INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY ENVIRONMENTAL HEALTH CRITERIA 66 KELEVAN This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organisation, or the World Health Organization. Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization World Health Orgnization Geneva, 1986 The International Programme on Chemical Safety (IPCS) is a joint venture of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization. The main objective of the IPCS is to carry out and disseminate evaluations of the effects of chemicals on human health and the quality of the environment. Supporting activities include the development of epidemiological, experimental laboratory, and risk-assessment methods that could produce internationally comparable results, and the development of manpower in the field of toxicology. Other activities carried out by the IPCS include the development of know-how for coping with chemical accidents, coordination of laboratory testing and epidemiological studies, and promotion of research on the mechanisms of the biological action of chemicals. ISBN 92 4 154266 7 The World Health Organization welcomes requests for permission to reproduce or translate its publications, in part or in full. Applications and enquiries should be addressed to the Office of Publications, World Health Organization, Geneva, Switzerland, which will be glad to provide the latest information on any changes made to the text, plans for new editions, and reprints and translations already available. (c) World Health Organization 1992 Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. CONTENTS ENVIRONMENTAL HEALTH CRITERIA FOR KELEVAN 1. SUMMARY AND CONCLUSIONS 2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS 2.1. Identity 2.2. Physical and chemical properties 2.3. Analytical methods 3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE 3.1. Man-made sources 3.2. Uses 4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION 4.1. Transport and distribution 4.2. Biotransformation 4.3. Abiotic degradation 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE 5.1. Environmental levels 5.1.1. Water 5.1.2. Soil 5.1.3. Food and animal feed 6. KINETICS AND METABOLISM 6.1. Absorption 6.2. Distribution, storage, metabolic transformation, and excretion 7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT 7.1. Aquatic organisms 7.2. Terrestrial organisms 7.3. Microorganisms 7.4. Appraisal 8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS 8.1. Single exposures 8.2. Short-term exposures 8.2.1. Oral 8.2.2. Dermal 8.2.3. Inhalation 8.3. Long-term exposure 8.4. Reproduction studies 8.5. Mutagenicity 8.6. Carcinogenicity 8.7. Other studies 9. EFFECTS ON MAN 10. EVALUATION OF THE HEALTH RISKS FOR MAN AND EFFECTS ON THE ENVIRONMENT 10.1. Evaluation of the health risks for man 10.2. Evaluation of environmental effects 10.3. Conclusions and recommendations REFERENCES TASK GROUP MEETING ON ENVIRONMENTAL HEALTH CRITERIA FOR THE ORGANOCHLORINE PESTICIDES Members Dr Z. Adamis, National Institute of Occupational Health, Budapest, Hungarya Dr L. Albert, Environmental Pollution Programme, National Institute of Biological Resource Research, Xalapa, Mexico (Vice-Chairman) b Dr Sakdiprayoon Deema, Ministry of Agriculture and Cooperatives, Bangkok, Thailandb Dr R. Goulding, Chairman of the Scientific Sub-committee, UK Pesticides Safety Precautions Scheme, Ministry of Agriculture, Fisheries and Food, London, United Kingdom (Chairman) a Dr Y. Hayashi, Pathology Division, National Institute of Hygienic Sciences, Tokyo, Japanb Dr S.K. Kashyap, National Institute of Occupational Health (Indian Council of Medical Research), Meghaninager, Ahmedabad, Indiaa Dr R. Kimbrough, Center for Environmental Health, Centers for Disease Control, Atlanta, Georgia, USA (Rapporteur) b Mr Y.T. Mosuro, Federal Ministry of Health, Food and Drug Administration and Laboratory Services, Oshodi, Nigeriab Dr Y. Osman, Occupational Health Department, Ministry of Health, Khartoum, Sudanb Dr L. Rosival, Centre of Hygiene, Research Institute of Preventive Medicine, Bratislava, Czechoslovakia (Chairman) b Dr F.W. van der Kreek, Ministry of Welfare, Health, and Culture, Leidschendam, Netherlandsb Dr D.C. Villeneuve, Environmental Contaminants Section, Environmental Health Centre, Tunney's Pasture, Ottawa, Ontario, Canada (Rapporteur) a Dr D. Wassermann, Department of Occupational Health, The Hebrew University, Haddassah Medical School, Jerusalem, Israel (Vice-Chairman) a Dr Xue Shou Zheng, School of Public Health, Shanghai Medical University, Shanghai, Chinab --------------------------------------------------------------------------- a Present at first Task Group meeting. b Present at second Task Group meeting. Representatives of Other Organizations Dr A. Berlin, Health and Safety Directorate, Commission of the European Communities, Luxembourgb Mrs M. Th. van der Venne, Health and Safety Directorate, Commission of the European Communities, Luxembourga Observers Dr C.J. Calo, European Chemical Industry Ecology and Toxicology Centre (ECETOC), Brussels, Belgiuma Dr D.M. Whitacre, International Group of National Associations of Agrochemical Manufacturers (GIFAP), Brussels, Belgiuma Dr A.A. van Kolfschoten, International Group of National Associations of Agrochemical Manufacturers (GIFAP), Brussels, Belgiumb Secretariat Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood Experimental Station, Huntingdon, United Kingdomb Dr M. Gilbert, International Register for Potentially Toxic Chemicals, United Nations Environment Programme, Geneva, Switzerlanda,b Ms B. Goelzer, Office of Occupational Health, World Health Organization, Geneva, Switzerlanda Dr Y. Hasegawa, Division of Environmental Health, Environmental Hazards and Food Protection, World Health Organization, Geneva, Switzerlanda Dr K.W. Jager, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland (Secretary)a,b Mr B. Labarthe, International Register for Potentially Toxic Chemicals, United Nations Environment Programme, Geneva, Switzerlanda Dr I.M. Lindquist, International Labour Organisation, Geneva, Swizterlanda Dr A. Pelfrene, Insecticides Development and Safe Use Unit, World Health Organization, Geneva, Switzerlandb Dr M. Vandekar, Pesticides Development and Safe Use Unit, World Health Organization, Geneva, Switzerlanda --------------------------------------------------------------------------- a Present at first Task Group meeting. b Present at second Task Group meeting. Secretariat (contd.) Dr T. Vermeire, National Institute for Public Health and Environmental Hygiene, Bilthoven, Netherlands (Temporary Adviser) b Mr J.D. Wilbourn, International Agency for Research on Cancer, Lyons, Francea --------------------------------------------------------------------------- a Present at first Task Group meeting. b Present at second Task Group meeting. NOTE TO READERS OF THE CRITERIA DOCUMENTS Every effort has been made to present information in the criteria documents as accurately as possible without unduly delaying their publication. In the interest of all users of the environmental health criteria documents, readers are kindly requested to communicate any errors that may have occurred to the Manager of the International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland, in order that they may be included in corrigenda, which will appear in subsequent volumes. * * * A detailed data profile and a legal file can be obtained from the International Register of Potentially Toxic Chemicals, Palais des Nations, 1211 Geneva 10, Switzerland (Telephone no. 988400 - 985850). ENVIRONMENTAL HEALTH CRITERIA FOR KELEVAN A WHO Task Group on Environmental Health Criteria for Organochlorine Pesticides other than DDT met in Geneva on 28 November - 2 December, 1983. Dr K.W. Jager opened the meeting on behalf of the Director-General. The Task Group reviewed and revised the draft criteria document. The Task Group concluded that the data on kelevan were too sparse to make an evaluation of the health risks for man or the effects on the environment. It recommended that the draft should be recirculated to the IPCS and IRPTC focal points with a request for further information. A second WHO Task Group was held in Geneva on 9 - 13 December, 1985 to review and revise an amended draft and to make an evaluation of the risks of kelevan for human health and the environment. The first drafts of the kelevan document were prepared by DR D.C. VILLENEUVE of Canada and DR S. DOBSON of the United Kingdom. The present draft was prepared by the IPCS Secretariat, updating the preliminary hazard assessment with new information received in more than 50 replies from Focal Points. The efforts of all who helped in the preparation and finalization of the document are gratefully acknowledged. * * * Partial financial support for the publication of this criteria document was kindly provided by the United States Department of Health and Human Services, through a contract from the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA - a WHO Collaborating Centre for Environmental Health Effects. The United Kingdom Department of Health and Social Security generously supported the costs of printing. 1. SUMMARY AND CONCLUSIONS Technical kelevan is a brownish solid substance with a molecular formula of C17H12Cl10O4. It is a chlordecone derivative and can be oxidized to chlordecone before determination by gas chromatography with electron capture detection. Kelevan has been used in a number of countries as an insecticide, mainly for the control of the potato beetle and the banana root borer. It is degraded quite rapidly by biotransformation and abiotic degradation to other caged structure products. The half-life of kelevan in soil has been reported to be 5 - 12 weeks. However, its major metabolite, chlordecone, persists in the soil for several years. There is very little leaching of kelevan and its caged- structure metabolites from the upper 10 cm of soil into lower layers and into drainage water. Carrots, grown after an early potato crop that had been treated with 300 g kelevan/ha, contained up to 0.02 mg kelevan/kg and 0.04 mg chlordecone/kg; no residues (< 0.01 mg/kg) were found in the potatoes. There are no data on levels of exposure to kelevan for the general population or in the work-place. A few data are available on the environmental toxicity of kelevan. The toxic threshold level for rainbow trout is of the order of 0.1 mg/litre, and the oral LD50 for honey bees is > 1 mg/bee. Domestic hens dosed with 20 mg kelevan/bird per day for 8 weeks did not show any adverse effects. A soil level of 2500 mg kelevan/kg did not affect the microflora over a 30-month period. However, the available data are too few to make an informed assessment of kelevan's likely impact on the environment, especially on a long-term basis. Kelevan is absorbed by experimental animals following ingestion, inhalation, and via the skin. It accumulates in the liver, brain, and in adipose tissue. It is metabolized to a certain extent to chlordecone, both compounds being mainly excreted with the bile into the faeces. It is moderately toxic according to the scale of Hodge & Sterner (1956) in single exposures (oral LD50 values for the rat range from 240 to 550 mg/kg body weight). Symptoms of poisoning include apathy, tremors, CNS hypersensitivity, and tonic-clonic convulsions. The no-observed-adverse-effect level in a 90-day oral study on rats was 5 mg/kg body weight. At higher levels (300 mg/kg diet in females and 1000 mg/kg diet in both sexes), liver hypertrophy occurred. In a 10-month oral study on rats, 0.28 mg/kg body weight per day was considered to be a threshold dose. Oral exposure to 14 mg/kg body weight per day for 4 months caused necrosis of the liver and kidneys in rats. No abnormalities were found in reproduction studies on mice when low doses (5 mg/kg diet) were given from 30 days prior to mating to 90 days after mating. Teratogenic effects have not been adequately evaluated. Kelevan was not mutagenic in systems using microorganisms. No carcinogenicity studies are available for kelevan, but there is sufficient evidence of carcinogenicity for chlordecone, a major metabolite, from studies on rats and mice. No adverse health effects on human beings have been reported from exposure to kelevan. In view of the sparsity of available data, it is quite impossible at this stage to arrive at an informed evaluation of keleven with regard to its danger for workers, the possible consumer hazards from food residues, or its impact on the environment. Therefore, since kelevan is converted to chlordecone in the mammalian body and in the environment, and the toxicity data available are similar to those on chlordecone, the evaluation of chlordecone should largely apply to kelevan, which, in practice, means that, unless kelevan is indispensable, it should not be used. 2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS 2.1. Identity Molecular formula: C17H12Cl10O4 CAS chemical name: 1,3,4-metheno-1 H-cyclobuta; cd pentalene- 2-pentanoic acid, 1,1a,3,3a,4,5,5a,5b, 6-decachloro-octa-hydro-2-hydroxy-gamma- oxo-ethyl ester Trade names: Despirol, Elevat, GC-9160, General Chemicals 9160 CAS registry number: 4234-79-1 Technical grade kelevan contains 94 - 98% pure kelevan, 0.1 - 2% chlordecone, and 0.5 - 4.0% inorganic salts (Maier-Bode, 1976). 2.2. Physical and Chemical Properties The technical material is a brownish substance. Some physical and chemical properties of kelevan are given in Table 1. 2.3. Analytical Methods Kelevan can be extracted from plant or animal tissues, or soils using methylene chloride, isopropanol, or acetone. It can be oxidized by refluxing with chromium trioxide in glacial acetic acid to yield chlordecone. The chlordecone is then determined by gas- liquid chromatography (GLC) techniques (Westlake et al., 1970). An analytical method using liquid chromatography/mass spectrometry has been described by Cairns et al. (1982). Table 1. Some physical and chemical properties of kelevan --------------------------------------------------------------------------- Physical state solid, powder Colour white Relative molecular mass 634.79 Melting point 91 °C Vapour pressure (20 °C) < 0.0014 Pa (= < 10-2 mm Hg) Solubility in water (20 °C) 5.5 mg/litre (readily soluble in most organic solvents) Decomposition > 170 °C --------------------------------------------------------------------------- From: Maier-Bode (1976). 3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE 3.1. Man-Made Sources Kelevan is a condensation product of chlordecone and ethyl levulinate (Gilbert et al., 1966). The synthesis and insecticidal action of kelevan were reported by Gilbert et al. (1966). Its synthesis has also been described by Heys et al. (1979). The only information available in relation to the production of kelevan was reported by Cannon et al. (1978), who stated that approximately 99% of the production of chlordecone was exported to the Federal Republic of Germany, where it served as a raw material in the manufacture of another pesticide compound kelevan. 3.2. Uses Reference has been made to the use of kelevan in central and southeastern Europe (Maier-Bode, 1976) and in South America (Cannon et al., 1978). Kelevan has mainly been used in the control of the potato beetle (Leptinotarsa decemlineata) on potatoes, the banana root borer on bananas, and Tanymecus palliatus on beets and corn. Both dust and wettable-powder formulations have been used (Maier- Bode, 1976). Responses received from 49 countries throughout the world indicated that kelevan had never been registered for use or used in 33 of them. In Spain, registration expired in 1975. In the Federal Republic of Germany, the use of kelevan has been forbidden since 1982. In Hungary and the USSR, kelevan is still registered, but is no longer used (personal communications to the IPCS and IRPTC, 1985). 4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION 4.1. Transport and Distribution Kelevan (determined as chlordecone) was shown in laboratory studies to have a half-life in soil of 6 - 12 weeks under dark conditions, and 5 - 10 weeks in diffused daylight (unpublished data summarized by Maier-Bode, 1976). Analysis of soil samples in various regions of Europe, where kelevan has been used to control the potato beetle, confirmed this relatively rapid degradation (unpublished data summarized by Maier-Bode, 1976). Soil treatment was carried out using 14C-kelevan at 1.5 kg/ha and, though initial residues in the soil were approximately 2 mg/kg, potatoes grown in the soil contained residues of < 0.001 mg/kg, after peeling (Klein, 1972). Kelevan residues resulting from use in the field were predicted on the basis of the volatilization, mineralization, and conversion rates obtained from laboratory tests. Field residues of the parent compound kelevan actually found in the field test were far lower than calculated (Scheunert et al., 1983). 14C-Kelevan was applied to a "potato field model ecosystem". The system was left to grow and ripen for 77 days. Approximately 95% of the applied radioactivity was recovered: 50.9% in soil, 42.4% in, and on, the potato plant, 1.6% in the air, and less than 0.001% in drainage water. Of approximately 50.9% contained in soil, 38% was between 0 and 5 cm deep, 12.9% between 5 and 10 cm, 0.01% between 10 and 15 cm, and less than 0.001% between 15 and 20 cm deep. Of the total of recovered radioactivity, 24.4% was unchanged kelevan, 40.5% kelvanic acid, 7.4% chlordecone, and 22.6% different non-identified kelevan metabolites. Neither intact kelevan nor its metabolites could be identified in potato fields containing less than 0.03% of the initial radioactivity, or in drainage water (Figge & Rehm, 1977; Figge, 1978). When 5.4 mg of 14C-kelevan was sprayed on potato leaves, 6.9% of the radioactivity was recovered from the plant, 26.3% from the soil, 0.9% in drainage water, and 65.9% was lost to the air over 11 weeks. Much of the kelevan had been converted to kelevanic acid including 68% of material recovered from soil and 65% of material from the plant (Sandrock et al., 1974). 4.2. Biotransformation Benigni et al. (1979) showed that kelevan was converted into chlordecone in Nicotinea alata cell cultures and also in field tests on potatoes and beets, and that the amount converted was proportional to the length of treatment (see also Carere & Morpurgo, 1981). In a laboratory study on 2 soil types, between 61 and 64% of applied kelevan was degraded by microorganisms and physical and chemical processes to kelevanic acid, in 4.5 months. In a second study, under both laboratory and field conditions, one-third of applied kelevan was degraded by microorganisms to chlordecone and other unidentified products, over 30 months (Figge et al., 1983). 4.3. Abiotic degradation Parlar et al. (1972) and Begum et al. (1973) studied the decomposition of kelevan in the solid state or dissolved in acetone, methanol, or n-hexane under the influence of ultra- violet radiation (UVR). Several dechlorination products were isolated, but the main degradation product was chlordecone. In the gaseous phase, both mirex and chlordecone were formed. Several photolysis products of kelevan have been described by Wilson & Zehr (1978). These mainly concern modifications in the side chain. Kelevan slowly hydrolyses in water forming products such as kelevanic acid and the carboxylic ester without the side chain, which are more readily soluble in water (Sandrock et al., 1974). 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE No data are available concerning the concentrations of kelevan in air, water, or food. 5.1. Environmental Levels 5.1.1. Water In laboratory experiments designed to ascertain runoff characteristics of kelevan from soil, no traces of kelevan were found in the runoff water (unpublished data summarized by Maier- Bode, 1976). 5.1.2. Soil Sandrock et al. (1974) studied the metabolism of 14C-kelevan in potatoes and soil, 11 weeks and again one year after application on leaves. Kelevanic acid (the principal metabolite), unmetabolized kelevan, chlordecone, and chlordecone acetic acid were identified in the soil, 11 weeks after application. Over 90% of the quantity applied was metabolized during the first crop growth period; the metabolites were products in which the side chain was shortened or eliminated, without apparent changes in the carbon skeleton. Chlordecone acetic acid was identified as the principal metabolite in the soil after 1 year. A dust or a suspension of 150 g kelevan aia/ha was applied to 3 different soils in Slovakia. Three months after application, approximately 30% of the kelevan was recovered as chlordecone. Kelevan residues in potatoes grown in all three soil types ranged from 0.001 - 0.004 mg/kg, whereas chlordecone was present in traces only (Madaric & Sackmauerova, 1974). 5.1.3. Food and animal feed When 14C-kelevan was applied to potato plants, neither the compound nor any of its caged structure products were detectable in the potato tubers (unpublished data summarized by Maier-Bode, 1976). Furthermore, detectable residues (> 0.01 mg/kg) were not found in other crops growing in the same field including winter wheat, winter rye, summer barley, and silo corn, even though the field had been treated with 150 g kelevan/ha, the year before. Carrots that had been planted in a field treated earlier in the season with 150 and 300 g kelevan/ha, showed residues of 0.02 and 0.04 mg kelevan/kg. Rape, planted in a field treated with 250 and 150 g kelevan/ha, showed residues in seed of 0.07 mg/kg at harvest (unpublished data summarized by Maier-Bode, 1976). Field studies using 14C-kelevan showed that total residues, both in soil and potatoes, mainly comprised hydrophilic metabolites including more --------------------------------------------------------------------------- a ai = active ingredient. than 80% kelevanic acid. Chordecone was also identified, but it was uncertain whether it was an impurity or a metabolite (Klein, 1972). Kelevan applied at 0.3 kg/ha increased the potato yield. At 0.6 kg/ha, its residues could be detected in the soil and the potato roots during the vegetative period (Krasnykh, 1980). Alfalfa, contaminated by spray-drift from the aerial spraying of potatoes with kelevan, contained 4.8 mg kelevan/kg, directly after spraying, 1.1 mg/kg, 3 days later, and 0.1 mg/kg, after 5 - 7 days. Fourteen days after spraying, kelevan could no longer be detected (Jonas, 1983). Residues of up to 0.02 and 0.04 mg/kg, respectively, of kelevan and chlordecone were found in carrots planted after a crop of early potatoes treated with the recommended application rate of 300 g kelevan/ha. No residues were found in the potatoes (< 0.01 mg/kg). Residues were also found in the leaves and roots of sugarbeets and in the seed and straw of summer and winter rape (up to 0.06 mg/kg) (Maier-Bode, 1976). Two groups of two, 200-kg steers were fed 0.05 or 0.1 mg kelevan/kg feed for 6 weeks. No kelevan was detected in muscle, kidneys, heart, or body fat, 2 and 4 weeks, respectively, after this feeding period. The liver, however, contained 0.02 - 0.1 mg kelevan/kg. Biopsies during the feeding period showed concentrations of up to 1.6 mg kelevan/kg in body fat (Jonas, 1983). 6. KINETICS AND METABOLISM 6.1. Absorption Kelevan can enter the body orally and by inhalation. It is also absorbed through the skin, as shown by acute and short-term dermal toxicity studies on rabbits (section 8.1, 8.2) (Maier-Bode, 1976). 6.2. Distribution, Storage, Metabolic Transformation, and Excretion Several unpublished studies have been summarized by Maier-Bode (1976). Male rats were administered 14C-kelevan intra-gastrically at 4.75 mg/kg body weight. As little as 3 h after administration, 14C activity was found in all tissues examined, but primarily in the liver. The resulting pattern of accumulation was similar to that of chlordecone in that it was greater in the heart, brain, liver, etc. than in adipose tissue. The levels of kelevan in mg/kg were as follows: serum 1.4, liver 20.9, heart 2.7, kidney 3.5, brain 1.1, fat 0.84, muscle 0.87. After 14 days, levels in all tissues were below 0.1 mg/kg, except for the liver, which contained 1.8 mg/kg. The liver still contained 0.3 mg/kg, 110 days later. The data also indicated that kelevan is excreted through the liver with the bile into the faeces and is not excreted to any great extent in the urine. It appears primarily as unchanged kelevan and also as chlordecone (Maier-Bode, 1976). These studies indicate that chlordecone is a metabolite of kelevan in the rat and suggest that kelevanic acid is an intermediate. In another study, a single oral dose of 4.75 mg 14C-kelevan/kg body weight, in carboxymethylcellulose, was given to 60 male rats by gavage (Maier-Bode, 1976). A considerable portion of the 14C was excreted through the liver with the bile into the intestine. Eight and 16 weeks later 14C could still be detected in organs and tissues. In a study on rats administered a single oral dose of 1.52 mg 14C-kelevan/kg body weight, it was possible to identify14C- chlordecone (as a transformation product partly as chlordecone- arginine) by thin-layer chromatography in the faeces and urine of the rats (Maier-Bode 1976). Daily doses of a kelevan suspension in water were given to 15 male and 15 female rats by gavage. The total dose in the course of 8 weeks was 10 mg kelevan/kg body weight (Maier-Bode, 1976). Three male and 3 female animals were killed and the tissues analysed, 1, 2, 4, 8, and 10 weeks after the first application. The liver, brain, and body fat were analysed for kelevan and chlordecone. The concentrations of kelevan and chlordecone, separately and combined, were approximately constant. The conclusion of the author was that there was no accumulation of kelevan or its metabolite chlordecone. The faeces collected from the surviving rats during the entire 10- week test period contained an average of 2.25 mg kelevan/kg and 0.84 mg chlordecone/kg. Neither kelevan nor chlordecone was found (< 0.02 mg/litre) in the urine of the animals. On the basis of the studies, the Task Group concluded that chlordecone is a metabolite of kelevan, but that the extent of this transformation is not known. It has to be taken into account that chlordecone is also an impurity of kelevan. The amounts of kelevan and chlordecone in the liver, brain, and body fat are almost equal. Because of the short duration of the study, nothing can be said of the half-life of kelevan and chlordecone, but on the basis of the 2-week depletion period, it appears that both half-lives are long. 7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT 7.1. Aquatic Organisms Studies on the toxicity of kelevan (LC50) for juvenile fish (rainbow trout) are reported in Table 2; no studies on other aquatic organisms are available. Two separate studies indicate a toxic threshold for rainbow trout of 0.1 mg/litre. Symptoms of sublethal poisoning include disturbed swimming coordination (Maier- Bode 1976). 7.2. Terrestrial Organisms Under laboratory conditions, the toxicity for bees of kelevan, at concentrations used in agriculture, was low (Tomaszewska, 1981). The LD50 of Despirol (wettable powder 50% kelevan) for honey bees was > 1 mg/bee (the maximum level tested) after testing orally, by inhalation, by prolonged contact, or by spraying. The toxicity of kelevan was lower for beneficial insects than for target species (Maier-Bode, 1976). Soil microarthropods (Collembola and Acarina) showed no change in absolute or relative, species to species, population numbers within 75 days of a single spraying of a potato crop at a rate of 300 g/ha (Hrlec & Ostrec, 1981). Five pheasants and 3 domestic doves dosed with kelevan as Despirol at 10 g/kg diet for 10 days did not show any effects during the dosing period or during the 10-day period following dosing. The amount of insecticide ingested averaged 101 mg/kg per day for pheasants and 250 mg/kg per day for doves (Maier-Bode, 1976). When large numbers of laying domestic hens were dosed at up to 20 mg/bird per day, for 8 weeks, no effects were observed on laying activity; histological examination of tissues at the end of the study did not reveal any differences between treated and control birds (Maier-Bode, 1976). 7.3. Microorganisms A laboratory study on microorganisms in two types of soil treated with between 500 and 2500 mg 14C-kelevan/kg showed that, whilst the organisms degraded kelevan, the insecticide caused no change in either total or relative numbers of microorganisms. The organisms were neither selected nor decimated by kelevan or its degradation products over a 30-month period (Figge et al., 1983). Table 2. Toxicity of kelevan for fisha ---------------------------------------------------------------------------------------------------- Species Life stage Length Water hardness Temperature Exposure time LC50 (cm) (dH01)b (°C) (h) (mg/litre) ---------------------------------------------------------------------------------------------------- Rainbow trout juvenile 7 - 9c 11 10 24 > 2 (Salmo gairdnerii) Rainbow trout juvenile 7 - 9c 11 10 72 1.0 Rainbow trout juvenile 6 - 10 1 14 96 1.5 Rainbow trout juvenile 6 - 10 9 14 96 2.2 ---------------------------------------------------------------------------------------------------- a From: Maier-Bode (1976). b 1 degree of hardness (dH0) corresponds to 10.0 mg Ca0/litre water. c For the studies on 7 - 9 cm trout, pH 6; pH not stated for other tests. 7.4. Appraisal The data on kelevan are few. There is no information on its immediate metabolite, kelevanic acid. Thus, it is difficult to come to firm conclusions about the environmental significance of kelevan. However, there are considerable data on the metabolite, chlordecone. This is known to be stable and persistent. It bioaccumulates and is more toxic for aquatic organisms than kelevan. Chlordecone has severe sublethal effects on birds (WHO, 1984). The interpretation of data for kelevan, therefore, needs to take into account the significance of chlordecone. 8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS 8.1. Single Exposures Data on the acute toxicity of kelevan are given in Table 3. A similar pattern of response to acutely toxic doses of kelevan was seen in the three species and included apathy, tremor, hyper- sensitivity, and tonic-clonic convulsions. Table 3. Acute toxicity of kelevan ------------------------------------------------------------------- Animal Sex Route Vehicle LD50 Reference (mg/kg body weight) ------------------------------------------------------------------- Rat M & F oral corn oil, 240 - 290 Maier-Bode (1976) soybean oil Rat oral 255 - 325 Kenaga & Allison (1969) Dog M & F oral corn oil, 400 - 550 Maier-Bode (1976) soybean oil Dog oral 400 - 500 Kenaga & Allison (1969) Rabbit M dermal corn oil 251 Maier-Bode (1976) Rabbit dermal 188 - 314 Kenaga & Allison (1969) ------------------------------------------------------------------- 8.2. Short-Term Exposures 8.2.1. Oral Male rats were administered kelevan by oral intubation at 29 mg/kg body weight for 20 consecutive days (Medical College, Virginia, 1968). No effects were observed on behaviour, organ weights, or in the histopathological examination of liver and kidneys. In a 90-day study (Medical College, Virginia, 1968), male and female rats were fed kelevan incorporated in the diet at levels of 0, 10, 30, 100, 300, or 1000 mg/kg. No animals died during the course of the study, but animals fed 1000 mg/kg showed a reduced weight gain. No treatment-related abnormalities were seen in food consumption, haematology, urinalysis, or histopathology. Dose- related liver hypertrophy was observed in females at 300 mg/kg diet and in both sexes at 1000 mg/kg diet. Thus, 100 mg kelevan/kg diet, equivalent to 5 mg/kg body weight per day, was a no-observed- adverse-effect level in this study. Albino rats were exposed to daily doses of 14 mg kelevan/kg body weight for 4 months, or, 2.8 or 0.28 mg/kg body weight for 10 months. Hyperaemia of internal organs and necrosis of the liver and kidneys were described, as well as lymphoid infiltration of interstitial tissue in the lung. At 0.28 mg/kg, these changes were reversible, and the author regarded this dose as a threshold dose (Boreiko, 1980). 8.2.2. Dermal Male and female rabbits were administered 25 or 50 mg Despirol/kg body weight (12.5 or 25 mg kelevan/kg body weight), 5 days per week, for 9 weeks. The material was administered as an aqueous paste to the shaved skin of the animals. There was no difference between the treatment groups and controls. Only a slight erythema was observed at the highest dose of kelevan (Medical College, Virginia, 1968). Kelevan, applied to the skin of rats, rabbits, and guinea-pigs, in either one dose of 2000 mg/kg or 20 doses of 100 mg/kg caused dystrophic changes in the liver and kidneys (Sasinovich et al., 1977). 8.2.3. Inhalation No adequately reported studies available. 8.3. Long-Term Exposure No studies available. 8.4. Reproduction Studies Reproduction was investigated in 100 male and 100 female BALB/C mice fed kelevan in the diet at 5 mg/kg, from 30 days prior to mating to 90 days after mating, over several litters (Ware & Good, 1967). No effects of treatment were observed on mortality, number of females producing litters, pregnancy period, number of litters, litter size, and sex ratio. Thirty pregnant CD-1 mice were given the minimal toxic dose of kelevan of 125 mg/kg body weight in 0.5 ml corn oil, by gavage, from day 8 to day 12 of pregnancy. Four animals died. There were no significant maternal weight changes nor effects on litter size or pup weights (Chernoff & Kavlock, 1983). It is known that chlordecone affects reproduction (WHO, 1984). The dose of 5 mg kelevan/kg per day may have been too low to elicit an effect on reproduction. The dose of 125 mg/kg apparently caused sufficient toxicity in the dams to kill four of the animals. The validity of both these studies, which were the only studies available for evaluation, is limited. 8.5. Mutagenicity Benigni et al. (1979) tested the mutagenic activity of kelevan and its metabolite chlordecone on Aspergillus nidulans. As pure compounds, both were negative (Carere & Morpurgo, 1981). Kelevan and its degradation products did not show any mutagenic activity in the Ames test with Salmonella typhimurium (Jaszczuk & Syrowatka, 1980). 8.6. Carcinogenicity No carcinogenicity studies are available for kelevan. However, there is sufficient evidence of the carcinogenicity of its metabolite chlordecone in animals (IARC, 1979; WHO, 1984) 8.7. Other Studies A single intragastric dose of 140 mg kelevan/kg body weight (approximately half the LD50), given to rats, decreased the rate of bile secretion on the first day. From day 3 onwards, it increased again, but it had not reached the level of the controls on day 5 (Glukhova et al., 1978, 1979). Kelevan sharply increased the levels of alanine aminotransferase and aspartate aminotransferase in blood serum and caused structural changes in the liver at this dose level. 9. EFFECTS ON MAN No adverse health effects on human beings from exposure to kelevan have been reported. 10. EVALUATION OF THE HEALTH RISKS FOR MAN AND EFFECTS ON THE ENVIRONMENT 10.1. Evaluation of the Health Risks for Man Kelevan, which is developed from chlordecone, is metabolized in the mammalian body and in the environment back to chlordecone. The acute toxicity of kelevan is similar to that of chlordecone, which may well be its active metabolite. Data on kelevan are sparse; several reports have not been published and are not available for scrutiny and others lack sufficient detail or are inadequate. No information exists on actual human exposure. The acute toxicity of kelevan in test animals is moderate (oral LD50s ranging from 240 to 550 mg/kg body weight, according to the scale of Hodge & Sterner (1956)), and similar to that of chlordecone. However, the no-observed-adverse-effect level of 5 mg/kg body weight per day observed in a 90-day oral study on the rat and a threshold level of 0.28 mg/kg body weight per day observed in a 10-month oral rat study, are very similar to those obtained with chlordecone (WHO, 1984). The pathological findings of liver hypertrophy and necrosis of liver and kidneys are also similar. Kelevan is not mutagenic in systems using microorganisms. No carcinogenicity studies are available. However, there is sufficient evidence of the carcinogenicity of its metabolite chlordecone for mice and rats (IARC, 1979; WHO, 1984). No adverse effects on human health due to exposure to kelevan have been reported. 10.2. Evaluation of Environmental Effects There have not been any reports of adverse effects on the environment due to exposure to kelevan. Available information suggests that the probability of deleterious effects on terrestrial organisms from kelevan is low. Its metabolite, chlordecone, is toxic for birds and microorganisms, though there is no indication of this for the parent compound. Aquatic data for kelevan are limited to one species and one life stage; it is moderately to highly toxic for juvenile rainbow trout. It is possible, but improbable, that local concentrations of kelevan after recommended agricultural use could exceed the toxic threshold for trout fry. The compound gives concern with aquatic organisms because its degradation product is both more persistent and more toxic for fish than the parent compound. 10.3. Conclusions and Recommendations In view of the sparsity of available data, it is impossible to arrive at an informed evaluation of kelevan with regard to its danger for workers, the possible consumer hazards from food residues, or its impact on the environment. Thus, as kelevan is converted to chlordecone in the mammalian body and in the environment, and as the available toxicity data are similar to those on chlordecone, the evaluation for chlordecone (WHO, 1984) should also largely apply to kelevan, unless further data to the contrary become available. In practice, this means that, unless kelevan is indispensable, it should not be used. REFERENCES ANONYMOUS (1978a) Kepone/mirex/hexachlorocyclopentadiene - an environmental assessment, Washington DC, US Department of Commerce, US National Technical Information Service (PB 280-289) (NCR). BEGUM, S., GOEB, S., PARLAR, H., & KORTE, F. (1973) Reaction behaviour of kelevan in solution, as a solid, and in gaseous phase under UV irradiation. 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