EBDC fact sheet

EBDCs are a group of fungicides that have been widely applied to crops throughout the world since the 1960s. From the late 1980s their use has caused much debate among regulators about their long-term effects on consumers and occupational users.

What are EBDCs?
Ethylenebisdithiocarbamates (EBDCs) are a group of non-systemic (surface acting) fungicides. EBDC active ingredients approved for use in the UK are mancozeb, maneb, zineb and zineb ethylene thiuram disulphide adduct (metiram)(1). Nabam is used in a number of countries and cufraneb has been superseded . Whilst referring to individual fungicides where appropriate, this fact sheet will focus on the generalised effects of EBDCs as a whole, because of the group's many common features.
    EBDCs are used on a wide range of crops world wide including potatoes, cereals, apples, pears, and leafy vegetables. They control many fungal diseases such as blight, leaf spot, rust, downy mildew and scab. Mancozeb is also used for seed treatment of cotton, potatoes, corn (maize), safflower, sorghum, peanuts, tomatoes, flax and cereal grains(2).
    The exact mode of action of EBDCs is not known. It is thought they act as fungicides by being metabolised to an isothiocyanate radical (containing nitrogen-carbon-sulphur atoms) which inactivates the sulphydryl (sulphur-hydrogen) groups in amino acids (building blocks for proteins) contained within individual fungal pathogen cells.

Usage
Mancozeb and maneb were first marketed in the early 1960s by the US agrochemical companies Rohm & Haas and Du Pont. (Du Pont no longer manufactures or markets maneb.)
    In the UK, most EBDC usage involves mancozeb, and to a lesser extent maneb, for control of blight in potatoes. In 1996, 1,008,000 kg of mancozeb was applied to 815,577 ha of arable crops. By weight applied, it was the 5th most used pesticide in this sector. Arable use of maneb totalled 152,000 kg(3).
    There is no indication that EBDC usage is declining in the UK.
    Internationally EBDCs are extensively used in a wide range of countries.

Acute toxicity
EBDCs have relatively low acute toxicity. They are categorised by WHO as Class III "unlikely to present an acute hazard in normal use"(4)  (except nabam, see below).

Mancozeb: The acute oral LD50 for rats is > 5,000 mg/kg. The acute dermal LD50 for rabbits is > 5,000 mg/kg and >10,000 for rats. It is a mild to moderate skin irritant and a moderate eye irritant(5).

Maneb: The acute oral LD50 for rats is > 5,000 mg/kg. The acute dermal LD50 for rats and rabbits is > 5,000 mg/kg. It is non-irritant to skin (from rabbit testing), a moderate eye irritant, and may cause irritation of nose and throat(6).

Metiram: The acute oral LD50 for rats is >10,000 mg/kg, for mice >5,400, guinea pigs 2,400-2,800. It is a mild skin and eye irritant(7).

Nabam: The acute oral LD50 for rats is 395 mg/kg. It is categorised by WHO as Class II "moderately hazardous."(8) 

Zineb: The acute oral LD50 for rats is >5,200 mg/kg. The acute dermal LD50 for rats is >6,000 mg/kg. It causes a slight irritation of skin and mucous membranes(9).

According to the US EPA, in spray or dust forms, the EBDCs as a whole are moderately irritating to the skin and respiratory membranes. Symptoms of poisoning include itching, scratchy throat, sneezing, coughing, inflammation of the nose or throat, and bronchitis(10). There is no evidence of neurotoxicity. However, EBDCs are partially broken down to carbon disulphide that is a neurotoxin capable of damaging nerve tissue(11).

Chronic effects
EBDCs are considered to have low mammalian toxicity. Of more concern is ethylenethiourea (ETU), an industrial contaminant and a breakdown product of EBDC active ingredients. ETU can be produced when EBDCs are used on stored produce, and also when contaminated fruit and/or vegetables are cooked. It can cause goitres (a condition in which the thyroid gland is enlarged), birth defects and cancer in exposed experimental animals(12). ETU has been classified as a probable human carcinogen by the US EPA(13).
    In 1989, the US EPA proposed to cancel 45 food-crop uses of three of the EBDCs (maneb, mancozeb and metiram), and all food uses of zineb(14). Later in 1992, EPA changed its position and reinstated some of the proposed uses it intended to cancel because of a re-assessment of dietary exposure. In the end EPA announced its intent to cancel the use of maneb, mancozeb and metiram for use on apricots, carrots, celery, collards, mustard greens, nectarines, peaches, rhubarb, spinach, beans and turnips. In addition, it banned mancozeb use for homegarden turf and food uses.
    At the same time, the EPA said exposure to EBDCs may pose increased occupational health risks of cancer, birth defects and thyroid disorders to mixers, loaders and applicators handling these formulations. This assessment resulted in changes to protective equipment requirements(15).
    According to the Pesticide Manual "very high levels" of EBDCs mancozeb and maneb have caused birth defects in test animals and, agrees with the US EPA's assessment of ETU(16).
    EBDCs have been reviewed by the UK Advisory Committee on Pesticides (ACP) in 1990 and 1991(17 ,18). It concluded that there was no evidence of a risk of cancer or other adverse health effects to consumers arising out of EBDC use in the UK. It agreed with the EPA that exposing rodents to ETU at high doses that persistently altered levels of thyroid stimulating hormone could cause tumours but also concluded that the tumours regressed when the dosing level ceased. It disagreed with EPA by taking the view that human and rodent thyroids differed in function, and that there was no risk of persistently high levels of hormone in humans and no risk of cancer causation.
    The 1997 the Food and Agriculture Organisation (FAO)/World Health (WHO) International Codex Committee Joint Meeting on Pesticides Residues agreed that EBDCs were toxic to the thyroid(19).

Reproductive effects
In a three-generation rat study involving mancozeb, at a dietary level of 50 mg/kg, there was reduced fertility but no indication of embryo toxicity or teratogenic effects. In another study in which pregnant rats were exposed to mancozeb by inhalation, toxic effects on the pups were observed only at doses (55 mg/m3) that were also toxic to the dams(20). 

Data gaps
The joint FAO/WHO meeting on Pesticide Residues, assessed the chronic toxicity of EBDCs in 1993. Its report concluded: Studies on 'observations in humans' for mancozeb, maneb, metiram and zineb would provide more valuable information for the evaluation of these compounds. In the case of mancozeb, the clarification of the genotoxic potential was also required(21).
    A data gap also exists in the information available on the mutagenicity of mancozeb and ETU. Mancozeb is thought to be similar to maneb, which was not mutagenic in the Ames Test(22).

Residues in food
Dithiocarbamate (a group that includes EBDCs) residues in food are measured collectively because analysis is accomplished by measuring carbon disulphide that all these chemicals liberate(23). Residues are regularly detected in fruit and vegetables, mostly at levels below the maximum residue levels (that shows consistency with good agricultural practice).
    In a UK survey on apricots carried out by the Working Party of Pesticides Residues (WPPR) in 1996, the Acceptable Daily Intake (ADI)(24)  [lifetime safe daily dose] for ETU was however exceeded(25). Researchers found 21% of 24 samples contained detectable residues of dithocarbamates, no MRLs have been set for dithiocarbamates in apricots. Relatively high dithiocarbamate residues at 17 mg/kg were found in one sample. Due to possible concerns regarding consumer exposure to toxicologically significant metobabolites ETU and iso-propylene thiourea, from the non-EBDC pesticide propineb, which may be associated with these residues, follow-up work was commissioned to determine the potential level of metabolite residues in this sample. Metabolite residues were not found.
    The WPPR report on the survey concluded that a risk assessment was carried out which indicated that the high dithiocarbamate residues detected would lead to a "small exceedance of the ADI" for a high level infant consumer of apricots. Because these levels are unlikely to occur the WPPR further concluded that no adverse effects on health would be expected from occasional exceedances of the ADI. However, clearly safety margins have been eroded.
    The UK Advisory Committee on Pesticides (ACP) reviewed residue data in 1991 on EBDCs and came to the view that "the data were variable in quality and often failed to meet current standards."(26)

Ecological effects
EBDCs are generally not toxic to wildlife. However, this is not the case with fish as maneb is highly toxic to fish, and mancozeb is generally toxic to a number of species.
    The 96-hour LC50 (lethal concentration for 50% of a test population) for maneb is 1 part per million (ppm) for bluegill sunfish. Its 48-hour LC50 is 1.9 ppm in rainbow trout, and the 58-hour LC50 is 1.8 ppm. Water can be contaminated by the inappropriate storage, use or disposal of maneb(27).
    Mancozeb is more toxic to warm-water than cold-water fish. Its 48 hour LC50 for goldfish is 9 mg/kg, and for rainbow trout it is 2.2 mg/kg(28).

Environmental fate
The EBDCs are generally unstable in the presence of moisture, oxygen, and in biological systems. They rapidly degrade to ETU. This focuses on the need for the assessment of environmental fate of ETU. The US EPA has either called for or is currently reviewing data on the behaviour of ETU in the environment(29).

Regulation
Swedish position
In Sweden, there has been concern about EBDCs since the early 1990s. This led to maneb being banned because of health and environmental reasons, and mancozeb being severely restricted. This action occurred because of worries over chronic occupational health effects associated with use, and because ETU is a mobile metabolite that may contaminate ground water. Mancozeb and maneb have been classified as carcinogenic by the criteria established by KEMI (the Swedish pesticide regulatory authority). Traditionally, there has been considerable demand for EBDC products within the farming community to control late blight in potatoes. The Swedish government aims eventually to phase out the use of these products completely.
    Mancozeb use is restricted by the fact it is only allowed for use with mixed non-14. EBDC formulations. In practice this means considerably lower amounts of EBDC are applied per season compared with mono-component formulations. With the combined efforts of regulators, research institutions and industry it has been possible to help farmers reduce pesticide use considerably in potatoes in recent years.
    There is an advisory service on late blight control programmes, which promotes the use of lower dose rates and resistant/tolerant potato varieties. There have been improvements in spraying equipment and spraying techniques, and better meteorologically-based prognosis methods are now available(30). These measures have meant quantities of EBDCs use have dropped from about 500 tonnes in 1991 to less than 100 tonnes by 1996(31).

Restriction in Norway
Mancozeb use will be phased out by the year 2000 because of long-term health concerns associated with its use(32).

European Union review
Under the EU Authorisations Directive 91/414/EEC, active ingredients are subject to review at EU level before they can go on the EU-approved 'positive list'. The first tranche of just under 90 active ingredients is being processed for review. Mancozeb, maneb, metiram are being reviewed by Italy as the rapporteur state.

Conclusions
The main concerns with EBDCs are the possible chronic health effects associated with the breakdown product ETU. The results of residue analysis in apricots indicate the ADI has been exceeded in the UK for this chemical - a rare but serious event. The US authorities banned maneb and mancozeb use on apricots is 1992 because of concerns over consumer exposure. This crop/residue combination does not even have a MRL set in the UK.
    The US, and a number of Scandinavian countries, have made concerted efforts to restrict EBDC use in recent years. Other national authorities should consider similar measures for products that are still widely in use.

References
1. Whitehead, R, (Ed.), The UK Pesticide Guide, CAB International/British Crop Protection Council (BCPC), 1997.
2. Mancozeb, Extoxnet , Pesticide Management Education Program, Cornell University, 5123 Comstock Hall, Ithaca, NY, US, 1992.
3. Pesticide Usage Survey Report 141: Arable Farm Crops in Great Britain 1996, MAFF Publications, London, UK, 1997.
4. The WHO Recommended Classification of Pesticides by Hazard, WHO/PCS/96.3, 1997.
5. Tomlin, C.D.S, (Ed.) The Pesticide Manual, BCPC, UK, 1997.
6. Ibid., p. 765
7. Op. cit. 5, p. 830.
8. Op. cit. 4.
9. Op cit. 5, p. 1,277
10. Op. cit. 2.
11. Ibid.
12. Op. cit. 2.
13. US EPA, EBDCs: notice of intent to cancel and conclusion of Special Review, 1992.
14. US EPA, EPA proposes cancellation of most uses of EBDC pesticides, 1989.
15. Op. cit. 13.
16. Op. cit. 5.
17. EBDCs Evaluation Document 16, MAFF Pesticides Safety Division January 1990.
18. EBDCs Evaluation Document 36, MAFF Pesticides Safety Division. April 1991.
19. Codex Alimentarius Commission, Progress report by WHO, CX/PR 98/5, December 1997.
20. Op. cit. 2.
21. Joint FAO/WHO Meeting of Pesticide Residues, Evaluations 1993, Part II Toxicology.
22. Op. cit. 2.
23. Op. cit. 5.
24. The ADI was set by the Food and Agriculture Organisation at 0.03 mg/kg/body weight. The ADI for ETU is much lower (ie of more concern) at 0.002 mg/kg/body weight (Op. cit 21).
25. Annual Report of the WPPR, 1996, MAFF/HSE, HMSO, London, 1997, p.10.
26. Annual Report of the Advisory Committee on Pesticides 1990, HMSO, London, 1991.
27. Maneb, Extoxnet Pesticide Information Notebook, Pesticide Management Education Program, Cornell University, 5123 Comstock Hall, Ithaca, NY, 1992.
28. Op. cit. 5
29. Op. cit. 12.
30. Bergkvist, P, Bernson, V, Jarl, S and Tornlund, M, Re-registration of pesticides in Sweden, Pesticide Outlook, December 1996.
31. Pers. Comm. Peter Bergkvist, KEMI, Sweden.
32. Pers. Comm. Trond Hofsvang, Norwegian Crop Research Institute, Norway.

[This article first appeared in Pesticides News No.39, March 1998, p20-21]