Absorption, Distribution and Excretion
Following administration of 1 mg/kg body weight (14)C chlorothalonil to male Sprague-Dawley rats by endotracheal instillation, gavage or dermal application, less than 6% of the administered dose was recovered in the blood or urine within 48 hr after dosing.
In rats, given a single, oral low dose (1.5mg/kg) of chlorothalonil, around 20-22% of the absorbed dose is excreted in bile and around 10% in urine. At higher dose (200 mg/kg) a considerably lower proportion (8%) of the absorbed dose is excreted in bile, indicating that this is a saturable process. These data indicate that overall absorption from the GI tract is in the order of 30-32% of the administered dose. The majority ... is excreted in feces with at least 80% of administered dose excreted by this route within 96 hr. Approximately 90% of the administered dose was excreted within 34-48 hr although excretion was less rapid at doses of 50 mg/kg and above. Highest tissue concentrations were observed in the kidney, approximately 0.1% of the dose. A similar metabolic profile was seen on repeated dosing and there was no evidence of bioaccumulation.
... Data for the monkey show that, following a single oral dose of 50 mg/kg, 1.8-4.15% of the dose appeared in urine with very low levels of thiol-derived metabolites appearing in urine. Fecal excretion predominated with around 92% of the dose eliminated via this route over 96 hr. Absorption and excretion were rapid and there was no evidence of bioaccumulation.
Low levels of /orally administered chlorothalonil to mouse/ were found in the tissues and urinary excretion indicated that at least 10% of the dose was absorbed with the majority (70-80%) of the dose excreted in feces.
For more Absorption, Distribution and Excretion (Complete) data for CHLOROTHALONIL (12 total), please visit the HSDB record page.

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Metabolism / Metabolites
When yeast cells were exposed to TCIN, derivatives formed resembled those formed by reaction of glutathione with TCIN in vitro. Coenzyme A and 2-mercaptoethanol also ... formed derivatives with TCIN in vitro. Infrared spectra and chromatography of the 4 derivatives ... indicated ... 1-4 halogens ... substituted by 2-mercaptoethanol. ... Daconil decomposed in fresh rumen contents with production of two unidentified metabolites.
In plants, 4-hydroxy-2,5,6-trichloroisophthalonitrile is found as a metabolite.
The metabolism of chlorothalonil was investigated in liver and gill cytosolic and microsomal fractions from channel catfish (Ictalurus punctatus) using HPLC. All fractions catalyzed the metabolism of chlorothalonil to polar metabolites. Chlorothalonil metabolism by cytosolic fractions was reduced markedly when glutathione was omitted from the reaction mixtures. The lack of microsomal metabolism in the presence of either NADPH or an NADPH-regenerating system indicated direct glutathione S-transferase catalyzed conjugation with glutathione without prior oxidation by cytochrome P450. Cytosolic and microsomal glutathione S-transferases from both tissues were also active toward 1-chloro-2,4-dinitrobenzene, a commonly employed reference substrate. In summary, channel catfish detoxified chlorothalonil in vitro by glutathione S-transferase-catalyzed glutathione conjugation in the liver and gill. The present report is the first to confirm microsomal glutathione S-transferase activity toward 1-chloro-2,4-dinitrobenzene in gill and toward chlorothalonil in liver, and also of gill cytosolic glutathione S-transferase activity towards chlorothalonil, in an aquatic species.
Male Sprague-Dawley rats were administered, via oral gavage, (14)C-chlorothalonil (purity 99.7%) at a dose level of 200 mg/kg in order to isolate and identify the urinary metabolites. Urine was collected 17, 24 and 48 hr after dosing. Urinary metabolites accounted for 2.4% of the administered dose and, except for 30% of the radiolabel which was non-extractable from the urine, were found to be trimethylthiomonochloro-isophthalonitrile and dimethylthiodichloro-isophthalonitrile. These thiols were excreted in urine both as free thiols and as their methylated derivatives. ...A metabolic pathway /was suggested/ such that hepatic metabolism proceeds through conjugation with GSH followed by enzymatic degradation. The smaller conjugates are then transported via the bloodstream to the kidney, where they are converted to thiol metabolites and excreted in the urine.
For more Metabolism/Metabolites (Complete) data for CHLOROTHALONIL (12 total), please visit the HSDB record page.
Organic nitriles are converted into cyanide ions through the action of cytochrome P450 enzymes in the liver. Cyanide is rapidly absorbed and distributed throughout the body. Cyanide is mainly metabolized into thiocyanate by either rhodanese or 3-mercaptopyruvate sulfur transferase. Cyanide metabolites are excreted in the urine. (L96)

Toxicity Summary
IDENTIFICATION AND USE: Chlorothalonil forms colorless and odorless crystals in pure form. It is a substituted benzene fungicide used to control fungal diseases in vegetables, fruit, turf, and ornamental plants. Chlorothalonil is registered for use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses. HUMAN EXPOSURE AND TOXICITY: Contact dermatitis was observed in a number of employees in a chlorothalonil manufacturing plant. There were 19 cases out of 103 employees. About 60% of the employees showed some kind of skin abnormality compared with 18.5% of employees not working with chlorothalonil. When the hygiene conditions of the plant were improved the overall proportion of skin abnormalities fell to about 20% and there were no cases of chlorothalonil contact dermatitis. One report concerned a Danish cabinet maker who developed dermatitis on his hands after 9 months of painting furniture with wood preservatives containing chlorothalonil. Another report referred to three cases: two with erythema on the face, particularly periorbitally, and one with eczema of the hands, in people engaged in similar work. Patients showed a positive reaction to patch tests with 0.01% chlorothalonil in acetone. Ocular exposures to chlorothalonil from employees at a packaging plant involved intense pain with mild to moderate conjunctivitis and irritation of the corneal surface. Ocular edema was also seen in more extensive exposures. With lesser exposures, complete recovery occurred within 24 hr. Recovery took slightly longer following extensive exposure. In no instance was corneal opacity observed. ANIMAL STUDIES: Instillation of chlorothalonil (96%) to rabbit eyes resulted in severe irritation with persistent corneal opacity, iris effects, and conjunctival irritation. In a carcinogenicity study in rats, chlorothalonil (98.1%) was administered in the diet up to 175 mg/kg/day for 116 weeks to males and 129 weeks to females. There were body weight decreases in both sexes at the high and mid doses. The non-glandular stomach was eroded and ulcerated. Histologically, there were compound-related effects on the kidneys, esophagus, stomach and duodenum. Chronic glomerulonephritis, hyperplasia of cortical tubules and pelvic/papillary epithelium tubular cysts, renal adenomas and carcinomas as well as stomach papillomas were present at all dose levels. Testing yielded negative results for chromosomal aberrations and micronuclei induction in either rats or Chinese hamsters administered gavage doses up to 5000 mg/kg/day for 2 days or mice receiving 2500 mg/kg/day for 2 consecutive days. In inhalation studies assessing genotoxic potential of chlorothalonil drift in mice, no significant difference in DNA damage was observed between exposed and control animals. ECOTOXICITY STUDIES: A larval rearing method was adapted to assess the chronic oral toxicity to honey bee larvae of the four most common pesticides detected in pollen and wax: fluvalinate, coumaphos, chlorothalonil, and chloropyrifos (tested alone and in all combinations). All pesticides at hive-residue levels triggered a significant increase in larval mortality compared to untreated larvae by over two fold, with a strong increase after 3 days of exposure. Among these four pesticides, honey bee larvae were most sensitive to chlorothalonil compared to adults. In an avian reproduction study using Mallard duck, reduction in eggshell thickness was seen at 100 ppm. At 250 ppm adult body weight, food consumption, and gonad development were affected, there were also effects on numbers of eggs laid, embryonic development, eggshell thickness, hatchability, and hatching survival. Worms reared in soil in which chlorothalonil had been incorporated (5 times the recommended application rate at 0.9 g in 4700 cu cm of soil) showed reduction in longevity of about 50% compared to controls after the beginning of treatment, and reproduction was virtually eliminated.
Organic nitriles decompose into cyanide ions both in vivo and in vitro. Consequently the primary mechanism of toxicity for organic nitriles is their production of toxic cyanide ions or hydrogen cyanide. Cyanide is an inhibitor of cytochrome c oxidase in the fourth complex of the electron transport chain (found in the membrane of the mitochondria of eukaryotic cells). It complexes with the ferric iron atom in this enzyme. The binding of cyanide to this cytochrome prevents transport of electrons from cytochrome c oxidase to oxygen. As a result, the electron transport chain is disrupted and the cell can no longer aerobically produce ATP for energy. Tissues that mainly depend on aerobic respiration, such as the central nervous system and the heart, are particularly affected. Cyanide is also known produce some of its toxic effects by binding to catalase, glutathione peroxidase, methemoglobin, hydroxocobalamin, phosphatase, tyrosinase, ascorbic acid oxidase, xanthine oxidase, succinic dehydrogenase, and Cu/Zn superoxide dismutase. Cyanide binds to the ferric ion of methemoglobin to form inactive cyanmethemoglobin. (L97)

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Toxicity Data
LC50 (rat) = 92 mg/m3
LD50: 2500 mg/kg (Intraperitoneal, Mouse) (T14)
LD50: 3700 mg/kg (Oral, Mouse) (T14)
LD50: >2500 mg/kg (Dermal, Rat) (T14)
LC50: 310 mg/m3 over 1 hour (Inhalation, Rat) (T14)

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Interactions
... Japanese medaka (Oryzias latipes) /were exposed/ to environmentally relevant concentrations of azinphos-methyl, chlorothalonil, endosulfan, and mixtures of all three ... Fry exposed to ... chlorothalonil and a combination of the chemicals showed reduced activity. Adult sex ratios were biased toward females ... with those exposed to azinphos-methyl, chlorothalonil, and the pesticide mixture departing significantly from an even sex ratio. There was no evidence of additive or synergistic effects of pesticide mixtures.
... Atrazine and chlorothalonil concentrations > or = 25 microg/L and 33.3 microg/L, respectively, caused significant decreases in D. tertiolecta population growth rate. At much higher concentrations (> or = 400 microg/L) chlorpyrifos also elicited a significant effect on D. tertiolecta population growth rate. The population growth rate EC50 values determined for D. tertiolecta were 64 microg/L for chlorothalonil, 69 microg/L for atrazine, and 769 microg/L for chlorpyrifos. Atrazine and chlorpyrifos in mixture displayed additive toxicity, whereas atrazine and chlorothalonil in mixture had a synergistic effect.

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Non-Human Toxicity Values
LD50 Mouse ip 2500 mg/kg
LD50 Mouse oral 3700 mg/kg
LD50 Rat dermal >2500 mg/kg
LD50 Rat ip 2500 mg/kg
For more Non-Human Toxicity Values (Complete) data for CHLOROTHALONIL (11 total), please visit the HSDB record page.

[1]. Low Dose Chlorothalonil Impairs Mouse Spermatogenesis Through the Intertwining of Estrogen Receptor Pathways With Histone and DNA Methylation.Chemosphere. 2019 Sep;230:384-395.

[2]. The Influence of Chlorothalonil on the Activity of Soil Microorganisms and Enzymes. Ecotoxicology. 2018 Nov;27(9):1188-1202.

Chlorothalonil can cause cancer according to an independent committee of scientific and health experts.
Chlorothalonil appears as colorless crystals or granules or light gray powder. Melting point 250-251 °C. No odor when pure; technical grade has a slightly pungent odor. A fungicide formulated as water-dispersible granules, wettable powder, or dust.
Chlorothalonil is a dinitrile that is benzene-1,3-dicarbonitrile substituted by four chloro groups. A non-systemic fungicide first introduced in the 1960s, it is used to control a range of diseases in a wide variety of crops. It has a role as an antifungal agrochemical. It is a dinitrile, a tetrachlorobenzene and an aromatic fungicide. It is functionally related to an isophthalonitrile.
Chlorothalonil has been reported in Curcuma longa with data available.
Chlorothalonil is a chemical compound of cyanide and a non-systemic fungicide. Chlorothalonil-containing products are sold under the names Bravo, Echo, and Daconil. It is used predominantly on peanuts, potatoes, and tomatoes. It is also used on golf courses and lawns and as an additive in some paints. (L597)

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Mechanism of Action
Administration of a monoglutathione conjugate to rats caused similar lesions in the kidney to parent chlorothalonil ... Studies undertaken in vitro using isolated kidney mitochondria have shown that respiration is inhibited in the presence of synthetic mono- and dithiol conjugates derived from chlorothalonil. ... A correlation appears to exist between the interspecies differences in susceptibility to renal toxicity and the differences in capacity to produce these thiol-derived metabolites as rats excrete more thiol-derived metabolites than dogs.
The effects on rodent kidneys is due to the formation of dithiols and trithiols from the action of renal beta-lyase on cysteine S-conjugates. These appear to derive from the glutathione conjugates of chlorothalonil.
Chlorothalonil (TCIN) suppressed both baseline and stimulated O(2)(-) production in a dose-dependent manner. Similar results were obtained using zymosan and phorbol 12-myristate-13-acetate. Inhibition of glutathione synthesis by pre-treatment with buthionine sulfoximine (BSO) enhanced the suppression of O(2)(-) production. Dithiothreitol (DTT) reduced TCIN-induced macrophage dysfunction. TCIN did not initiate lipid peroxidation in macrophages
Available data on metabolism of chlorothalonil in rats and dogs indicates that the parent chemical is conjugated in liver to glutathione or cysteine-S-conjugates. These conjugates are then absorbed from the gastrointestinal tract. Cysteine-S-conjugates, glutathione conjugates, or mercapturic acids reaching the kidney come into contact with proximal tubular cells, where eventual "activation" of pre-mercapturic acids occurs through the action of cysteine conjugate beta-lyase, an enzyme found in the cytosol and mitochondria of the cells of the renal proximal tubules. Nephrotoxicity of cysteine-S-conjugates through activation to thiol metabolites is related to renal cortical mitochondrial dysfunction. Respiratory control has been shown to be disrupted by the di- and tri-thiol analogs of chlorothalonil. Osmotic changes occur within the renal cortical tubular cells as a result of toxic insult by the thiol metabolites of chlorothalonil, resulting in vacuolar degeneration followed by cellular regeneration.

C8CL4N2

265.9

263.881

C, 36.14; Cl, 53.33; N, 10.54

1897-45-6

Chlorothalonil-13C2;2767332-24-9

15910

White to off-white solid powder

1.7±0.1 g/cm3

350.5±37.0 °C at 760 mmHg

250-251ºC

153.8±20.7 °C

0.0±0.8 mmHg at 25°C

1.633

2.88

0

2

0

14

284

0

ClC1C(C#N)=C(C(=C(C=1C#N)Cl)Cl)Cl

CRQQGFGUEAVUIL-UHFFFAOYSA-N

InChI=1S/C8Cl4N2/c9-5-3(1-13)6(10)8(12)7(11)4(5)2-14

1,3-Benzenedicarbonitrile, 2,4,5,6-tetrachloro-

Chlorothalonil; DAC 2787; Daconil; Daconil M;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~33.33 mg/mL (~125.34 mM）

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.40 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (9.40 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (9.40 mM)

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 (Please use freshly prepared in vivo formulations for optimal results.)