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Activity: Herbicide (Diphenyl ether)
Structure:

Adverse Effects:
Blood
Body Weight Decrease
Bone
Cancer: Possible Human Carcinogen - LIVER
Liver
Stomach
Environmental

• See also: Fomesafen, sodium

Decreased plasma cholesterol and triglycerides and increased liver weights (reversible at 7 days post-treatment) were observed at 50 mg/kg/day (only dose tested) when administered in the diet of rats for 4 weeks.
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)

-- 3. Chronic toxicity. EPA has not established the RfD for fomesafen. For the purposes of this tolerance, based upon available chronic toxicity data, the RfD of 0.0025 mg/kg/day was used. This RfD is based on the NOEL of 0.25 mg/kg/day from the rat carcinogenicity study. A 100-fold uncertainty factor was used to calculate this RfD. At the LOEL of 5.0 mg/kg/day there was liver toxicity and decreased body weight.
-- iii. Reproductive toxicity study. In the 2-generation reproductive toxicity study in rats, the parental (systemic) NOEL was 12.5 mg/kg/ day, based on decreased body weight and liver necrosis at the LOEL of 50 mg/kg/day. The reproductive and developmental (pup) NOELs were 2.5 mg/kg/day, based on decreased pup body weight and reduced litter size at the LOEL of 12.5 mg/kg/day.
-- v. Conclusion. Based on the rat reproductive toxicity study discussed above, the pup LOEL (decreased body weight and reduced litter size) occurred at levels below the maternal NOEL and demonstrates post- natal pup toxicity unrelated to maternal effects. These results are suggestive of a special sensitivity for infants and children following post-natal exposure. Therefore, EPA recommends applying an extra 10- fold uncertainty (safety) factor in the chronic risk analysis. The low percentage of the RfD occupied by the most highly exposed child subgroup (4.8% of the RfD; 48% using the extra 10-fold factor) demonstrates that post-natal risks to infants and children are low.
Ref: Federal Register. November 19, 1997. Fomesafen; Pesticide Tolerances for Emergency Exemptions. Final Rule.
http://www.fluoridealert.org/pesticides/Fomesafen.FR.Nov.19.1997.htm

Bone (click on for all fluorinated pesticides)

Acute toxicity. EPA has selected the developmental NOEL of 7.5 mg/kg/day from the oral rat developmental toxicity study for the acute dietary endpoint; at the lowest observed effect level (LOEL) of 50 mg/ kg/day, fetuses had delayed or partial ossification and extra ribs.
Ref: Federal Register. July 9, 1997. [OPP-300512; FRL-5729-5] RIN 2070-AB78 http://www.fluoridealert.org/pesticides/Fomesafen.FR.July.9.1997.htm

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

Group C--Possible Human Carcinogen. Reviewed 8/ 27/ 86.
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

-- Decreased plasma cholesterol and triglycerides and increased liver weights (reversible at 7 days post-treatment) were observed at 50 mg/kg/day (only dose tested) when administered in the diet of rats for 4 weeks. In a 90-day rat study, dietary administration of 5 mg/kg/day (LOEL) produced alterations in lipid metabolism and increases in liver weight. The NOEL was 0.25 mg/kg/day. In a 26-week dog study, dietary administration of 25 mg/kg/day (LOEL) produced alterations in lipid metabolism and liver changes (changes not defined). The NOEL was 1 mg/ kg/day. Liver toxicity (increased liver masses, discolored hepatocytes, and pigmented Kupffer cells) was observed in a 2-year rat feeding study at 50 mg/kg/day (LOEL). The NOEL was 5 mg/kg/day. Metabolism studies have shown that fomesafen accumulates in the liver. EPA believes that there is sufficient evidence for listing fomesafen on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available hepatic 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.

-- 4. Carcinogenicity. Fomesafen is classified as a Group C carcinogen with a Q^* of 1.9 x 10^-1 (mg/kg/ day)^-1. This classification was based on: (i) Increases in both adenomas and carcinomas at several dose levels in both sexes of mice; (ii) some evidence of reduced latency for the time of tumor appearance; (iii) limited evidence of mutagenic effects; and, (iv) the structural similarity of fomesafen to other biphenyl ether herbicides which have been shown to be carcinogenic.
-- iii. Cancer risk. Based on exposure levels for drinking water, as given above, the estimate of cancer risk is 2.7 x 10^-6. This figure is an overestimate, as it was arrived at based on several very conservative assumptions. Estimates used were calculated based on data from only one small scale study conducted in NC, for use of fomesafen on soybeans at a vulnerable site. This represents a worst case scenario, so is not representative of the ``average'' conditions of use. Additionally, there is language on the product label warning of the potential of fomesafen to leach to ground water in vulnerable areas. Vulnerable areas in this case refers to areas where soils are permeable (sand and silt loams) and the water table is shallow. The majority of areas of soybean production, and potential use of fomesafen, will not likely be vulnerable sites, thus the data used from the one small scale study greatly overestimates levels which could actually occur. Further, it is assumed that this exaggerated level will occur in all drinking water throughout the US, and that each individual consumes 2 liters of drinking water per day.
-- When considering structural similarities with other chemicals, fomesafen falls into the class of ``biphenyl ether'' chemical compounds; this means that this group of chemicals have structural similarities, including a biphenyl ether group, in common. This is used as a piece of supporting evidence for the classification of fomesafen as a Group C carcinogen, since other chemicals of this group (with similar structure) have been found to be carcinogens. However, other indications of the carcinogenicity of fomesafen (i.e., increases of adenomas and carcinomas in a mouse study, limited evidence of mutagenic effects) were also used in deciding this cancer classification. At this time, the Agency does not have sufficient understanding of the structural relationship to the mechanism of toxicity of these chemicals to conclude that they may be combined for the purposes of conducting a risk assessment. Although fomesafen contains some chemical structures in common with other chemicals that have been found to be carcinogens, EPA does not yet fully understand the implications of such a relationship, nor how, or if, these structures relate to the toxicological activity of the chemical. For the purposes of this tolerance action, therefore, EPA has not assumed that fomesafen has a common mechanism of toxicity with other substances.
Ref: Federal Register. November 19, 1997. Fomesafen; Pesticide Tolerances for Emergency Exemptions. Final Rule.
http://www.fluoridealert.org/pesticides/Fomesafen.FR.Nov.19.1997.htm

Liver (click on for all fluorinated pesticides)

-- 4. Carcinogenicity. Fomesafen is classified as a Group C carcinogen with a Q^* of 1.9 x 10^-1 (mg/kg/ day)^-1. This classification was based on: (i) Increases in both adenomas and carcinomas at several dose levels in both sexes of mice; (ii) some evidence of reduced latency for the time of tumor appearance; (iii) limited evidence of mutagenic effects; and, (iv) the structural similarity of fomesafen to other biphenyl ether herbicides which have been shown to be carcinogenic.
-- When considering structural similarities with other chemicals, fomesafen falls into the class of ``biphenyl ether'' chemical compounds; this means that this group of chemicals have structural similarities, including a biphenyl ether group, in common. This is used as a piece of supporting evidence for the classification of fomesafen as a Group C carcinogen, since other chemicals of this group (with similar structure) have been found to be carcinogens. However, other indications of the carcinogenicity of fomesafen (i.e., increases of adenomas and carcinomas in a mouse study, limited evidence of mutagenic effects) were also used in deciding this cancer classification. At this time, the Agency does not have sufficient understanding of the structural relationship to the mechanism of toxicity of these chemicals to conclude that they may be combined for the purposes of conducting a risk assessment. Although fomesafen contains some chemical structures in common with other chemicals that have been found to be carcinogens, EPA does not yet fully understand the implications of such a relationship, nor how, or if, these structures relate to the toxicological activity of the chemical. For the purposes of this tolerance action, therefore, EPA has not assumed that fomesafen has a common mechanism of toxicity with other substances.
Ref: Federal Register. November 19, 1997. Fomesafen; Pesticide Tolerances for Emergency Exemptions. Final Rule.
http://www.fluoridealert.org/pesticides/Fomesafen.FR.Nov.19.1997.htm

-- Decreased plasma cholesterol and triglycerides and increased liver weights (reversible at 7 days post-treatment) were observed at 50 mg/kg/day (only dose tested) when administered in the diet of rats for 4 weeks. In a 90-day rat study, dietary administration of 5 mg/kg/day (LOEL) produced alterations in lipid metabolism and increases in liver weight. The NOEL was 0.25 mg/kg/day. In a 26-week dog study, dietary administration of 25 mg/kg/day (LOEL) produced alterations in lipid metabolism and liver changes (changes not defined). The NOEL was 1 mg/ kg/day. Liver toxicity (increased liver masses, discolored hepatocytes, and pigmented Kupffer cells) was observed in a 2-year rat feeding study at 50 mg/kg/day (LOEL). The NOEL was 5 mg/kg/day. Metabolism studies have shown that fomesafen accumulates in the liver. EPA believes that there is sufficient evidence for listing fomesafen on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available hepatic 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.

-- Classification -- C; possible human carcinogen.
-- Animal Carcinogenicity Data. Limited. Sixty-four Charles River CD-1 mice/sex/dose group were dosed for 2 years with fomesafen at 0, 1, 5, 100 and 1000 ppm by dietary incorporation. A double-size control group was used. At 12 months, 24 mice/sex from the controls and 12 mice/sex from the treated groups were killed. In male mice at termination, the incidence of liver adenomas was significantly increased at 1, 100 and 1000 ppm when compared with controls. The incidences of liver carcinomas and a combination of liver adenomas and carcinomas were significantly increased at 1000 ppm. In the females, the incidence of adenomas was increased at 100 and 1000 ppm and carcinomas were increased at 1000 ppm when compared with controls. The incidence of adenomas and carcinomas combined was significantly increased at 100 and 1000 ppm. Both sexes, therefore, showed a progression from benign to malignant tumors with increased dose. Some liver tumors (adenomas and carcinomas) were apparent at the 52-week interval kill. There was increased mortality in the males at 100 and 1000 ppm and in the females at 1000 ppm, due to liver toxicity forcing termination of the study. The 1000 ppm animals were killed at 79 weeks (males) or 89 weeks (females). The MTD appeared to be exceeded at 100 ppm in the males and 1000 ppm in the females. The tumor increases occurred at dose levels of fomesafen that were both below and above the MTD (Huntingdon, 1985).
Ref: US EPA. Fomesafen (CASRN 72178-02-0). IRIS (Integrated Risk Information System).

-- PubMed Abstract: Administration of herbicide fomesafen and of fomesafen combined with one dose of iron to 44 mice during 3 to 14 months caused hyperplastic and preneoplastic changes in the liver tissue which had been described in experimental carcinogenesis* small groups of altered hepatocytes storing glycogen or lipids and foci of small basophilic liver cells occurred as early as after 3 months. Altered hepatocytes were found more frequently in mice getting fomesafen and iron. Later nodular hyperplasia of liver cells developed with nodes 3-20 mm in diameter which mostly consisted of altered hepatocytes with plenty of glycogen. After 12 and 14 month-lasting administration of fomesafen and fomesafen with iron, the hepatocellular carcinoma was proved in 5 mice. In 4 mice, the preneoplastic changes in liver tissue were accompanied by micronodular hyperplasia of liver cells which did not participate on the development of big nodes and hepatocellular carcinoma.
Ref: Cesk Patol 1998. Apr;34(2):67-71. [Morphologic findings in liver tissue in mice after long-term administration of the herbicide fomesafan] by Chlumska A, Fakan F, Krijt J.
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query_old?uid=9624829&form=6&db=m&Dopt=b

Stomach (click on for all fluorinated pesticides)

-- 2. Short - and intermediate - term toxicity. EPA has selected the NOEL of 10 mg/kg/day from the oral rabbit developmental toxicity study for calculation of short- and intermediate-term margins of exposure (MOEs). At the LOEL of 40 mg/kg/day, maternal toxicity included stomach mucosal erosion and death.
Ref: Federal Register. November 19, 1997. Fomesafen; Pesticide Tolerances for Emergency Exemptions. Final Rule.
http://www.fluoridealert.org/pesticides/Fomesafen.FR.Nov.19.1997.htm