Absorption, Distribution and Excretion
Mancozeb's absorption through the skin and mucous membranes is likely very limited. Ethylenethiourea is a degradation product and metabolite of ethylene bis(dithiocarbamate) bactericides. Following a single oral administration of 14C-labeled ethylenethiourea to pregnant rats, peak radioactivity in maternal blood persisted for 2 hours, with uniform distribution in erythrocytes and plasma. Radioactivity levels were uniformly distributed across multiple maternal tissues, but lower in the embryo. 24 hours after treatment, radioactivity was relatively cleared from all tested tissues except blood, with 72.8% of total radioactivity excreted in urine. The elution pattern of the metabolites isolated by Sephadex indicated low degradation of ethylenethiourea. Mancozeb appears to be rapidly absorbed from the gastrointestinal tract, distributed to target organs, and almost completely excreted within 96 hours.
Rats were administered 20 mg (14)C-mancozeb daily via gastric tube for 7 consecutive days (equivalent to approximately 100 mg/kg body weight), and were sacrificed one day after the last administration. Radioactivity in excrement and organs was measured. Total radioactivity was detected in feces, urine, organs and tissues, and cadavers at 71%, 16%, 0.31%, and 0.96%, respectively. Specifically, the radioactivity was 0.19% in the liver, 0.076% in the kidneys, 0.003% in the thyroid gland, and less than 0.01% in all other organs. The majority of the markers in the feces were mancozeb, indicating that mancozeb is poorly absorbed in the gastrointestinal tract…
This study investigated the pharmacokinetics of ¹⁴C-mancozeb (11.54 mCi/g = 25,619 dpm/ug; suspended in 0.5% methylcellulose distilled water) in Sprague-Dawley CD rats (both male and female). Rats were administered a single oral dose of 1.5 mg/kg (Group A) or 100 mg/kg (Group B) of 14C-mancozeb, or a pulsed (oral) dose of 1.5 mg/kg (Group C) of 14C-mancozeb, all of which had been supplemented with non-radiolabeled mancozeb (84% purity; 15 ppm active ingredient) via diet for two weeks prior. Rats were sacrificed 96 hours after administration of 14C-mancozeb. In rats administered 1.5 mg/kg (Group D) and 100 mg/kg (Group E), bile cannulation was performed in both male and female rats to assess drug excretion in bile 24 hours later. Approximately half of the orally administered mancozeb dose was absorbed. Results showed that pharmacokinetics were non-linear within the 100 mg/kg and 1.5 mg/kg dose ranges. Absorption was moderately rapid (peak concentrations were reached at 3 and 6 hours for 1.5 mg/kg and 100 mg/kg doses, respectively). Drug elimination was biphasic. Most of the oral dose was excreted in feces and urine within 24 hours, with roughly equal amounts excreted in feces and urine. A small amount (2-9%) was excreted in bile. The highest drug concentrations were found in the thyroid gland, but the peak concentration in the thyroid was not directly proportional to the dose. Compared to the 1.5 mg/kg dose group, the 14C concentration of 14C-mancozeb in the thyroid gland of the 100 mg/kg dose group was significantly lower than the corresponding peak plasma concentration, indicating that the high-dose group had reached saturation. Pre-addition of non-radiolabeled mancozeb to the diet had no significant effect on the in vivo distribution or excretion of 14C-mancozeb. The in vivo conversion rate of mancozeb to thiourea was 6.8%.

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Metabolism/Metabolites
…Mancozeb is metabolized to the degradation product ethylene thiourea, which may itself be toxic.
In oral metabolism studies in rats using radiolabeled mancozeb and other ethylene dithiocarbamate (EBDC) compounds, the in vivo metabolic conversion rate (by weight) of EBDC to ethylene thiourea (ETU) was 7.5%.
In plants, the major metabolite is ethylene thiourea, which is further metabolized. Ethylene thiourea monosulfide, ethylene thiourea disulfide, and sulfur are also metabolites.
The major metabolite is ethylene thiourea, which accounts for approximately 24% of the bioavailable dose in urine and bile. Ethylene thiourea residues in the thyroid and liver were less than 1 ppm and undetectable after 24 hours.

Toxicity Summary
Identification and Uses: Mancozeb is a grayish-yellow, free-flowing powder. It is widely used to control various fungal diseases in a wide range of field crops, fruits, nuts, vegetables, and ornamental plants. It can also be used as a seed treatment/protectant. Human Exposure and Toxicity: Exposure to mancozeb can lead to toxic epidermal necrolysis (TEN), a life-threatening, high-mortality mucocutaneous skin disease. There have been case reports of florists experiencing pompholyx and allergic reactions after exposure to mancozeb. One woman reported developing extensive dermatitis after storing mancozeb powder in her garage. An epidemiological study suggests that pregnant women living near banana plantations sprayed with mancozeb may be exposed to manganese through the environment; high concentrations of manganese are a neurotoxin. Another study indicates an increased risk of melanoma in individuals exposed to mancozeb, particularly those with occupational sun exposure. Research has found an association between mancozeb exposure and a significant increase in the frequency of cells with chromosomal structural aberrations and the number of sister chromatid exchanges per cell in peripheral blood lymphocytes. Mancozeb exhibits mild immunomodulatory effects under low-dose, long-term occupational exposure. Animal studies: These compounds generally have low acute toxicity. Animal studies have shown that contact dermatitis and thyroid hyperplasia may occur after exposure. Mancozeb is a potent skin sensitizer in guinea pigs. Cross-sensitization between mancozeb, zineb, and mancozeb has been observed. In rats, thyroid follicular cell hyperplasia was observed at doses of 100 ppm and higher. Mancozeb has a dose-dependent damaging effect on the gonads of both male and female rats. The dose level was 140–1400 mg/kg body weight, twice weekly for 4.5 months. All dose levels affected reproductive and endocrine structures, leading to decreased fertility. In rat developmental studies, increased placental resorption, external hemorrhage, and wavy rib deformities were observed; no embryotoxicity was observed without maternal toxicity. Rats treated with mancozeb exhibited dose-dependent depression, lethargy, decreased muscle tone, impaired coordination, mild limb paralysis, and paralysis, accompanied by general weakness, loss of appetite, and extreme weakness. Mutagenicity: Negative in bacterial and in vitro mammalian cell systems, in vivo chromosomal damage assays, and mammalian cell transformation assays. Positive in vitro sister chromatid exchange assay in Chinese hamster ovary cells. At different test doses, mancozeb induced various types of chromosomal aberrations in male mouse bone marrow cells. Mutagenic activity of mancozeb was detected using Salmonella Typhimurium strains TA97a, TA98, TA100, and TA102, all of which were negative. In vivo, comet assays in rats treated with mancozeb detected its ability to induce DNA damage and increase micronucleus frequency. Acute treatment with mancozeb inhibited cytochrome P450-mediated metabolism. Mancozeb is metabolized to ethylene thiourea (ETU). ETU is a carcinogen based on its role in the development of thyroid cancer and other cancers in rodents. ETU is known to cause decreased thyroxine (T4) levels and increased thyroid-stimulating hormone (TSH) levels in rodents. Ecotoxicity studies: In the seasonally breeding wild bird, the Amandava, mancozeb significantly reduced plasma T4, T3, and TSH levels. The toxic effects of mancozeb observed in birds and mammals are likely due to hormonal imbalances. Avian reproductive studies have found that mancozeb affects reproduction in the following ways: egg production, early and late embryo survival, hatching rate, chick weight at hatching and 14 days of age, and the number of surviving chicks at 14 days of age. Tadpoles showed reduced growth rates after exposure to mancozeb. Chronic studies in freshwater organisms showed that mancozeb caused decreased activity, shortened body length, and prolonged time to first egg-laying in Daphnia, and reduced survival in Gizzard gnats without observed growth effects. These effects observed in freshwater species are likely due to hormonal imbalances. Studies have shown that exposure to mancozeb significantly affects plant metabolism in lettuce, with mature leaves often experiencing more severe effects than young leaves.
Interactions
Mancozeb, a dithiocarbamate fungicide, has been found to produce toxicological effects on various cells, primarily through the generation of free radicals, which may alter the cell's antioxidant defense system… This study investigated the effects of mancozeb (0.2, 2, and 5 μg/mL), mancozeb + ascorbic acid (100 μg/mL), ascorbic acid alone, or control culture medium alone on rat thymocyte viability, apoptosis, intracellular reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), and ATP levels in vitro. The results showed that mancozeb-treated cells exhibited concentration-dependent increases in low diploid cells and ROS production, followed by significant decreases in cell viability, MMP, and ATP levels. In cell cultures treated with 0.2 and 2 μg/mL mancozeb, ascorbic acid significantly reduced cytotoxicity, significantly decreased reactive oxygen species (ROS) levels, and increased mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) levels. In cells treated with 5 μg/mL mancozeb, ascorbic acid failed to reduce toxicity and instead increased the apoptosis rate of thymocytes. These results suggest that ROS play a crucial role in mancozeb-induced toxicity by altering mitochondrial function. While ascorbic acid administration reduced the toxicity of cells treated with low concentrations of mancozeb, it may have been able to induce apoptosis in the presence of high concentrations. This study demonstrates that non-toxic doses of pesticides can induce cellular changes that increase cellular sensitivity to other toxins or stresses. Pesticide exposure is an environmental risk factor for Parkinson's disease. Manganese (Mn) is an essential element for the human body, but high-dose exposure can lead to neurological dysfunction. Manganese-containing dithiocarbamates, such as mancozeb (MB) and mancozeb (MZ), are primarily used as insecticides. Studies have shown that MB can enhance dopaminergic damage induced by subtoxic doses of the Parkinson's disease mimic MPTP. However, its mechanism of action remains unclear. Activation of nuclear factor κB (NF-κB) is closely related to MPTP toxicity. Manganese can stimulate NF-κB activation and induce neuronal damage through an NF-κB-dependent mechanism. We hypothesize that MB and MZ enhance the toxicity of the active metabolite of MPTP (methyl-4-phenylpyridinium ion, MPP(+)) by activating NF-κB. We confirmed NF-κB activation using Western blot analysis and NF-κB-responsive element-driven luciferase reporter gene assays. Western blot data showed that NF-κB p65 underwent nuclear translocation and IκB-α degradation 4 hours after MB and MZ treatment. NF-κB response element luciferase reporter gene assays confirmed that MB and MZ activate NF-κB. NF-κB inhibitors (SN50) have also been shown to mitigate cytotoxicity induced by combined MB or MZ treatment with MPP(+). This study suggests that NF-κB activation is the reason why MB and MZ enhance MPP(+)-induced cytotoxicity. Current risk assessments are primarily based on the no-observed adverse effect level (NOAEL) for individual compounds. Humans are exposed to mixtures of various chemicals, and recent studies in our laboratory have shown that even at doses below the NOAEL for their anti-androgenic effects, combined exposure to endocrine disruptors can still have adverse effects on male sexual development. Therefore, we initiated a large project to investigate the combined effects of low-dose endocrine disrupting pesticides. In a preliminary mixed-dose exploration study, we administered five different doses of a fungicide mixture containing iprodione, mancozeb, cyclophosphamide, tebuconazole, and prochloraz to pregnant and lactating rats by gavage. The mixing ratios were chosen based on the dosage of each individual pesticide, none of which had been observed to affect gestation or pup survival in our laboratory. Doses ranged from 25% to 100% of the mixture. All dosages resulted in prolonged gestation, while dosages exceeding 25% led to impaired parturition, significantly reducing the number of live pups and increasing perinatal mortality. Sexual differentiation was affected in 25% or more of the pups, manifested as impaired anorectal distance in both male and female pups at birth, with male pups exhibiting genital tuberculosis, increased nipple retention, and reduced prostate and epididymal weight by day 13 postnatally. These results indicate that endocrine-disrupting pesticide dosages, which appear to have no effect on gestation, parturition, and pup mortality when used alone, can have significant adverse effects on these endpoints when used in combination with other pesticides. Furthermore, offspring sexual differentiation was also affected…
…This study investigated the permanent effects of combined exposure to five endocrine disrupting pesticides (cyclooxygenazole, mancozeb, propiconazole, tebuconazole, and iprodione) on reproductive and neurobehavioral outcomes. Pregnant and lactating female rats were treated with three different doses of the five pesticide mixture or two different doses of a single pesticide. Adverse effects were observed in juvenile and adult male offspring in the group treated with the highest dose of the mixture. These adverse effects included decreased prostate and epididymal weight, increased testicular weight, prostate histopathological changes, increased mammary gland density, decreased sperm count, and decreased spatial learning ability. Since no significant effects were observed after single-compound exposure at the doses included in the highest mixture, these results suggest that pesticide mixtures have cumulative adverse effects.
For more complete interaction data on mancozeb (a total of 6 pesticides), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 5 g/kg
Dermal LD50 in rats: >10,000 mg/kg body weight
Dermal LD50 in rabbits: >5,000 mg/kg body weight

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.

According to the U.S. Environmental Protection Agency (EPA), mancozeb may be carcinogenic. Mancozeb is a registered general-purpose fungicide belonging to the ethylene dithiocarbamate (EBDC) class of compounds. EBDCs are fungicides used to prevent field crop diseases and protect harvested crops from damage during storage or transportation. Mancozeb is used to protect a variety of fruits, vegetables, nuts, and crops from a variety of diseases, including potato late blight, leaf spot, apple and pear scab, and rose rust. It is also used for seed treatment of cotton, potatoes, corn, safflower, sorghum, peanuts, tomatoes, flax, and cereals. See also: Mancozeb (note moved to). Mechanism of Action…This study shows that non-toxic doses of pesticides can induce cellular changes that increase cellular sensitivity to other toxins or stresses. Pesticide exposure is an environmental risk factor for Parkinson's disease. Manganese (Mn) is an essential element for the human body, but high-dose exposure can lead to neurological dysfunction. Manganese-containing dithiocarbamate pesticides, such as mancozeb (MB) and mancozeb (MZ), are currently the most widely used pesticides. Studies have shown that MB can enhance dopaminergic damage induced by subtoxic doses of the Parkinson's disease mimic MPTP. However, the mechanism of this effect remains unclear. Activation of nuclear factor κB (NF-κB) is associated with MPTP toxicity. Manganese can stimulate NF-κB activation and induce neuronal damage through an NF-κB-dependent mechanism. We hypothesize that MB and MZ enhance the toxicity of the active metabolite of MPTP (methyl-4-phenylpyridinium ion, MPP(+)) by activating NF-κB. We confirmed NF-κB activation using Western blot analysis and NF-κB-responsive element-driven luciferase reporter gene assays. Western blot data showed that NF-κB p65 underwent nuclear translocation and IκB-α degradation 4 hours after MB and MZ treatment. NF-κB response element luciferase reporter gene assays confirmed that MB and MZ activate NF-κB. NF-κB inhibitors (SN50) were also shown to alleviate cytotoxicity induced by combined MB or MZ treatment with MPP(+). This study indicates that NF-κB activation is the reason why MB and MZ enhance MPP(+)-induced cytotoxicity. Mancozeb (manganese/zinc ethylene dithiocarbamate) is an organometallic bactericide associated with neurotoxicity and neurodegenerative diseases in humans. In high-throughput screening of KCNQ2 channel (a key channel regulating neuronal excitability) modulators, mancozeb was found to significantly enhance KCNQ2 activity. Electrophysiological validation confirmed that mancozeb can act as a KCNQ2 receptor activator with an EC50 value of 0.92 ± 0.23 μM. Further research indicates that manganese ethylene dithiocarbamate (rather than zinc ethylene dithiocarbamate) is the active ingredient exerting a positive regulatory effect. Furthermore, the compound remains effective when the metal ion is replaced by an iron ion; however, the enhancing activity is lost when the metal ion is replaced by a sodium ion, highlighting the importance of the metal ion. However, iron ions alone (Fe(3+)), individual organic ligands, or mixtures of iron ions and organic ligands showed no enhancing effect, suggesting that the active ingredient is a specific complex, rather than two independent additive or synergistic components. Our research suggests that the enhancing effect of the KCNQ2 potassium channel may be a potential mechanism by which mancozeb exerts neurotoxicity. Toxicogenomics holds promise for elucidating gene-environment interactions, thereby identifying genes affected by specific chemicals in the early stages of toxicological responses and establishing parallel relationships between different organisms. Mancozeb, a fungicide widely used in agriculture, is a manganese and zinc-containing ethylene dithiocarbamate complex. Exposure to this pesticide has been associated with idiopathic Parkinson's disease and cancer. Given the high conservation of many signaling pathways and their molecular composition in eukaryotes, we used Saccharomyces cerevisiae to explore the molecular mechanisms of mancozeb toxicity and adaptation based on expression proteomics. We employed two-dimensional electrophoresis quantitative proteomics to analyze the early overall response to mancozeb. The complex expression changes induced by mancozeb 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 putative major transcriptional activators (e.g., Yap1, Msn2/Msn4, Met4, Hsf1, Aft1, Pdr1, Skn7, Rpn4p, Gcn4) that are associated with yeast stress (especially oxidative stress), protein translation initiation and folding, dissociation of protein aggregates, and degradation of damaged proteins. …Animal studies have provided evidence of a mechanistic link between certain pesticides and the development and progression of Parkinson's disease or Parkinson's-like symptoms. Two fungicides, mancozeb and dextrose, exhibited dose-dependent toxicity to rat dopaminergic cells. Both the organic components and manganese ions of the fungicides contributed to the toxicity…
For more complete data on the mechanisms of action of mancozeb (a total of 6 fungicides), please visit the HSDB record page.

C8H12MNN4S8ZN

541.1

538.749

C, 17.76; H, 2.24; Mn, 10.15; N, 10.36; S, 47.41; Zn, 12.08

8018-01-7

3034368

Light yellow to yellow solid powder

1.92 g/cm3

308.2ºC at 760 mmHg

192-194°C

138 °C

0.000692mmHg at 25°C

0.608

4

8

6

22

108

0

S=C(S)NCCNC(S)=S.[S-]C([S-])=NCCN=C([S-])[S-].[Mn+2].[Zn+2]

CHNQZRKUZPNOOH-UHFFFAOYSA-J

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

zincmanganese(2+)N-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate

Acarie M; Agrox 16D; Blecar MN; Carmazine; Caswell No. 913A; CCRIS 2495;

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 : 1~98 mg/mL (1.51 ~200.14 mM )
H2O :~1 mg/mL (~1.51 mM)
Ethanol : ~49 mg/mL

5% DMSO + 40% PEG300 + 5% Tween 80 + 50% ddH2O: 2.4mg/ml (4.90mM) (Please use freshly prepared in vivo formulations for optimal results.)