Cendazim (4–60 μM; 24 h) exhibited no effect on HeLa cell viability in the CCK-8 experiment [3].

Carbendazim (wall gavage; 100, 500 mg/kg; once daily with diet; 28 days) causes a rise in triglyceride (TG) levels and myocardial array buildup by activating antenna array action [2].

Animal/Disease Models: 6weeks old male ICR mice [2]
Doses: 100 and 500 mg/kg
Route of Administration: po (oral gavage); 100 and 500 mg/kg; one time/day diet; 28-day
Experimental Results: and lipogenesis and TG synthesis The relative mRNA levels of some key genes were increased. Upregulates IL-1b and IL-6 mRNA levels in mouse liver. Serum concentrations of 2 proinflammatory cytokines, IL-1b and IL-6, were increased at 500 mg/kg. However, in adipose tissue, only IL-1b was Dramatically increased in the CBZ-500 treatment group compared with the control group.

Absorption, Distribution and Excretion
Following a single oral dose of 3 mg/kg in male rats, 66% of the drug was excreted in the urine within 6 hours. Metabolisms/Metabolites Easily absorbed by plants. One degradation product is 2-aminobenzimidazole. …Two metabolites, methyl 5-hydroxy-2-benzimidazole carbamate (5-HBC) and 2-aminobenzimidazole (2-AB), are rapidly generated in rats after intravenous injection of 12 mg/kg. Peak concentrations in the liver and kidneys are reached 15 minutes after intravenous injection. The highest concentration of unmetabolized carbendazim is observed in the blood. 5-HBC is dominant in organs. 2-AB is present in small amounts. The bioavailability of oral 14C-carbendazim (12 mg/kg) is approximately 85%. The distribution of the radioactive material is not uniform in subcellular components, with the highest concentration in the cytosol and the lowest in the microsomes. ...
Carbamate compounds are enzymatically hydrolyzed in the liver; degradation products are excreted via the kidneys and liver. (L793)

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Biological half-life
After intravenous injection of 12 mg/kg (14)C-carbendazim in rats, its metabolic kinetics conformed to a two-compartment open system model. The α-phase half-lives were 0.16 hours (liver) and 0.25 hours (kidney), respectively, and the β-phase half-lives were 2.15 hours and 6.15 hours, respectively. Two metabolites, methyl 5-hydroxy-2-benzimidazole carbamate (5-HBC) and 2-aminobenzimidazole (2-AB), were rapidly generated. Peak concentrations were reached in the liver and kidneys 15 minutes after intravenous injection. The highest concentration in the blood was unmetabolized carbendazim. 5-HBC was dominant in all organs. Only a small amount of 2-AB was present. The bioavailability of oral 14C-carbendazim (12 mg/kg) was approximately 85%. The distribution of radioactivity in subcellular components is uneven, with the highest concentration in the cytosol and the lowest in the microsomes. Elimination of 14C-carbendazim in urine exhibits a biphasic pattern. The half-lives of the α-phase are 1.4 hours (intravenous injection) and 2.5 hours (oral administration), while the half-lives of the β-phase are 11.2 hours and 12.1 hours, respectively. Regardless of the route of administration, 95% of the radioactive material in urine is 5-HCB. The concentrations of unmetabolized carbendazim in the blood and the concentrations of 5-HCB in the urine may be valuable for the diagnosis of acute carbendazim poisoning.

Toxicity Summary
Identification and Uses: Carbendazim is a white powder, a systemic foliar and soil fungicide that can be absorbed through roots and green tissues. Human Exposure and Toxicity: Paired studies were conducted on all six human chromosomes (1 and 8, 11 and 18, and X and 17). Abnormalities were classified as chromosome loss (including centromere-positive micronuclei), chromosome gain, nondisjunction, or polyploidy. Animal Studies: Previous studies have shown that carbendazim may interfere with mitosis, thereby disrupting or inhibiting microtubule function and leading to apoptosis. Even low doses of carbendazim have shown toxicity, affecting the liver and causing specific changes in hematological and biochemical parameters in rats. Male rats (n=6 per dose group) were administered 200, 3400, and 5000 mg/kg of the drug by gavage, 5 days a week for 2 weeks. In the 3400 mg/kg/day dose group, 2 out of 6 rats died. In all dosage groups, gross and microscopic adverse reactions were observed in the testes, as well as a decrease or absence of sperm in the epididymis. Testicular volume was reduced, color was abnormal, and signs of seminiferous tubule degeneration and azoospermia were observed. Morphological changes were also observed in the duodenum (edema and focal necrosis), bone marrow (decrease in hematopoietic factors), and liver (decrease in large globular vacuoles) in the 3400 mg/kg/day dosage group. One-year-old beagles (4 males and 4 females) were divided into four groups and fed diets supplemented with carbendazim at doses of 0, 100, 500, and 2500 mg/kg for 3 months. Compared with pre-experimental levels and the control group, female beagles in the medium-dose group showed a trend towards increased cholesterol levels at 1, 2, and 3 months. Cholesterol levels were also increased in female beagles in the high-dose group. Changes were observed in thymus weight in male beagles in the low- and medium-dose groups, and prostate weight in male beagles in the medium-dose group. Pregnant rats were administered gavage during days 6-15 of gestation at doses up to 80 mg/kg/day. Pregnant rabbits were administered similar gavage during days 6-18 of gestation at doses up to 160 mg/kg/day. In rats, fetal death and resorption rates were 29% in the control group, 48% in the 20 mg/kg group, 64% in the 40 mg/kg group, and 73% in the 80 mg/kg group. In rabbits, no fetal death or resorption was observed in the control group, while the proportion of fetal death or resorption was 15-33% in the carbendazim-treated groups. There was no difference in mean live fetal weight between rats and rabbits, and no malformations were found. Carbendazim induced chromosomal aberrations in sperm cells, with a high incidence of aneuploidy. Carbendazim induced micronucleus formation in mouse bone marrow cells. 2,3-Diaminophenazine (DAP) and 2-amino-3-hydroxyphenazine (AHP) were detected in the mutagenic carbendazim samples. Carbenine samples at concentrations as low as 5 ppm or 10 ppm of DAP or AHP showed positive reactions and activation in the Salmonella/Ames test at a concentration of 5000 μg/plate. Purified carbenine is not mutagenic. Ecotoxicity studies: Amazonian fish are slightly less sensitive to carbenine than temperate fish, with LC50 values ranging from 1648 to 4238 μg/L; Amazonian invertebrates show significantly higher resistance than their temperate counterparts, with LC50 values exceeding 16000 μg/L. In plants, carbenine can cause methylation or demethylation of certain genes and alter their expression. Carbenine targets β-tubulin in actively dividing cells. It binds to microtubules, interfering with cellular functions such as meiosis and intracellular transport (A15332). Toxicity Data: Acute oral LD50 in rats >15000 mg/kg, in dogs >2500 mg/kg. Interactions: This study investigated the effects of licorice water extract on carbendazim-induced testicular toxicity in albino rats. After carbendazim administration, testicular weight, diameter, and seminiferous tubule germinal epithelium height were significantly reduced. Histological results showed seminiferous tubule degeneration, spermatogenic cell loss, and apoptosis. Furthermore, carbendazim led to increased levels of malondialdehyde (MDA, a marker of lipid peroxidation) in the testes and decreased the activities of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). Co-administration of licorice extract with carbendazim improved the histomorphological and histopathological changes in carbendazim-treated animals. In addition, licorice treatment significantly reduced MDA levels and increased the activities of SOD and CAT. Based on the current findings, we conclude that licorice water extract can alleviate the testicular toxicity of carbendazim, an effect likely attributed to the antioxidant properties of one or more of its components. 2,5-Hexanedione (2,5-HD) is a paclitaxel-like microtubule assembly promoter, while carbendazim (CBZ) is a colchicine-like microtubule assembly inhibitor; both are environmental testicular toxins that target and disrupt microtubule function in Sertoli cells. At the molecular level, these two toxins have opposite effects on microtubule assembly, but both share a common physiological effect of inhibiting Sertoli cell microtubule-dependent function. By investigating co-exposure to 2,5-HD and CBZ, we sought to determine whether CBZ antagonizes or exacerbates the effects of initial 2,5-HD exposure. In vitro experiments showed that 2,5-HD treatment shortened the microtubule assembly delay time and increased the maximum assembly rate. Carbamazepine (CBZ) treatment restored 2,5-HD-induced changes in microtubule assembly to normal in vitro. In in vivo experiments, adult male rats were given 1% 2,5-HD solution in their drinking water for 2.5 weeks. Twenty-four hours before testicular assessment, CBZ (200 mg/kg body weight) was administered by gavage, and unilateral efferent tubule ligation was performed simultaneously. Testicular effect indicators (testicular weight, histopathological changes [sloughing and vacuolation], and seminiferous tubule diameter) all showed significant changes after combined exposure. Compared with the single-toxin exposure group (with the control group as a reference), the combined exposure group showed different seminiferous tubule diameters, an additive effect of vacuolation percentage, or a sloughing percentage greater than the additive effect. Therefore, CBZ combined exposure did not antagonize the effects of initial 2,5-HD exposure, contrary to the expectation that their molecular effects on microtubule assembly were the sole cause of their combined toxicity; instead, 2,5-HD and CBZ worked together to exacerbate testicular damage. Detailed toxicity tests were conducted to determine whether the effects of copper-cadmium mixtures and copper-carbendazim mixtures on C. elegans were similar to those of the single compounds. Effects on reproductive processes, larval stage length, reproductive stage length, and body length were analyzed. Dose-response data were compared with additive models, and four patterns deviating from additive relationships were examined: no deviation, synergistic/antagonistic deviation, dose-ratio-dependent deviation, and dose-level-dependent deviation. During exposure, the effect of cadmium-copper on reproduction shifted from a synergistic effect to a dose-ratio-dependent deviation from an additive relationship. Higher cadmium content in the mixture was associated with lower toxicity; higher copper content was associated with higher toxicity. The effect of copper-carbendazim on reproduction was synergistic at low dose levels and antagonistic at high dose levels, and was time-independent. The effects of the mixtures on the larval and reproductive stages were similar to those of the single components. The conclusion is that the observed toxic interactions were less time-dependent, and no effect on reproductive time was found. The additive model underestimated the effects of the mixtures on reproduction and body length.
The fungicide carbendazim methyl-2-benzimidazole carbamate (MBC) is known to cause male reproductive toxicity. This study aimed to investigate the effect of the antioxidant vitamin E on MBC-induced testicular toxicity. High-performance liquid chromatography (HPLC) analysis showed that in rats treated with carbendazim plus vitamin E, the levels of MBC in the testes and serum were 57.40±3.38 nmol/g and 14.10±0.84 nmol/mL, respectively, significantly lower than those in rats treated with carbendazim alone (240±15.60 nmol/g and 318.70±22.52 nmol/mL, respectively). MBC treatment significantly reduced testicular weight, while the combined use of vitamin E restored testicular weight to normal. Histomorphometry analysis showed that compared with the control group, the seminiferous tubules and lumen diameters of rats in the MBC treatment group were significantly reduced (P<0.05), while the seminiferous tubules and lumen diameters of rats in the vitamin E+MBC treatment group remained normal. Following MBC treatment, testicular interstitial cells were dispersed and hypertrophied. Multiple histopathological changes were observed in the testicular tissue of rats in the MBC treatment group, while these changes were not observed in the testicular tissue of rats in the vitamin E + MBC combined treatment group. In conclusion, combined administration of vitamin E and MBC can prevent MBC-induced toxicity.
For more complete data on interactions of carbendazim (18 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats (sesame oil) >15,000 mg/kg
Intraperitoneal LD50 in male rats (0.9% saline and Tween 80 solvent) >2,000 mg/kg body weight (data from table)
Oral LD50 in male mice (propylene glycol solvent) 15,000 mg/kg body weight (data from table)
Intraperitoneal LD50 in male/female mice (sesame oil solvent) >15,000 mg/kg body weight (data from table)
For more complete non-human toxicity data for carbendazim (15 in total), please visit the HSDB record page. Visit the HSDB record page.

[1]. Carbendazim.

[2]. Oral Exposure of Mice to Carbendazim Induces Hepatic Lipid Metabolism Disorder and Gut Microbiota Dysbiosis. Toxicol Sci. 2015 Sep;147(1):116-26.

[3]. Enhanced antitumor activity of carbendazim on HeLa cervical cancer cells by aptamer mediated controlled release. RSC Advances.

Therapeutic Uses
/EXPL THER/ Benzimidazole fungicides benomyl and carbendazim are believed to target microtubules. Benzimidazole is metabolized into carbendazim, which has been explored as an anticancer drug in a phase I clinical trial. We further characterized the cytotoxicity of benomyl and carbendazim in 12 human cell lines and primary cultures of patient tumor cells to elucidate their mechanisms of action and anticancer activity spectrum. Cytotoxicity was assessed using a short-term fluorescent microculture cytotoxicity assay and correlated with the activity of other anticancer drugs and gene expression assessed by cDNA microarray analysis. Benzimidazole activity was generally higher than that of its metabolite carbendazim. Both showed high correlations with several marketed and experimental anticancer drugs, but weak correlations with known resistance mechanisms. Furthermore, these benzimazole compounds were highly correlated with activity-related genes of various standard and experimental anticancer drugs with different mechanisms of action, indicating a broad range of mechanisms of action. In patient tumor samples, benomyl showed higher activity in hematologic malignancies than in solid tumors, while carbendazim showed the opposite. In summary, benomyl and carbendazim exhibit interesting and diverse cytotoxic mechanisms of action, appearing suitable as lead compounds for the development of novel anticancer drugs. Carbendazim inhibits microtubule assembly, thereby blocking mitosis and inhibiting cancer cell proliferation. Therefore, carbendazim is being explored as an anticancer drug. Data showed that carbendazim can increase CYP1A1 mRNA and protein expression and promoter activity. Furthermore, carbendazim activates the transcriptional activity of aryl hydrocarbon response elements and induces nuclear translocation of the aryl hydrocarbon receptor (AhR), indicating that AhR is activated. Benomyl-induced CYP1A1 expression can be blocked by AhR antagonists and completely disappears in AhR signaling-deficient cells. These results indicate that benomyl activates AhR, thereby stimulating CYP1A1 expression. To understand whether AhR-induced metabolic enzymes convert benomyl into less toxic metabolites, this study used Hoechst 33342 staining to detect benomyl-induced nuclear changes and flow cytometry to detect sub-G0/G1 phase cell populations to monitor benomyl-induced apoptosis. Benomyl induced fewer apoptosis in Hepa-1c1c7 cells than in AhR-signal-deficient Hepa-1c1c7 mutant cells. Pretreatment with β-NF (an AhR agonist that highly induces CYP1A1 expression) reduced benomyl-induced cell death. Furthermore, lower AhR levels correlated with lower cell viability after carbendazim treatment, including hepatocellular carcinoma cells and their AhR RNA-interfered derivatives, embryonic kidney cells, bladder cancer cells, and AhR-signal-deficient Hepa-1c1c7 cells. In conclusion, carbendazim is an AhR agonist. In cells with AhR signaling, carbendazim exhibits lower toxicity. This report provides clues suggesting that carbendazim induces cell death more effectively in tissues lacking AhR signaling than in tissues with AhR signaling, offering important insights for its application in cancer chemotherapy. The results of this study indicate that FB642/carbendazim/ increases apoptosis in all detected tumor cell lines, may induce G2/M phase uncoupling, may selectively kill p53-deficient cells, and exhibits antitumor activity in drug-resistant and multidrug-resistant cell lines. FB642 can induce apoptosis, especially in p53-deficient cells; it has significant in vivo activity against various mouse and human tumors; and its toxicity is acceptable in animal studies. These properties make FB642 an ideal candidate for further evaluation in clinical trials for cancer patients. /FB642/

C9H9N3O2

191.19

191.069

10605-21-7

Carbendazim-d4;291765-95-2;Carbendazimb-d3;1255507-88-0

25429

White to off-white solid powder

1.4±0.1 g/cm3

406.1±28.0 °C at 760 mmHg

>300 °C(lit.)

199.4±24.0 °C

0.0±1.0 mmHg at 25°C

1.650

2.1

2

3

2

14

222

0

TWFZGCMQGLPBSX-UHFFFAOYSA-N

InChI=1S/C9H9N3O2/c1-14-9(13)12-8-10-6-4-2-3-5-7(6)11-8/h2-5H,1H3,(H2,10,11,12,13)

methyl N-(1H-benzimidazol-2-yl)carbamate

Carbendazole. FB462; Mercarzole

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 : ~6.8 mg/mL (~35.57 mM)

Solubility in Formulation 1: ≥ 0.5 mg/mL (2.62 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 5.0 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: ≥ 0.5 mg/mL (2.62 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 5.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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