Metiram
(endorsed 2011)
Guideline
Metiram degrades in the environment to ethylene thiourea (ETU), hence the health-based guideline for metiram is based on the toxicity of ETU. Based on human health concerns, the environmental degradant of metiram, ETU, in drinking water should not exceed 0.009 mg/L.
Related chemicals
Metiram (CAS 9006-42-2) belongs to the ethylenebis-dithiocarbamate class of chemicals. Other pesticides in this class include mancozeb 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 metiram, 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: Metiram is a fungicide for the control of early and late blight in potatoes, and fungal diseases in apples, pears, grapevines, stone fruit, turf and certain vegetable crops.
There are registered products that contain metiram in Australia. The products are intended for professional use and are available as concentrated solutions to be applied in diluted form using ground or hand-held sprays. Data on currently registered products are available from the Australian Pesticides and Veterinary Medicines Authority.
Exposure sources: Metiram hydrolyses rapidly in the environment to ETU and carbon disulfide (), both of which have higher toxicity than metiram. It is considered highly unlikely that residues of metiram or its degradants will be present in food. Metiram residues are grouped with other dithiocarbamates (mancozeb, metham, metiram, propineb, thiram, zineb and ziram) in the maximum residue limit definition.
Agricultural use of metiram may potentially lead to contamination of source waters by both metiram and ETU through adsorption into soil and subsequent entry into groundwater.
Typical values in Australian drinking water
Metiram and ETU have been monitored in some drinking water supplies in Australia, with values below the limit of quantitation (Barwon Water 2007). The highest measured value in a public drinking water well in the USA was reported to be 0.21 µg/L (USEPA 2005).
Treatment of drinking water
Powdered activated carbon filtration, granulated activated carbon filtration, and reverse osmosis have been demonstrated to be highly effective processes at removing certain pesticides including dithiocarbamates (USEPA 2001). Dithiocarbamates are also degraded by hydrogen peroxide, ultraviolet irradiation and Fenton-type advanced oxidation processes (Ikehata and El-Din 2006).
ETU is degraded by ozone at 3 mg/L and chlorine dioxide at 20 mg/L, producing several degradation compounds (Hwang et al. 2003).
Measurement
The analytical methods for metiram rely on acid hydrolysis to release , which is then measured colorimetrically or by gas chromatography. Metiram degrades in the environment to ETU, hence the analytical methods reported are for the determination of ETU in water. United States Environmental Protection Agency (USEPA) Method 509 for the determination of ETU in water using gas chromatography with nitrogen-phosphorus detector can achieve a limit of quantitation (LOQ) of 2.7 µg/L (Munch and Graves 1992). After extraction with dichloromethane in the presence of thiourea and sodium L-ascorbate, ETU can be analysed by gas chromatography with alkali flame ionization detection and mass spectrometric confirmation. The LOQ is less than 0.1 µg/L in water (Van Der Poll et al. 1993). ETU in water can also be analysed by fluorimetric determination based on the inhibitory effect of ETU on the oxidation of thiamine to thiochrome by mercury(II) (Pérez-Ruiz et al. 1998). ETU has been determined in water by a cathodic stripping voltammetry method, with a LOQ of 1.4 µg/L (Carvalho et al. 2004).
History of the health values
The current acceptable daily intake (ADI) for metiram is 0.02 mg per kg body weight (mg/kg bw), based on a lowest-observed-effect level (LOEL) at the lowest dose tested of 5 mg/kg bw/day from a short-term (26 week) gavage study in monkeys and 250-fold safety factor. The LOEL is based on decreased thyroxine levels at the lowest dose tested of 5 mg/kg bw/day and above. Decreased serum triiodothyronine levels, and partially reversible thyroid enlargement and hyperplasia were seen at doses of 15 and 75 mg/kg bw/day, following a 15-week recovery period. A no-observed-effect level (NOEL) was not demonstrated in this study. The ADI incorporates a safety factor of 200, and was first established in 1988. There is currently no ADI for ETU.
A health value has not been previously established by NHMRC.
Health considerations
Metabolism: Metiram is readily absorbed via the gastrointestinal tract and is widely distributed in tissues and blood. It is moderately metabolised to ETU, and hydrolysed to carbon disulfide (). It is slowly excreted as ETU in the urine and faeces, and as in the breath within 7 days.
Acute effects: Metiram has low acute oral and dermal toxicity. It is a skin sensitiser in guinea pigs. ETU has low acute oral toxicity.
Short-term effects: In a 3-month dietary study with metiram in rats, atrophy of skeletal muscle fibres in females was seen at 15 mg/kg bw/day, and hind-limb paralysis in females was seen at the highest dose tested, 45 mg/kg bw/day. Reversible decreases in iodine uptake into the thyroid were seen at all doses tested, and reversible decreases in thyroxine levels were seen at 45 mg/kg bw/day.
In a 26-week oral gavage study with metiram in monkeys, levels of thyroxine and triiodothyronine in the thyroid gland were decreased at the lowest dose tested of 5 mg/kg bw/day and above. Decreases in serum thyroxine and partially reversible increases in thyroid weight and thyroid hyperplasia were seen at the next highest doses of 15 mg/kg bw/day and 75 mg/kg bw/day (highest dose tested). A NOEL was not obtained in this study. The LOEL of 5 mg/kg bw/day in this study, with 250-fold safety factor, is the basis for the current ADI for metiram.
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 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 (8 mg/kg bw/day), decreased levels of thyroxine and increased levels of thyroid stimulating hormone in serum, and increased absolute thyroid weights (10 mg/kg bw/day), thyroid adenomas (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: In 96-week studies with metiram in mice and 2-year studies in rats by dietary administration, there was decreased food consumption and bodyweight gain at the highest dose tested, 150 mg/kg bw/day, in mice, and an increased incidence of skeletal muscle atrophy at the highest dose tested, 16 mg/kg bw/day, in rats. No other effects were seen in these studies.
In a 1-year rat study with ETU, there was increased thyroid vascularisation and thyroid acinar cell papillation at the lowest dose tested, 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 occurred 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, 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 thyroid stimulating hormone (TSH), thyroid cell hypertrophy and hyperplasia and thyroid adenomas and carcinomas were observed at the lowest dose tested, 16 mg/kg bw/day.
Carcinogenicity: Based on a 2-year study in mice and rats, there is no evidence of carcinogenicity for metiram. 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: Metiram 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: A 3-generation reproduction study and developmental studies in rats and rabbits did not produce any evidence of effects on reproductive parameters or foetal development. Developmental studies on rats and rabbits with ETU showed effects on development only at dose levels well in excess of the likely level of human exposure.
Poisons Schedule: Metiram 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 metiram, 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 metiram 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.
Barwon Water (2007) Annual Drinking Water Quality Report, Victoria.
Carvalho LMd., Nascimento PCd, Bohrer D, Del-Fabro L (2004). Determination of ethylenethiourea (ETU) at trace levels in water samples by cathodic stripping voltammetry. Electroanalysis, 16(18):1508-1513.
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.
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):1341-6.
Ikehata K, El-Din MG (2006). Aqueous pesticide degradation by hydrogen peroxide/ultraviolet irradiation and Fenton-type advanced oxidation processes: a review. Journal of Environmental Engineering and Science, 5(2):81-135.
Munch DJ, Graves RL (1992). Method 509 Determination of ethylene thiourea (ETU) in water using gas chromatography with nitrogen-phosphorus detector, Revision 1.0, U.S. Environmantal Protection Agency, Cincinnati, Ohio.
Pérez-Ruiz T, Martínez-Lozano C, Tomás V, Sanz A, Martín J (1998) Flow-injection spectrofluorimetric determination of ethylenethiourea. Fresenius’ Journal of Analytical Chemistry, 362(4):1432-1130.
Tomlin CD (ed) (2006). The Pesticide Manual: a world compendium, 14th Edition, British Crop Production Council, UK.
USEPA (United States Environmental Protection Agency) (2001) The Incorporation of Water Treatment Effects on Pesticide Removal and Transformations in Food Quality Protection Act (FQPA) Drinking Water Assessments, Office of Pesticide Programs Science Policy, USEPA, Washington, D.C.
USEPA (United States Environmental Protection Agency) (2005) Reregistration Elegibility Desicion for Metiram, EPA 73R-05-017, USEPA.
Van Der Poll JM, Versluis-De Haan GG, De Wilde O (1993). Determination of ethylenethiourea in water samples by gas chromatography with alkali flame ionization detection and mass spectrometric confirmation Journal of Chromatography A, 643(1-2): 163-168.
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