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Activity: Herbicide (Aryloxyphenoxy propionic acid)

Structure:

Adverse Effects:
Body Weight Decrease
Bone
Cancer: Probable Human Carcinogen - LIVER
Cholesterol
Endocrine: Testicular
Endocrine: Thyroid
Heart
Kidney
Liver

-- 1) 2-Year Feeding (carcinogenicity) - mouse: Dietary levels tested: 0, 0.03, 0.065, and 0.6 mg/kg/day; B6C3F1 mice (50/sex/dose) were administered haloxyfop-methyl in the diet for 24 months. High-dose males exhibited a reduced body weight gain, elevated alkaline phosphatase levels, and an increase in relative liver weights. Histopathological observations of the livers from high-dose males and females were characterized by an alteration of the tinctorial staining properties of the hepatocytes. Based on the above effects the LEL for systemic toxicity is 0.6 mg/kg/day. The NOEL for systemic toxicity is 0.065 mg/kg/day.; core grade minimum (Dow Chemical U.S.A., 1985c)
-- 2-Generation Reproduction - rat: Dietary levels tested: 0, 0.01, 0.65, and 1.0 mg/kg/day; Groups Sprague-Dawley rats (30/sex/dose) were administered haloxyfop-methyl. The F0 generation was dosed for 8 weeks and the F1 generation for 11 weeks after each generation was mated. The only apparent effect was reduced body weights of the offspring in the F1a litters at weaning, at 21 days in all treatment groups, and in the 1 mg/kg/day groups of the F1b males and females and F2a males. Although statistically significant, the reductions are not large, amount to 10% or less. It is questionable whether this is a true toxic effect in all exposure groups, since it was not seen in subsequent litters except at the high-dose. No organ weights or histopathological examinations were performed. No maternal or reproductive toxicity was observed at any dose tested. The LEL for developmental toxicity is 1 mg/kg/day based on reduced weanling weight in F1a, F1b, and F2a litters. The NOEL for developmental toxicity is 0.065 mg/kg/day.; core grade supplementary (Dow Chemical U.S.A., 1985b)
-- 5) Developmental toxicity - rat: Dose levels tested: 0, 0.1, 1.0, 7.5, 10, and 25 mg/kg/day; Groups of pregnant Fischer 344 rats (10/dose) were administered haloxyfop-methyl orally during days 6 through 15 of gestation. At the 7.5 mg/kg/day dose a decrease in weight gain and food consumption accompanied by an increase in water intake during gestation was observed. Additional maternal toxicity was observed at 10 and 25 mg/kg/day, including a decrease in weight gain and food consumption accompanied by an increase in liver weight. An increase in the incidence of resorptions was also observed at 10 and 25 mg/kg/day. At 7.5 mg/kg/day, a significant incidence of delayed ossification of the centra of the thoracic vertebra was observed. The NOEL and LEL for maternal toxicity are 1 and 7.5 mg/kg/day, respectively. The NOEL and LEL for developmental toxicity are 1 and 7.5 mg/kg/day, respectively; core grade guideline (Dow Chemical U.S.A., 1983a)
-- 6) Developmental toxicity - rabbit: Dose levels tested: 0, 3, 7.5, and 15 mg/kg/day; Inseminated New Zealand White rabbits (Dams: 27, 28, 30, and 25 for the control, low-, mid-, and high-dose, respectively) were administered haloxyfop-methyl by gavage on days 6 through 18 of gestation. No evidence of developmental toxicity was observed at any dose tested. At the 7.5 mg/kg/day dose level reduced body weight gain on days 6 to 18 was observed. Therefore the NOEL and LEL for maternal toxicity is 3 and 7.5 mg/kg/day, respectively.; core grade minimum (Dow Chemical Co., 1985)
-- 7) Developmental toxicity - rabbit: Dose levels tested: 0, 1.0, 7.5, and 20 mg/kg/day; Inseminated New Zealand White rabbits (30/dose) were administered haloxyfop-methyl orally on days 6 through 18 of gestation. At 20 mg/kg/day, 4/31 pregnant animals died between days 18 and 24 of gestation with 1/31 pregnant animals dead on day 8 of gestation. A decrease in weight gain was also observed at 20 mg/kg/day. Body weight gain at the 7.5 mg/kg/day was comparable to controls. At 20 mg/kg/day, a significant increase in the incidence of resorbed implantations was reported. The LEL for maternal toxicity is 20 mg/kg/day based on dam mortality and decreased weight gain. The NOEL for maternal toxicity is 7.5 mg/kg/day. The LEL for fetotoxicity is 20 mg/kg/day based on the increase in resorptions. The NOEL for fetotoxicity is 7.5 mg/kg/day; core grade guideline (Dow Chemical U.S.A., 1983b)
Ref: Health Assessment. US EPA Integrated Risk Information System (IRIS).
http://www.fluoridealert.org/pesticides/Haloxyfop.Methyl.IRIS.htm

Bone (click on for all fluorinated pesticides)

-- 5) Developmental toxicity - rat: Dose levels tested: 0, 0.1, 1.0, 7.5, 10, and 25 mg/kg/day; Groups of pregnant Fischer 344 rats (10/dose) were administered haloxyfop-methyl orally during days 6 through 15 of gestation. At the 7.5 mg/kg/day dose a decrease in weight gain and food consumption accompanied by an increase in water intake during gestation was observed. Additional maternal toxicity was observed at 10 and 25 mg/kg/day, including a decrease in weight gain and food consumption accompanied by an increase in liver weight. An increase in the incidence of resorptions was also observed at 10 and 25 mg/kg/day. At 7.5 mg/kg/day, a significant incidence of delayed ossification of the centra of the thoracic vertebra was observed. The NOEL and LEL for maternal toxicity are 1 and 7.5 mg/kg/day, respectively. The NOEL and LEL for developmental toxicity are 1 and 7.5 mg/kg/day, respectively; core grade guideline (Dow Chemical U.S.A., 1983a)
Ref: Health Assessment. US EPA Integrated Risk Information System (IRIS).
http://www.fluoridealert.org/pesticides/Haloxyfop.Methyl.IRIS.htm

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

Group B -- Probable Human Carcinogen. Liver tumors [adenomas (M), carcinomas (F) & adenomas/carcinomas (M & F)]; B6C3F1 mice.
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 9/ 18/ 89.
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

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. Except for haloxyfop-methyl, all of the other chemicals produced positive results in at least one of the mutagenicity assays...
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.
Note: Except for Nitrofen, all the pesticides cited above are fluorinated.

Cholesterol (click on for all fluorinated pesticides)

-- 13-Week Feeding - dog: Dietary levels tested: 0, 2, 5, and 20 mg/kg/day; Beagle dogs (4/sex/dose level) were administered haloxyfop-methyl in the diet for 13 weeks. A statistically significant decrease in serum cholesterol values was reported for males fed 2 mg/kg/day. A statistically significant decrease in serum cholesterol values was reported for males and females fed 5 mg/kg/day. A significant decrease in male and female triiodothyronine and free thyroxine values was accompanied by a significant decrease in male and female relative thyroid/parathyroid weights. Hepatic peroxisomal fatty acid beta-oxidation was increased in males and females fed 5 mg/kg/day. Histological changes reported at this level were hepatocellular enlargement with increased glycogen content, decrease in follicular size and hypertrophy of the follicular epithelial cells of the thyroid, and decrease size of the testicular tubules. The LEL for systemic toxicity is 2 mg/kg/day, the lowest dose tested, based on decreases in serum cholesterol values in males. A NOEL for systemic toxicity was not established; core grade minimum (Dow Chemical Co., 1987a)
Ref: Health Assessment. US EPA Integrated Risk Information System (IRIS).
http://www.fluoridealert.org/pesticides/Haloxyfop.Methyl.IRIS.htm

Endocrine: Testicular (click on for all fluorinated pesticides)

-- 2) 13-Week Feeding - dog: Dietary levels tested: 0, 2, 5, and 20 mg/kg/day; Beagle dogs (4/sex/dose level) were administered haloxyfop-methyl in the diet for 13 weeks. A statistically significant decrease in serum cholesterol values was reported for males fed 2 mg/kg/day. A statistically significant decrease in serum cholesterol values was reported for males and females fed 5 mg/kg/day. A significant decrease in male and female triiodothyronine and free thyroxine values was accompanied by a significant decrease in male and female relative thyroid/parathyroid weights. Hepatic peroxisomal fatty acid beta-oxidation was increased in males and females fed 5 mg/kg/day. Histological changes reported at this level were hepatocellular enlargement with increased glycogen content, decrease in follicular size and hypertrophy of the follicular epithelial cells of the thyroid, and decrease size of the testicular tubules. The LEL for systemic toxicity is 2 mg/kg/day, the lowest dose tested, based on decreases in serum cholesterol values in males. A NOEL for systemic toxicity was not established; core grade minimum (Dow Chemical Co., 1987a)
-- 4) 16-Week Feeding - rat: Dietary levels tested: 0, 0.002, 0.02, 0.2, and 2 mg/kg/day; CDF Fischer 344 rats (15/sex/group) were administered haloxyfop- methyl in the diet for 16 weeks. A significant dose-related increase in relative liver weight was reported for male rats of the 0.002, 0.02, 0.2, and 2.0 mg/kg/day levels by 4, 5, 11, and 44%, respectively. Female relative liver weights were increased significantly (4%) at the 2.0 mg/kg/day levels. Males fed the 0.2 and 2.0 mg/kg/day levels showed enlarged hepatocytes and increased cytoplasmic homogeneity. An increase in hepatocellular cytoplasmic homogeneity was reported for females at 2.0 mg/kg/day. A significant decrease in relative testes weight (5%) accompanied by atrophy of the seminiferous tubules were reported for males fed the 2.0 mg/kg/day level. The LEL for systemic toxicity is 0.002 mg/kg/day, the lowest dose tested, based on a dose related increase in relative liver weight in males. A NOEL for systemic toxicity was not established.; core grade minimum (Dow Chemical U.S.A., 1982a)
-- Critical Effect: Reduced relative kidney weights in F0, F1, and F2b adults; Reduced fertility in the F1/F2b generation. 3-Generation Rat Reproduction Study. Dow Chemical U.S.A.,1985a. NOEL: 0.005 mg/kg/day; LEL: 0.05 mg/kg/day....
Ref: Health Assessment. US EPA Integrated Risk Information System (IRIS).
http://www.fluoridealert.org/pesticides/Haloxyfop.Methyl.IRIS.htm

Endocrine: Thyroid (click on for all fluorinated pesticides)

-- 2) 13-Week Feeding - dog: Dietary levels tested: 0, 2, 5, and 20 mg/kg/day; Beagle dogs (4/sex/dose level) were administered haloxyfop-methyl in the diet for 13 weeks. A statistically significant decrease in serum cholesterol values was reported for males fed 2 mg/kg/day. A statistically significant decrease in serum cholesterol values was reported for males and females fed 5 mg/kg/day. A significant decrease in male and female triiodothyronine and free thyroxine values was accompanied by a significant decrease in male and female relative thyroid/parathyroid weights. Hepatic peroxisomal fatty acid beta-oxidation was increased in males and females fed 5 mg/kg/day. Histological changes reported at this level were hepatocellular enlargement with increased glycogen content, decrease in follicular size and hypertrophy of the follicular epithelial cells of the thyroid, and decrease size of the testicular tubules. The LEL for systemic toxicity is 2 mg/kg/day, the lowest dose tested, based on decreases in serum cholesterol values in males. A NOEL for systemic toxicity was not established; core grade minimum (Dow Chemical Co., 1987a)
Ref: Health Assessment. US EPA Integrated Risk Information System (IRIS).
http://www.fluoridealert.org/pesticides/Haloxyfop.Methyl.IRIS.htm

Heart (click on for all fluorinated pesticides)

-- 7) 36-Week Feeding - mouse: Dietary levels tested: 0, 0.02, and 2.0 mg/kg/day; B6C3F1 mice (10/sex/group) were administered haloxyfop-methyl in the diet for 9 months. A significant increase in serum alkaline phosphatase was reported for males at the 2.0 mg/kg/day level with a slight increase in serum alkaline phosphatase for females. The liver was slightly enlarged and darkened for both males and females at 2.0 mg/kg/day. A significant increase in the liver absolute weight and organ-to-body weight ratio of both males and females fed 2.0 mg/kg/day was observed. Males also exhibited a significant decrease in kidney and heart weights compared with the control organ weight. Livers of males and females at the 2.0 mg/kg/day dose exhibited an enlargement of centrilobular hepatocytes cells with an increase cytoplasmic homogenity and increased eosinophilia. Kidneys of males fed 2.0 mg/kg/day showed a decrease of cytoplasmic vacuolation of the proximal convoluted tubular cells. Based on the above effects, the LEL for systemic toxicity is 2.0 mg/kg/day. The NOEL for systemic toxicity is 0.02 mg/kg/day; core supplementary (Dow Chemical U.S.A., 1982d)
Ref: Health Assessment. US EPA Integrated Risk Information System (IRIS).
http://www.fluoridealert.org/pesticides/Haloxyfop.Methyl.IRIS.htm

Kidney (click on for all fluorinated pesticides)

-- 3) 13-Week Feeding - monkey: Dietary levels tested: 0, 2, 10, and 30 mg/kg/day; Cynomolgus monkeys (4/sex/dose level) were administered haloxyfop- methyl by nasogastric intubation for 13 weeks. A statistically significant decrease in triglyceride values was reported for males and females dosed at 2 mg/kg/day. The statistically significant decrease in triglyceride values in males and females dosed at 10 mg/kg/day was accompanied by a nonsignificant decrease (15%) in cholesterol values for females at this level. Female livers appeared pale with an accentuated lobular pattern. Slight hepatocellular hypertrophy was observed for male and females at this level. Relative kidney weights were significantly increase for males and females by 12 and 37%, respectively. The LEL for systemic toxicity is 2 mg/kg/day, the lowest dose tested, based on a statistically significant decrease in triglyceride values in males and females. A NOEL for systemic toxicity was not established; core grade minimum (Dow Chemical Co., 1987b)
-- 7) 36-Week Feeding - mouse: Dietary levels tested: 0, 0.02, and 2.0 mg/kg/day; B6C3F1 mice (10/sex/group) were administered haloxyfop-methyl in the diet for 9 months. A significant increase in serum alkaline phosphatase was reported for males at the 2.0 mg/kg/day level with a slight increase in serum alkaline phosphatase for females. The liver was slightly enlarged and darkened for both males and females at 2.0 mg/kg/day. A significant increase in the liver absolute weight and organ-to-body weight ratio of both males and females fed 2.0 mg/kg/day was observed. Males also exhibited a significant decrease in kidney and heart weights compared with the control organ weight. Livers of males and females at the 2.0 mg/kg/day dose exhibited an enlargement of centrilobular hepatocytes cells with an increase cytoplasmic homogenity and increased eosinophilia. Kidneys of males fed 2.0 mg/kg/day showed a decrease of cytoplasmic vacuolation of the proximal convoluted tubular cells. Based on the above effects, the LEL for systemic toxicity is 2.0 mg/kg/day. The NOEL for systemic toxicity is 0.02 mg/kg/day; core supplementary (Dow Chemical U.S.A., 1982d)
-- Critical Effect: Reduced relative kidney weights in F0, F1, and F2b adults; Reduced fertility in the F1/F2b generation. 3-Generation Rat Reproduction Study. Dow Chemical U.S.A.,1985a. NOEL: 0.005 mg/kg/day; LEL: 0.05 mg/kg/day.... Signs of toxicity in parental rats at 1 mg/kg/day level were reduced body weight gain and reduced food consumption without increased mortality or obvious toxicity to the offspring. In addition, a significant increase in relative liver weight and enlarged livers were observed, however this finding was more frequent in males than females. A significant decrease in relative kidney weight was observed at 0.05 and 1 mg/kg/day, but it again occurred more frequently in the F0, F1, and F2b adult male rats. Renal pigmentation was also reported at 1 mg/kg/day for male and female adult rats after the gross and histopathological examinations. Based on decreases in relative kidney weights, the LEL for systemic toxicity is 0.05 mg/kg/day. The NOEL for systemic toxicity is 0.005 mg/kg/day.
-- 4) 2-Year Feeding (carcinogenicity) - rat: Dietary levels tested: Male: 0, 0.01, 0.03, 0.065, and 0.1 mg/kg/day; Female: 0, 0.01, 0.03, 0.065, and 1.0 mg/kg/day; CDF Fischer 344 rats (50/sex/dose) were administered haloxyfop- methyl in the diet for 2 years. No effects were observed in the male at any dose tested. The LEL for systemic toxicity is 1 mg/kg/day based on a significant decrease in female absolute (8%) and relative (9%) kidney weights accompanied by a significant increase in the incidence (24/50) in renal pigmentation reported for females of this level. Kidney function was not impaired as the urinalysis parameters between test and control values were comparable. The NOEL for systemic toxicity is 0.065 mg/kg/day; core grade guideline for chronic toxicity (Dow Chemical U.S.A., 1984b)
Ref: Health Assessment. US EPA Integrated Risk Information System (IRIS).
http://www.fluoridealert.org/pesticides/Haloxyfop.Methyl.IRIS.htm

Liver (click on for all fluorinated pesticides)

Group B -- Probable Human Carcinogen. Liver tumors [adenomas (M), carcinomas (F) & adenomas/carcinomas (M & F)]; B6C3F1 mice.
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 9/ 18/ 89.
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

"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

-- 1) 2-Year Feeding (carcinogenicity) - mouse: Dietary levels tested: 0, 0.03, 0.065, and 0.6 mg/kg/day; B6C3F1 mice (50/sex/dose) were administered haloxyfop-methyl in the diet for 24 months. High-dose males exhibited a reduced body weight gain, elevated alkaline phosphatase levels, and an increase in relative liver weights. Histopathological observations of the livers from high-dose males and females were characterized by an alteration of the tinctorial staining properties of the hepatocytes. Based on the above effects the LEL for systemic toxicity is 0.6 mg/kg/day. The NOEL for systemic toxicity is 0.065 mg/kg/day.; core grade minimum (Dow Chemical U.S.A., 1985c)
-- 4) 16-Week Feeding - rat: Dietary levels tested: 0, 0.002, 0.02, 0.2, and 2 mg/kg/day; CDF Fischer 344 rats (15/sex/group) were administered haloxyfop- methyl in the diet for 16 weeks. A significant dose-related increase in relative liver weight was reported for male rats of the 0.002, 0.02, 0.2, and 2.0 mg/kg/day levels by 4, 5, 11, and 44%, respectively. Female relative liver weights were increased significantly (4%) at the 2.0 mg/kg/day levels. Males fed the 0.2 and 2.0 mg/kg/day levels showed enlarged hepatocytes and increased cytoplasmic homogeneity. An increase in hepatocellular cytoplasmic homogeneity was reported for females at 2.0 mg/kg/day. A significant decrease in relative testes weight (5%) accompanied by atrophy of the seminiferous tubules were reported for males fed the 2.0 mg/kg/day level. The LEL for systemic toxicity is 0.002 mg/kg/day, the lowest dose tested, based on a dose related increase in relative liver weight in males. A NOEL for systemic toxicity was not established.; core grade minimum (Dow Chemical U.S.A., 1982a)
-- 7) 36-Week Feeding - mouse: Dietary levels tested: 0, 0.02, and 2.0 mg/kg/day; B6C3F1 mice (10/sex/group) were administered haloxyfop-methyl in the diet for 9 months. A significant increase in serum alkaline phosphatase was reported for males at the 2.0 mg/kg/day level with a slight increase in serum alkaline phosphatase for females. The liver was slightly enlarged and darkened for both males and females at 2.0 mg/kg/day. A significant increase in the liver absolute weight and organ-to-body weight ratio of both males and females fed 2.0 mg/kg/day was observed. Males also exhibited a significant decrease in kidney and heart weights compared with the control organ weight. Livers of males and females at the 2.0 mg/kg/day dose exhibited an enlargement of centrilobular hepatocytes cells with an increase cytoplasmic homogenity and increased eosinophilia. Kidneys of males fed 2.0 mg/kg/day showed a decrease of cytoplasmic vacuolation of the proximal convoluted tubular cells. Based on the above effects, the LEL for systemic toxicity is 2.0 mg/kg/day. The NOEL for systemic toxicity is 0.02 mg/kg/day; core supplementary (Dow Chemical U.S.A., 1982d)
-- Critical Effect: Reduced relative kidney weights in F0, F1, and F2b adults; Reduced fertility in the F1/F2b generation. 3-Generation Rat Reproduction Study. Dow Chemical U.S.A.,1985a. NOEL: 0.005 mg/kg/day; LEL: 0.05 mg/kg/day.... Signs of toxicity in parental rats at 1 mg/kg/day level were reduced body weight gain and reduced food consumption without increased mortality or obvious toxicity to the offspring. In addition, a significant increase in relative liver weight and enlarged livers were observed, however this finding was more frequent in males than females. A significant decrease in relative kidney weight was observed at 0.05 and 1 mg/kg/day, but it again occurred more frequently in the F0, F1, and F2b adult male rats. Renal pigmentation was also reported at 1 mg/kg/day for male and female adult rats after the gross and histopathological examinations. Based on decreases in relative kidney weights, the LEL for systemic toxicity is 0.05 mg/kg/day. The NOEL for systemic toxicity is 0.005 mg/kg/day.
Ref: Health Assessment. US EPA Integrated Risk Information System (IRIS).
http://www.fluoridealert.org/pesticides/Haloxyfop.Methyl.IRIS.htm