Return to Tolylfluanid Index Page

Activity: Fungicide, Insecticide (phenylsulfamide)
Structure:

Adverse Effects:
Body Weight Decrease
Bone - including Arthrogryposis
Cancer: Likely to be Carcinogenic to Humans - THYROID
Clastogenic
Cytotoxic
Endocrine: Thyroid
Eye
Kidney
Liver
Reproductive/Developmental
Thyroid
Environmental

Body Weight Decrease (click on for all fluorinated pesticides)

-- 90-Day oral toxicity rodents (rat). NOAEL = 20.1 milligram/kilogram/ day (mg/kg/day) male (M) LOAEL = 108 mg/kg/ day, based on changes in clinical blood chemistry associated with the liver and thyroid (M) NOAEL = 131 mg/kg/day female (F) LOAEL = 736.1 mg/kg/ day, based on changes in clinical blood chemistry associated with the liver and thyroid and decreased body weights (F)
-- 90-Day oral toxicity in nonrodents (dog). NOAEL = 23.1/25 mg/kg/ day (F/M) LOAEL = 67.2/69.4 (F/ M) mg/kg/day, based on decreased body weight gains and changes in liver structure and function in both sexes
-- Prenatal developmental in rodents (rat). Maternal NOAEL = not determined LOAEL = 100 mg/kg/ day, based on decreased body weight gains and food consumption.
-- Prenatal developmental in rodents (rat). Maternal NOAEL = 100 mg/kg/day LOAEL = 300 mg/kg/ day, based on dose- related decreased body weight gains during the dosing interval. Developmental NOAEL > 1,000 mg/kg/day (HDT) LOAEL = not identified
-- Prenatal developmental in nonrodents (rabbit). Maternal NOAEL = 25 mg/kg/day LOAEL = 70 mg/kg/day, based on evidence of hepatotoxicity (increased glutamate dehydrogenase (GLDH) and triglyceride levels and gross and microscopic liver pathology) and decreased food consumption and equivocal decreases in body weight gain. Developmental NOAEL = 25 mg/kg/day LOAEL= 70 mg/kg/day, based on increased malformations (arthrogryposis of front extremities and small orbital cavity/folded retina) and variations (floating rib and accelerated ossification).
-- 2-Generation reproduction and fertility effects (rat). Parental/systemic NOAEL = 7.9-10.5 mg/ kg/day LOAEL = 57.5-78.0 mg/ kg/day, based on decreased body weights, body weight gains, and liver weights in the P females Reproductive NOAEL = 7.9-10.5 mg/kg/day LOAEL = 57.5-78.0 mg/ kg/day, based on reduced litter size Offspring NOAEL = 7.9- 10.5 mg/kg/day LOAEL = 57.5-78.0 mg/ kg/day, based on decreased pup weights, increased pup deaths and related pup viability indices.
-- 2-Generation reproduction and effects (rat). Parental/Systemic NOAEL = 20.1-26.3 mg/ fertility kg/day LOAEL = 83.4-109.5 mg/ kg/day, based on decreased body weights and body weight gains Reproductive NOAEL = 83.4 - 109.5 mg/kg/ day LOAEL = 335.6-492.4 mg/kg/day, based on decreased mean litter size Offspring NOAEL = 20.1-26.3 mg/kg/day LOAEL = 83.4-109.5 mg/ kg/day, based on decreased pup weights
-- 2-Generation reproduction and fertility effects (rat). Parental/Systemic NOAEL = 75 mg/kg/day LOAEL = 375 mg/kg/ day, based on decreased body weights and body weight gains for both generations Reproductive NOAEL > 375 mg/kg/day (HDT) LOAEL not established Offspring NOAEL = 75 mg/kg/day LOAEL = 375 mg/kg/ day, based on decreased survival and reduced body weights during lactation
-- Chronic toxicity (dog). NOAEL = 12.5 mg/kg/ day LOAEL = 62.5 mg/kg/ day (M), based on decreased body weight gains
Ref: Federal Register: September 25, 2002. Tolylfluanid; Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluoridealert.org/pesticides/Tolylfluanid.FR.Sept25.2002.htm

Bone (click on for all fluorinated pesticides)

See Tables on accumulation in bone and teeth excerpted from:
February 2005 European Commission Report: Final addendum to the Draft Assessment Report (DAR) - public version - Initial risk assessment provided by the rapporteur Member State Finland for the existing active substance TOLYLFLUANID of the second stage of the review programme referred to in Article 8(2) of Council Directive 91/414/EEC
http://www.fluorideaction.org/pesticides/epage.tolylfluanid.bone.eu.html

In all species tested, the concentrations of fluoride in the bone and teeth were increased in a dose-related manner. At high doses, this increase was associated with discolouration, particularly of the skull cap and incisors, in both sexes but starting at lower doses in male rats. In long-term studies, rats at 7500 ppm, equal to 500 mg/kg bw per day, required treatment for overgrown incisors more frequently than controls, presumably because fluoride deposition in the incisors had increased their strength and thus decreased the wear on these teeth. Hyperostosis of the skull and sternum was seen at high doses in mice and rats of either sex, and histopathological changes were seen in the bones of female mice at 300 ppm (equal to 120 mg/kg bw per day) and female rats at 1500 ppm (equal to 100 mg/kg bw per day). In both sexes, increased fluoride deposition was seen at 300 ppm, equal to 76 mg/kg bw per day, in mice and 18 mg/kg bw per day in rats. The NOAEL for fluoride deposition was 60 ppm, equal to 15 mg/kg bw per day, in mice, and 60 ppm, equal to 3.6 mg/kg bw per day, in rats. In dogs, the fluoride concentration in bone was increased in males at doses of 80 mg/kg bw per day and in females at 20 mg/kg bw per day and above, while the fluoride concentration in teeth was increased in males at 80 mg/kg bw per day and in females at all doses including the lowest one tested, 5 mg/kg bw per day, although not in a dose-related manner. The increase in fluoride deposition raises concern because mottling of dental enamel (or dental fluorosis) occurs in humans after exposure to high concentrations of fluoride, particularly where water has a high concentration of fluoride or has been inappropriately supplemented. While this is mainly a cosmetic defect, it is generally recognized as adverse. (page 254-255)
..........The Meeting established an ADI of 0–0.08 mg/kg bw on the basis of the NOAEL of 60 ppm, equal to 3.6 mg/kg bw per day, in the 2-year study in rats, in which increased fluoride deposition was seen at higher doses, and a safety factor of 50. This safety factor was used because of the limited differences noted between species in the deposition of fluoride in bones and teeth after administration of tolylfluanid. The NOAEL in the 2-year study in rats treated in the diet was used in preference to the LOAEL of 5 mg/kg bw per day in the 1-year study in dogs given tolylfluanid by capsule, as increased fluoride concentrations were seen only in the teeth and the low dose in the study in dogs, without a clear dose–response relationship... (page 256)
..........Metabolism involves cleavage of the fluorodichloromethylthio group from tolylfluanid to form N,N-dimethyl-N’-p-tolysulfamide (dimethylaminosulfotoluidine, DMST). The fluorodichloromethylsulfenyl side-chain undergoes further metabolism to form thiazolidine-2-thioxo-4-carboxylic acid, which is the main metabolite in the urine of rats and is of toxicological significance because of its potential anti-thyroid effects. Dimethyltolylsulfamide is also further metabolized, producing a range of metabolites that are not of toxicological significance. The release of the fluoride ion and its distribution in the body have not been clearly characterized. (page 254)
..........Studies that would provide information useful for continued evaluation of the compound (page 257)
• Further characterization of the distribution and excretion of fluoride and thiazolidine-2-thione4-carboxylic acid, particularly in milk
• Investigation of the cause of decreased pup survival during lactation
• Further observations in humans
Ref: Pesticide residues in food - 2002. Report of the Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Core Assessment Group on Pesticide Residues. Rome, Italy. 16- 25 September 2002. ISBN 92-5-104858-4.
http://www.fluorideaction.org/pesticides/tolylfluanid.fao.2002.pdf

Toxicity - General: The skeletal system (bones and teeth), liver and thyroid were identified as target organs in the animal studies.
Ref: US EPA Pesticide Fact Sheet. Reason for Issuance: Import Tolerance. September 2002.
http://www.fluorideaction.org/pesticides/tolylfluanid.epa.facts.2002.pdf

Chronic toxicity studies on tolylfluanid were done in the rat, mouse and dog. Tolylfluanid was tested in two rat chronic dietary studies. Increased growth of the incisors of the upper jaw and skeletal changes (hyperostosis in the skull and ribs) resulted from the high fluorine content of the compound...
Ref: Federal Register: August 11, 1997 (Volume 62, Number 154). Page 42980-42986. Notice of Filing of Pesticide Petitions.
http://www.fluoridealert.org/pesticides/Tolyfluanid.FR.August.1997.htm

-- Prenatal developmental in nonrodents (rabbit). Developmental NOAEL = 25 mg/kg/day LOAEL= 70 mg/kg/day, based on increased malformations (arthrogryposis [see definition below] of front extremities and small orbital cavity/folded retina) and variations (floating rib and accelerated ossification).
-- 2-Generation reproduction and fertility effects (rat). Parental/systemic NOAEL not established LOAEL = 15.9-21.5 mg/ kg/day, based on hardened crania of P generation animals Reproductive NOAEL not established LOAEL = 15.9-21.5 mg/ kg/day, based on increased clinical signs of toxicity Offspring NOAEL > 15.9-21.5 mg/kg/day (HDT) LOAEL not established
-- Combined chronic toxicity/carcinogenicity rodents (rat): NOAEL = 18.1/21.1 mg/ kg/day (M/F); LOAEL = 90.1/105.2 mg/ kg/day (M/F), based on skeletal changes. Evidence of thyroid follicular cell adenomas and/or carcinomas in high- dose males and females.
-- Combined chronic toxicity/carcinogenicity rodents (rat): NOAEL = 20/20 mg/kg/ day (M/F); LOAEL = 80/110 mg/kg/day (M/F), based on bone hyperostosis in males and females. Evidence of thyroid follicular cell adenomas and/or carcinomas in high- dose males and females.
-- -- Carcinogenicity rodents (mouse): NOAEL = 76.3/123.9 mg/kg/day (M/F) LOAEL = 375.8/610.8 mg/kg/day (M/F), based on skeletal, liver, and kidney changes. No evidence of carcinogenicity.
Ref: Federal Register: September 25, 2002. Tolylfluanid; Pesticide Tolerance. Final Rule. Federal Register. http://www.fluoridealert.org/pesticides/Tolylfluanid.FR.Sept25.2002.htm

WHAT IS ARTHROGRYPOSIS? Published by AVENUES A National Support Group for Arthrogryposis Multiplex Congenita - http://www.sonnet.com/avenues/pamphlet.html "Arthrogryposis" (Arthrogryposis Multiplex Congenita) is a term describing the presence of multiple joint contractures at birth. A contracture is a limitation in the range of motion of a joint. In some cases, few joints maybe affected and the range of motion may be nearly normal. In the "classic" case of Arthrogryposis, hands, wrists, elbows, shoulders, hips, feet, and knees are affected. In the most severe cases, nearly every body joint may be involved, including the jaw and back. Frequently, the joint contractures are accompanied by muscle weakness which further limits movement. Arthrogryposis is relatively rare, occurring in perhaps one in 3,000 births... There is a wide variation in the degree to which muscles and joints are affected in those with Arthrogryposis. In some cases, Arthrogryposis may be accompanied by other conditions, such as central nervous system disorders, which complicate the picture... In general, there are four causes for limitation of joint movement before birth: (1) Muscles do not develop properly (atrophy). In most cases, the specific cause for muscular atrophy cannot be identified. Suspected causes include muscle diseases (for example, congenital muscular dystrophies), maternal fever during pregnancy, and viruses which may damage cells which transmit nerve impulses to the muscles. (2) There is not sufficient room in the uterus for normal movement. For example, the mother may lack normal amount of amniotic fluid, or have an abnormally shaped uterus. (3) Central nervous system and spinal cord are malformed. In these cases, Arthrogryposis is usually accompanied by a wide range of other conditions. (4) Tendons, bones, joints or joint linings may develop abnormally. For example, tendons may not be connected to the proper place in a joint.

Cancer: Likely to be Carcinogenic to Humans - THYROID (click on for all fluorinated pesticides)

Likely to be Carcinogenic to Humans. Thyroid tumors in male and female Wistar rats. Linear low-dose extrapolation approach recommended.
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

-- Cancer Classification: ``Likely to be carcinogenic to humans'' by the oral route, based on thyroid tumors in high-dose male and female rats. The FQPA SF Committee further recommended a linear low-dose extrapolation approach for the quantification of human cancer risk based on the thyroid tumors in rats. Q1* = 1.59 x 10-\3\ based upon male rat thyroid adenomas and/or carcinomas combined... Cancer. A partially refined, cancer dietary exposure assessment was conducted for the general U.S. population using the same assumptions as were used in the chronic risk assessment (listed in the preceding section). Import share data generated within the Agency were used in the assessment to estimate what proportion of the grape, apple, hop, and tomato consumed in the United States are imported. Modified DEEM\TM\ processing factors based on the results of processing studies were used for raisins and apple and grape juice/juice concentrates. Default DEEM\TM\ processing factors were used for all other processed commodities The cancer risk estimate is 1.2 x 10-\6\ for the general U.S. population.
Ref: Federal Register: September 25, 2002. Tolylfluanid; Pesticide Tolerance. Final Rule. Federal Register. http://www.fluoridealert.org/pesticides/Tolylfluanid.FR.Sept25.2002.htm

Clastogenic and Cytotoxic (click on for all fluorinated pesticides)

-- Bacterial gene mutation assay. Tolylfluanid was cytotoxic to all strains at = 8 [mu]g/plate +/ - S9 and precipitated from solutions in all strains at 5,000 [mu]g/plate +/- S9. There were no reproducible, dose- related differences in the number of revertant colonies in any strain or dose over the background. Positive controls induced appropriate response.
-- Metabolite--WAK 6698. Bacterial gene mutation assay. Metabolite was cytotoxic at doses £=158 [mu]g/plate in the initial assay and 1,581 [mu]g/plate in the repeat assay. There was no evidence of a significant increase in mutant colonies over background in any strains tested in the initial or repeat mutagenicity assays. Positive controls induced appropriate response.
-- Technical. In vitro mammalian cell gene mutation assay. Cytotoxicity was observed at concentrations 1 to 10 [mu]g/milliliter (mL) -S9 and 5 to 10 [mu]g/mL +S9. Over the ranges tested clastogenic effects included increased incidences of metaphases with aberrations including gaps, metaphases excluding gaps, metaphases with exchanges, and metaphases with polyploidy were observed. Tolyfluanid is clastogenic both in the presence and in the absence of S9 activation.
Ref: Federal Register: September 25, 2002. Tolylfluanid; Pesticide Tolerance. Final Rule. Federal Register. http://www.fluoridealert.org/pesticides/Tolylfluanid.FR.Sept25.2002.htm

Endocrine: Thyroid (click on for all fluorinated pesticides)

Toxicity - General: The skeletal system (bones and teeth), liver and thyroid were identified as target organs in the animal studies.
Ref: US EPA Pesticide Fact Sheet. Reason for Issuance: Import Tolerance. September 2002.
http://www.fluorideaction.org/pesticides/tolylfluanid.epa.facts.2002.pdf

-- Cancer Classification: ``Likely to be carcinogenic to humans'' by the oral route, based on thyroid tumors in high-dose male and female rats. The FQPA SF Committee further recommended a linear low-dose extrapolation approach for the quantification of human cancer risk based on the thyroid tumors in rats. Q₁* = 1.59 x 10-\3\ based upon male rat thyroid adenomas and/or carcinomas combined.
-- Combined chronic toxicity/carcinogenicity rodents (rat): NOAEL = 18.1/21.1 mg/ kg/day (M/F); LOAEL = 90.1/105.2 mg/ kg/day (M/F), based on skeletal changes. Evidence of thyroid follicular cell adenomas and/or carcinomas in high- dose males and females.
-- Combined chronic toxicity/carcinogenicity rodents (rat): NOAEL = 20/20 mg/kg/ day (M/F); LOAEL = 80/110 mg/kg/day (M/F), based on bone hyperostosis in males and females Evidence of thyroid follicular cell adenomas and/or carcinomas in high- dose males and females.
-- Non-guideline (rat) thyroid function: Thyroid-stimulating hormone levels significantly increased (168-425%) in high-dose males and females. Slightly increased T3 levels in males rats above 119.3 mg/ kg/day.
-- Metabolite Non-guideline (mice). In vitro investigation of TTCA goitrogenic properties. Tolylfluanid's metabolite TTCA was shown to reversibly inhibit thyroid peroxidase (TPO)- mediated reactions involved with the initial stages of thyroid hormone synthesis... TTCA, unlike tolylfluanid, behaves as a goitrogenic compound with a potency approximately equal to propylthiouracil (PTU), a known thionamide inhibitor of initial thyroid hormone synthesis.
Ref: Federal Register: September 25, 2002. Tolylfluanid; Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluorideaction.org/pesticides/tolylfluanid.fr.sept25.2002.htm

Eye (click on for all fluorinated pesticides)

-- Prenatal developmental toxicity/rabbit LOAEL = 70 mg/kg/day based on increased malformations (arthrogryposis of front extremities and small orbital cavity/folded retina) and variations (floating ribs and accelerated ossification).
Ref: Federal Register: September 25, 2002. Tolylfluanid; Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluoridealert.org/pesticides/Tolylfluanid.FR.Sept25.2002.htm

Kidney (click on for all fluorinated pesticides)

-- Carcinogenicity rodents (mouse). NOAEL = 76.3/123.9 mg/ kg/day (M/F) LOAEL = 375.8/610.8 mg/kg/day (M/F), based on skeletal, liver, and kidney changes No evidence of carcinogenicity
Ref: Federal Register: September 25, 2002. Tolylfluanid; Pesticide Tolerance. Final Rule. Federal Register. http://www.fluoridealert.org/pesticides/Tolylfluanid.FR.Sept25.2002.htm

Chronic toxicity. Chronic toxicity studies on tolylfluanid were done in the rat, mouse and dog. Tolylfluanid was tested in two rat chronic dietary studies. Increased growth of the incisors of the upper jaw and skeletal changes (hyperostosis in the skull and ribs) resulted from the high fluorine content of the compound. Hepatotoxicity and renal toxicity were seen in rats, mice, and dogs. Hepatotoxicity was evidenced by hepatocellular cytoplasmic changes, vacuolation, and focal fatty changes in rats, hepatocellular hypertrophy and single cell necrosis in mice, decreased liver enzymes in rats, and increased liver enzymes in mice and dogs. Renal toxicity (microscopic kidney lesions, increased relative kidney weights, effects on urinalysis parameters) was probably attributable to the effects of fluoride on renal tubules. A second chronic toxicity study in dogs is currently ongoing (results not yet available).
Ref: Federal Register: August 11, 1997 (Volume 62, Number 154). Page 42980-42986. Notice of Filing of Pesticide Petitions.
http://www.fluoridealert.org/pesticides/Tolyfluanid.FR.August.1997.htm

Liver (click on for all fluorinated pesticides)

Toxicity - General: The skeletal system (bones and teeth), liver and thyroid were identified as target organs in the animal studies.
Ref: US EPA Pesticide Fact Sheet. Reason for Issuance: Import Tolerance. September 2002.
http://www.fluorideaction.org/pesticides/tolylfluanid.epa.facts.2002.pdf

-- 90-Day oral toxicity rodents (rat). NOAEL = 20.1 milligram/kilogram/ day (mg/kg/day) male (M) LOAEL = 108 mg/kg/ day, based on changes in clinical blood chemistry associated with the liver and thyroid (M) NOAEL = 131 mg/kg/day female (F) LOAEL = 736.1 mg/kg/ day, based on changes in clinical blood chemistry associated with the liver and thyroid and decreased body weights (F)
-- 90-Day oral toxicity in nonrodents (dog). NOAEL = 23.1/25 mg/kg/ day (F/M) LOAEL = 67.2/69.4 (F/ M) mg/kg/day, based on decreased body weight gains and changes in liver structure and function in both sexes
-- Prenatal developmental in nonrodents (rabbit). Maternal NOAEL = 25 mg/kg/day LOAEL = 70 mg/kg/day, based on evidence of hepatotoxicity (increased glutamate dehydrogenase (GLDH) and triglyceride levels and gross and microscopic liver pathology) and decreased food consumption and equivocal decreases in body weight gain. Developmental NOAEL = 25 mg/kg/day LOAEL= 70 mg/kg/day, based on increased malformations (arthrogryposis of front extremities and small orbital cavity/folded retina) and variations (floating rib and accelerated ossification).
-- 2-Generation reproduction and fertility effects (rat). Parental/systemic NOAEL = 7.9-10.5 mg/ kg/day LOAEL = 57.5-78.0 mg/ kg/day, based on decreased body weights, body weight gains, and liver weights in the P females Reproductive NOAEL = 7.9-10.5 mg/kg/day LOAEL = 57.5-78.0 mg/ kg/day, based on reduced litter size Offspring NOAEL = 7.9- 10.5 mg/kg/day LOAEL = 57.5-78.0 mg/ kg/day, based on decreased pup weights, increased pup deaths and related pup viability indices.
-- Carcinogenicity rodents (mouse). NOAEL = 76.3/123.9 mg/ kg/day (M/F) LOAEL = 375.8/610.8 mg/kg/day (M/F), based on skeletal, liver, and kidney changes No evidence of carcinogenicity
Ref: Federal Register: September 25, 2002. Tolylfluanid; Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluoridealert.org/pesticides/Tolylfluanid.FR.Sept25.2002.htm

Reproductive / Developmental (click on for all fluorinated pesticides)

-- Prenatal developmental in nonrodents (rabbit). Developmental NOAEL = 25 mg/kg/day LOAEL= 70 mg/kg/day, based on increased malformations (arthrogryposis [see definition below•] of front extremities and small orbital cavity/folded retina) and variations (floating rib and accelerated ossification).
-- 2-Generation reproduction and fertility effects (rat). Parental/systemic NOAEL not established LOAEL = 15.9-21.5 mg/ kg/day, based on hardened crania of P generation animals Reproductive NOAEL not established LOAEL = 15.9-21.5 mg/ kg/day, based on increased clinical signs of toxicity Offspring NOAEL > 15.9-21.5 mg/kg/day (HDT) LOAEL not established
-- Combined chronic toxicity/carcinogenicity rodents (rat): NOAEL = 18.1/21.1 mg/ kg/day (M/F); LOAEL = 90.1/105.2 mg/ kg/day (M/F), based on skeletal changes. Evidence of thyroid follicular cell adenomas and/or carcinomas in high- dose males and females.
-- Combined chronic toxicity/carcinogenicity rodents (rat): NOAEL = 20/20 mg/kg/ day (M/F); LOAEL = 80/110 mg/kg/day (M/F), based on bone hyperostosis in males and females. Evidence of thyroid follicular cell adenomas and/or carcinomas in high- dose males and females.
Ref: Federal Register: September 25, 2002. Tolylfluanid; Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluoridealert.org/pesticides/Tolylfluanid.FR.Sept25.2002.htm

Thyroid (click on for all fluorinated pesticides)

Likely to be Carcinogenic to Humans. Thyroid tumors in male and female Wistar rats. Linear low-dose extrapolation approach recommended.
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