Physicochemical Properties
| Molecular Formula | C8H12MNN4S8ZN |
| Molecular Weight | 541.1 |
| Exact Mass | 538.749 |
| Elemental Analysis | C, 17.76; H, 2.24; Mn, 10.15; N, 10.36; S, 47.41; Zn, 12.08 |
| CAS # | 8018-01-7 |
| PubChem CID | 3034368 |
| Appearance | Light yellow to yellow solid powder |
| Density | 1.92 g/cm3 |
| Boiling Point | 308.2ºC at 760 mmHg |
| Melting Point | 192-194°C |
| Flash Point | 138 °C |
| Vapour Pressure | 0.000692mmHg at 25°C |
| LogP | 0.608 |
| Hydrogen Bond Donor Count | 4 |
| Hydrogen Bond Acceptor Count | 8 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 22 |
| Complexity | 108 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | S=C(S)NCCNC(S)=S.[S-]C([S-])=NCCN=C([S-])[S-].[Mn+2].[Zn+2] |
| InChi Key | CHNQZRKUZPNOOH-UHFFFAOYSA-J |
| InChi Code | InChI=1S/2C4H8N2S4.Mn.Zn/c2*7-3(8)5-1-2-6-4(9)10/h2*1-2H2,(H2,5,7,8)(H2,6,9,10)/q2*+2/p-4 |
| Chemical Name | zincmanganese(2+)N-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate |
| Synonyms | Acarie M; Agrox 16D; Blecar MN; Carmazine; Caswell No. 913A; CCRIS 2495; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Absorption of /mancozeb/ across skin and mucous membranes is probably very limited. Ethylenethiourea is a decomposition product and metabolite of the ethylenebis(dithiocarbamate) group of fungicides. Following administration of single oral doses of (14)C ethylenethiourea to pregnant rats, maternal blood maintained peak radioactivity for 2 hr, and the radioactivity was dispersed uniformly between the RBC and plasma. The level of radioactivity was distributed equally among several maternal tissues but was present in lower amounts in embryos. 24 hr after treatment all tissues examined, except blood, were relatively clear of radioactivity, and 72.8% of the total radioactivity given had been excreted in the urine. Elution patterns of metabolites for Sephadex separation suggested that ethylenethiourea was degraded very little. /Ethylenebis(dithiocarbamate) group of fungicides/ Mancozeb appears to be rapidly absorbed from the gastrointestinal tract, distributed to target organs and excreted almost totally by 96 hr. Rats dosed via a stomach tube with 20 mg (14)C-mancozeb per day for 7 days (equivalent to approx 100 mg/kg body weight) were killed one day after the last dose and the radioactivity in excreta and organs was measured. In the feces, urine, organs and tissues, and carcass, 71%, 16%, 0.31%, and 0.96% of the total radioactivity was detected, respectively. Specifically, the liver contained 0.19%, the kidneys, 0.076%, the thyroid gland, 0.003%, and all other organs, < 0.01%. Most of the labeled material in the feces was mancozeb, indicating that mancozeb was poorly absorbed from the gastrointestinal tract ... The pharmacokinetics of (14)C-mancozeb (11.54 mCi/g = 25,619 dpm/ug; suspended in 0.5% methylcellulose in distilled water) were studied in Sprague-Dawley CD rats (both sexes) treated with a single oral dose of 1.5 (Group A) or 100 mg/kg (Group B) or a pulse (oral) dose of 1.5 mg/kg (14)C-mancozeb (Group C) which followed 2 weeks of dietary administration of nonradiolabelled mancozeb (84% pure; 15 ppm a.i.). Rats were terminated 96 hours after (14)C-mancozeb treatment. Bile cannulation occurred in both sexes of rat treated at 1.5 (Group D) and 100 mg/kg (Group E) for assessment of excretion in bile at 24 hours. Approximately half of the oral dose of mancozeb was absorbed in rats. Results showed non-linear kinetics occurred between 100 and 1.5 mg/kg. Absorption was moderately rapid (peak levels in 3 and 6 hours at 1.5 and 100 mg/kg, respectively). Elimination was biphasic. Most of the oral dose was eliminated in excreta within 24 hours-evenly divided between feces and urine. Small amounts were excreted in the bile (2-9%). Thyroid contained the greatest concentrations and peak concentrations in thyroid were not proportional to dose. Thyroid (14)C-concentrations were disproportionately less than the respective peak blood levels after 100 mg/kg than after 1.5 mg/kg (14)C-mancozeb indicating saturation at the high dose. Pretreatment with dietary nonradiolabelled mancozeb did not significantly affect the disposition or excretion of (14)C-mancozeb. The in vivo conversion of mancozeb to ETU was determined to be 6.8%. Metabolism / Metabolites ... Mancozeb /is/ metabolized to the degradation product ethylene thiourea, which may have toxic properties of its own. In oral rat metabolism studies conducted with radiolabeled mancozeb and other /ethylenebisdithiocarbamate compounds (EBDC)/, the in vivo metabolic conversion of EBDC to ETU (ethylenethiourea) was 7.5% on a weight-to-weight basis. In plants, the principal metabolite is ethylenethiourea, which undergoes further metabolism. Ethylenethiuram monosulfide, ethylenethiuroum disulfide, and sulfur are also metabolites. The major metabolite is ethylene thiourea comprising almost 24% of the bio-available dose in urine and bile. Ethylene thiourea residues in the thyroid and the liver were less than 1 ppm and were nondetectable after 24 hr. |
| Toxicity/Toxicokinetics |
Toxicity Summary IDENTIFICATION AND USE: Mancozeb is a greyish-yellow free-flowing powder. It is used for control of many fungal diseases in a wide range of field crops, fruits, nuts, vegetables, and ornamentals. It is also used as seed treatment/protectant. HUMAN EXPOSURE AND TOXICITY: Exposure could lead to toxic epidermal necrolysis (TEN), which is a life-threatening mucocutaneous disease with high mortality. There has been a case of dyshidrotic eczema and sensitization to mancozeb in a florist. A widespread dermatitis was reported by a woman following storage of mancozeb powder in a garage. An epidemiological study suggests that pregnant women living near banana plantations aerially sprayed with mancozeb may be environmentally exposed to Mn, which is a neurotoxicant at high concentrations. Another study demonstrated an augmented risk of cutaneous melanoma among subjects with exposure to mancozeb, in particular among those with occupational sun exposure. There appeared to be an association between mancozeb exposure and a significant increase in the frequencies of cells with structural chromosome aberrations and the number of sister chromatid exchanges per cell in peripheral blood lymphocytes. Slight immunomodulator effect of mancozeb in conditions of low-level, prolonged occupational exposure was observed. ANIMAL STUDIES: Compounds of this class usually have low acute toxicity. Studies in animals suggest that contact dermatitis and thyroid hyperplasia may occur after exposure. Mancozeb was a potent dermal sensitizer in the guinea pig. Cross-sensitization was observed between mancozeb, zineb and maneb. In rats, thyroid follicular cell hyperplasia was seen at 100 ppm and higher doses. Mancozeb exerts dose-dependent damaging effects on the gonads of rats of both sexes. The dose level was 140-1400 mg mancozeb/kg body weight, given twice a week for 4.5 months. Both reproductive and endocrine structures were affected at all dose levels, leading to decreased fertility. In developmental studies in rats, increase in resorbed litters, external hemorrhage and wavy ribs have been observed; no embryotoxicity in absence of maternal toxicity. Rats treated with mancozeb showed dose-dependent signs of depression, adynamia, decreased tonus, disturbances in coordination, paresis, and paralysis of extremities combined with general weakness, lack of appetite, and prostration. Mutagenicity: Bacterial and in vitro mammalian cell systems, chromosome damage in vivo and in mammalian cell transformation tests were negative. Sister chromatid exchanges in Chinese hamster ovary cells in vitro was positive. Mancozeb induces a number of different types of chromosomal aberrations in the bone marrow cells of male mice at various test doses. Mancozeb was examined for its possible mutagenic activity using Salmonella typhimurium tester strains TA97a, TA98, TA100, and TA102 with negative results. In rats treated with mancozeb in vivo, it induced DNA damage as detected by the comet assay and increased the frequency of micronuclei. Acute treatments with mancozeb inhibit cytochrome P450 mediated metabolism. Mancozeb is metabolized to ethylene thiourea (ETU). ETU is a carcinogen, based on thyroid and other cancers in rodents, ETU is also known to cause decreases of thyroxine (T4) and increases in thyroid-stimulating hormone (TSH) in rodents. ECOTOXICITY STUDIES: In a seasonally breeding wildlife bird, Red Munia (Amandava amandava) plasma T4, T3 and TSH were significantly decreased in response to mancozeb. Mancozeb toxicity effects noted in both birds and mammals could be a result of possible hormonal disruptions. The avian reproductive studies noted reproductive effects such as reductions in: egg production; early and late embryo viability; hatchability; offspring weight at hatch and 14-days of age; and the number of 14-day old survivors. Reduced growth rates were noted in tadpoles exposed to mancozeb. Chronic testing in freshwater organisms showed immobility, length and time until first brood in Daphnia and reduced survival and lack of growth effects in fathead minnow. These effects noted in freshwater species could be a result of possible hormonal disruptions. Lettuce exposure to mancozeb was shown to have a significant impact on plant metabolism, with mature leaves tending to be more extensively affected than younger leaves. Interactions Mancozeb, as a dithiocarbamate fungicide, has been found to exhibit toxicological manifestations in different cells, mainly by generation of free radicals which may alter antioxidant defense systems in cells ... In the present study, the effects of mancozeb (0.2, 2 and 5 ug/mL) or mancozeb+ascorbic acid (100 ug/mL), or ascorbic acid alone or control medium alone on the levels of cell viability, apoptosis, intracellular reactive oxygen species production (ROS), mitochondrial membrane potential (MMP) and ATP levels in rat thymocytes were examined in vitro. Cells treated with mancozeb displayed a concentration-dependent increase of hypodiploid cells and ROS production followed by markedly decreased viability of the cells, MMP and ATP levels. Application of ascorbic acid significantly reduced cytotoxicity in cell cultures treated with 0.2 and 2 ug/mL of mancozeb, together with significantly decreased ROS levels and increased MMP and ATP levels. In cells treated with 5 ug/mL of mancozeb, ascorbic acid failed to reduce toxicity while simultaneously increasing the apoptosis rate of thymocytes. These results suggest that ROS plays a significant role in mancozeb-induced toxicity, through alteration of mitochondrial function. Ascorbic acid administration reduced the toxicity rate in cells treated with lower mancozeb concentrations, while it may have the ability to shift cells from necrosis to apoptosis in the presence of highest mancozeb concentrations. ... This study demonstrates that non-toxic doses of pesticides can induce cellular changes that increase cell sensitivity to other toxins or stress. Pesticide exposure is an environmental risk factor for Parkinson's disease. Manganese (Mn) is essential but high dose exposure may results in neurological dysfunction. Mn-containing dithiocarbamates, maneb (MB) and mancozeb (MZ), are primarily used as pesticides. Studies have shown that MB can augment dopaminergic damage triggered by sub-toxic doses of Parkinsonian mimetic MPTP. However, the mechanism underlying this effect is not clear. Activation of nuclear factor kappa B (NF-kB) has been implicated in MPTP toxicity. Mn stimulates the activation of NF-kB and subsequently induces neuronal injury via an NF-kB dependent mechanism. We speculate that MB and MZ enhance MPTP active metabolite (methyl-4-phenylpyridine ion, MPP(+)) toxicity by activating NF-kB. The activation of NF-kB was observed using Western blot analysis and NF-kB response element driven Luciferase reporter assay. Western blot data demonstrated the nuclear translocation of NF-kB p65 and the degradation of IkB-alpha after MB and MZ 4-hr treatments. Results of NF-kB response element luciferase reporter assay confirmed that MB and MZ activated NF-kB. The NF-kB inhibitor (SN50) was also shown to alleviate cytotoxicity induced by co-treatment of MB or MZ and MPP(+). This study demonstrates that activation of NF-kB is responsible for the potentiated toxic effect of MB and MZ on MPP(+) induced cytotoxicity. Risk assessment is currently based on the no observed adverse effect levels (NOAELs) for single compounds. Humans are exposed to a mixture of chemicals and recent studies in our laboratory have shown that combined exposure to endocrine disrupters can cause adverse effects on male sexual development, even though the doses of the single compounds are below their individual NOAELs for anti-androgenic effects. Consequently, we have initiated a large project where the purpose is to study mixture effects of endocrine disrupting pesticides at low doses. In the initial range-finding mixture studies, rats were gavaged during gestation and lactation with five doses of a mixture of the fungicides procymidone, mancozeb, epoxyconazole, tebuconazole and prochloraz. The mixture ratio was chosen according to the doses of each individual pesticide that produced no observable effects on pregnancy length and pup survival in our laboratory and the dose levels used ranged from 25 to 100% of this mixture. All dose levels caused increased gestation length and dose levels above 25% caused impaired parturition leading to markedly decreased number of live born offspring and high pup perinatal mortality. The sexual differentiation of the pups was affected at 25% and higher as anogenital distance was affected in both male and female offspring at birth and the male offspring exhibited malformations of the genital tubercle, increased nipple retention, and decreased prostate and epididymis weights at pup day 13. The results show that doses of endocrine disrupting pesticides, which appear to induce no effects on gestation length, parturition and pup mortality when judged on their own, induced marked adverse effects on these endpoints in concert with other pesticides. In addition, the sexual differentiation of the offspring was affected ... ... In this study the permanent reproductive and neurobehavioral effects of combined exposure to five endocrine disrupting pesticides, epoxiconazole, mancozeb, prochloraz, tebuconazole and procymidone, were examined. Pregnant and lactating rat dams were dosed with a mixture of the five pesticides at three different doses, or with the individual pesticides at one of two doses. Adverse effects were observed in young and adult male offspring from the group exposed to the highest dose of the mixture. These included reduced prostate and epididymis weights, increased testes weights, altered prostate histopathology, increased density of mammary glands, reduced sperm counts, and decreased spatial learning. As no significant effects were seen following single compound exposure at the doses included in the highest mixture dose, these results indicate cumulative adverse effects of the pesticide mixture. For more Interactions (Complete) data for Mancozeb (6 total), please visit the HSDB record page. Non-Human Toxicity Values LD50 Rat oral 5 g/kg LD50 Rat dermal >10,000 mg/kg bw LD50 Rabbit dermal >5000 mg/kg bw |
| References | Pavlovic V, Cekic S, Kamenov B, Ciric M, Krtinic D. The Effect of Ascorbic Acid on Mancozeb-Induced Toxicity in Rat Thymocytes. Folia Biol (Praha). 2015;61(3):116-23. |
| Additional Infomation |
Mancozeb can cause cancer according to The Environmental Protection Agency (EPA). Mancozeb is registered as a general use fungicide that is a member of the chemical class known as ethylene bisdithiocarbamates (EBDCs). The EBDCs are fungicides used to prevent crop damage in the field and to protect harvested crops from deterioration in storage or transport. Mancozeb is used to protect many fruit, vegetable, nut and field crops against a wide spectrum of diseases, including potato blight, leaf spot, scab (on apples and pears) and rust (on roses). It is also used for seed treatment of cotton, potatoes, corn, safflower, sorghum, peanuts, tomatoes, flax and cereal grains See also: Mancozeb (annotation moved to). Mechanism of Action ... This study demonstrates that non-toxic doses of pesticides can induce cellular changes that increase cell sensitivity to other toxins or stress. Pesticide exposure is an environmental risk factor for Parkinson's disease. Manganese (Mn) is essential but high dose exposure may result in neurological dysfunction. Mn-containing dithiocarbamates, maneb (MB) and mancozeb (MZ), are primarily used as pesticides. Studies have shown that MB can augment dopaminergic damage triggered by sub-toxic doses of Parkinsonian mimetic MPTP. However, the mechanism underlying this effect is not clear. Activation of nuclear factor kappa B (NF-kB) has been implicated in MPTP toxicity. Mn stimulates the activation of NF-kB and subsequently induces neuronal injury via an NF-kB dependent mechanism. We speculate that MB and MZ enhance MPTP active metabolite (methyl-4-phenylpyridine ion, MPP(+)) toxicity by activating NF-kB. The activation of NF-kB was observed using Western blot analysis and NF-kB response element driven Luciferase reporter assay. Western blot data demonstrated the nuclear translocation of NF-kB p65 and the degradation of IkB-alpha after MB and MZ 4-hr treatments. Results of NF-kB response element luciferase reporter assay confirmed that MB and MZ activated NF-kB. The NF-kB inhibitor (SN50) was also shown to alleviate cytotoxicity induced by co-treatment of MB or MZ and MPP(+). This study demonstrates that activation of NF-kB is responsible for the potentiated toxic effect of MB and MZ on MPP(+) induced cytotoxicity. Mancozeb (manganese/zinc ethylene bis-dithiocarbamate) is an organometallic fungicide that has been associated with human neurotoxicity and neurodegeneration. In a high-throughput screen for modulators of KCNQ2 channel, a fundamental player modulating neuronal excitability, Mancozeb, was found to significantly potentiate KCNQ2 activity. Mancozeb was validated electrophysiologically as a KCNQ2 activator with an EC50 value of 0.92 +/- 0.23 uM. Further examination showed that manganese but not zinc ethylene bis-dithiocarbamate is the active component for the positive modulation effects. In addition, the compounds are effective when the metal ions are substituted by iron but lack potentiation activity when the metal ions are substituted by sodium, signifying the importance of the metal ion. However, the iron (Fe(3+)) alone, organic ligands alone or the mixture of iron with the organic ligand did not show any potentiation effect, suggesting as the active ingredient is a specific complex rather than two separate additive or synergistic components. Our study suggests that potentiation on KCNQ2 potassium channels might be the possible mechanism of Mancozeb toxicity in the nervous system. Toxicogenomics has the potential to elucidate gene-environment interactions to identify genes that are affected by a particular chemical at the early stages of the toxicological response and to establish parallelisms between different organisms. The fungicide mancozeb, widely used in agriculture, is an ethylene-bis-dithiocarbamate complex with manganese and zinc. Exposure to this pesticide has been linked to the development of idiopathic Parkinson's disease and cancer. Given that many signaling pathways and their molecular components are substantially conserved among eukaryotic organisms, we used Saccharomyces cerevisiae to get insights into the molecular mechanisms of mancozeb toxicity and adaptation based on expression proteomics. The early global response to mancozeb was analyzed by quantitative proteomics using 2-DE. The target genes (e.g. TSA1, TSA2, SOD1, SOD2, AHP1, GRE2, GRX1, CYS3, PRE3, PRE6, PRE8, PRE9, EFT1, RPS5, TIF11, HSP31, HSP26, HSP104, HSP60, HSP70-family) and the putative main transcription activators (e.g. Yap1, Msn2/Msn4, Met4, Hsf1, Aft1, Pdr1, Skn7, Rpn4p, Gcn4) of the complex mancozeb-induced expression changes are related with yeast response to stress, in particular to oxidative stress, protein translation initiation and protein folding, disassembling of protein aggregates and degradation of damaged proteins. ... Animal studies offer evidence for the basis of a mechanistic association with some pesticides and the development of PD or Parkinsonian features. Two fungicides, mancozeb and maneb, have dose-dependent toxicity on dopaminergic cells in rats. Both the organic component of the fungicide as well as the manganese ion contributed to the toxicity ... For more Mechanism of Action (Complete) data for Mancozeb (6 total), please visit the HSDB record page. |
Solubility Data
| Solubility (In Vitro) |
DMSO : 1~98 mg/mL (1.51 ~200.14 mM ) H2O :~1 mg/mL (~1.51 mM) Ethanol : ~49 mg/mL |
| Solubility (In Vivo) | 5% DMSO + 40% PEG300 + 5% Tween 80 + 50% ddH2O: 2.4mg/ml (4.90mM) (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8481 mL | 9.2404 mL | 18.4809 mL | |
| 5 mM | 0.3696 mL | 1.8481 mL | 3.6962 mL | |
| 10 mM | 0.1848 mL | 0.9240 mL | 1.8481 mL |