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Fipronil (Rhone Poulenc). June 2000 Article in Pesticide News, No. 48.

[This article first appeared in Pesticides News No.48, June 2000, p20]



Fipronil is an insecticide discovered and developed by Rhône-Poulenc between 1985-87 and placed on the market in 1993. Although effective against a variety of pests, there are concerns about its environmental and human health effects. Actively marketed in many industrialised and developing countries its, worldwide use is increasing.

Fipronil is a member of the phenyl pyrazole class of pesticides, which are principally chemicals with a herbicidal effect(1). Fipronil, however, acts as an insecticide with contact and stomach action. It is sparingly soluble in water(2); is stable at normal temperatures for one year but not stable in the presence of metal ions and is degraded by sunlight to produce a variety of metabolites one of which (fipronil-desulfinyl (MB 46513)) is extremely stable and is more toxic than the parent compound(3).

In 1997, production was around 480 tonnes per annum, and was expected to rise to 800 tonnes by 2000(4). Production takes place at the Rhône-Poulenc Biochimie plant at Saint-Aubin-LŹs-Elbeuf, France(5), but approval has recently been gained for another production plant in China which will ensure the synthesis, formulation and distribution for the insecticide Regent in the Chinese market(6).

Between 1987 and 1996 fipronil was evaluated on more than 250 insect pests on 60 crops worldwide(7) and crop protection accounted for about 39% of total fipronil production in 1997(8).
Fipronil is marketed under the trade name Regent for use against major lepidopterous and orthopterous pests on a wide range of field and horticultural crops and against coleopterous larvae in soils(9). It is also employed for cockroach and ant control(10) under the trade names Goliath and Nexa including in the US, where it is also used against pests of field corn, golf courses and commercial turf(11) (trade name Chipco Choice). It has been used under the trade name Adonis for locust control in Madagascar(12 13 14) and in Kazakhstan(15).
Fipronil also controls termite pests and was shown to be effective in field trials in Africa(16 17) and Australia(18). It is marketed under the name Termidor(19).
In 1999, 400,000 hectares were treated with Regent. It became the leading imported product in the area of rice insecticides, the second biggest crop protection market after cotton in China(20).
Fipronil under the trade name Frontline or Top Spot is also used to control fleas, ticks and mites on domestic animals(21 22) and as a pour-on or dip for cattle to control ticks(23). In the UK, provisional approval for five years has been granted for fipronil use as a public hygiene insecticide(24).

Mode of action
Fipronil is an extremely active molecule and is a potent disruptor of the insect central nervous system via the (-aminobutyric acid (GABA) regulated chloride channel(25). Despite the fact that the GABA channel is important in nerve transmission in both vertebrate and invertebrate animals(26), and that fipronil does bind to the GABA receptor in vertebrates, the binding is ‘less tight” which offers a degree of selectivity(27).

Environmental fate
Field persistence is low-moderate in water and soil (half-life 10-130 hours (h) in water and 45-530 h in soil) with three major degradates formed in soil – RPA 20076 (amide), MB46513 (fipronil-desulfinyl), and RPA 104615 and two major metabolites in water, including MB 45950 (sulfide). Under aerobic conditions in soil several metabolites have been identified, including RPA 200766 and MB 46136 (sulfone)(28).
Fipronil’s half-life on treated vegetation has been determined at 3-7 months, depending on the substrate and the habitat where it is applied(29).
Laboratory studies show direct and indirect photolysis, volatilization, and hydrolysis as contributors to fipronil field dissipation(30). Of the major degradates identified in laboratory studies, only two (MB 46136 and RPA 200766) were found in field studies at amounts greater than the limit of detection(31).
Fipronil residues tend to stay in the upper 15 cm of soil and exhibit low potential to leach to groundwater(32).
In aquatic environments, fipronil residues rapidly move from the water to the sediment with over 95% of the residues being found in or on the sediments within one week of application(33).
Metabolic studies showed that there was a potential for bioaccumulation of the photodegradate MB 46513 in fatty tissues(34).

Acute toxicity
Fipronil is classed as a WHO Class II moderately hazardous pesticide and has a rat acute oral LD50 (the dose required to kill half a population of lab animals) is 97 mg/kg(35). It is less toxic to mammals than to some birds, fish and most invertebrates.
Fipronil has moderate acute toxicity by the oral and inhalation routes in rats. Dermal absorption in rats is less than 1% after 24 h and toxicity is considered to be low. In contrast, it is of moderate dermal toxicity to rabbits(36).
The photodegradate MB46513 appears to have a higher acute toxicity to mammals than fipronil itself by a factor of about 10(37).

Chronic effects
Fipronil is neurotoxic in both rats and dogs as shown in the acute and sub-chronic screening in the rat, developmental neurotoxicity and chronic carcinogenicity studies in the rat and in two chronic dog studies(38).
There has been a low incidence of severe skin reactions to Frontline Spray treatment, Top Spot for Cats and Top Spot for Dogs, mostly resulting in skin irritation and/or hair loss at the site of application. There is some suggestion that dogs are more severely affected than cats(39).
Fipronil is carcinogenic to rats at doses of 300 ppm in males (12.68 mg/kg/day) and females (16.75 mg/kg/day)(40), causing thyroid cancer related to disruption in the thyroid-pituitary status(41). However fipronil was not carcinogenic to female mice when administered at doses of 30 ppm(42 43).
Fipronil is associated with reproductive effects in rats fed 95.4% fipronil continuously in the diet at 300 ppm based on clinical signs of toxicity, decreased litter size, decreased body weights, decrease in the percentage of animals mating, reduction in fertility index, reduced post-implantation survival and offspring postnatal survivability, and delay in physical development(44).

Human health
There have been very few studies undertaken with human subjects, although human cells have been used in some carcinogenicity studies in which no adverse effects were detected(45).
Fipronil has been classified as a Group C (Possible Human) Carcinogen based on an increase in thyroid follicular cell tumours in both sexes of the rat(46). In contrast, thyroid tumours induced by fipronil in rats are not considered of relevance to human health in the UK(47).
Two Top Spot products were determined by the New York State Department of Environmental Conservation to pose no significant exposure risks to workers applying the product. However, concerns were raised about human exposure to Frontline spray treatment in 1996 leading to a denial of registration for the spray product. Commercial pet groomers and veterinarians were considered to be at risk from chronic exposure via inhalation and dermal absorption during the application of the spray, assuming that they may have to treat up to 20 large dogs per day(48).

Effects on wildlife
Laboratory toxicity tests

Fipronil is highly toxic to certain groups of gallinaceous birds (Acute LD50 for Bobwhite quail = 11.3 mg/kg), while being relatively innocuous to passerines (LD50 for field sparrow = 1120 mg/kg) and wildfowl (LD50for Mallard duck > 2150 mg/kg)(49).
    The LD50 of fipronil for the fringe-toed lizard (Acanthodactylus dumerili) [Lacertidae] has been estimated at 30 Ķg a.i./g body weight in laboratory tests, indicating that it is highly toxic. Mortality was delayed and lizards died during the four weeks after treatment(50). Locomotor activity, prey consumption and body weight remained significantly lower in lizards fed fipronil treated prey than in the control group for 2-4 weeks after treatment. Data on other lizard species is not available(51).
Toxicity of fipronil to fish varies with species. It is very highly toxic to bluegill sunfish (LC50  (Lethal Concentration) (96 h) = 85 Ķg/l), highly toxic to rainbow trout (LC50 (96 h) = 248 Ķg/l) and highly toxic to European carp (LC50 (96 h) = 430 Ķg/l)(52 53). It is very highly toxic to one of the African tilapia (Oreochromis niloticus) (LC50 (96 h) = 42 Ķg/l)(54). Fipronil affects larval growth in rainbow trout at concentrations greater than 0.0066 ppm(55).
Fipronil is also toxic to a wide range of aquatic invertebrates, very highly toxic to shrimps and other crustacea and very highly toxic to oysters(56 57).
Fipronil is highly toxic to bees(58) and termites(59). It had the highest acute toxicity for the parasitoid Bracon hebetor [Hymenoptera: Braconidae] with an LC50 of 0.09 ng/cm*, and the second highest Risk Quotient (RQ) of the seven insecticides tested by the FAO Locustox study(60). It appears to reduce the longevity and fecundity of female braconid parasitoids and ‘long term effects on reproduction are to be foreseen with fipronil’(61). Fipronil was given the highest hazard ranking for beneficial tenebrionid beetles of six insecticides tested in the Locustox study(62). It is virtually non-toxic to earthworms(63).
The metabolite MB 461(36) is more toxic than the parent to avian species tested (very highly toxic to upland game birds and moderately toxic to waterfowl on an acute oral basis)(64). The metabolite MB 46136 is more toxic than the parent to freshwater fish (6.3 times more toxic to rainbow trout and 3.3 times more toxic to bluegill sunfish). Metabolites MB 46136 and MB 45950 are more toxic than the parent to freshwater invertebrates (MB 46136 is 6.6 times more toxic and MB 45950 is 1.9 times more toxic)(65).

Field studies
Few studies of effects on wildlife have been carried out, but studies of the non-target impact from emergency applications of fipronil (Adonis 7,5) as barrier sprays for locust control in Madagascar showed adverse impacts of fipronil on termites (Coarctotermes spp.), which appear to be very severe and long-lived. There were also indications of adverse effects in the short-term on several other invertebrate groups, one species of lizard (Mabuya elegans) and several species of birds (including the Madagascar bee-eater)(66).
Non-target effects on some insects (predatory and detritivorous beetles, some parasitic wasps and bees) were also found in field trials of fipronil for desert locust control in Mauritania(67) and very low doses (0.6-2.0 g a.i./ha) used against grasshoppers in Niger caused impacts on non-target insects comparable with those found with other insecticides used in grasshopper control(68). The implications of this for other wildlife and ecology of the habitat remain unknown but appear unlikely to be severe.
Grasshopper control in Siberia resulted in a greater impact on non-target invertebrate wildlife from fipronil than from chlorpyrifos(69).

Sustainable agriculture
There is conflicting evidence over the suitability of fipronil for use in Integrated Pest Management (IPM), which is generally recognised as a route towards more ecologically sustainable agriculture. Field study results range from good selectivity by fipronil for certain beneficial insects and lower toxicity than (the highly toxic) methyl parathion and endosulfan(70); through slight and transitory decline in abundance of certain predators and parasitoids and little difference between fipronil and other insecticides(71 72 73); to reductions in beneficial arthropods and poorer crop damage prevention than a comparative insecticide(74).
Trials in Vietnam have suggested that fipronil use is incompatible with IPM in rice due to disruption of natural enemies and adverse effects on aquatic organisms(75 76). The study also questioned whether fipronil acted as a stimulant to plant growth(77). This finding and the effects on aquatic organisms were disputed by the manufacturers(78), but the disruption of natural enemies was not.
The Locustox study concluded that fipronil is relatively toxic to the beneficial invertebrates tested (natural enemies and soil insects)(79).
There are also potentially negative impacts for sustainable agricultural practices in rangeland in Madagascar from fipronil use in locust control, if reduced termite activity affects soil nutrient cycling and water infiltration into soil. However, further study would be necessary to confirm this possibility(80).

Developing country problems
There are few issues unique to fipronil in relation to its use in developing countries – most are relevant to all pesticide use. However, the following risks are noted in relation to fipronil because of its specific characteristics and the conditions and situations under which it may be used in less developed nations:

Fipronil is a highly effective, broad spectrum insecticide with potential value for control of a wide range of crop, public hygiene, amenity and veterinary pests. It can generally be applied at low to very low dose rates to achieve effective pest control.
Questions have been raised about fipronil’s suitability for use in IPM and studies suggest that this must be evaluated on a case by case basis. In certain situations it may disrupt natural enemy populations, depending on the groups and species involved and the timing of application.
Its acute toxicity varies widely even in animals within the same groups (see above). This means that the toxicological findings from results on standard test animals are not necessarily applicable to animals in the wild. Testing on local species seems particularly important in determining suitability of fipronil based products for registration in different countries or habitats and the likely risk to non-target wildlife.
Fipronil use requires careful consideration where contamination of the aquatic environment is likely, due to its high toxicity to some fish and aquatic invertebrates.
The dose levels at which fipronil produces thyroid cancer in rats are very high and unlikely to occur in normal conditions of use. There is also dispute as to whether this is relevant to human health risk. However, in developing countries where illiteracy, lack of protective clothing and use of insecticide drums increase the risk of human contact with the product at above recommended dose rates, a precautionary approach may be warranted.
In general, it would appear unwise to use fipronil-based insecticide without environmental monitoring to accompany its use, in situations, regions or countries where it has not been used before and where its use may lead to its introduction into the wider environment or bring it into contact with people.

The fact sheet was written by staff at the Natural Resources Institute. An expanded version is available in a Fipronil Briefing Document from PAN UK.

1. Atelier International Fipronil/lutte antiacridienne, Rhône-Poulenc, Lyon, 3-5 May 1995.
2. Evaluation on: Fipronil use as a public hygiene insecticide, Issue No. 187, The Health and safety Executive, UK, 1999.
3. Fipronil for use on Rice (Regent, Icon) and Pets (Frontline), HED Risk Assessment, Chemical 129121, Barcodes D242090, D245656, D245627, & D241676, Cases 288765, 031271, 060305, & 061662, Submissions S535772, S541670, S541551, S534929, USEPA Washington DC 20460, US, Office of Prevention, Pesticides and Toxic Substances, 1998, 90 pp + 3 attachments.
4. Rhône-Poulenc Agro to boost fipronil production, Agrow 1997, 294, 17.
5. Ibid.
6. Aventis CropScience Chinese Insecticide Joint Venture Approved, 2000, http://www2.aventis.com/press/pr_071.htm
7. HM Hamon, H Gamboa and JEM Garcia, 1996, Fipronil: a major advance for the control of boll weevil in Columbia, In: GA Herzog, DA Hardee (chairs), RJ Ottens, CS Ireland and JV Nelms (eds.), Proceedings Beltwide Cotton Conferences US, vol. 2, Jan 9-12 1996, Nasville, TN, Cotton insect research and control conference, NCC, Memphis, TN, pp. 990-994.
8. Op. cit. 4.
9. ‘Fipronil’ Worldwide Technical Bulletin, Rhône-Poulenc, Research Triangle Park, NC, US, 1996, 20pp.
10. Ibid.
11. New Pesticide Fact Sheet, 1996, US EPA, Office of Prevention, Pesticides and Toxic Substances, Washington DC, 20460, EPA-737-F-96-005. http://www.epa.gov/fedrgstr/EPA-PEST/199...ay-12/pr-736DIR/Facts/Factsheet.txt.html
12. Meeting of the World Bank Panel to evaluate the Migratory Locust situation in Madagascar, Antananarivo, Madagascar, 18-22 May 1998, 37pp.
13. GGM Schulten, H Dobson, M Lecoq, EE, de Miranda and R Peveling, Madagascar Mission de formulation d’un programme de lutte antiacridienne ŗ court, moyen et long termes, Unpublished Report to FAO, 1999, 120 pp.
14. M Lecoq, Current and future perspectives of the migratory locust plague in Madagascar, Advances in Applied Acridology, 2000, pp.20.
15. Quarterly report on the state of acridid outbreaks, Northern Hemisphere, March 2000, No.1, Association of Applied Acridologists International (AAAI), University of Wyoming, US, 2000, 39 pp.
16. Plant Protection Research Institute, Biennial Report, 1996/97.
17. Tran Van Canh, ZJ Keli and A Coulibaly, Control of termites and black ants damaging rubber plantations in Africa, In: Symposium on Natural rubber (Hevea brasiliensis), Vol 2 – physiology and exploitation and crop protection and planting methods sessions, Ho Chi Minh City, Brickendonbury (UK), International Rubber Research and Development Board, 1998, pp.115-121.
18. B Ahmed, JRJ French, P Kwint, and G Webb, Laboratory evaluation of fipronil (a phenyl pyrazole) as a candidate termiticide in the protection of wood against the subterranean termite, Coptotermes acinaciformis (Froggatt) Rhinotermitidae, The International Research Group on Wood Preservation, IRG/WP/97-10225, Paper prepared for the twenty eighth Annual meeting, Whistler, BC, Canada, 25-30 May 1997, 7pp.
19. Op. cit. 4.
20. Op. cit. 6.
21. SL Cutler, Ectopic Psoroptes cuniculi infestation in a pet rabbit, Journal of Small Animal Practice, 1998, 39(2), 86-87.
22. MJ Hutchinson, DE Jacobs, MT Fox, P Jeannin, and JM Postal, Evaluation of flea control strategies using fipronil on cats in a controlled simulated home environment, Veterinary Record, 1998, 142(14), 356-357.
23. RB Davey, EH Ahrens, JE George, JS Hunter III and P Jeannin, Therapeutic and persistent efficacy of fipronil against Boophilus microplus (Acari: Ixodidae) on cattle, Veterinary Parasitology, 1998, 74(2-4), 261-276.
24. Op. cit. 2.
25. Op. cit. 9.
26. DB Grant, JR Bloomquist, HH Ayad, and AE Chalmers, A comparison of mammalian and insect GABA receptor chloride channels, Pesticide Science, 1990, 30, 355-356.
27. Op. cit. 1.
28. JE Mulrooney, DA Wolfenbarger, KD Howard, Deepa-Goli and D Goli, Efficacy of ultra low volume and high volume applications of fipronil against the boll weevil, Journal of Cotton Science, 1998, 2(3), 110-116.
29. YT Belayneh, Amendment III to the USAID/Madagascar supplemental environmental assessment for locust control program: Options for including fipronil as an anti-locust insecticide, Unpublished report, USAID, Washington DC, September 1998, 36+ix+18+14 pp.
30. KK Ngim and DG Crosby, Environmental fate of fipronil in california rice fields, Ngim and Crosby, Department of Environmental Toxicology,1997, http://agchem.ucdavis.edu/colloq/kngim.htm
31. Op. cit. 28.
32. Op. cit. 11.
33. A Bobe, JF Cooper, CM Coste, and MA Muller, Behaviour of fipronil in soil under Sahelian Plain field conditions, Pestic. Sci., 1998, 52(3), 275-281.
34. Op. cit. 3.
35. WHO, Classification of Pesticides by Hazard 1998-1999, International Programme on Chemical Safety, WHO/IPCS/98.21.
36. Op. cit. 3.
37. Op. cit. 3.
38. Op. cit. 2.
39. Op. cit. 3.
40. Op. cit. 11.
41. PM Hurley, RN Hill and RJ Whiting, Mode of Carcinogenic Action of Pesticides Inducing Thyroid Follicular Cell Tumors in Rodents, Environmental Health Perspectives, 1998, 106(8), 437-445.
42. Op. cit. 11.
43. Op. cit. 2
44. Op. cit. 11.
45. New York State Dept. of Environment and Conservation, Division of Solid and hazardous materials, letter to Kandy Walker Duke, Rhône Merieux, Nov. 1996.
46. Op. cit. 3.
47. Op. cit. 2.
48. Op. cit. 3.
49. N Hamon, R Shaw and H Yang, Worldwide Development of Fipronil Insecticide, In: GA Herzog, Op. cit. 7, pp.759-765.
50. R Peveling, Toxicity of fungal and chemical locust control agents to lizards, Advances in Applied Acridology, 2000, AAAI, University of Wyoming, US, pp.17.
51. R Peveling and SA Demba, Effect of Metarhizium flavoviride, chlorpyrifos, and fipronil on Acanthodactylus dumerili (Milne Edwards, 1829) (Squamata: Lacertidae), LUBILOSA bioassays in Akjoujt, Mauritania, Nov. 1996-Feb. 1997, 32pp.
52. Op. cit. 9.
53. Op. cit. 11.
54. AO Diallo, M Diagne, KB Ndour, and J Lahr, Laboratory toxicity tests with eight acridicides on Oreochromis niloticus (Pices, Cichlidae), In: JW Everts, D Mbaye, O Barry and W Mullie (eds.), Environmental side-effects of locust and grasshopper control, Vol. 3, LOCUSTOX Project – GCP/SEN/041/NET, FAO, Dakar, Senegal, 1998, pp.188-204.
55. Op. cit. 11.
56. Op. cit. 11.
57. Lahr, A Badji, KB Ndour, AO Diallo, Acute toxicity tests with Streptocephalus sudanicus (Branchipoda, Anostraca) and Anisops sardeus (Hemiptera, Notonectidae) using insecticides for Desert Locust control, In: JW Everts, Op. cit. 54, pp.39-57.
58. Op. cit. 9.
59. Op. cit. 18.
60. A Danfa, B Fall and H van der Valk, Acute toxicity tests with Bracon hebetor Say (Hymenoptera: Braconidae), using different locust control insecticides in the Sahel, In: JW Everts, Op. cit. 54, pp.117-136.
61. Ibid.
62. H van der Valk, H Diakhatť and A Seck, The toxicity of locust control insecticides to Pimelia senegalensis and Trachyderma hispida (Coleoptera: Tenebrionidae), In: JW Everts, Op. cit. 54, pp.72-100.
63. Op. cit. 9.
64. Op. cit. 29.
65. Op. cit. 11.
66. CCD Tingle and AN McWilliam, Evaluation of short-term impact on non-target organisms of two pesticides used in emergency locust control in Madagascar, Final Report to DFID, Unpublished Report, NRI, Chatham, 1999, 28+9+6+5+12+xxix pp.
67. G Balanca and MN De Visscher, Impacts on nontarget insects of a new insecticide compound used against the desert locust [Schistocerca gregaria (Forskal)], Archives of environmental contamination and toxicology, 1997, 32(1), 58-62.
68. G Balanca and MN De Visscher, Effects of very low doses of fipronil on grasshoppers and non-target insects following field trials for grasshopper control, Crop Protection, 1997, 16(6), 553-564.
69. I Solokov, Fipronil versus chlorpyrifos: which is softer on non-target organisms in Siberia? Advances in Applied Acridology, AAAI, University of Wyoming, 2000, US, pp.17-18.
70. NM Hamon, H Gamboa and JEM Garcia, Fipronil: a major advance for the control of boll weevil in Columbia. In: GA Herzog, Op. cit. 7, pp.990-994.
71. AN Sparks Jr., JW Norman, DW Spurgeon and JR Raulston, 1997, Comparative efficacy of fipronil and guthion for boll weevil control, In: GA Herzog, OP. cit. 7, pp.1040-1043.
72. PG Tillman and JE Mulrooney, 1997, Tolerance of natural enemies to selected insecticides applied at ultra low volumes, In: Herzog, Op. cit. 7, pp. 1312-1313.
73. R Peveling, Environmental impact of fungal and chemical control agents on non-target arthropods, Advances in Applied Acridology, 2000, p.17.
74. RD Parker and RL Huffman, Evaluation of insecticides for boll weevil control and impact on non-target arthropods on non-transgenic and transgenic B.t. cotton cultivars, In: Herzog, Op. cit. 7, pp.1216-1221.
75. S Johnsen, Le Thi Thu Huong Kim Thuy Ngoc and Trinh Dieu Thuy, Some ecological effects of fipronil (‘Regent’), (-cyhalothrin (‘Karate’), in Vietnamese rice fields, DANIDA, 1997, 14 + xxvi pp.
76. S Johnsen, Le Thi Thu Huong, Kim Thuy Ngoc and Trinh Dieu Thuy, Insecticides disrupt IPM, Pesticides News, 1998, 39, 12-13.
77. Op. cit. 75.
78. AL Bostian and ND Long, Rhône-Poulenc Agro position paper on: DANIDA Report: Some ecological effects of fipronil (‘Regent’), (-cyhalothrin (‘Karate’), in Vietnamese rice fields, Report/file number ALB/R0897-235, 1998, 9 pp.
79. JW Everts, D Mbaye, O Barry and W Mullie (eds.), Environmental side-effects of locust and grasshopper control, Vol. 3, LOCUSTOX Project – GCP/SEN/041/NET, FAO, Dakar, Senegal, 1998, 207 pp.
80. Op. cit. 66.
81. JW Everts, Ecotoxicology for risk assessment in arid zones; some key issues. Archives of Environmental Toxicology and Contamination 1997, 32(1), 1-10.
82. J Lahr, Ecotoxicology of organisms adapted to a life in temporary freshwater ponds in arid and semi-arid regions, Archives of Environmental Toxicology and Contamination, 1997, 32(1), 50-57.

[This article first appeared in Pesticides News No.48, June 2000, p20]