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Toxicity Effects

CAS Registry Number: 104206-82-8

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 2.

Names 1

    Human Toxicity Excerpts

    • HUMAN EXPOSURE STUDIES: ... Mesotrione (2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione) inhibits 4-hydroxyphenyl pyruvate dioxygenase (HPPD). ... The mesotrione study was performed to determine the magnitude and duration of the effect on tyrosine catabolism. Additionally, the urinary excretion of unchanged mesotrione was measured to assess the importance of this route of clearance and to help develop a strategy for monitoring occupational exposure. /Three groups, each consisting of six male volunteers between 19 and 53 years, were given a single oral dose of either 0.1, 0.5 or 4 mg mesotrione/kg./ ... Plasma tyrosine concentrations were monitored and the urinary excretion of mesotrione and tyrosine metabolites was measured. ... Administration of mesotrione resulted in an increase in tyrosine concentrations, which reached a maximum of approximately 300 nmol/mL following a dose of 4 mg/kg body weight. Concentrations returned to those of background within 2 days of dosing. Urinary excretion of tyrosine metabolites was increased during the 24 hr immediately following a dose of 4 mg mesotrione/kg, but returned to background levels during the following 24 hr period. ... /The/ minimal and transient effects of mesotrione minimize the likelihood of a clinical effect in the event of systemic exposure occurring during occupational use.[Hall MG et al; Br J Clin Pharmacol 52 (2): 169-77 (2001)] **PEER REVIEWED** PubMed Abstract Full text: PMC2014534
    • OTHER TOXICITY INFORMATION: Mechanistic studies show that the toxic effects of /mesotrione/ are largely attributable to increased plasma tyrosine levels following 4-hydroxyphenyl pyruvate dioxygenase (HPPD) inhibition. Tyrosine levels are increased to a greater extent in rats (particularly males) due to differences in the activity of enzymes in the tyrosine catabolic pathway. Studies show that the mouse is more predictive of the response in humans. Human volunteer study (single oral dose) shows a NOAEL of 0.5 mg/kg bw.[European Commission; Standing Committee on the Food Chain and Animal Health for Mestrione (104206-82-8) SANCO/1416/2001 (April 2003). Available from, as of October 15, 2003: http://europa.eu.int/comm/food/plant/protection/evaluation/newactive/list1-20_en.pdf] **PEER REVIEWED**

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    Non-Human Toxicity Excerpts

    • LABORATORY ANIMALS: Acute Exposure: It is a mild eye irritant, but is not a dermal irritant or a dermal sensitizer.[USEPA/Office of Pesticide Programs; Pesticide Fact Sheet- Mesotrione (June 2001). Available from, as of July 24, 2014: http://www.epa.gov/opp00001/chem_search/reg_actions/registration/fs_PC-122990_04-Jun-01.pdf] **PEER REVIEWED**
    • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Mesotrione (batch P17, a light beige powder, 96.8% w/w purity) 0, 7.5, 100 and 2500 ppm was administered to 64 Alpk:APfSD (Wistar-derived) rats/sex by dietary route for 1 year (12 rats/sex/group at interim kill) or 2 (52/sex/group) years. In addition, 20 male and 20 female rats were exposed to 1 or 2.5 ppm ZA 1296 /mesotrione/ by dietary route for 2 years to investigate ocular toxicity. Mean doses received for males were: 0.06, 0.16, 0.48, 6.48 and 159.89 mg ZA 1296/kg/day, and mean values for females were 0.08, 0.19, 0.57, 7.68 and 189.48 mg ZA1296/kg/day, for nominal dietary levels of 1, 2.5, 7.5, 100 and 2500 ppm ZA1296, respectively. The male groups fed ZA 1296 were terminated when survival reached 25%. Groups 2 and 3, fed 1 and 2.5 ppm, were terminated in weeks 92 and 93 while the remaining male groups and control were terminated in weeks 97 or 98. The female groups survived to scheduled termination and there was no evidence of an effect on mortality. Significant reduction in bodyweight was reported in males fed 1 and 2.5 ppm during second year of study (10 and 11% respectively, compared to controls, week 91). The treatment related ophthalmoscopic findings were seen in >7.5 ppm ZA 1296 treated male rats and the high dose group female rats. Increased eye keratitis was observed in > 100 ppm ZA 1296 treated female rats in microscopic findings. Increased liver weight, liver weight to body weight ratio, increased incidence of pale liver and hepatocyte fat vacuolation were observed in > 7.5 ppm ZA 1296 treated male rats. NOEL for male rats: < 1 ppm (0.06 mg/kg/day) due to decreased body weights; NOEL for female rats: 2.5 ppm (0.19 mg/kg/day) due to increased clinical signs of cloudy eyes in 7.5 ppm and up ZA 1296 treated rats. No carcinogenic potential.[California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summary for Mesotrione (104206-82-8) p.2 (July 6, 2012). Available from, as of June 26, 2014: http://www.cdpr.ca.gov/docs/risk/toxsums/toxsumlist.htm] **PEER REVIEWED**
    • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: In subchronic and chronic oral studies, ocular lesions, liver and kidney effects, and/or body weight decrements were the major adverse effects seen in the rat, mouse, and dog. Plasma tyrosine levels were increased in the rat, mouse and dog in the chronic and reproduction studies in which levels were measured. The ocular, liver and kidney effects are believed to be mediated by the high tyrosine levels in the blood caused by inhibition of the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD). ...There was no evidence of carcinogenic potential in either the rat chronic toxicity/carcinogenicity or mouse carcinogenicity studies and no concern for mutagenicity.[USEPA/Office of Pesticide Programs; Pesticide Fact Sheet- Mesotrione (June 2001). Available from, as of July 24, 2014: http://www.epa.gov/opp00001/chem_search/reg_actions/registration/fs_PC-122990_04-Jun-01.pdf] **PEER REVIEWED**
    • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Increased incidence of thyroid adenomas in female rats only at the highest dose level in the 2 year rat study was associated with increased plasma tyrosine concentration.[European Commission; Standing Committee on the Food Chain and Animal Health for Mestrione (104206-82-8) SANCO/1416/2001 p.9 (April 2003). Available from, as of June 25, 2014: http://ec.europa.eu/food/plant/protection/evaluation/newactive/list1-20_en.pdf] **PEER REVIEWED**
    • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Ocular opacity, increased liver and kidney weights ... were seen in rat studies at significantly lower dose levels than mouse and dog studies. ... Lowest relevant NOAEL: 7.7 mg/kg bw/d (rat 2 year study).[European Commission; Standing Committee on the Food Chain and Animal Health for Mestrione (104206-82-8) SANCO/1416/2001 p.9 (April 2003). Available from, as of June 25, 2014: http://ec.europa.eu/food/plant/protection/evaluation/newactive/list1-20_en.pdf] **PEER REVIEWED**
    • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ...Time mated female /Alderly Park/ (AP) rats, New Zealand White rabbits and AP mice received up to 1000, 500 or 600 mg/kg/day mesotrione respectively by oral gavage. Prior to parturition animals were killed and their uteri examined for live fetuses and intrauterine deaths. ...At high doses of mesotrione there were no teratogenic effects in the rat, the rabbit and the mouse. In the rat and the rabbit noteworthy changes were confined to high dose level i.e. reduced fetal bodyweight, at the limit dose in the rat and a low level of whole litter losses in the rabbit at the high dose levels of 250 and 500 mg/kg/day. There were no noteworthy changes in the mouse at any dose level tested. Following treatment with mesotrione at a range of dose levels in the rat and the rabbit, differences from concurrent control were observed in the number of fetuses showing minor skeletal defects. A marginal difference was also observed in the mouse, but only at the highest dose level tested.[Lewis RW, Provan M; Toxicologist 54 (1): 334 (2000)] **PEER REVIEWED**
    • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Reduced/delayed ossification in rat, rabbit and mouse studies in the absence of overt maternal toxicity[European Commission; Standing Committee on the Food Chain and Animal Health for Mestrione (104206-82-8) SANCO/1416/2001 p.9 (April 2003). Available from, as of June 25, 2014: http://ec.europa.eu/food/plant/protection/evaluation/newactive/list1-20_en.pdf] **PEER REVIEWED**
    • LABORATORY ANIMALS: Neurotoxicity: No evidence of neuropathology in acute and sub-chronic neurotoxicity studies in the rat. Sciatic nerve demyelination in the chronic rat study was associated with increased plasma tyrosine concentration.[European Commission; Standing Committee on the Food Chain and Animal Health for Mestrione (104206-82-8) SANCO/1416/2001 p.9 (April 2003). Available from, as of June 25, 2014: http://ec.europa.eu/food/plant/protection/evaluation/newactive/list1-20_en.pdf] **PEER REVIEWED**
    • LABORATORY ANIMALS: Neurotoxicity: No evidence of neurotoxicity or neuropathology was seen in the acute and subchronic neurotoxicity studies.[USEPA/Office of Pesticide Programs; Pesticide Fact Sheet- Mesotrione (June 2001). Available from, as of July 24, 2014: http://www.epa.gov/opp00001/chem_search/reg_actions/registration/fs_PC-122990_04-Jun-01.pdf] **PEER REVIEWED**
    • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: In the subchronic toxicity dog study, the high-dose females had decreased absolute and relative brain weights; however, no microscopic abnormalities were noted in any brain tissue from the highdose group and the effect was not observed in the chronic toxicity dog study.[USEPA/Office of Pesticide Programs; Pesticide Fact Sheet- Mesotrione (June 2001). Available from, as of July 24, 2014: http://www.epa.gov/opp00001/chem_search/reg_actions/registration/fs_PC-122990_04-Jun-01.pdf] **PEER REVIEWED**

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    Human Toxicity Values

    • None found

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    Non-Human Toxicity Values

    • LD50 Rat dermal >2000 mg/kg[Crop Protection Handbook Volume 100, Meister Media Worldwide, Willoughby, OH 2014, p. 402] **PEER REVIEWED**
    • LD50 Rat oral >5000 mg/kg[Crop Protection Handbook Volume 100, Meister Media Worldwide, Willoughby, OH 2014, p. 402] **PEER REVIEWED**

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    Absorption, Distribution And Excretion

    • Approximately 70% /mestrione was absorbed/ within 72 hours. /Mestrione was/ widely distributed, highest residues in liver and kidney at 72 hours. No evidence of accumulation. 65-70% excreted within 72 hours, mainly via urine (55%)[European Commission; Standing Committee on the Food Chain and Animal Health for Mestrione (104206-82-8) SANCO/1416/2001 (April 2003). Available from, as of October 15, 2003: http://europa.eu.int/comm/food/plant/protection/evaluation/newactive/list1-20_en.pdf] **PEER REVIEWED**
    • NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione (2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione) are inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD). NTBC has been successfully used as a treatment for hereditary tyrosinaemia type 1 (HT-1), while mesotrione has been developed as an herbicide. The pharmacokinetics of the two compounds were investigated in healthy male volunteers following single oral administration. The aim of the NTBC study was to assess the bioequivalence of two different formulations and to determine the extent of the induced tyrosinaemia. The mesotrione study was performed to determine the magnitude and duration of the effect on tyrosine catabolism. Additionally, the urinary excretion of unchanged mesotrione was measured to assess the importance of this route of clearance and to help develop a strategy for monitoring occupational exposure. ... A total of 28 volunteers participated in two separate studies with the compounds. In the first study, the relative bioavailability of NTBC from liquid and capsule formulations was compared and the effect on plasma tyrosine concentrations measured. In the second study the pharmacokinetics of mesotrione were determined at three doses. Plasma tyrosine concentrations were monitored and the urinary excretion of mesotrione and tyrosine metabolites was measured. Both compounds were well tolerated at the dose levels studied. Peak plasma concentrations of NTBC were rapidly attained following a single oral dose of 1 mg x kg(-1) body weight of either formulation and the half-life in plasma was approximately 54 hr. There were no statistical differences in mean (+/- s.d.) AUC(0,infinity) (capsule 602 +/- 154 vs solution 602 +/- 146 ug x ml(-1) hr) or t1/2 (capsule 55 +/- 13 vs solution 54 +/- 8 hr) and these parameters supported the bioequivalence of the two formulations. Mesotrione was also rapidly absorbed, with a significant proportion of the dose eliminated unchanged in urine. The plasma half-life was approximately 1 hr and was independent of dose and AUC(0,infinity) and Cmax increased linearly with dose. Following administration of 1 mg NTBC x kg(-1) in either formulation, the concentrations of tyrosine in plasma increased to approximately 1100 nmol x ml(-1). Concentrations were still approximately 8 times those of background at 14 days after dosing, but had returned to background levels within 2 months of the second dose. Administration of mesotrione resulted in an increase in tyrosine concentrations which reached a maximum of approximately 300 nmol x ml(-1) following a dose of 4 mg x kg(-1) body weight. Concentrations returned to those of background within 2 days of dosing. Urinary excretion of tyrosine metabolites was increased during the 24 hr immediately following a dose of 4 mg mesotrione x kg(-1), but returned to background levels during the following 24 hr period. ...[Hall MN et al; Br J Clin Pharmacol 52 (2): 169-77 (2001)] **PEER REVIEWED** PubMed Abstract Full text: PMC2014534

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    Metabolism/Metabolites

    • Limited metabolism, up to 5% metabolized by hydroxylation.[European Commission; Standing Committee on the Food Chain and Animal Health for Mestrione (104206-82-8) SANCO/1416/2001 (April 2003). Available from, as of October 15, 2003: http://europa.eu.int/comm/food/plant/protection/evaluation/newactive/list1-20_en.pdf] **PEER REVIEWED**
    • The metabolic fate of [(14)C]-2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione (mesotrione) has been determined in the male and female rat and mouse following a single oral dose of either 1 or 100 mg/kg, in rat given 14 consecutive oral doses of 1 mg/kg, and in the surgically prepared, bile duct-cannulated rat following a single oral dose of 50 mg/kg. ...Mesotrione was extensively absorbed and rapidly excreted via urine in both rat and mouse. ...The major metabolic pathway was hydroxylation of the aromatic ring.[Gledhill AJ et al; Xenobiotica 31 (10): 733-47 (2001)] **PEER REVIEWED** PubMed Abstract

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    Tsca Test Submissions

    • None found

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    Footnotes

    1 Source: the NTP's CEBS database.

    2 Source: the National Library of Medicine's Hazardous Substance Database, 02/28/2017.

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