Carbendazim

Carbendazim is a fungicide of major concern due to its suspected hormone disrupting effects. It has been highlighted by Friends of the Earth as one of their ‘filthy four’ pesticides as it could be harmful to human health and the environment. 

Carbendazim is a systemic benzimidazole fungicide(1) that plays a very important role in plant disease control(2). It was first reported in 1973(3) and was developed by BASF, Hoeschst (now part of Bayer) and Dupont(4). Carbendazim is used to control a broad range of diseases on arable crops (cereals, oilseed rape), fruits, vegetables and ornamentals(5). It is also used in post-harvest food storage, and as a seed pre-planting treatment(6). It is frequently sold in combination with other fungicides, such as triazoles, dithiocarbamates and dicarboximides(7). Carbendazim works by inhibiting the development of fungi probably by interfering with spindle formation at mitosis (cell division)(8).

Usage
Carbendazim has extensive applications worldwide(9), with the global market worth over $200 million at user level, equivalent to over 12000 tones active ingredient(10). It is particularly applied in Europe and the Far East(11). In China, production is over 8000 tonnes per year, and 1000 tonnes are produced every year in India, where the increasing consumption of carbendazim has now reached over 700 tonnes per annum(12). In Great Britain, the annual area treated in 2001 was 819,398 hectares, with arable crops accounting for 95% (718,757 hectares) of this use(13). For example, 38.6% of the winter oil seed rape grown (197,463 ha) in Great Britain is given at least one treatment of carbendazim, and 24% (71,548 ha) is given two treatments(14). Over the years, there has been a gradual reduction in carbendazim use – in 1996 just over two million hectares were treated with carbendazim in Great Britain, compared to nearly 1.8 million hectares in 1999 and 821,000 hectares in 2000(15). This is because modern conazole and strobilurin fungicides are more efficacious(16). 

Acute toxicity
Carbendazim is classified by the World Health Organisation (WHO) as ‘unlikely to present hazard in normal use’(17). The acute oral LD50 (dose at which half the sample is dead) for rats is >15000 mg/kg and >2500 mg/kg for dogs(18). On the basis of the analysis of rat, dog and rabbit studies, the UK Advisory Committee of Pesticides (ACP) evaluation concluded that carbendazim is of low toxicity to rodent and non-rodent species via the oral, dermal, inhalational and intraperitoneal routes’(19). 
    The primary source of carbendazim exposure for the public at large is dietary intake(20); this is discussed further below. For agricultural workers, occupational exposure during manufacture or use is considered to be within acceptable levels(21). The International Programme for Chemical Safety (IPCS) do not indicate that there is a danger of exposure to carbendazim during its production and use in agriculture. As workers are most likely to suffer exposure through skin contact or inhalation, risk can be controlled by the use of protective clothing(22) and the use of a dust mask is recommended(23).

Chronic effects
Carcinogenicity
Research on mice showed increased tumours in two out of three studies(24). However, in reviewing other data, the Scientific Committee on Plants showed there was no DNA-reactive effect so they concluded ‘these mouse liver tumours could not be interpreted as predicting a carcinogenic hazard to humans’(25). This conclusion was also reached by the ACP evaluation of carbendazim in 1992(26).

Reproductive effects
Carbendazim is a suspected endocrine disruptor(27). It has been included by the European Commission on a priority list of chemicals that are believed to affect hormone function(28). Friends of the Earth have found evidence that carbendazim can damage the development of mammals in the womb. A study by Mantovani and others(29), showed animals exposed to carbendazim in the womb to have serious deformities such as lack of eyes and hydrocephalus (water on the brain). Carbendazim can disrupt the development of sperm and damage testicular development in adult rats. For example one study of benomyl (which has carbendazim as its main metabolite) found ‘testicular atrophy and degeneration and foetotoxicity’(30). However, despite the known effects of hormone-disrupting chemicals, on wildlife(31), in providing their opinion on carbendazim the Scientific Committee on Plants found there were only minor signs of reproductive toxicity at high doses and no effects on development in the absence of maternal and/or paternal toxicity. 

Mutagenic effects
Carbendazim is not a heritable gene mutagen(32). Nonetheless, it does affect the chromosomes. Recently researchers testing the effect of carbendazim on cultured human lymphocytes concluded that it is obvious carbendazim is a potent aneugen (affects the number of chromosomes) even at low exposures(33). This is due to inhibition of polymerisation of tubulin, the protein that is essential for the segregation of chromosomes during cell division(34): Apart from aneuploidy, the opinion of the Scientific Committee on Plants is that ‘there is no evidence that any other form of damage to genetic material is induced’(35) by carbendazim. 

Effects on wildlife and the environment
Carbendazim is said to be harmful to fish or other aquatic life(36) – laboratory tests have shown high toxicity for aquatic organisms, for example LC50 (i.e. the concentration at which half the sample is dead) for rainbow trout 0.36 mg/litre, 5.5 mg/litre for bluegill sunfish(37), 0.098 mg/litre for mysid shrimp(38) and 0.087 mg/litre for aquatic invertebrates(39) . However, it is probable that this high toxicity is unlikely to be seen in the field, because carbendazim is strongly adsorbed to sediment(40). Thus, sediment-living organisms would probably receive high exposure(41). 
    As carbendazim is so strongly adsorbed on soil organic matter(42) it is unsurprising that it may diminish earthworm populations(43) – earthworms have been shown to be adversely affected (population and reproductive effects) at the recommended rates of application(44). In a study on the effects of carbendazim on three genera of potworm, one genera that lived in or close to the litter layer where carbendazim tends to be bound showed a decrease in number, whilst the other two genera which live deeper in the soil, showed an increase(45). 
    Carbendazim has a half-life (time taken for half the sample to decay) of 6-12 months on bare soil and 3-6 months on turf(46) and is mainly decomposed by microorganisms(47). One study demonstrated that whilst carbendazim had some effect on soil microflora, the effects were never long lasting and concluded it had low toxicity against microbial activities(48). Plants readily absorb carbendazim(49), leading to concerns over phytotoxicity. One study on tobacco found evidence of weak phytotoxicity, meaning it could be damaging to healthy, non-target plants, especially at higher doses(50).
    Carbendazim has a low acute toxicity for birds(51) – the oral LD50 for quail is 5828 – 15595 mg/kg(52). The WHO state that carbendazim is not toxic to bees(53), though tests with benomyl on the natural arthropod enemies of pests including hover flies, ladybirds and predatory mites found reproduction was affected in at least one mite and one insect species(54). 

Resistance
Resistance is a very serious problem(55). It has been seen in, for example, apple scab, eyespot and Botrytis. To combat resistance, carbendazim is often combined with other fungicides with different modes of action(56) and integrated plant disease management strategies are being developed. Researchers in China have developed a strain of the biological control agent Trichoderma harzianum which survives much higher doses of carbendazim than the recommended rate of control(57).

Residues in food
Carbendazim has been in the news because of issues over residues in foodstuffs. It is one of the twelve most commonly detected pesticides in EU monitoring programmes(58). In 2000, it was found in baby food made by Heinz and Milupa and sold in Tesco and Waitrose(59). Additionally, in 2000, one third of all pears, 16% of apples tested(60), and over a quarter (27%) of apple juice samples contained carbendazim residues(61). Although carbendazim was only found in low doses on all the samples, it is an issue because babies are especially vulnerable(62), and apples and pears are amongst those foodstuffs most commonly eaten by toddlers(63).
    Some retailers (the Co-op in particular) are trying to eliminate the hazards of such residues in foods. Whilst they have banned several pesticides, others which they would like to ban, including carbendazim, remain in use (with permission) because suitable alternatives are not available.

Regulatory status
In the US, carbendazim is not approved(64). Carbendazim was one of the 90 pesticides from the first listing issued in 1992 by the EC for review under the Agricultural directive 91/414, with Germany acting as the rapporteur state(65). However, it is still undergoing the review process. The big agrochemical companies AgroEvo (now part of Bayer), Dupont and BASF make up a carbendazim task force that predated this review programme(66). 

Conclusions
Carbendazim is a fungicide of major concern due to its suspected hormone disrupting effects. It has been highlighted by Friends of the Earth as one of their ‘filthy four’ pesticides(67) as it could be harmful to human health and the environment. In the UK, its use is declining as more effective fungicides come onto the market. Nevertheless, until more alternatives are found, it is likely that this ‘gender bending’ fungicide will be considered to have an essential use, and hence will remain permitted in Europe and in use around the globe. (HM)

References
1. Advisory Committee on Pesticides, Evaluation on Carbendazim, Evaluation of Fully Approved or Provisionally Approved Products, No. 58, Ministry of Agriculture, Fisheries and Food , July 1992.
2. Quian Y, Transformation and expression of the resistance gene to carbendazim into Trichoderma harzianum, Resistant Pest Management, Vol. 8, Summer 1996.
3. Hicks, B, Generic pesticides – the products and markets, Agrow Reports, PJB Publications, 1998.
4. Hicks, Ibid.
5. Hicks, Ibid.
6. MAFF, Op. cit. 1.
7. Hicks, Op. cit. 3.
8. MAFF, Op. cit. 1.
9. WHO/FAO Joint Meeting on Pesticides Residues (JMPR) Report, Carbendazim (072), 1994.
10. Hicks, Op. cit. 3.
11. Hicks, Ibid.
12. Hicks, Ibid.
13. Data from MAFF Pesticide Usage Surveys in Great Britain, 1997-2001.
14. MAFF, Op. cit. 13.
15. MAFF, Ibid.
16. Miles Thomas pers. comm. Central Science Laboratory, UK.
17. The WHO Recommended classification of pesticides by hazard and guidelines to classification 1998-1999, International Programme on Chemical Safety, 1999.
18. Tomlin CDS (Ed.) Pesticides Manual 12th Edition, British Crop Protection Council, 2000.
19. MAFF, Op. cit. 1.
20. IPCS International Programme on Chemical Safety, Carbendazim health and safety guide, number 82, WHO Geneva, 1993.
21. IPCS, Ibid..
22. IPCS, Ibid.
23. WHO/FAO Data sheets on pesticides No. 89, Carbendazim, November 1996.
24. Scientific Committee on Plants, Preliminary opinion of the scientific committee on plants regarding the evaluation of benomyl, carbendazim and thiophanate-methyl in the context of council directive 91/414/EEC concerning the placing of the plant protection products on the market. http://europa.eu.int/comm/food/fs/sc/scp/out98_ppp_en.html, 2001.
25. European Commission, Ibid.
26. MAFF, Op. cit. 1.
27. Friends of the Earth, Endocrine disrupting pesticides – European priority list, briefing, February 2001
28. Commission of the European Communities, Community Strategy for Endocrine Disruptors, a range of substances suspected of interfering with the hormone systems of humans and wildlife, COM 706 final, 1999.
29. Mantovani, A., Maranghi, F., Ricciardi, C., Macri, C., Stazi, A.V., Attias, L. and Zapponi, G.A., Developmental toxicity of carbendazim: Camparison of no-observed-adverse-effect level and benchmark dose approach, Food and Chemical Toxicology, 1998, 36: 37-45.
30. Du Pont, 1991, cited by Scientific Committee on Plants, Preliminary opinion of the scientific committee on plants regarding the evaluation of benomyl, carbendazim and the thiophanate-methyl in the context of council directive 91/414/EEC concerning the placing of the plant protection products on the market. http://europa.eu.int/comm/food/fs/sc/scp/out98_ppp_en.html, 2001.
31. Friends of the Earth Press release, 1 December 2000.
32. IPCS, Op. cit. 20.
33. Mahmood R and Parry JM, Induction of mircronuclei and chromosome non-disjunction after short-term exposure to carbendazim in cultured human lymphocytes, 31st annual meeting of the EEMS, Ghent, Belgium, 2001.
34. European Commission, Op. cit. 24.
35. European Commission, Ibid.
36. Pesticides Safety Directorate, Pesticides 2001, The stationary office, 2001.
37. WHO/FAO, Op. cit. 23.
38. JMPR Monographs, Carbendazim (Pesticides residues in food: 1995 evaluations Part II Toxicological and Environmental) www.inchem.org/documents/jmpr/jmpmono/v95pr.19.htm, 1995.
39. JMPR, Ibid.
40. IPCS, Op. cit. 20.
41. IPCS, Ibid.
42. Moser T and Rombke R Effects of Carbendazim on the abundance of the Encnytraeid genera Achaeta, Enchytraeus and Fridericia in Terrestrial Model Systems and in the field. Fifth International Colloquium on Enchytraedicae, Wageningen, www.dow.wau.nl/soil_quality/enchycol/moser.htm, April 2002.
43. WHO/FAO, Op. cit. 23.
44. IPCS, Op. cit. 20.
45. Moser, Op. cit. 42.
46. JMPR, Op. cit. 38.
47. Tomlin, Op. cit. 18.
48. Helweg, A Mikrobiologisk Nedbrydning og effect af maleinhydrazid, carbendazim og 2-aminobenzimidazol I jord, statens planteavlsforøg, 1983
49. Tomlin, Op. cit. 18.
50. Garcia PC, et al, Is the application of carbendazim harmful to healthy plants? Evidence of weak phytotoxicity in tobacco, Journal of Agricultural and Food Chemistry, 50, 279-283, 2002.
51. JMPR, Op. cit. 38.
52. Tomlin, Op. cit. 18.
53. WHO/FAO, Op. cit. 23.
54. JMPR, Op. cit. 38.
55. Quain, cited by Quian Y, Op. cit. 2.
56. JMPR, Op. cit. 38.
57. Quian, Op. cit. 2.
58. Monitoring of Pesticide Residues in Products of Plant Origin in the European Union and Norway- Report 1997 http://europa.eu.int/comm/food/fs/inspections/fnaoi/reports/annual_eu/
fnaoi_rep_norw_1996_en.html
.
59. Friends of the Earth, Op. cit. 31.
60. Friends of the Earth, Press release 01 July 2001 and Pesticides Residues Committee Quarterly reports 2000.
61. Friends of the Earth, Press release 28 February 2001 and Pesticides Residues Committee First Quarterly report 2001.
62. Friends of the Earth, Ibid.
63. National Diet Survey, cited by Friends of the Earth, Press release 28 February 2001.
64. Hicks, Op. cit. 3.
65. Hicks, Op. cit. 3.
66. Hicks, Ibid.
67. Friends of the Earth, The ‘Filthy Four’ pesticides, briefing, May 2000.

[This article first appeared in Pesticides News No. 57, September 2002, pages 20-21]