Mancozeb
(endorsed 2011)
Guideline
Mancozeb degrades in the environment to ethylene thiourea (ETU), hence the health-based guideline for mancozeb has been based on the toxicity of ETU. Based on human health concerns, ETU in drinking water should not exceed 0.009 mg/L.
Related chemicals
Mancozeb (CAS 8018-01-7; Ethylene thiourea CAS 96-45-7) belongs to the ethylenebis-dithiocarbamate class of chemicals. Other pesticides in this class include metiram and zineb (Tomlin 2006).
Human risk statement
With good water quality management practices, the exposure of the general population is expected to be well below levels that may cause health concerns.
If present in drinking water as a result of a spillage or through misuse, the environmental degradant of mancozeb, ethylene thiourea (ETU), would not be a health concern unless the concentration exceeded 0.009 mg/L. Excursions above this level would need to occur over a significant period to be a health concern, as the health-based guideline is based on long-term effects.
With good water quality management practices, pesticides should not be detected in source waters used for drinking water supplies. Persistent detection of pesticides may indicate inappropriate use or accidental spillage, and investigation is required in line with established procedures in the risk management plan for the particular water source.
General description
Uses: Mancozeb is a broad spectrum fungicide for the control of fungal diseases in tree fruits, vegetable crops, field crops, and grapes, sod crops (lawns), ornamental plants and harvested seed.
There are registered products that contain mancozeb in Australia. The products are intended for professional use and are available as concentrated solutions to be applied in diluted form using ground and aerial spray. Data on currently registered products are available from the Australian Pesticides and Veterinary Medicines Authority.
Exposure sources: Mancozeb hydrolyses rapidly in the environment to ETU and carbon disulfide (), both of which have higher toxicity than mancozeb. It is considered highly unlikely that residues of mancozeb or its degradants will be present in food. Mancozeb residues are grouped with other dithiocarbamates (mancozeb, metham, metiram, propineb, thiram, zineb and ziram) in the maximum residue limit definition.
Agricultural use of mancozeb may potentially lead to contamination of source waters by both mancozeb and ETU through adsorption into soil and subsequent entry into ground water.
Typical values in Australian drinking water
No occurrence data for mancozeb or ETU in Australian waters were found. In the USA, the predicted surface and groundwater concentrations for ETU were 0.1–25.2 µg/L and 0.21 µg/L, respectively (USEPA 2005). The parent compound is short-lived in soil and water and is not expected to reach water used for human consumption (USEPA 2005).
Treatment of drinking water
Chlorine dioxide and ozonation appear moderately effective at removing mancozeb and ETU from water, however these processes produce as-yet undefined degradation products (Hwang et al. 2003).
Measurement
Mancozeb can be measured in water by liquid chromatography mass spectrometry with an electrospray interface, with a limit of detection of 0.04 µg/L (Hanada et al. 2002). ETU can be measured by gas chromatrography with nitrogen-phosphorous detector, with a limit of detection of 2.7 µg/L (USEPA 1992).
History of the health values
The current acceptable daily intake (ADI) for mancozeb is 0.006 mg per kg of bodyweight (mg/kg bw), based on a no-observed-effect level (NOEL) of 0.6 mg/kg bw/day from a long-term (1-year) dietary study in dogs. The NOEL is based on decreased iodine uptake into thyroid tissue at doses of 2.4 mg/kg bw/day and above. The ADI incorporates a safety factor of 100 and was first established in 1993. There is currently no ADI for ETU.
A health value has not been previously established by NHMRC.
Health considerations
Metabolism: Mancozeb is rapidly and extensively absorbed from the gastrointestinal tract of rats and widely distributed in tissues, particularly the thyroid. A small percentage (3–6%) is metabolised to ETU. Excretion is rapid, mainly as unchanged compound in faeces and urine, and is almost complete by 5 days. ETU is also excreted in the urine.
Acute effects: Mancozeb is of low acute oral and dermal toxicity in mammals. It is a skin sensitiser in humans, based on reports from occupational exposure. ETU has low acute oral toxicity.
Short-term effects: Short-term dietary studies with mancozeb were conducted in mice, rats and dogs. Thyroid hyperplasia was observed in rats at 7.5 mg/kg bw/day. Histopathological changes were also observed in other organs at 30 mg/kg bw/day and above in dogs and mice. In rats, organ weight and histopathological changes were observed in several organs at 60 mg/kg bw/day, as well as decreased serum thyroxine levels. In dogs, decreased bodyweight gain and serum thyroxine levels, as well as clinical chemistry changes were seen at 150 mg/kg bw/day.
In short-term studies with ETU, the thyroid was the target organ. In a dietary study in rats over 14 days, histological changes including thyroid hyperplasia, bone marrow depletion, and lymphatic lesions occurred from 25 mg/kg bw/day. When administered in the drinking water of rats over 28 days, decreased levels of thyroxine and serum triiodothyronine, increased levels of thyroid stimulating hormone in serum, and thyroid follicular necrosis were seen at doses from 10.6 mg/kg bw/day. Other effects seen at 17.6 mg/kg bw/day and above include proximal tubule kidney cell hypertrophy and vacuolisation.
In 3- and 4-month dietary studies in rats and mice with ETU, effects in rats included follicular cell hypertrophy and thyroid hyperplasia from 3 mg/kg bw/day and above. At higher doses there was also increased relative thyroid weight and decreased iodine uptake into the thyroid at 8 mg/kg bw/day; decreased levels of thyroxine and increased levels of thyroid stimulating hormone in serum, and increased absolute thyroid weights at 10 mg/kg bw/day; and thyroid adenomas at 12.5 mg/kg bw/day. In mice, thyroid adenomas and pituicyte vacuolisation occurred from 12.5 mg/kg bw/day, hepatocellular hypertrophy from 37.5 mg/kg bw/day, and thyroid hyperplasia from 75 mg/kg bw/day. The lowest overall NOEL was 2 mg/kg bw/day (rats) in these studies.
Long-term effects: Long-term dietary studies with mancozeb were conducted in mice, rats and dogs. Decreased iodine uptake into the thyroid was reported at 2.4 mg/kg bw/day in dogs and thyroid hyperplasia at 3 mg/kg bw/day in rats. In mice, effects were confined to decreased bodyweight gain at 150 mg/kg bw/day. The lowest overall NOEL was 0.6 mg/kg bw/day in dogs. This NOEL is the basis for the current ADI.
In a 1-year rat study with ETU, there was increased thyroid vascularisation and thyroid acinar cell papillation at the lowest dose tested of 0.025 mg/kg bw/day. At 1.25 mg/kg bw/day, there was decreased bodyweight gain. Increased relative thyroid weight occurred at 7 mg/kg bw/day and thyroid tumours at 15 mg/kg bw/day.
In a 2-year rat study with ETU, thyroid hyperplasia, elevated TSH and decreased triiodothyronine and thyroxine were seen at the lowest dose of 0.25 mg/kg bw/day. Thyroid carcinomas were observed at 8.7 mg/kg bw/day. In a 2-year mouse study with ETU, decreased bodyweight gain, increased TSH, thyroid cell hypertrophy and hyperplasia and thyroid adenomas and carcinomas were observed at the lowest dose tested of 16 mg/kg bw/day.
Carcinogenicity: Based on long-term studies in rats with both mancozeb and ETU, there was evidence of an increased incidence of tumours (adenomas and carcinomas) in the thyroid at high dose levels only, which are well in excess of the likely level of human exposure. In mice, ETU produced thyroid follicular-cell tumours and tumours of the liver and anterior pituitary gland. However, due to its nongenotoxicity and disturbance of thyroid function, ETU would not be expected to produce thyroid cancer in humans exposed to concentrations that do not alter thyroid hormone homeostasis.
Genotoxicity: Mancozeb is not considered to be genotoxic, based on in vitro and in vivo short-term studies. ETU was positive in some in vitro short-term assays, but overall, it is not considered to be genotoxic.
Reproductive and developmental effects: Two and three-generation reproduction studies in rats and developmental studies in mice, rats and rabbits did not produce any evidence of effects on reproductive parameters or foetal development. Developmental studies in rats and rabbits with ETU caused effects on development only at dose levels well in excess of the likely level of human exposure.
Poisons Schedule: Mancozeb is included in Schedule 5 of the Standard for the Uniform Scheduling of Medicines and Poisons No.1, 2010 (the Poisons Standard)(DoHA 2010). Current versions of the Poisons Standard should be consulted for further information.
Derivation of the health-based guideline
The health-based guideline of 0.009 mg/L for the degradant of mancozeb, ETU, was determined as follows:
where:
0.25 mg/kg bw/day is the LOEL based on a long-term (2-year) dietary study in rats on ETU.
70 kg is taken as the average weight of an adult.
The proportionality factor is 1 since mancozeb has no residues in food and is degraded to ETU in the environment. It is assumed, therefore, that 100% of the ADI (nominal in this case) for ETU will arise from the consumption of drinking water.
2 L/day is the estimated maximum amount of water consumed by an adult.
1000 is the safety factor applied to the LOEL for ETU derived from animal studies. This safety factor incorporates a factor of 10 for interspecies extrapolation, 10 for intraspecies variation, and an additional factor of 10 because a LOEL was used to derive the guideline.
References
NOTE: The toxicological information used in developing this fact sheet is from reports and data held by the Department of Health, Office of Chemical Safety.
DoHA (2010) The Poisons Standard; Schedule 1-Standard for the Uniform Scheduling of Medicines and Poisons, Department of Health and Ageing, Commonwealth of Australia, Canberra.
Hanada Y, Tanizaki T, Koga M, Shiraishi H, Soma M (2002). LC/MS studies on characterization and determination of N,N’-ethylenebisdithiocarbamate fungicides in environmental water samples. Analytical Sciences, 18:441-444.
Hwang ES, Cash JN, Zabik MJ (2003). Determination of degradation products and pathways of mancozeb and ethylenethiourea (ETU) in solutions due to ozone and chlorine dioxide treatments. Journal of Agricultural and Food Chemistry, 51(5):1341-1346.
Tomlin CD (ed) (2006). The Pesticide Manual: a world compendium, 14th Edition, British Crop Production Council, UK.
USEPA (United States Environmental Protection Agency) (1992). Method 509 - Determination of Ethylene Thiourea (ETU) in Water Using Gas Chromatography with a Nitrogen-Phosphorus Detector. Revision 1.0.
USEPA (United States Environmental Protection Agency) (2005). Reregistration Eligibility Decision for Mancozeb. EPA 738-R-04-012.USEPA.
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