Return to Penoxsulam Index Page

Activity: Herbicide (triazolopyrimidine)
Structure:

Adverse Effects:
Bladder
Body Weight Decrease
Cancer: classified as Suggestive Evidence of Carcinogenicity (Mononuclear cell leukemia)
Endocrine: Testicular
Kidney
Leukemia
Liver
Skin

Environmental:
• Penoxsulam is expected to be very mobile in the environment with six degradation products of toxicological concern to be even more mobile than the parent compound.
• Data are not available to fully characterize these degradates and their respective degradation pathways.
• Potential to leach to ground water

Bladder (click on for all fluorinated pesticides)

-- Subchronic toxicity. Dietary exposure to penoxsulam identified the liver and/or urinary tract (kidneys and bladder) as target organs in rats, mice, and dogs following a 4-week and 13-week administration. Effects on the liver were reflected in increased liver weights and hepatocellular hypertrophy, but these effects were not associated with increases in mixed function oxidase (MFO) enzyme activity. Effects noted in the kidneys included crystal deposition, most likely from precipitation of penoxsulam from the urine, with resultant irritation, inflammation, and hyperplasia of renal pelvic transitional epithelium. Other than the crystal deposition in the kidneys, all effects following subchronic exposure to rats appeared to be reversible. Very high doses were associated with significant decreases in body weight, weight gain, and feed consumption.
-- Chronic toxicity. Chronic exposure in the dog indicated that the renal effects were not exacerbated with long-term exposure. Following long-term exposure in rats, the kidneys and urinary bladder were the primary target organs. Histologic changes seen at the end of 2 years of exposure consisted of inflammation and hyperplasia of the renal pelvic transitional epithelium, crystal deposition in the kidneys and urinary bladder, and hyperplasia of the mucosa of the urinary bladder...
Ref: August 6, 2003. Federal Register: August 6, 2003 (Volume 68, Number 151)] [Notices] [Page 46609-46613]. Penoxsulam; Notice of Filing a Pesticide Petition To Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluorideaction.org/pesticides/penoxsulam.fr.aug.6.2003.htm

In subchronic and chronic feeding studies in rats and dogs, the most sensitive target organ was the urothelium of the urinary system. Due to limited solubility in urine, penoxsulam (and/or its metabolites) formed crystals/calculi, which were regularly observed in the pelvis of the kidney and the lumen of the urinary bladder. These crystals/calculi apparently irritated the urothelium in these organs and following repeated dosing lead to numerous secondary effects which resulted in significant damage to the urinary system. In various studies, these secondary effects were manifested as altered clinical chemistry parameters (increased blood urea nitrogen), altered urinalyses parameters (increased urine volume, decreased urine specific gravity), increased absolute and relative kidney weights, gross pathological findings in the kidneys (calculi and roughened surface), and a variety of histopathological findings in the kidney and urinary bladder, particularly hyperplasia, inflammation and mineralization in the pelvic epithelium of the kidney and hyperplasia in the mucosa of the urinary bladder.
Reference: September 2004. US EPA Fact Sheet on Penoxsulam. Page 4.
http://www.fluorideaction.org/pesticides/penoxsulam.epa.fact.sheet.2004.pdf

Body Weight Decrease (click on for all fluorinated pesticides)

(Pages 24-25) In a two-generation reproduction toxicity study (MRID 45830920), XDE-638 (97.7% ai, lot #B-765-44, TSN102058) was administered to 30 male and 30 female Crl:CD (SD) IGS BR rats/dose at dietary concentrations that provided 0,30, 100, or 300 mg/kg/day. On litter was produced in each generation. Fo and F1 parental animals were administered test or control diet for 10 weeks prior to mating, throughout mating, gestation, and lactation and until sacrifice... Absolute body weights of the high-dose F1 males were significantly (p≤0.05; 88-94% of controls) less than those of the controls throughout the study... Food consumption by the high-dose F1 males was significantly less (p≤0.05; 92-93% of controls) than that of the control group for the first two weeks of premating. Body weights of the high-dose Fo and F1 dams were significantly lower (p≤0.05; 87-94% of controls) than that of controls from GD 21 through lactation day 14. The most pronounced effect on body wieght gains during gestation was for days 14-21 when the high-dose Fo and F1 dams had weight gains 79% and 82%, respectively, of the control group levels. Weight changes by the high-dose dams during the first week of lactation consisted of marked weight loss during days 1-4 and a lower weight gain than the controls for days 4-7.... Food consumption by the high-dose Fo dams was significantly less (p≤0.05; 76-88% of controls) than that of the controls on lactation days 1-11. Food consumption by the high dose F1 dams was significantly (p≤0.05; 70-72% of controls) less than that of the controls on lactation days 1-7... High-dose male and female pups from both generations had significantly lower (p≤0.05) body weights on lactation days 4-21 compared with controls.
Ref: June 18, 2007 - Penoxsulam. Human Health Risk Assessment for Proposed Uses on Fish and Shellfish. Docket: EPA-HQ-OPP-2006-0076-0004. USEPA.
http://www.fluorideaction.org/pesticides/EPA-HQ-OPP-2006-0076-0004.pdf

-- Subchronic toxicity. Dietary exposure to penoxsulam identified the liver and/or urinary tract (kidneys and bladder) as target organs in rats, mice, and dogs following a 4-week and 13-week administration. Effects on the liver were reflected in increased liver weights and hepatocellular hypertrophy, but these effects were not associated with increases in mixed function oxidase (MFO) enzyme activity. Effects noted in the kidneys included crystal deposition, most likely from precipitation of penoxsulam from the urine, with resultant irritation, inflammation, and hyperplasia of renal pelvic transitional epithelium. Other than the crystal deposition in the kidneys, all effects following subchronic exposure to rats appeared to be reversible. Very high doses were associated with significant decreases in body weight, weight gain, and feed consumption.
-- Reproductive and developmental toxicity. Penoxsulam did not have any effect on reproductive parameters at dose levels that induced treatment-related effects in parental rats. At the highest dosage tested (HDT) (300 mg/kg/day), body weights and weight gains in both males and females were depressed, liver and/or kidney weights were increased, and histologic changes were noted in the liver (males) and kidneys (females). At 100 mg/kg/day, increased liver weights were recorded in males, with no histologic correlate, and histologic changes noted in the kidneys of females. Transient decreases in pup body weights were seen at the HDT, but dietary concentrations were targeted for adults and consumption of treated diets by the pups resulted in dose levels to the pups approximately 3-fold higher than in adults. A teratogenic potential was not demonstrated for penoxsulam in either rats or rabbits.
Ref: August 6, 2003. Federal Register: August 6, 2003 (Volume 68, Number 151)] [Notices] [Page 46609-46613]. Penoxsulam; Notice of Filing a Pesticide Petition To Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluorideaction.org/pesticides/penoxsulam.fr.aug.6.2003.htm

Cancer (click on for all fluorinated pesticides)

Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential. Mononuclear cell leukemia in Male Fischer 344 rats. Although dosing in male mice was not considered to be adequate, an additional mouse carcinogenicity study was not required.
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

-- Carcinogenicity: Evidence of carcinogenicity in male rats based on possibly treatment related increase incidence of Large Granular Lymphocyte (LGL) Leukemia at 5, 50, & 250 mg/kg/day. Also increase severity at 250 mg/kg/day. Female rats - negative for carcinogenicity, but dosing was only marginally adequate.
-- Carcinogenicity-mice: In males, negative for carcinogenicity at doses tested. Dosing inadequate.
-- The Agency (US EPA) has classified penoxsulam as Suggestive Evidence of Carcinogenicity, But not sufficient to assess human carcinogenic potential and, therefore, quantification of human cancer risk is not required. The weight-of-the-evidence for this classification is as follows: a. Evidence of carcinogenicity (mononuclear cell leukemia (MNCL)) was seen in one sex (males) of one species (rat).b. There was an increased incidence of MNCL at all dose levels with all incidences exceeding the laboratory historical control, however, the dose-response was flat over a wide range of doses. c. Although MNCL is recognized as a common neoplasm in Fischer rats, the mechanism of producing MNCL is not completely understood. Therefore, the significance of MNCL and its biological relevance for human cancer risk remains uncertain and cannot be discounted ...
Ref: September 24, 2004. Penoxsulam Pesticide tolerance. Final Rule. Federal Register.
http://www.fluorideaction.org/pesticides/penoxsulam.fr.sept.24.04.htm

Endocrine: Testicular (click on for all fluorinated pesticides)

-- Significant dose-related effects in the two-generation reproduction study were limited to the delay in preputial separation.
-- 2-Generation Reproduction and fertility effects in rats - Reproductive/Offspring LOAEL = 100 mg/kg/day based on delayed preputial separation
Ref: September 24, 2004. Penoxsulam Pesticide tolerance. Final Rule. Federal Register.
http://www.fluorideaction.org/pesticides/penoxsulam.fr.sept.24.04.htm

-- Preputial separation, an indicator of sexual maturation, was significantly (p#0.05) delayed in mid and high dose F1 males. The mean age at which preputial separation was attained for the control, low, mid, and high dose groups was 43.6, 44.0, 45.5, and 46.0 days, respectively. In addition, at the mid dose, 1 animal did not separate and at the high dose, 3 animals did not separate whereas all animals at the control and low doses did separate. The delay in preputial separation at the mid and high doses was considered to be a treatment-related effect.
-- Endocrine Disruption. For penoxsulam, effects which indicate potential endocrine disruption include kidney lesions (crystals) in female rats and delay in preputial separation in male rats. When the appropriate screening and/or testing protocols being considered under the Agency‘s EDSP have been developed, penoxsulam may be subjected to additional screening and/or testing to better characterize effects related to endocrine disruption.
Reference: September 2004. US EPA Fact Sheet on Penoxsulam. Page 4.
http://www.fluorideaction.org/pesticides/penoxsulam.epa.fact.sheet.2004.pdf

Kidney (click on for all fluorinated pesticides)

-- Subchronic toxicity. Dietary exposure to penoxsulam identified the liver and/or urinary tract (kidneys and bladder) as target organs in rats, mice, and dogs following a 4-week and 13-week administration... Effects noted in the kidneys included crystal deposition, most likely from precipitation of penoxsulam from the urine, with resultant irritation, inflammation, and hyperplasia of renal pelvic transitional epithelium. Other than the crystal deposition in the kidneys, all effects following subchronic exposure to rats appeared to be reversible...
-- Chronic toxicity. Chronic exposure in the dog indicated that the renal effects were not exacerbated with long-term exposure. Following long-term exposure in rats, the kidneys and urinary bladder were the primary target organs. Histologic changes seen at the end of 2 years of exposure consisted of inflammation and hyperplasia of the renal pelvic transitional epithelium, crystal deposition in the kidneys and urinary bladder, and hyperplasia of the mucosa of the urinary bladder...
-- Reproductive and developmental toxicity. Penoxsulam did not have any effect on reproductive parameters at dose levels that induced treatment-related effects in parental rats. At the highest dosage tested (HDT) (300 mg/kg/day), body weights and weight gains in both males and females were depressed, liver and/or kidney weights were increased, and histologic changes were noted in the liver (males) and kidneys (females). At 100 mg/kg/day, increased liver weights were recorded in males, with no histologic correlate, and histologic changes noted in the kidneys of females...
Ref: August 6, 2003. Federal Register: August 6, 2003 (Volume 68, Number 151)] [Notices] [Page 46609-46613]. Penoxsulam; Notice of Filing a Pesticide Petition To Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluorideaction.org/pesticides/penoxsulam.fr.aug.6.2003.htm

-- Endocrine Disruption. For penoxsulam, effects which indicate potential endocrine disruption include kidney lesions (crystals) in female rats and delay in preputial separation in male rats. When the appropriate screening and/or testing protocols being considered under the Agency‘s EDSP have been developed, penoxsulam may be subjected to additional screening and/or testing to better characterize effects related to endocrine disruption.
Reference: September 2004. US EPA Fact Sheet on Penoxsulam. Page 4.
http://www.fluorideaction.org/pesticides/penoxsulam.epa.fact.sheet.2004.pdf

Leukemia (click on for all fluorinated pesticides)

Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential. Mononuclear cell leukemia in Male Fischer 344 rats. Although dosing in male mice was not considered to be adequate, an additional mouse carcinogenicity study was not required.
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

-- Carcinogenicity: Evidence of carcinogenicity in male rats based on possibly treatment related increase incidence of Large Granular Lymphocyte (LGL) Leukemia at 5, 50, & 250 mg/kg/day. Also increase severity at 250 mg/kg/day. Female rats - negative for carcinogenicity, but dosing was only marginally adequate.
-- Carcinogenicity-mice: In males, negative for carcinogenicity at doses tested. Dosing inadequate.
-- The Agency (US EPA) has classified penoxsulam as Suggestive Evidence of Carcinogenicity, But not sufficient to assess human carcinogenic potential and, therefore, quantification of human cancer risk is not required. The weight-of-the-evidence for this classification is as follows: a. Evidence of carcinogenicity (mononuclear cell leukemia (MNCL)) was seen in one sex (males) of one species (rat).b. There was an increased incidence of MNCL at all dose levels with all incidences exceeding the laboratory historical control, however, the dose-response was flat over a wide range of doses. c. Although MNCL is recognized as a common neoplasm in Fischer rats, the mechanism of producing MNCL is not completely understood. Therefore, the significance of MNCL and its biological relevance for human cancer risk remains uncertain and cannot be discounted ...
Ref: September 24, 2004. Penoxsulam Pesticide tolerance. Final Rule. Federal Register.
http://www.fluorideaction.org/pesticides/penoxsulam.fr.sept.24.04.htm

-- Chronic toxicity. Chronic exposure in the dog indicated that the renal effects were not exacerbated with long-term exposure. Following long-term exposure in rats, the kidneys and urinary bladder were the primary target organs. Histologic changes seen at the end of 2 years of exposure consisted of inflammation and hyperplasia of the renal pelvic transitional epithelium, crystal deposition in the kidneys and urinary bladder, and hyperplasia of the mucosa of the urinary bladder. In the mouse, the liver was the primary target organ, and histologic changes consisted of hepatocellular hypertrophy. There were no treatment-related increases in tumors in either rats or mice. The incidence of mononuclear cell leukemia (Fischer rat leukemia) was increased in all groups of treated male rats compared to the concurrent controls. However, the incidences in the treated groups were identical across a 50-fold increase in dosage, and well within the range of control values reported in the literature.
Ref: August 6, 2003. Federal Register: August 6, 2003 (Volume 68, Number 151)] [Notices] [Page 46609-46613]. Penoxsulam; Notice of Filing a Pesticide Petition To Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluorideaction.org/pesticides/penoxsulam.fr.aug.6.2003.htm

In a carcinogenicity study in rats, male and female rats were given penoxsulam in the diet for two years at dose levels of 0, 5, 50 or 250 mg/kg/day. In this study, there was a statistically significant increased incidence of malignant large granular lymphocyte (LGL) leukemia in each of the male treatment groups. The incidence was 24%, 60%, 58% and 60% in the control, low, mid and high dose level groups respectively. There was no dose response with all treated male groups having an approximately 2.5 fold increase over control animals. The incidence in the male treatment groups exceeded the conducting laboratory‘s historical control mean (28.5%) and range (16-40%), but fell within the National Toxicology Program (NTP) historical control data base of mean (50.5%) and range (32-74 %). There was also an increased severity (Stage 3) of LGL leukemia in all the treated male groups compared to the control group. There was no increase in incidence or severity of LGL leukemia for the treated female rats in this study. The dose levels in this study were considered to be adequate in male rats and marginally adequate in female rats to assess the carcinogenicity of penoxsulam.
Reference: September 2004. US EPA Fact Sheet on Penoxsulam. Page 4.
http://www.fluorideaction.org/pesticides/penoxsulam.epa.fact.sheet.2004.pdf

Liver (click on for all fluorinated pesticides)

-- Subchronic toxicity. Dietary exposure to penoxsulam identified the liver and/or urinary tract (kidneys and bladder) as target organs in rats, mice, and dogs following a 4-week and 13-week administration. Effects on the liver were reflected in increased liver weights and hepatocellular hypertrophy, but these effects were not associated with increases in mixed function oxidase (MFO) enzyme activity... Other than the crystal deposition in the kidneys, all effects following subchronic exposure to rats appeared to be reversible. Very high doses were associated with significant decreases in body weight, weight gain, and feed consumption.
-- Reproductive and developmental toxicity. Penoxsulam did not have any effect on reproductive parameters at dose levels that induced treatment-related effects in parental rats. At the highest dosage tested (HDT) (300 mg/kg/day), body weights and weight gains in both males and females were depressed, liver and/or kidney weights were increased, and histologic changes were noted in the liver (males) and kidneys (females). At 100 mg/kg/day, increased liver weights were recorded in males, with no histologic correlate, and histologic changes noted in the kidneys of females...
Ref: August 6, 2003. Federal Register: August 6, 2003 (Volume 68, Number 151)] [Notices] [Page 46609-46613]. Penoxsulam; Notice of Filing a Pesticide Petition To Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluorideaction.org/pesticides/penoxsulam.fr.aug.6.2003.htm

Skin (click on for all fluorinated pesticides)

(Page 22-23): In a developmental toxicity study (MRID 45830917) XDE-638 (Penoxsulam; 97.5% ai, lot #ND05167938, TSN101773) was administered to 25 time-mated female CD rats/dose by gavage in 0.5% aqueous METHOCEL at dose levels of 0, 100, 500, or 1000 mg/kg bw/day on gestation days (GD) 6 through 20, inclusive. On GD 21, surviving females were sacrificed and necropsied. All fetuses were weighed sexed, and examined for external alterations. Approximately one-half of the fetuses from each litter were subjected to visceral examination, and the remaining one-half were subjected to skeletal examinaiton... Malformations were observed in 0, 2, 2 and 3 fetuses and in 0/24, 2/24, 1/25, and 2/22 litters from the control, low-, mid-, and high-dose groups, respectively.... An apparently rare external malformation (cutis laxis*) was observed in 2 fetuses in single litters at both the 500 and 1000 mg/kg/day dose levels. However, based on a weight-of-the-evidence consideration of all the available information/data, it is concluded that the cutis laxis observed inthis study most likely has a genetic etiology. There is insufficient information to conclude that it is a treatment-related effect due to the test material. Therefore, the development toxicity LOAEL for penoxsulam in CD rats is not identied (>1000 mg/kg day), and the developmental toxicity NOAEL is 1000 mg/kg day.
Ref: June 18, 2007 - Penoxsulam. Human Health Risk Assessment for Proposed Uses on Fish and Shellfish. Docket: EPA-HQ-OPP-2006-0076-0004. USEPA.
http://www.fluorideaction.org/pesticides/EPA-HQ-OPP-2006-0076-0004.pdf

NOTE FROM FAN: We could not find the term cutix laxis, only the term Cutis Laxa.
* Definition of Cutis laxa: Pathophysiology: Cutix laxa is characterized by degenerative changes in the elastic fibers resulting in loose, pendulous skin. The skin is sagging, redundant, and stretchable, with reduced elastic recoil.
Ref: eMedicine site: Cutis Laxa (Elastolysis). http://www.emedicine.com/derm/topic93.htm
from Merck.com: : Cutis laxa is a rare disorder of connective tissue that causes the skin to stretch easily and hang in loose folds... Sometimes only the skin is affected, but connective tissues throughout the body can be affected. Cutis laxa is usually hereditary. In some kinds of cutis laxa, the abnormal genes cause problems unrelated to connective tissues - for example, mental retardation.... http://www.merck.com/mmhe/sec23/ch279/ch279e.html