Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluorideaction.org/pesticides/lactofen.fr.sept.24.2004.htm

-- Subchronic feeding-- 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 LOEL was 200 ppm based on: increased WBC; decreased hematocrit, hemoglobin and RBC; increased alkaline phosphatase, 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. In general, effects were slight in the 200 ppm groups, and moderate to severe in the 1,000 ppm groups.
Ref: Federal Register: February 25, 1998 [Page 9532-9540]. Notice of Filing of Pesticide Petition.
http://www.fluoridealert.org/pesticides/Lactofen.FR.Feb.1998.htm

Endocrine: Ovary (click on for all fluorinated pesticides)

-- Subchronic feeding-- 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 LOEL was 200 ppm based on: increased WBC; decreased hematocrit, hemoglobin and RBC; increased alkaline phosphatase, 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. In general, effects were slight in the 200 ppm groups, and moderate to severe in the 1,000 ppm groups.
Ref: Federal Register: February 25, 1998 [Page 9532-9540]. Notice of Filing of Pesticide Petition.
http://www.fluoridealert.org/pesticides/Lactofen.FR.Feb.1998.htm

Endocrine: Testicular (click on for all fluorinated pesticides)

-- Subchronic feeding-- 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 LOEL was 200 ppm based on: increased WBC; decreased hematocrit, hemoglobin and RBC; increased alkaline phosphatase, 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. In general, effects were slight in the 200 ppm groups, and moderate to severe in the 1,000 ppm groups.
-- Reproduction-- Rats. Groups of male and female rats were fed 0, 50, 500 or 2,000 ppm of Lactofen Technical continuously in their diets for 2-generations. Adult systemic toxicity (mortality, reduced body weight, increased liver and spleen weight, decreased kidney weight and histological changes in the liver and testes) was observed at levels of 500 ppm and greater.
Ref: Federal Register: February 25, 1998 [Page 9532-9540]. Notice of Filing of Pesticide Petition.
http://www.fluoridealert.org/pesticides/Lactofen.FR.Feb.1998.htm

90-Day Feeding - mouse: LEL=200 ppm (increased leucocytes, decreased Hct, Hgb, WBC); increased alkaline phosphatase, SGOT, SGPT, cholesterol; increased liver weight and enlarged spleen, liver and heart; liver vacuolation necrosis of individual hepatocytes, biliary hyperplasia, extramedullary hematopoiesis, kidney nephrosis and fibrosis; follicular atreria, abnormal sperm forms); core grade minimum (PPG Industries, 1983b)
Ref: US EPA IRIS. (Online October 11, 2003). Available at
Toxnet.

Endocrine: Thymus (click on for all fluorinated pesticides)

-- Subchronic feeding-- 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 LOEL was 200 ppm based on: increased WBC; decreased hematocrit, hemoglobin and RBC; increased alkaline phosphatase, 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. In general, effects were slight in the 200 ppm groups, and moderate to severe in the 1,000 ppm groups.
Ref: Federal Register: February 25, 1998 [Page 9532-9540]. Notice of Filing of Pesticide Petition.
http://www.fluoridealert.org/pesticides/Lactofen.FR.Feb.1998.htm

Endocrine: Thyroid (click on for all fluorinated pesticides)

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.
Ref: Sept 24, 2004. Lactofen. Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluorideaction.org/pesticides/lactofen.fr.sept.24.2004.htm

Eye (click on for all fluorinated pesticides)

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.
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.

Kidney (click on for all fluorinated pesticides)

Chronic toxicity--dogs. NOAEL = 0.79 mg/kg/day. 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.
Ref: Sept 24, 2004. Lactofen. Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluorideaction.org/pesticides/lactofen.fr.sept.24.2004.htm

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.

Chronic Toxicity- A complete chronic data base supported by appropriate subchronic studies for lactofen is available to the Agency. Lactofen Technical 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. Based on the Lowest Effect Level (LEL) of 1.5 mg/ kg/day in the 18-month mouse feeding study and an uncertainty factor of 1,000, a reference dose (RfD) of 0.002 mg/kg/day has been established for lactofen. An uncertainty factor of 1,000 was used since a clear NOEL was not established.
-- Reproduction-- Rats. Groups of male and female rats were fed 0, 50, 500 or 2,000 ppm of Lactofen Technical continuously in their diets for 2-generations. Adult systemic toxicity (mortality, reduced body weight, increased liver and spleen weight, decreased kidney weight and histological changes in the liver and testes) was observed at levels of 500 ppm and greater.
-- Chronic/carcinogenicity feeding study-- Rat-- 24-month. In a 2- year chronic feeding/oncogenicity study of Lactofen Technical in rats at dosages of 0, 500, 1,000 and 2,000 ppm in the diet, an increase in liver neoplastic nodules and foci of cellular alteration was observed in both sexes at 2,000 ppm. The NOEL for systemic toxicity is 500 ppm based on kidney and liver pigmentation.
Ref: Federal Register: February 25, 1998 [Page 9532-9540]. Notice of Filing of Pesticide Petition.
http://www.fluoridealert.org/pesticides/Lactofen.FR.Feb.1998.htm

Liver (click on for all fluorinated pesticides)

Likely to be Carcinogenic to Humans at High Doses. Not Likely to be Carcinogenic to Humans at Low Doses. Hepatocellular carcinomas (M); Hepatocellular adenomas & carcinomas (M & F); CD-mice. Liver neoplastic nodules; Sprague-Dawley rats (M & F). MOE approach should be used for estimating human cancer risk, using a NOAEL of 2 ppm (0.3 mg/kg/day)
Ref:
April 26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the Office of Pesticide Programs. From: Jess Rowland, Chief Science Information Management Branch Health Effect Division (7509C) Office of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf

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.
Ref: Sept 24, 2004. Lactofen. Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluorideaction.org/pesticides/lactofen.fr.sept.24.2004.htm

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.

Chronic/carcinogenicity feeding study-- Mouse-- 24-month. In a dietary 18-month oncogenicity study in mice at dosages of 10, 50 and 250 ppm Lactofen Technical, an increase in liver adenomas and carcinomas, cataracts and liver pigmentation was observed at 250 ppm. The lowest dose, 10 ppm, was the LOEL based on increased liver weight and hepatocytomegaly.
-- Chronic/carcinogenicity feeding study-- Rat-- 24-month. In a 2- year chronic feeding/oncogenicity study of Lactofen Technical in rats at dosages of 0, 500, 1,000 and 2,000 ppm in the diet, an increase in liver neoplastic nodules and foci of cellular alteration was observed in both sexes at 2,000 ppm. The NOEL for systemic toxicity is 500 ppm based on kidney and liver pigmentation.
-- Carcinogenicity. The Toxicology Branch Peer Review Committee has determined that lactofen meets the criterion for a B2 (possible human) carcinogen since it caused an increase in liver tumors (adenomas and/or carcinomas) in two species. Based on the mouse oncogenicity study, a human upper-bound potency estimate (Q1*) was calculated as 0.17 (mg/kg/day).
-- More importantly, evidence summarized above suggest that carcinogenic effects observed in rodent liver related to long term lactofen consumption are attributable to peroxisomal proliferation as opposed to a direct genotoxic effect. This mechanism of action would more appropriately be regulated as a threshold effect (similar to RfD comparisons) as opposed to a non-threshold effect with a quantitative potency factor derived from low dose extrapolations. This change in the hazard assessment process for lactofen would have a profound effect on the exposure and risk assessments for this chemical.
Ref: Federal Register: February 25, 1998 [Page 9532-9540]. Notice of Filing of Pesticide Petition.
http://www.fluoridealert.org/pesticides/Lactofen.FR.Feb.1998.htm

Reproductive (click on for all fluorinated pesticides)

Reproduction and fertility effects
Parental/Systemic NOAEL = 2.6 mg/kg/day.
Parental/Systemic LOAEL = 26.2 mg/kg/day based on mortality and decreased male fertility.
Reproductive NOAEL = 2.6 mg/kg/day.
Reproductive LOAEL = 26.2 mg/kg/day based on decreased male fertility.

Ref: Sept 24, 2004. Lactofen. Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluorideaction.org/pesticides/lactofen.fr.sept.24.2004.htm

Spleen (click on for all fluorinated pesticides)

-- Subchronic feeding-- 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 LOEL was 200 ppm based on: increased WBC; decreased hematocrit, hemoglobin and RBC; increased alkaline phosphatase, 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. In general, effects were slight in the 200 ppm groups, and moderate to severe in the 1,000 ppm groups.
-- Reproduction-- Rats. Groups of male and female rats were fed 0, 50, 500 or 2,000 ppm of Lactofen Technical continuously in their diets for 2-generations. Adult systemic toxicity (mortality, reduced body weight, increased liver and spleen weight, decreased kidney weight and histological changes in the liver and testes) was
observed at levels of 500 ppm and greater.
Ref: Federal Register: February 25, 1998 [Page 9532-9540]. Notice of Filing of Pesticide Petition.
http://www.fluoridealert.org/pesticides/Lactofen.FR.Feb.1998.htm

Environmental (click on for all fluorinated pesticides)

Phototoxic Pesticide. Light-dependent peroxidizing herbicides (LDPHs). US EPA identified the organofluorine herbicides Acifluorfen, Azafenidin, Carfentrazone-ethyl, Flumiclorac-penty, Flumioxazin, Fluthiacet-methyl, Fomesafen, Lactofen, Oxadiargyl, Oxadiazon, Oxyfluorfen, Sulfentrazone, Thidiazimin as phototoxic pesticides that act by inhibiting protoporphyringen oxidase in the heme and chlorophyll biosynthetic pathway. [10 out of the 13 pesticides that EPA identified are organofluorines].
SEE http://www.fluoridealert.org/pesticides/PHOTOTOXICITY.PAGE.htm
Ref: December 11, 2001 - US EPA. Revised Environmental Fate and Effects Division Preliminary Risk Assessment for the Oxyfluorfen Reregistration Eligibility Decision Document - also at:
http://www.epa.gov/oppsrrd1/reregistration/oxyfluorfen/oxyefedchap.pdf

Ref: Acute Aquatic Ecotoxicity Summaries for Lactofen on All Taxa Groups. PAN Pesticides Database - Chemical Toxicity Studies on Aquatic Organisms.
http://www.pesticideinfo.org/List_AquireAcuteSum.jsp?Rec_Id=PC35974
Common Name Scientific Name Avg Species LC50 (ug/L) LC50 Std Dev Number of Studies Avg Species Rating Outlier Result for Organism Group?

Fish

Bluegill Lepomis macrochirus 766.7 942.8 3 Highly Toxic  
Rainbow trout,donaldson trout Oncorhynchus mykiss 1,900 1,800 2 Moderately Toxic  

 
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