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
In male rats, following a single oral admin of 3 mg/kg, 66% was eliminated in the urine within 6 hr.

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Metabolism / Metabolites
Readily absorbed by plants. One degradation product is 2-aminobenzimidazole.
... Two metabolites: methyl 5-hydroxy-2-benzimidazolecarbamate (5-HBC) and 2-aminobenzimidazole (2-AB) were formed very rapidly /in rats admin 12 mg/kg iv/. Their peak concentrations in liver and kidney were 15 min after i.v. injection. Unchanged carbendazim was found in highest concentrations in blood. 5-HBC prevails in organs. 2-AB was present only in minor amounts. The extent of bioavailability in orally administered 14C-carbendazim (12 mg/kg) was about 85%. The disposition of radioactivity in subcellular fractions was not uniform, its highest concentration was in cytosol, the lowest in microsomes. ...
The carbamates are hydrolyzed enzymatically by the liver; degradation products are excreted by the kidneys and the liver. (L793)

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Biological Half-Life
The disappearance of (14)C-carbendazim in rat (i.v. 12 mg/kg) followed the kinetics of a two-compartment open-system model. Half-lives of the alpha-phase were 0.16 hr (liver), 0.25 hr (kidney), and of the beta-phase: 2.15 hr, 6.15 hr, respectively. Two metabolites: methyl 5-hydroxy-2-benzimidazolecarbamate (5-HBC) and 2-aminobenzimidazole (2-AB) were formed very rapidly. Their peak concentrations in liver and kidney were 15 min after i.v. injection. Unchanged carbendazim was found in highest concentrations in blood. 5-HBC prevails in organs. 2-AB was present only in minor amounts. The extent of bioavailability in orally administered 14C-carbendazim (12 mg/kg) was about 85%. The disposition of radioactivity in subcellular fractions was not uniform, its highest concentration was in cytosol, the lowest in microsomes. The elimination of (14)C-carbendazim in urine is biphasic. Half-lives of the alpha-phase were 1.4 hr (i.v.) and 2.5 hr (oral), and of the beta-phase 11.2 hr and 12.1 hr, respectively. Irrespective of the route of administration, 95% of the radioactivity in urine was composed of 5-HBC. The concentration of unchanged carbendazim in blood and of 5-HBC in urine may be of diagnostic value in acute poisoning with carbendazim.

Toxicity Summary
IDENTIFICATION AND USE: Carbendazim is a white powder. it is a systemic leaf and soil fungicide, absorbed through the roots and green tissues. HUMAN EXPOSURE AND TOXICITY: Six human chromosomes were investigated in pairs (1 and 8, 11 and 18, and X and 17). Abnormalities were classified as chromosome loss (including centromeric positive micronuclei), chromosome gain, non-disjunction, or polyploidy. ANIMAL STUDIES: Previous studies indicate that carbendazim may interfere with mitosis and thus may disrupt or inhibit microtubule function resulting in apoptosis. Carbendazim even at low dose exhibited toxicity, affected the liver and also caused specific changes in hematological and biochemical parameters in the rat. Male rats (6 per dose level) were gavaged with 200, 3400 and 5000 mg/kg 5 days/wk for 2 wk. Two out of the 6 rats died at the dose level of 3400 mg/kg per day. At all dose levels, gross and microscopic evidence of adverse effects on the testes and reduction or absence of sperm in the epididymides was seen. The testes were small and discolored, with tubular degeneration and evidence of aspermatogenesis. At the dose level of 3400 mg/kg per day, there were also morphological changes in the duodenum (edema and focal necrosis), bone marrow (reduction in the blood forming elements) and liver (decrease in the large globular shaped vacuoles). Groups of 1 yr old beagles (4 males, 4 females) were admin carbendazim in the diet for 3 months at dietary levels of 0, 100, 500 and 2500 mg/kg. Females at the mid dose level showed a trend toward incr cholesterol levels at 1, 2 and 3 months compared with the pre-test and control values. High dose females also had elevated cholesterol levels. Organ to body weight changes were observed in the case of the thymus of low and mid dose males and the prostate of mid dose males. Groups of pregnant rats were administered carbendazim by gavage on days 6-15 of gestation at dose levels up to 80 mg/kg/day. Groups of pregnant rabbits were similarly administered up to 160 mg/kg/day on days 6-18 of gestation. In the rats, dead and resorbed fetuses accounted for 29% of conceptions in controls, 48% at 20 mg/kg, 64% at 40 mg/kg, and 73% at 80 mg/kg. In rabbits, no dead or resorbed fetuses were seen in controls whereas 15-33% were found in carbendazim-treated rabbits. There were no differences among rats or rabbits in mean weight of live fetuses, and there were no malformations. Carbendazim induced chromosome aberrations in spermatids with a high incidence of aneuploidy. Carbendazim induced micronuclei in mouse bone marrow cells. 2,3-diaminophenazine (DAP) and 2-amino-3-hydroxyphenazine (AHP) were detected in mutagenic carbendazim samples. Carbendazim samples containing DAP or AHP at levels as low as 5 or 10 ppm, respectively, were positive in the Salmonella/Ames test with activation when tested at 5000 ug/plate. Purified carbendazim was not mutagenic. ECOTOXICITY STUDIES: Amazonian fish appeared to be slightly less sensitive for carbendazim than temperate fish with LC50 values ranging between 1648 and 4238 ug/L, and Amazonian invertebrates were found to be significantly more resistant than their temperate counterparts, with LC50 values higher than 16000 ug/L. In plants, carbendazim causes methylation or demethylation of certain genes and changes the expression of these genes.
Carbendazim targets beta tubulin in actively dividing cells. It binds to microtubules, interfering with cell functions, such as meiosis and intracellular transportation (A15332).

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Toxicity Data
Acute oral LD50 for rats is >15000 mg/kg and >2500 mg/kg for dogs

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Interactions
... The present work studied the effect of licorice aqueous extract on carbendazim-induced testicular toxicity in albino rats. Administration of carbendazim induced significant decrease in testis weight, diameter, and germinal epithelial height of the seminiferous tubules. Histological results revealed degeneration of seminiferous tubules, loss of spermatogenic cells, and apoptosis. Moreover, carbendazim caused elevation of testicular malondialdehyde (MDA), marker of lipid peroxidation, and reduced the activity of the antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT). Coadministration of licorice extract with carbendazim improved the histomorphological and histopathological changes observed in animals treated with carbendazim. In addition, licorice treatment leads to a significant decrease in the level of MDA and increase in the activities of SOD and CAT. According to the present results, it is concluded that licorice aqueous extract can improve the testicular toxicity of carbendazim and this effect may be attributed to antioxidant properties of one or more of its constituents.
2,5-Hexanedione (2,5-HD), a taxol-like promoter of microtubule assembly, and carbendazim (CBZ), a colchicine-like inhibitor of microtubule assembly, are two environmental testicular toxicants that target and disrupt microtubule function in Sertoli cells. At the molecular level, these two toxicants have opposite effects on microtubule assembly, yet they share the common physiologic effect of inhibiting microtubule-dependent functions of Sertoli cells. By studying a combined exposure to 2,5-HD and CBZ, we sought to determine whether CBZ would antagonize or exacerbate the effects of an initial 2,5-HD exposure. In vitro, 2,5-HD-treated tubulin had a decreased lag time and an increased maximal velocity of microtubule assembly. These 2,5-HD-induced in vitro alterations in microtubule assembly were normalized by CBZ exposure. In vivo, adult male rats were exposed to a 1% solution of 2,5-HD in the drinking water for 2.5 weeks. CBZ was administered by gavage (200 mg/kg body weight) at the same time as unilateral surgical ligation of the efferent ducts, 24 hr before evaluation of the testis. Measures of testicular effect (testis weight, histopathologic changes [sloughing and vacuolization], and seminiferous tubule diameters) were all significantly altered with combined exposure. The testicular effects in the combined exposure group were either different (seminiferous tubule diameters), additive (% vacuolization), or greater than additive (% sloughing) compared to the effects of the individual toxicant exposure groups referenced to the controls. Therefore, CBZ coexposure does not antagonize the effects of an initial 2,5-HD exposure, as might be expected if their molecular effects on microtubule assembly were solely responsible for their combined toxicity; instead, 2,5-HD and CBZ act together to exacerbate the testicular injury.
... Detailed toxicity tests were performed to determine whether effects of mixtures of copper-cadmium and copper-carbendazim on Caenorhabditis elegans were similar to the effects of the individual compounds. Effects on the course of reproduction, the length of the juvenile period, the length of the reproductive period, and body length were analyzed. Dose-response data were compared to the additive model and tested for four deviation patterns from additivity: No deviation, synergistic/antagonistic deviation, dose ratio-dependent deviation, dose level-dependent deviation. During the exposure, the cadmium-copper effect on reproduction changed from a synergistic, to a dose ratio-dependent deviation from additivity. More cadmium in the mixture decreased the toxicity and more copper increased the toxicity. The effect of copper-carbendazim on reproduction was synergistic at low dose levels and antagonistic at high dose levels and independent of time. Mixture effects on the juvenile and reproductive period were similar to single component effects. It was concluded that the observed time-dependence of toxic interactions was small and that interactions on the timing of reproduction were not found. The additive model underestimated mixture effects on reproduction and body length.
The fungicide Carbendazim Methyl-2-benzimidazole carbamate (MBC) is known to produce male reproductive toxicity. The present study has been undertaken to investigate the impact of vitamin E, an antioxidant against the testicular toxicity induced by MBC. HPLC analysis showed that the amount of MBC in testis and serum was 57.40 +/- 3.38 nmol/g and 14.10 +/- 0.84 nmol/mL, respectively, in rats treated with carbendazim + vitamin-E, which were significantly lower than that of rats treated with carbendazim alone (240 +/- 15.60 nmol/g and 318.70 +/- 22.52 nmol/mL, respectively). MBC treatment significantly decreased the testicular weight while co-administration of vitamin-E registered normal testicular weight. Histomorphometric analysis revealed a significant decrease (P < 0.05) in the diameter of the seminiferous tubules and lumen in MBC-treated rats compared to control whereas they remained normal in vitamin E + MBC-treated rats. Leydig cells appeared dispersed and hypertrophic after MBC treatment. Various histopathological changes were observed in testis of rats treated with MBC whereas these changes were absent in vitamin-E + MBC-treated rat testis. In conclusion protection against MBC-induced toxicity was observed with co-administration of vitamin E with MBC.
For more Interactions (Complete) data for CARBENDAZIM (18 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral (in sesame oil) >15,000 mg/kg
LD50 Rat (male) ip in 0.9% saline and Tween 80 vehicle >2,000 mg/kg bw /from table/
LD50 Mouse (male) oral in propylene glycol vehicle 15,000 mg/kg bw /from table/
LD50 Mouse (male/female) ip in sesame oil vehicle >15,000 mg/kg bw /from table/
For more Non-Human Toxicity Values (Complete) data for CARBENDAZIM (15 total), please 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/ The benzimidazoles, benomyl and carbendazim, are fungicides suggested to target microtubules. Benomyl is metabolized to carbendazim, which has already been explored as an anticancer drug in phase 1 clinical trials. We further characterized the cytotoxic properties of benomyl and carbendazim in 12 human cell lines and in primary cultures of patient tumor cells with the overall aims of elucidating mechanisms of action and anticancer activity spectrum. Cytotoxicity was assessed in the short-term fluorometric microculture cytotoxicity assay and was correlated with the activity of other anticancer drugs and gene expression assessed by cDNA microarray analysis. Benomyl was generally more potent than its metabolite, carbendazim. Both showed high drug activity correlations with several established and experimental anticancer drugs, but modest association with established mechanisms of drug resistance. Furthermore, these benzimidazoles showed high correlations with genes considered relevant for the activity of several mechanistically different standard and experimental anticancer drugs, indicating multiple and broad mechanisms of action. In patient tumor samples, benomyl tended to be more active in hematological compared with solid tumor malignancies, whereas the opposite was observed for carbendazim. In conclusion, benomyl and carbendazim show interesting and diverse cytotoxic mechanisms of action and seem suitable as lead compounds for the development of new anticancer drugs.
/EXPL THER/ Carbendazim inhibits microtubule assembly, thus blocking mitosis and inhibiting cancer cell proliferation. Accordingly, carbendazim is being explored as an anticancer drug. Data show that carbendazim increased mRNA and protein expressions and promoter activity of CYP1A1. In addition, carbendazim activated transcriptional activity of the aryl hydrocarbon response element, and induced nuclear translocation of the aryl hydrocarbon receptor (AhR), a sign the AhR is activated. Carbendazim-induced CYP1A1 expression was blocked by AhR antagonists, and was abolished in AhR signal-deficient cells. Results demonstrated that carbendazim activated the AhR, thereby stimulating CYP1A1 expression. In order to understand whether AhR-induced metabolic enzymes turn carbendazim into less-toxic metabolites, Hoechst 33,342 staining to reveal carbendazim-induced nuclear changes and flow cytometry to reveal the subG0/G1 population were applied to monitor carbendazim-induced cell apoptosis. Carbendazim induced less apoptosis in Hepa-1c1c7 cells than in AhR signal-deficient Hepa-1c1c7 mutant cells. Pretreatment with beta-NF, an AhR agonist that highly induces CYP1A1 expression, decreased carbendazim-induced cell death. In addition, the lower the level of AhR was, the lower the vitality present in carbendazim-treated cells, including hepatoma cells and their derivatives with AhR RNA interference, also embryonic kidney cells, bladder carcinoma cells, and AhR signal-deficient Hepa-1c1c7 cells. In summary, carbendazim is an AhR agonist. The toxicity of carbendazim was lower in cells with the AhR signal. This report provides clues indicating that carbendazim is more potent at inducing cell death in tissues without than in those with the AhR signal, an important reference for applying carbendazim in cancer chemotherapy.
/EXPL THER/ ... The results of this present study indicate that FB642 /carbendazim/ increases the degree of apoptosis in all examined tumor cell lines, may induce G2/M uncoupling, may selectively kill p53 abnormal cells, and exhibits antitumor activity in drug- and multidrug-resistant cell lines. The induction of apoptosis by FB642, particularly in p53-deficient cells, its impressive in vivo activity against a broad spectrum of murine and human tumors, as well as an acceptable toxicity profile in animals, make FB642 an excellent candidate for further evaluation in clinical trials in 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.)