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US Food Tolerances

Activity: Herbicide (pyridazinone)
Structure:

Adverse Effects:
Blood
Body Weight Decrease
Bone
Cancer: Possible Human Carcinogen - LIVER
Cholesterol
Endocrine: Ovary
Endocrine: Thyroid
Endocrine: Uterus
Kidney
Liver
Spleen
Environmental

Blood (click on for all fluorinated pesticides)

--Chronic Toxicity and Carcinogenicity. In a 6-month toxicity study, norflurazon technical was administered in the diet to male and female beagle dogs (4/sex/group) at dose levels of 0, 50, 150, or 450 ppm (0, 1.53, 5.02, and 14.27 mg/kg for males; 0, 1.58, 4.77, and 17.75 mg/kg for females). At the 150 ppm dose level, liver weight was increased by 38% in male dogs and by 23% in female dogs. Thyroid weight was increased by 33% in male dogs and 37% in female dogs at this dose level. Also noted at the 150 ppm dose level were increases in cholesterol in both sexes (23-40% in males, 6-34% in females), a decrease in SGPT (36-38% in males, 13-20% in females) and SGOT (4-23% in males, 13-23% in females). At the 450 ppm dose level, similar changes were observed in male and female dogs, with the additional observation of a decrease in red cell count in female dogs (79-92% of control). The systemic NOEL was determined to be 50 ppm (1.53 mg/kg/day [males]; 1.58 mg/kg/day [females] )...
Ref: US EPA REREGISTRATION ELIGIBILITY DECISION NORFLURAZON. LIST A. CASE 0229.
http://www.fluoridealert.org/pesticides/norflurazon.red.epa.pdf

Body Weight Decrease (click on for all fluorinated pesticides)

-- Developmental and Reproductive Toxicity In a developmental toxicity (teratology) study, rats of the Sprague-Dawley strain received either 0, 100, 200, or 400 mg/kg/day norflurazon technical by oral gavage on gestation days 6 through 15 inclusive. The maternal toxicity NOEL was determined to be < 100 mg/kg/day, and the maternal toxicity LEL was determined to be < 100 mg/kg/day, based on reductions in body weight gain for the period of dosing and for the dosing plus post-dosing period. The developmental toxicity NOEL was determined to be > 400 mg/kg/day, and the developmental toxicity LEL was determined to be > 400 mg/kg/day...
-- The studies examining developmental and reproductive toxicity of norflurazon were considered by the Health Effects Division RfD/Peer Review Committee in a meeting held March 16, 1995. Overall, the committee concluded that treatment with norflurazon was associated with reproductive toxicity in the form of increased pup death, increased stillborn pups, and increased pup deaths between days 5-14 of lactation at a dose of 1500 ppm. Developmental toxicity was not evident in treated rats, but developmental toxicity in rabbits was evident at a dose of 60 mg/kg/day in the form of decreased mean fetal weight, slight delays in ossification of the skull and limbs, and an increase in the incidence of 13th ribs. These developmental effects occurred at a dose that was maternally toxic.
Ref: US EPA REREGISTRATION ELIGIBILITY DECISION NORFLURAZON. LIST A. CASE 0229.
http://www.fluoridealert.org/pesticides/norflurazon.red.epa.pdf

Bone (click on for all fluorinated pesticides)

For females (13-50 years) population subgroup, the acute No Observed Adverse Effects Level (NOAEL) of 10 mg/kg/day was established based on increased incidence in skeletal variations observed in the developmental toxicity study in rabbits at the Lowest Observed Adverse Effect Level (LOAEL) of 30 mg/kg/day... The FQPA safety factor to account for the enhanced sensitivity of infants and children be reduced to 3X based on increased incidence in skeletal variations observed in the developmental toxicity study in rabbits. This determination is based on the following: the toxicity database is adequate; the development toxicity studies in the rat and rabbit are acceptable as an multi-generation study; a developmental neurotoxic study is not required because there is no indication of increased susceptibility in young rats to norflurazon exposure; and there are currently no residential uses for norflurazon. The FQPA safety factor is applicable to only females 13-50 population subgroup for acute dietary risk assessment.
Ref: US EPA May 31, 2002. Tolerance Reassessment Progress and Risk Management Decision.
http://www.fluoridealert.org/pesticides/norflurazon.tred.may31.2002.pdf

A developmental toxicity study was conducted in New Zealand White rabbits, which received either 0, 10, 30, or 60 mg/kg/day norflurazon technical by oral gavage on gestation days 7 through 19 inclusive... The developmental toxicity NOEL was determined to be 30 mg/kg/day, and the developmental toxicity LEL was determined to be 60 mg/kg/day, based on statistically significant increases in the fetal incidence of incompletely ossified frontal bones, 16 caudal vertebrae, unossified first metacarpal, unossified middle phalanx of the fifth digit of the forelimb, and unossified proximal epiphysis of the tibia at the 60 mg/kg/day dose level.
Ref: US EPA Reregistration Eligibility Decision: Norflurazon. http://www.fluoridealert.org/pesticides/norflurazon.red.epa.pdf

-- A nine-month oral toxicity study (MRID 00091056) was conducted using the F generation of rats from a two-year carcinogenicity study (MRID 00082019). In this study, rats were given technical norflurazon in the diet at dose levels of 0, 125, 250, or 500 ppm (0, 6.25, 12.5, and 25 mg/kg/day) for 39 weeks. There were no significant effects of norflurazon on survival, body weight, body weight gain, food consumption, food efficiency, hematology, or clinical chemistry in male or female rats at any dose level tested. At 500 ppm, liver weight was increased by 14% and 23% in male and female rats respectively, at 39 weeks. Kidney weight was not significantly affected, but the incidence of hyaline pigment deposition (many tubules) in male rats and hyaline pigment deposition (few tubules) in female rats was increased, as was the incidence of medullary congestion in high dose female rats... (guideline: non-guideline study; classified as core supplementary; MRID 00091056).
-- Developmental and Reproductive Toxicity In a developmental toxicity (teratology) study, rats of the Sprague-Dawley strain received either 0, 100, 200, or 400 mg/kg/day norflurazon technical by oral gavage on gestation days 6 through 15 inclusive. The maternal toxicity NOEL was determined to be < 100 mg/kg/day, and the maternal toxicity LEL was determined to be < 100 mg/kg/day, based on reductions in body weight gain for the period of dosing and for the dosing plus post-dosing period. The developmental toxicity NOEL was determined to be > 400 mg/kg/day, and the developmental toxicity LEL was determined to be > 400 mg/kg/day. Developmental toxicity was suggested at the 400 mg/kg/day dose level in the form of an increase in bipartite thoracic vertebrae (10th-13th) and an increase in rudimentary 14th ribs. However, these increases were not statistically significant and are believed to be secondary to maternal effects at the high dose (guideline 83-3; MRID 00063621).
-- A developmental toxicity study was conducted in New Zealand White rabbits, which received either 0, 10, 30, or 60 mg/kg/day norflurazon technical by oral gavage on gestation days 7 through 19 inclusive. The maternal toxicity NOEL was determined to be 30 mg/kg/day, and the maternal toxicity LEL was determined to be 60 mg/kg/day, based on decreased body weight gain and clinical toxicity (abortion) at this dose level. The developmental toxicity NOEL was determined to be 30 mg/kg/day, and the developmental toxicity LEL was determined to be 60 mg/kg/day, based on statistically significant increases in the fetal incidence of incompletely ossified frontal bones, 16 caudal vertebrae, unossified first metacarpal, unossified middle phalanx of the fifth digit of the forelimb, and unossified proximal epiphysis of the tibia at the 60 mg/kg/day dose level. A 12% decrease in mean fetal weight was also observed at the 60 mg/kg/day dose level (guideline 83-3; MRID 00131151 and 00131152).
-- The studies examining developmental and reproductive toxicity of norflurazon were considered by the Health Effects Division RfD/Peer Review Committee in a meeting held March 16, 1995. Overall, the committee concluded that treatment with norflurazon was associated with reproductive toxicity in the form of increased pup death, increased stillborn pups, and increased pup deaths between days 5-14 of lactation at a dose of 1500 ppm. Developmental toxicity was not evident in treated rats, but developmental toxicity in rabbits was evident at a dose of 60 mg/kg/day in the form of decreased mean fetal weight, slight delays in ossification of the skull and limbs, and an increase in the incidence of 13th ribs. These developmental effects occurred at a dose that was maternally toxic.
-- Toxic Endpoints of Concern Identified for Use in Risk Assessment. The Health Effects Division's (HED) Less than Lifetime Committee selected the following toxicology endpoints for use in risk assessment for norflurazon (Toxicology Endpoint Selection Document, 4/21/95): The endpoint selected for the acute dietary risk assessment is a NOEL of 30 mg/kg/day. This is the developmental NOEL based on increased skeletal variations observed at the dose of 60 mg/kg/day in a rabbit developmental toxicity study.
Ref: US EPA REREGISTRATION ELIGIBILITY DECISION NORFLURAZON. LIST A. CASE 0229.
http://www.fluoridealert.org/pesticides/norflurazon.red.epa.pdf

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

Group C -- Possible Human Carcinogen. Statistically significant increase in comparison to controls in liver adenomas & combined liver adenomas & carcinomas, as well as the statistically significant positive trend for these hepatocellular adenomas & combined adenomas & carcinomas; CD-1 mice (M).
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 C--Possible Human Carcinogen. Reviewed 11/ 2/ 90.
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

As a result of the July 18, 1990 meeting of the OPP/Health Effects Division Carcinogenicity Peer Review Committee, norflurazon was classified as a non quantifiable Group C - possible human carcinogen - based upon statistically significant pair-wise comparisons of the incidence of liver adenomas and combined liver adenomas/ carcinomas as well as statistically positive trends for these lesions in male CD-1 mice receiving 218.8 mg/kg/day norflurazon technical in the diet for up to 104 weeks (MRID 00111649).
Ref: US EPA REREGISTRATION ELIGIBILITY DECISION NORFLURAZON. LIST A. CASE 0229.
http://www.fluoridealert.org/pesticides/norflurazon.red.epa.pdf

Cholesterol (click on for all fluorinated pesticides)

A 90-day rat feeding study at nominal dosages of 0, 12.5, 25.0 and 125.0 mg/kg/day... at the mid-dose level there were increases of cholesterol in both sexes (23 to 40 percent in males, 6 to 34 percent in females), a decrease in SGPT (36 to 38 percent in males, 13 to 20 percent in females) and SGOT (4 to 23 percent in males, 13 to 23 percent in females). At the highest level, similar changes were observed in male and female dogs, with the additional observation of a decrease in red cell count in female dogs (79 to 92 percent of control). The systemic NOEL was determined to be 1.53 mg/kg/day for males and 1.58 mg/kg/day for females. The systemic LEL was determined to be 5.02 mg/kg/day for males and 4.77 mg/kg/day for females, based on increased absolute and relative liver weight and increased cholesterol in both sexes.
Ref: Federal Register: July 29, 1996 [Page 39347-39351]. Norflurazon; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Norflurazon.FR.July.29.1996.htm

The chronic NOAEL of 1.5 mg/kg/day was established based on increased absolute and relative liver weight and increased cholesterol in both sexes in a 6-month feeding study in dogs at the LOAEL of 4.77 mg/kg/day... The acute and chronic dietary exposure analyses are based on the Dietary Exposure Evaluation Model (DEEM TM .) The acute dietary exposure estimates used the entire distribution of single day food consumption. The chronic dietary exposure estimates the three day average consumption for each population subgroup. The DEEM TM analysis was conducted using consumption data from the USDA 1989-92 Continuing Surveys for Food Intake by Individuals (CSFII).
Ref: US EPA May 31, 2002. Tolerance Reassessment Progress and Risk Management Decision.
http://www.fluoridealert.org/pesticides/Norflurazon.TRED.May31.2002.pdf

Endocrine: Ovary (click on for all fluorinated pesticides)

-- A two-year carcinogenicity study was conducted in male and female CD-1 HaM/ICR Swiss mice in which 125 mice/sex/dose were administered technical norflurazon in the diet at dose levels of 0, 85, 340, or 1360 ppm (0, 12.8, 58.7, or 218.8 mg/kg/day) for 100-104 weeks... Increased incidences of enlarged spleen, nephritis, swollen/enlarged liver, and nodular enlargement of the liver were observed in high dose male mice, while increased incidences of pyelonephritis, enlarged liver, and cystic ovaries were observed in high dose female mice. Carcinogenic potential was evidenced by an increased incidence of hepatic adenoma and combined adenoma/carcinoma in high dose male mice. The systemic NOEL was determined to be 12.8 mg/kg/day (85 ppm) for male mice, and 58.7 mg/kg/day (340 ppm) for female mice. The systemic LEL was determined to be 58.7 mg/kg/day (340 ppm) for male mice, based on the increased incidence of enlarged spleen, increased absolute and relative liver weight, and increased incidence of nephritis. The systemic LEL was determined to be 218.8 mg/kg/day (1360 ppm) for female mice, based on the increased incidence of enlarged liver and cystic ovaries, the increased absolute and relative liver weight, and the increased incidence of pyelonephritis (guideline ¤83-2; MRID 00111649).
Ref: US EPA REREGISTRATION ELIGIBILITY DECISION NORFLURAZON. LIST A. CASE 0229.
http://www.fluoridealert.org/PESTICIDES/Norflurazon.RED.EPA.pdf

-- A nine-month oral toxicity study (MRID 00091056) was conducted using the F generation of rats from a two-year carcinogenicity study (MRID 00082019). In this study, rats were given technical norflurazon in the diet at dose levels of 0, 125, 250, or 500 ppm (0, 6.25, 12.5, and 25 mg/kg/day) for 39 weeks... At 500 ppm... Thyroid weight was decreased in males by approximately 30% vs control, while thyroid weight was increased in females between 11-47% vs control. Gonadal weight (left gonad) was increased in female rats by 30%. At 250 ppm, thyroid weight was decreased by 30% in male rats, but was increased by 11-29% in female rats. However, there were no reported microscopic alterations in this organ at any dose level tested. Gonadal weight in female rats was increased by 17% vs. control. The systemic NOEL was determined to be 250 ppm (12.5 mg/kg/day) in both sexes. The systemic LEL was determined to be 500 ppm (25 mg/kg/day) in both sexes, based on the dose-related increase in liver weight in male and female rats at 39 weeks, the increase in gonad weight of females, and the microscopic changes observed in kidneys of both sexes. Although dramatic effects on thyroid weight were observed at 250 ppm in both sexes, there were no data indicating any alteration in histology of this organ. Thus, the weight change, while indicative of an effect of norflurazon, is not supported as a toxic effect based on available data (guideline: non-guideline study; classified as core supplementary; MRID 00091056).
Ref: US EPA REREGISTRATION ELIGIBILITY DECISION NORFLURAZON. LIST A. CASE 0229.
http://www.fluoridealert.org/PESTICIDES/Norflurazon.RED.EPA.pdf

Endocrine: Thyroid (click on for all fluorinated pesticides)

Congestion of the liver, hepatocyte swelling and increased liver weights, and increase in colloid vacuole in the thyroid were observed in dogs fed 450 ppm (10.25 mg/kg/day) norflurazon for 6 months. The NOEL was 150 ppm (3.75 mg/kg/day). An oral RfD of 0.04 mg/ kg/day has been determined. Increased relative liver weight and hypertrophy of the thyroid with depletion of colloid were seen in rats fed 2,500 ppm (125 mg/kg/day) norflurazon for 90 days. The NOEL was 500 ppm (25 mg/kg/day). Hepatic hyperplasia and hypertrophy and increased relative liver weight were noted in a 28-day feeding study in rats. The LOEL was 1,000 ppm (50 mg/kg/day) and the NOEL was 500 ppm (25 mg/kg/ day). Increased relative liver weight and diffuse and smooth granular livers were seen in a 28-day feeding study in mice. The LOEL was 2,520 ppm (328 mg/kg/day) and the NOEL was 420 ppm (55 mg/kg/day). EPA believes that there is sufficient evidence for listing norflurazon on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available hepatic and thyroid toxicity data.
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.

-- A nine-month oral toxicity study (MRID 00091056) was conducted using the F generation of rats from a two-year carcinogenicity study (MRID 00082019). In this study, rats were given technical norflurazon in the diet at dose levels of 0, 125, 250, or 500 ppm (0, 6.25, 12.5, and 25 mg/kg/day) for 39 weeks... At 500 ppm... Thyroid weight was decreased in males by approximately 30% vs control, while thyroid weight was increased in females between 11-47% vs control. Gonadal weight (left gonad) was increased in female rats by 30%. At 250 ppm, thyroid weight was decreased by 30% in male rats, but was increased by 11-29% in female rats. However, there were no reported microscopic alterations in this organ at any dose level tested. Gonadal weight in female rats was increased by 17% vs. control. The systemic NOEL was determined to be 250 ppm (12.5 mg/kg/day) in both sexes. The systemic LEL was determined to be 500 ppm (25 mg/kg/day) in both sexes, based on the dose-related increase in liver weight in male and female rats at 39 weeks, the increase in gonad weight of females, and the microscopic changes observed in kidneys of both sexes. Although dramatic effects on thyroid weight were observed at 250 ppm in both sexes, there were no data indicating any alteration in histology of this organ. Thus, the weight change, while indicative of an effect of norflurazon, is not supported as a toxic effect based on available data (guideline: non-guideline study; classified as core supplementary; MRID 00091056).
-- A chronic toxicity and carcinogenicity study was conducted in Sprague-Dawley rats. In this study, technical norflurazon was administered in the diet at dose levels of 0, 125, 375, or 1025 ppm (0, 6.25, 18.75, or 51.25 mg/kg/day) for 104 weeks... The weight of the thyroid was also increased at the 1025 ppm dose in male rats at 104 weeks. An increased incidence of hydronephrosis was observed in high dose male rats at 52 weeks vs control, while the incidence of nephritis was increased in male rats (terminal sacrifice + dying on test) at the 1025 ppm dose. The incidence of tubular casts was increased in female rats at the high dose in those rats surviving to study termination. Other microscopic alterations observed at the high dose included an increased incidence of parathyroid hyperplasia (both sexes), hemosiderin pigment deposition in the spleen (males only) and liver (both sexes), and endometritis and squamous metaplasia of the uterus (females). The systemic NOEL was determined to be 375 ppm (18.75 mg/kg/day) for both sexes. The systemic LEL was determined to be 1025 ppm (51.25 mg/kg/day) in both sexes, based on the increased kidney weight and accompanying microscopic pathologic changes, as well as the increase in liver weight in male and female rats and the increase in thyroid weight in males. There was no evidence of carcinogenicity for norflurazon (guideline 83-5; MRIDs 00111617 and 00082019). As a result of the July 18, 1990 meeting of the OPP/Health Effects Division Carcinogenicity Peer Review Committee, norflurazon was classified as a non quantifiable Group C - possible human carcinogen - based upon statistically significant pair-wise comparisons of the incidence of liver adenomas and combined liver adenomas/ carcinomas as well as statistically positive trends for these lesions in male CD-1 mice receiving 218.8 mg/kg/day norflurazon technical in the diet for up to 104 weeks (MRID 00111649).
Ref: US EPA REREGISTRATION ELIGIBILITY DECISION NORFLURAZON. LIST A. CASE 0229.
http://www.fluoridealert.org/PESTICIDES/Norflurazon.RED.EPA.pdf

Endocrine: Uterus (click on for all fluorinated pesticides)

-- A two-year carcinogenicity study was conducted in male and female CD-1 HaM/ICR Swiss mice in which 125 mice/sex/dose were administered technical norflurazon in the diet at dose levels of 0, 85, 340, or 1360 ppm (0, 12.8, 58.7, or 218.8 mg/kg/day) for 100-104 weeks... Increased incidences of enlarged spleen, nephritis, swollen/enlarged liver, and nodular enlargement of the liver were observed in high dose male mice, while increased incidences of pyelonephritis, enlarged liver, and cystic ovaries were observed in high dose female mice. Carcinogenic potential was evidenced by an increased incidence of hepatic adenoma and combined adenoma/carcinoma in high dose male mice. The systemic NOEL was determined to be 12.8 mg/kg/day (85 ppm) for male mice, and 58.7 mg/kg/day (340 ppm) for female mice. The systemic LEL was determined to be 58.7 mg/kg/day (340 ppm) for male mice, based on the increased incidence of enlarged spleen, increased absolute and relative liver weight, and increased incidence of nephritis. The systemic LEL was determined to be 218.8 mg/kg/day (1360 ppm) for female mice, based on the increased incidence of enlarged liver and cystic ovaries, the increased absolute and relative liver weight, and the increased incidence of pyelonephritis (guideline ¤83-2; MRID 00111649).
-- A chronic toxicity and carcinogenicity study was conducted in Sprague-Dawley rats. In this study, technical norflurazon was administered in the diet at dose levels of 0, 125, 375, or 1025 ppm (0, 6.25, 18.75, or 51.25 mg/kg/day) for 104 weeks... Other microscopic alterations observed at the high dose included an increased incidence of parathyroid hyperplasia (both sexes), hemosiderin pigment deposition in the spleen (males only) and liver (both sexes), and endometritis and squamous metaplasia of the uterus (females). The systemic NOEL was determined to be 375 ppm (18.75 mg/kg/day) for both sexes. The systemic LEL was determined to be 1025 ppm (51.25 mg/kg/day) in both sexes, based on the increased kidney weight and accompanying microscopic pathologic changes, as well as the increase in liver weight in male and female rats and the increase in thyroid weight in males. There was no evidence of carcinogenicity for norflurazon (guideline 83-5; MRIDs 00111617 and 00082019). As a result of the July 18, 1990 meeting of the OPP/Health Effects Division Carcinogenicity Peer Review Committee, norflurazon was classified as a non quantifiable Group C - possible human carcinogen - based upon statistically significant pair-wise comparisons of the incidence of liver adenomas and combined liver adenomas/ carcinomas as well as statistically positive trends for these lesions in male CD-1 mice receiving 218.8 mg/kg/day norflurazon technical in the diet for up to 104 weeks (MRID 00111649).
Ref: US EPA REREGISTRATION ELIGIBILITY DECISION NORFLURAZON. LIST A. CASE 0229.
http://www.fluoridealert.org/PESTICIDES/Norflurazon.RED.EPA.pdf

Kidney (click on for all fluorinated pesticides)

-- A two-year carcinogenicity study was conducted in male and female CD-1 HaM/ICR Swiss mice in which 125 mice/sex/dose were administered technical norflurazon in the diet at dose levels of 0, 85, 340, or 1360 ppm (0, 12.8, 58.7, or 218.8 mg/kg/day) for 100-104 weeks... The systemic LEL was determined to be 58.7 mg/kg/day (340 ppm) for male mice, based on the increased incidence of enlarged spleen, increased absolute and relative liver weight, and increased incidence of nephritis...
-- A chronic toxicity and carcinogenicity study was conducted in Sprague-Dawley rats. In this study, technical norflurazon was administered in the diet at dose levels of 0, 125, 375, or 1025 ppm (0, 6.25, 18.75, or 51.25 mg/kg/day) for 104 weeks... The systemic LEL was determined to be 1025 ppm (51.25 mg/kg/day) in both sexes, based on the increased kidney weight and accompanying microscopic pathologic changes, as well as the increase in liver weight in male and female rats and the increase in thyroid weight in males...
-- A 2-generation reproductive toxicity study was conducted in male and female Wistar rats. In this study, norflurazon technical was administered in the diet at dose levels of 0, 150, 750, or 1500 ppm over 2 generations (0, 10.2, 50.8, or 102.5 mg/kg/day for F males; 0, 12.1, 0 62.0, or 129.7 mg/kg/day for F females; 0, 13.2, 67.8, or 138.6 0 mg/kg/day for F males; 17.1, 81.7, and 173.0 mg/kg/day for F1 1 females). The NOEL for systemic toxicity was determined to be 150 ppm (10.2 mg/kg/day for males and 12.1 mg/kg/day for females), and the systemic toxicity LEL was determined to be 750 ppm (50.8 mg/kg/day for males and 62.0 mg/kg/day for females), based on significant increases in liver and kidney weights observed in both generations of parental rats and the increased incidence of hepatocellular hypertrophy in both generations of parental rats...
-- A nine-month oral toxicity study (MRID 00091056) was conducted using the F generation of rats from a two-year carcinogenicity study (MRID 00082019). In this study, rats were given technical norflurazon in the diet at dose levels of 0, 125, 250, or 500 ppm (0, 6.25, 12.5, and 25 mg/kg/day) for 39 weeks... Kidney weight was not significantly affected, but the incidence of hyaline pigment deposition (many tubules) in male rats and hyaline pigment deposition (few tubules) in female rats was increased, as was the incidence of medullary congestion in high dose female rats. The incidence of tubular degeneration was increased in both sexes at the 500 ppm dose level. ... The systemic LEL was determined to be 500 ppm (25 mg/kg/day) in both sexes, based on the dose-related increase in liver weight in male and female rats at 39 weeks, the increase in gonad weight of females, and the microscopic changes observed in kidneys of both sexes. Although dramatic effects on thyroid weight were observed at 250 ppm in both sexes, there were no data indicating any alteration in histology of this organ. Thus, the weight change, while indicative of an effect of norflurazon, is not supported as a toxic effect based on available data (guideline: non-guideline study; classified as core supplementary; MRID 00091056).
Ref: US EPA REREGISTRATION ELIGIBILITY DECISION NORFLURAZON. LIST A. CASE 0229.
http://www.fluoridealert.org/PESTICIDES/Norflurazon.RED.EPA.pdf

Liver (click on for all fluorinated pesticides)

Group C -- Possible Human Carcinogen. Statistically significant increase in comparison to controls in liver adenomas & combined liver adenomas & carcinomas, as well as the statistically significant positive trend for these hepatocellular adenomas & combined adenomas & carcinomas; CD-1 mice (M).
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

-- A two-year carcinogenicity study was conducted in male and female CD-1 HaM/ICR Swiss mice in which 125 mice/sex/dose were administered technical norflurazon in the diet at dose levels of 0, 85, 340, or 1360 ppm (0, 12.8, 58.7, or 218.8 mg/kg/day) for 100-104 weeks... Liver weight was increased by 9% and 15% in male and female mice at the 340 ppm dose level, and by 27% and 21% at the 1360 ppm dose level, respectively. The liver to body weight ratio was increased by 19% and 4% in male and female mice at the 340 ppm dose level, and by 43% and 19% at the 1360 ppm dose level, respectively. Increased incidences of enlarged spleen, nephritis, swollen/enlarged liver, and nodular enlargement of the liver were observed in high dose male mice, while increased incidences of pyelonephritis, enlarged liver, and cystic ovaries were observed in high dose female mice. Carcinogenic potential was evidenced by an increased incidence of hepatic adenoma and combined adenoma/carcinoma in high dose male mice. The systemic NOEL was determined to be 12.8 mg/kg/day (85 ppm) for male mice, and 58.7 mg/kg/day (340 ppm) for female mice. The systemic LEL was determined to be 58.7 mg/kg/day (340 ppm) for male mice, based on the increased incidence of enlarged spleen, increased absolute and relative liver weight, and increased incidence of nephritis. The systemic LEL was determined to be 218.8 mg/kg/day (1360 ppm) for female mice, based on the increased incidence of enlarged liver and cystic ovaries, the increased absolute and relative liver weight, and the increased incidence of pyelonephritis (guideline ¤83-2; MRID 00111649).
-- As a result of the July 18, 1990 meeting of the OPP/Health Effects Division Carcinogenicity Peer Review Committee, norflurazon was classified as a non quantifiable Group C - possible human carcinogen - based upon statistically significant pair-wise comparisons of the incidence of liver adenomas and combined liver adenomas/ carcinomas as well as statistically positive trends for these lesions in male CD-1 mice receiving 218.8 mg/kg/day norflurazon technical in the diet for up to 104 weeks (MRID 00111649).
-- A 2-generation reproductive toxicity study was conducted in male and female Wistar rats. In this study, norflurazon technical was administered in the diet at dose levels of 0, 150, 750, or 1500 ppm over 2 generations (0, 10.2, 50.8, or 102.5 mg/kg/day for F males; 0, 12.1, 0 62.0, or 129.7 mg/kg/day for F females; 0, 13.2, 67.8, or 138.6 0 mg/kg/day for F males; 17.1, 81.7, and 173.0 mg/kg/day for F1 1 females). The NOEL for systemic toxicity was determined to be 150 ppm (10.2 mg/kg/day for males and 12.1 mg/kg/day for females), and the systemic toxicity LEL was determined to be 750 ppm (50.8 mg/kg/day for males and 62.0 mg/kg/day for females), based on significant increases in liver and kidney weights observed in both generations of parental rats and the increased incidence of hepatocellular hypertrophy in both generations of parental rats...
Ref: US EPA REREGISTRATION ELIGIBILITY DECISION NORFLURAZON. LIST A. CASE 0229.
http://www.fluoridealert.org/PESTICIDES/Norflurazon.RED.EPA.pdf

Congestion of the liver, hepatocyte swelling and increased liver weights, and increase in colloid vacuole in the thyroid were observed in dogs fed 450 ppm (10.25 mg/kg/day) norflurazon for 6 months. The NOEL was 150 ppm (3.75 mg/kg/day). An oral RfD of 0.04 mg/ kg/day has been determined. Increased relative liver weight and hypertrophy of the thyroid with depletion of colloid were seen in rats fed 2,500 ppm (125 mg/kg/day) norflurazon for 90 days. The NOEL was 500 ppm (25 mg/kg/day). Hepatic hyperplasia and hypertrophy and increased relative liver weight were noted in a 28-day feeding study in rats. The LOEL was 1,000 ppm (50 mg/kg/day) and the NOEL was 500 ppm (25 mg/kg/ day). Increased relative liver weight and diffuse and smooth granular livers were seen in a 28-day feeding study in mice. The LOEL was 2,520 ppm (328 mg/kg/day) and the NOEL was 420 ppm (55 mg/kg/day). EPA believes that there is sufficient evidence for listing norflurazon on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available hepatic and thyroid toxicity data.
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.

The chronic NOAEL of 1.5 mg/kg/day was established based on increased absolute and relative liver weight and increased cholesterol in both sexes in a 6-month feeding study in dogs at the LOAEL of 4.77 mg/kg/day... The acute and chronic dietary exposure analyses are based on the Dietary Exposure Evaluation Model (DEEM TM .) The acute dietary exposure estimates used the entire distribution of single day food consumption. The chronic dietary exposure estimates the three day average consumption for each population subgroup. The DEEM TM analysis was conducted using consumption data from the USDA 1989-92 Continuing Surveys for Food Intake by Individuals (CSFII).
Ref: US EPA May 31, 2002. Tolerance Reassessment Progress and Risk Management Decision.
http://www.fluoridealert.org/pesticides/Norflurazon.TRED.May31.2002.pdf

Spleen (click on for all fluorinated pesticides)

- A two-year carcinogenicity study was conducted in male and female CD-1 HaM/ICR Swiss mice in which 125 mice/sex/dose were administered technical norflurazon in the diet at dose levels of 0, 85, 340, or 1360 ppm (0, 12.8, 58.7, or 218.8 mg/kg/day) for 100-104 weeks. No significant effects were observed on body weight, body weight gain, clinical toxicity, or food consumption at any dose level tested. Liver weight was increased by 9% and 15% in male and female mice at the 340 ppm dose level, and by 27% and 21% at the 1360 ppm dose level, respectively. The liver to body weight ratio was increased by 19% and 4% in male and female mice at the 340 ppm dose level, and by 43% and 19% at the 1360 ppm dose level, respectively. Increased incidences of enlarged spleen, nephritis, swollen/enlarged liver, and nodular enlargement of the liver were observed in high dose male mice, while increased incidences of pyelonephritis, enlarged liver, and cystic ovaries were observed in high dose female mice. Carcinogenic potential was evidenced by an increased incidence of hepatic adenoma and combined adenoma/carcinoma in high dose male mice. The systemic NOEL was determined to be 12.8 mg/kg/day (85 ppm) for male mice, and 58.7 mg/kg/day (340 ppm) for female mice. The systemic LEL was determined to be 58.7 mg/kg/day (340 ppm) for male mice, based on the increased incidence of enlarged spleen, increased absolute and relative liver weight, and increased incidence of nephritis. The systemic LEL was determined to be 218.8 mg/kg/day (1360 ppm) for female mice, based on the increased incidence of enlarged liver and cystic ovaries, the increased absolute and relative liver weight, and the increased incidence of pyelonephritis (guideline ¤83-2; MRID 00111649).
-- A chronic toxicity and carcinogenicity study was conducted in Sprague-Dawley rats. In this study, technical norflurazon was administered in the diet at dose levels of 0, 125, 375, or 1025 ppm (0, 6.25, 18.75, or 51.25 mg/kg/day) for 104 weeks.,, Other microscopic alterations observed at the high dose included an increased incidence of parathyroid hyperplasia (both sexes), hemosiderin pigment deposition in the spleen (males only) and liver (both sexes), and endometritis and squamous metaplasia of the uterus (females). The systemic NOEL was determined to be 375 ppm (18.75 mg/kg/day) for both sexes...
Ref: US EPA REREGISTRATION ELIGIBILITY DECISION NORFLURAZON. LIST A. CASE 0229.
http://www.fluoridealert.org/PESTICIDES/Norflurazon.RED.EPA.pdf