Adverse Effects
Picolinafen
CAS No.
137641-05-5
 
 

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Activity: Herbicide (Pyridinecarboxylic acid)
Structure:


Adverse Effects:
Anemia
Blood
Body Weight Decrease

Bone
Endocrine: Adrenal gland

Endocrine: Thyroid
Liver
Spleen
Environmental

In Canada, a maximum residue limit (MRL) of 0.05 ppm will be proposed for residues of picolinafen on wheat and barley grain.
February 17, 2003 - Canada. Picolinafen. Regulatory Note REG2003-02. Alternative Strategies and Regulatory Affairs Division, Pest Management Regulatory Agency.
http://www.fluorideaction.org/pesticides/picolinafen.canada.feb.2003.pdf


Anemia and Blood (click on for all fluorinated pesticides)

-- In the rat 2-generation reproduction study, reproduction function, reproductive parameters and litter parameters were not influenced by treatment in the first and second generation (P1/P2) parental animals at any dose level up to and including 500 ppm (equal to 39 and 42 mg/kg bw/d in males and females, respectively), the highest dose tested. Hematological findings, increased spleen weights, and histopathological findings indicative of regenerative hemolytic anemia were noted for P1/P2 males and females at 250 ppm (equal to 19 and 21 mg/kg bw/d for males and females, respectively) and above. Hematological findings including lower red blood cell count, hemoglobin, and hematocrit were also noted for male and female second generation (F2) pups at 250 ppm and above on lactation day 21 (only time point evaluated). Although the hematological findings noted in the F2 offspring may be secondary to maternal toxicity, a direct treatment-related effect cannot be dismissed; therefore, these findings were considered to be toxicologically relevant. The NOAEL for parental and offspring toxicity was 50 ppm (equal to 3.7 and 4.0 mg/kg bw/d in males and females, respectively). On the basis of the parental and offspring NOAELs in the rat 2-generation reproductive toxicity study (one litter/generation), there was no indication that neonates were quantitatively more sensitive than adults to the toxic effects of picolinafen.
-- Hematological and histopathological findings indicative of regenerative hemolytic anemia were noted in all species tested. The most sensitive species appears to be the rat. The most appropriate NOAEL for regenerative hemolytic anemia is 50 ppm (equal to 2.4 and 3.0 mg/kg bw/d for males and females, respectively), as determined in the 2-year rat dietary study. The MOE for regenerative hemolytic anemia is 171 compared to the ADI.
Ref: February 17, 2003 - Canada. Picolinafen. Regulatory Note REG2003-02. Alternative Strategies and Regulatory Affairs Division, Pest Management Regulatory Agency.
http://www.fluorideaction.org/pesticides/picolinafen.canada.feb.2003.pdf

Body Weight Decrease (click on for all fluorinated pesticides)

-- In dogs fed picolinafen at dietary concentrations of 0, 50, 150 or 1500 ppm for 12 months body weight gains were decreased in all groups of treated males... Enlarged thyroids and increased thyroid weights were observed at 1500 ppm. Increased follicular hypertrophy in the thyroid was observed in both sexes at 1500 ppm and hyperplasia in the thyroid was observed in females at 1500 ppm. A NOEL could not be established in this study since body weight gain was reduced at all tested doses. The LOEL in this study was 50 ppm, equal to 1.4 mg/kg bw/day in males and 1.6 mg/kg bw/day in females.
Ref: Public Release Summary on Evaluation of the new active PICOLINAFEN in the products SNIPER HERBICIDE & PARAGON HERBICIDE. Australia. National Registration Authority for Agricultural and Veterinary Chemicals November 2000.
http://www.nra.gov.au/publications/prspic.pdf

Determination of Acceptable Daily Intake. The most appropriate NOAEL of 1.4 mg/kg bw/d in the 1-year dietary study in dogs is recommended as the basis for the acceptable daily intake (ADI). Treatment-related findings at the lowest observed adverse effect level (LOAEL), the next highest dose level, included lower body weight and body-weight gain for males (approximately 20 and 48%, respectively). A safety factor of 100 to account for intraspecies and interspecies variations was considered to be adequate; no additional safety factors are required. The recommended ADI is 0.014 mg/kg bw/d.
Ref: Nov 2005 - AC 900001 (Picolinafen). Proposed Regulatory Decision Document. PRDD2005-5. Canadian Pest Management Regulatory Agency (PMRA).
http://www.fluorideaction.org/pesticides/picolinafen.canada.nov05.pdf

Bone (click on for all fluorinated pesticides)

-- In a developmental study, picolinafen was given to rabbits by oral gavage at 0, 5, 20 or 50 mg/kg bw/day on days 6-28 of gestation... The number of resorptions was slightly increased at 50 mg/kg bw/day and an increased incidence of fused sternal centra was observed in foetuses at 50 mg/kg bw/day. The NOEL for maternal toxicity in this study was 5 mg/kg bw/day and the NOEL for embryotoxicity and foetotoxicity was 20 mg/kg bw/day.
-- -- Picolinafen was given to pregnant rats by oral gavage at 0, 100, 500 or 1000 mg/kg bw/day on days 6 to 19 of gestation... The incidence of bipartite ossification in the thoracic vertebrae in foetuses at 1000 mg/kg bw/day was increased, but no other alterations were observed. Since a NOEL for maternal toxicity was not established in this study, a follow-up study using 0, 5, 25 or 50 mg/kg bw/day was conducted. No treatment-related effects were observed on dams or on foetal development... In a developmental study, picolinafen was given to rabbits by oral gavage at 0, 5, 20 or 50 mg/kg bw/day on days 6-28 of gestation. Soft or liquid faeces were observed at 50 mg/kg bw/day and body weight gain and food consumption were reduced at 20 and 50 mg/kg bw/day... The number of resorptions was slightly increased at 50 mg/kg bw/day and an increased incidence of fused sternal centra was observed in foetuses at 50 mg/kg bw/day. The NOEL for maternal toxicity in this study was 5 mg/kg bw/day and the NOEL for embryotoxicity and foetotoxicity was 20 mg/kg bw/day.
Ref: Public Release Summary on Evaluation of the new active PICOLINAFEN in the products SNIPER HERBICIDE & PARAGON HERBICIDE. Australia. National Registration Authority for Agricultural and Veterinary Chemicals November 2000.

http://www.nra.gov.au/publications/prspic.pdf

Histopathological findings were generally characterized by increased incidence/severity of hemosiderin deposition in the spleen and/or Kupffer cells of the liver and extramedullary hematopoiesis in the spleen and/or liver. Under normal physiological conditions a certain amount of hemosiderin deposition is routinely observed in the spleen due to normal breakdown of effete red blood cells; however, for all species tested, increased incidence/severity were noted for both sexes at the higher dose levels. The increased incidence/severity of extramedullary hematopoiesis was most likely a compensatory response to the increased hemolysis of red blood cells noted for all species tested. Other histopathological findings associated with regenerative hemolytic anemia included increased erythropoietic activity in the bone marrow and liver at higher doses. This was noted in rats following 28-day dietary administration at 1000 ppm and was indicated by a change in the myeloid:erythroid ratio from 2:1 in the controls to 1:1 in rats at 1000 ppm. For males, this shift to a more immature, stronger population of red cells at 1000 ppm was considered to account for the slight but significant decrease in erythrocyte osmotic fragility. For females, this correlated with an increased incidence of erythropoiesis in the bone marrow (femur/joint and sternum).
Ref: February 17, 2003 - Canada. Picolinafen. Regulatory Note REG2003-02. Alternative Strategies and Regulatory Affairs Division, Pest Management Regulatory Agency.
http://www.fluorideaction.org/pesticides/picolinafen.canada.feb.2003.pdf

Endocrine: Adrenal (click on for all fluorinated pesticides)

In the 78-week dietary study, there was no evidence to indicate that picolinafen was oncogenic in the mouse. In the rat 2-year dietary study, there was a non-statistically significant, increased incidence of benign neoplasms (benign pheochromocytomas) in the adrenal gland medullary region for males at 500 ppm (highest dose tested). The incidence was within recent historical control data for benign medullary neoplasms. In addition, there was no decrease in the time-to-appearance of the induced tumour and no dose-response relationship in proliferative changes usually associated with neoplasms, benign or malignant, in the adrenal medulla. Published literature indicates that proliferative lesions of the adrenal medulla in male rats occurs at relatively high incidences and can be spontaneous (age-related) in nature. Based on these findings, the slight increased incidence of benign neoplasms in the adrenal gland medullary region noted for males at 500 ppm, was most likely spontaneous in nature and not treatment-related. The weight of evidence suggests that picolinafen is not likely to be oncogenic in humans.
Ref: February 17, 2003 - Canada. Picolinafen. Regulatory Note REG2003-02. Alternative Strategies and Regulatory Affairs Division, Pest Management Regulatory Agency.
http://www.fluorideaction.org/pesticides/picolinafen.canada.feb.2003.pdf

Endocrine: Thyroid (click on for all fluorinated pesticides)

-- In a study in which groups of two dogs per sex were fed picolinafen at dietary concentrations of 0, 100, 1000, 2000, or 10000 ppm for 28 days, food consumption and body weight gain were reduced at 10000 ppm... Thyroid weight was increased in a dose-related manner in dogs at all doses and thyroid enlargement accompanied by histopathological changes was observed at 1000 ppm.
-- In groups of four dogs per sex fed picolinafen at dietary concentrations of 0, 50, 500 or 2500 ppm for 90 days haemoglobin... Thyroids were enlarged at 2500 ppm and thyroid weights were increased in males at 500 ppm and in females at 2500 ppm... Follicular hypertrophy was observed in the thyroid at 500 and 2500 ppm with hyperplasia at 2500 ppm. The NOEL in this study was 50 ppm equal to 1.7 mg/kg bw/day in males and 1.8 mg/kg bw/day in females.
-- In dogs fed picolinafen at dietary concentrations of 0, 50, 150 or 1500 ppm for 12 months body weight gains were decreased in all groups of treated males... Enlarged thyroids and increased thyroid weights were observed at 1500 ppm. Increased follicular hypertrophy in the thyroid was observed in both sexes at 1500 ppm and hyperplasia in the thyroid was observed in females at 1500 ppm. A NOEL could not be established in this study since body weight gain was reduced at all tested doses. The LOEL in this study was 50 ppm, equal to 1.4 mg/kg bw/day in males and 1.6 mg/kg bw/day in females.
Ref: Public Release Summary on Evaluation of the new active PICOLINAFEN in the products SNIPER HERBICIDE & PARAGON HERBICIDE. Australia. National Registration Authority for Agricultural and Veterinary Chemicals November 2000.
http://www.nra.gov.au/publications/prspic.pdf

-- Although findings indicative of hemolytic anemia were noted in dogs following 90-day and 1-year dietary administration, the main target organ appeared to be the thyroid as indicated by increased thyroid weight, diffuse hypertrophy of the thyroid follicular epithelial cells, and scattered foci of thyroid follicular cell hyperplasia, at 500 ppm (17.3 and 20.2 mg/kg bw/d and above for males and females, respectively) and above following 90-day dietary administration and at 1500 ppm (42.7 and 47.1 mg/kg bw/d for males and females, respectively) and above following 1-year dietary administration (the differences noted following 90-day and 1-year dietary administration were due to dose selection). Hormone levels (thyroxine, tri-iodothyronine and thyroid stimulating hormone [TSH]) were not determined. Lower body weight and/or body-weight gain were also noted in dogs at 2500 ppm (equal to 87.5 and 92.1 mg/kg bw/d for males and females, respectively) following 90-day dietary administration and at 150 ppm (1.7 and 1.8 mg/kg bw/d and above for males and females, respectively) and above following 1-year dietary administration. The NOAEL following 90-day dietary administration was 50 ppm (equal to 1.7 and 1.8 mg/kg bw/d for males and females, respectively). The NOAEL following 1-year dietary administration was 50 ppm (equal to 1.4 and 1.6 mg/kg bw/d for males and females, respectively).
-- The treatment-related findings noted in the thyroid (increased thyroid weight, diffuse hypertrophy of the thyroid follicular epithelial cells, and scattered foci of thyroid follicular cell hyperplasia) in dogs following 90-day and 1-year dietary administration may be suggestive of a neurotoxicity potential. Similar lesions were not observed in the rat (including neonates) or mouse following subchronic or chronic dietary exposure and there was no other evidence in any species tested to indicate a neurotoxicity potential. Thyroid hormone (thyroxine, tri-iodothyronine, and TSH) levels were not determined. Thyroid hormones are crucial to normal growth and development in the central nervous system and in the absence of the hormone, brain development can be retarded; therefore, in the absence of thyroid hormone data and in the absence of any human data, these lesions cannot be disregarded and must be considered relevant to humans.
Ref: February 17, 2003 - Canada. Picolinafen. Regulatory Note REG2003-02. Alternative Strategies and Regulatory Affairs Division, Pest Management Regulatory Agency.
http://www.fluorideaction.org/pesticides/picolinafen.canada.feb.2003.pdf

Occupational exposure will be predominately via the dermal route, and of short- to intermediate-term duration. Although a 4-week repeat dose dermal toxicity study is available, it is not considered adequate for occupational and bystander risk assessment since it does not adequately account for the treatment-related findings noted in the thyroid in dogs following 90-day and 1-year dietary administration. To account for these findings, it is recommended that the dog 90 day dietary study be used for the proposed exposure scenarios. The recommended NOAEL is 1.7 mg/kg bw/d. A safety factor of 100 to account for intraspecies and interspecies variations is considered to be adequate; no additional safety factors were used because there was an adequate MOE to the NOAEL of 4.4 mg/kg bw/d for thyroid effects in the 1-year dietary dog study.
Ref: Nov 2005 - AC 900001 (Picolinafen). Proposed Regulatory Decision Document. PRDD2005-5. Canadian Pest Management Regulatory Agency (PMRA).
http://www.fluorideaction.org/pesticides/picolinafen.canada.nov05.pdf

Liver (click on for all fluorinated pesticides)

-- Fat, liver and kidneys contained the highest amounts of picolinafen metabolites labelled on the pyridine ring, whereas the blood, liver, spleen and lungs contained the highest amounts of picolinafen metabolites labelled on the aniline ring.
-- Short-Term Studies All mice fed picolinafen at dietary concentrations of 0, 100, 1000, 2000, 3500 or 7000 ppm for 28 days... Discolouration of the extremities, discoloured organs (kidney, liver, lungs, testes and heart) and haematological changes (increased MCH, MCHC, reticulocyte and Heinz bodies numbers) were observed at 3500 and 7000 ppm. Spleen and liver weights were increased at 2000 ppm and the breakdown products of blood cells accumulated in the liver and spleen and the production of blood cells in the spleen were increased in males at 1000 ppm and females at 2000 ppm. The severity of these histopathological changes increased in a dose-related manner.
-- In a study in which groups of two dogs per sex were fed picolinafen at dietary concentrations of 0, 100, 1000, 2000, or 10000 ppm for 28 days, ... Livers were enlarged, liver weights and liver glycogen increased and serum cholesterol was increased in males at 1000 ppm and females at 2000 ppm.
-- In mice fed picolinafen at dietary concentrations of 0, 50, 500, 1000 or 2000 ppm for 13 week... Liver weight and pigment deposition were increased at 2000 ppm with other histopathological changes observed in the liver of males at 500 ppm and females at 1000 ppm. The spleens of some mice were enlarged and spleen weights were increased in females at 1000 ppm...
- In rats fed picolinafen at dietary concentrations of 0, 80, 400 or 800 ppm ... Liver to body weight ratios were increased in males at 800 ppm and females at 400 and 800 ppm. Pigment deposition was increased in the liver and spleen at 400 and 800 ppm. The NOEL in this study was 80 ppm, equal to 6.4 mg/kg bw/day in males and 6.8 mg/kg bw/day in females.
-- Long-Term Studies In mice fed picolinafen at dietary concentrations of 0, 40, 400 or 800 ppm for 18 months, there was no increase in the incidence of neoplasms... Increased liver weights and histopathological changes were observed in females at 800 ppm with histopathological changes observed in the livers of males at 400 and 800 ppm.
Ref: Public Release Summary on Evaluation of the new active PICOLINAFEN in the products SNIPER HERBICIDE & PARAGON HERBICIDE. Australia. National Registration Authority for Agricultural and Veterinary Chemicals November 2000.

http://www.nra.gov.au/publications/prspic.pdf

Following subchronic and chronic administration, mice also exhibited treatment-related findings in the liver, including centrilobular hepatocellular hypertrophy and hepatocellular vacuolation. These were noted following 28-day, 90-day and 78-week dietary administration. The NOAELs for mice were 23.4, 10.2, and 6.9 mg/kg bw/d following 28-day, 90-day, and 78-week dietary administration, respectively.
Ref: February 17, 2003 - Canada. Picolinafen. Regulatory Note REG2003-02. Alternative Strategies and Regulatory Affairs Division, Pest Management Regulatory Agency.
http://www.fluorideaction.org/pesticides/picolinafen.canada.feb.2003.pdf

Spleen (click on for all fluorinated pesticides)

-- Fat, liver and kidneys contained the highest amounts of picolinafen metabolites labelled on the pyridine ring, whereas the blood, liver, spleen and lungs contained the highest amounts of picolinafen metabolites labelled on the aniline ring.
-- Short-Term Studies. All mice fed picolinafen at dietary concentrations of 0, 100, 1000, 2000, 3500 or 7000 ppm for 28 days survived, but body weight gain was reduced in males at 7000 ppm... Spleen and liver weights were increased at 2000 ppm and the breakdown products of blood cells accumulated in the liver and spleen and the production of blood cells in the spleen were increased in males at 1000 ppm and females at 2000 ppm. The severity of these histopathological changes increased in a dose-related manner.
-- In mice fed picolinafen at dietary concentrations of 0, 50, 500, 1000 or 2000 ppm for 13 weeks, food consumption was decreased in males at 1000 and 2000 ppm... The spleens of some mice were enlarged and spleen weights were increased in females at 1000 ppm. Pigment deposition was increased in the spleen at 500 ppm and extramedullary haematopoiesis was increased in females at 500 ppm males at 1000 ppm. The NOEL in this study was 50 ppm, equal to 10 mg/kg bw/day in males and 13 mg/kg bw/day in females.
-- In mice fed picolinafen at dietary concentrations of 0, 50, 500, 1000 or 2000 ppm for 13 weeks, food consumption was decreased in males at 1000 and 2000 ppm... The spleens of some mice were enlarged and spleen weights were increased in females at 1000 ppm. Pigment deposition was increased in the spleen at 500 ppm and extramedullary haematopoiesis was increased in females at 500 ppm males at 1000 ppm. The NOEL in this study was 50 ppm, equal to 10 mg/kg bw/day in males and 13 mg/kg bw/day in females.
-- In rats fed picolinafen at dietary concentrations of 0, 80, 400 or 800 ppm for 13 weeks body weight gain was slightly reduced in females at 800 ppm... Spleen weights were increased at 400 and 800 ppm in males and 800 ppm in females. Liver to body weight ratios were increased in males at 800 ppm and females at 400 and 800 ppm. Pigment deposition was increased in the liver and spleen at 400 and 800 ppm. The NOEL in this study was 80 ppm, equal to 6.4 mg/kg bw/day in males and 6.8 mg/kg bw/day in females.
-- Long-Term Studies In mice fed picolinafen at dietary concentrations of 0, 40, 400 or 800 ppm for 18 months, there was no increase in the incidence of neoplasms... Splenic enlargement was slightly increased in incidence in females at 400 and 800 ppm. Extramedullary haematopoiesis was observed in the spleens of mice at 800 ppm with increased pigment deposition observed in males at 800 ppm and females at 400 and 800 ppm. The NOEL in this study was 40 ppm, equal to 6.9 mg/kg bw/day for males and 8.2 mg/kg bw/day for females.
-- In rats fed picolinafen at dietary concentrations of 0, 50, 250, or 500 ppm for 24 months there was no increase in the incidence of neoplasms. Haemoglobin, Hct and RBC were reduced at 3 and 6 months only at 250 and 500 ppm. Spleen weights were increased at 500 ppm and the amount of brown pigment observed in the spleen was increased at 250 and 500 ppm at both 12 and 24 months. The NOEL in this study was 50 ppm, equal to 2.4 mg/kg bw/day for males and 3.0 mg/kg bw/day for females.
-- Rats were fed picolinafen at dietary concentration of 0, 50, 250 or 500 ppm in a two-generation reproduction study... The spleen also showed congestion, increased amounts of brown pigment and extramedullary haematopoiesis at 250 and 500 ppm... The NOEL in this study is 50 ppm, equal to 3.7 mg/kg bw/day for males and 4.2 mg/kg bw/day for females.
-- Picolinafen was given to pregnant rats by oral gavage at 0, 100, 500 or 1000 mg/kg bw/day on days 6 to 19 of gestation. One dam at 1000 mg/kg bw/day appeared emaciated and body weight losses associated with reduced food consumption were observed on days 6-12 of gestation at 500 mg/kg bw/day. Spleen weights were increased in dams at 100 mg/kg bw/day and liver to body weight ratios were slightly increased at 500 mg/kg bw/day... The incidence and severity of extramedullary haematopoiesis and haemosiderosis in the spleen was increased in a dose dependent manner in all treated groups...
-- In a developmental study, picolinafen was given to rabbits by oral gavage at 0, 5, 20 or 50 mg/kg bw/day on days 6-28 of gestation... Congestion and haemosiderosis in the spleen were increased in incidence and severity at 20 and 50 mg/kg bw/day and increased extramedullary haematopoiesis was observed at 50 mg/kg bw/day.
Ref: Public Release Summary on Evaluation of the new active PICOLINAFEN in the products SNIPER HERBICIDE & PARAGON HERBICIDE. Australia. National Registration Authority for Agricultural and Veterinary Chemicals November 2000.
http://www.nra.gov.au/publications/prspic.pdf

Environmental (click on for all fluorinated pesticides)

- Potential of major transformation product (CL 153815) to leach and contaminate groundwater (page 71) :

-- The major transformation product: CL 153815 is classified as persistent in soil under anaerobic conditions (page 22). The transformation product, CL 153815, meets the criterion for persistence in sediment. The CL 153815 half-life in sediment (645 days) exceeds the TSMP Track 1 cut-off criterion (≥ 365 days). - (page 44)

Fate Process for CL 153815 - Major Transformation Product:
(page 71)
Anaerobic soil persistent
Aerobic water layer slightly persistent
Aerobic water / anaerobic sediment moderately persistent.
Anaerobic water / anaerobic sediment persistent
Anaerobic water layer persistent
Anaerobic sediment layer persistent

Ref: Nov 2005 - AC 900001 (Picolinafen). Proposed Regulatory Decision Document. PRDD2005-5. Canadian Pest Management Regulatory Agency (PMRA).
http://www.fluorideaction.org/pesticides/picolinafen.canada.nov05.pdf

 
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